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What changed in Karyopharm Therapeutics Inc.'s 10-K — 2022 vs 2023

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Paragraph-level year-over-year comparison of Karyopharm Therapeutics Inc.'s 2022 and 2023 10-K annual filings, covering the Business, Risk Factors, Legal Proceedings, Cybersecurity, MD&A and Market Risk sections. Every new, removed and edited paragraph is highlighted side-by-side so you can see exactly what management changed in the 2023 report.

+735 added−643 removedSource: 10-K (2024-02-29) vs 10-K (2023-02-17)

Top changes in Karyopharm Therapeutics Inc.'s 2023 10-K

735 paragraphs added · 643 removed · 489 edited across 7 sections

Item 1. Business

Business — how the company describes what it does

242 edited+124 added−95 removed392 unchanged
Biggest changeThe new regulation will, among other things: • strengthen the rules on placing devices on the market and reinforce surveillance once they are available; • establish explicit provisions on manufacturers’ responsibilities for the follow-up of the quality, performance and safety of devices placed on the market; • improve the traceability of medical devices throughout the supply chain to the end-user or patient through a unique identification number; • set up a central database to provide patients, healthcare professionals and the public with comprehensive information on products available in the EU; and • strengthen rules for the assessment of certain high-risk devices, such as implants, which may have to undergo an additional check by experts before they are placed on the market. 39 Table of Contents Pediatric Studies Prior to obtaining a marketing authorization in the EU, sponsors have to demonstrate compliance with all measures included in an EMA-approved Pediatric Investigation Plan (“PIP”) covering all subsets of the pediatric population, unless the EMA has granted a product-specific waiver, a class waiver or a deferral for one or more of the measures included in the PIP.
Biggest changeThe IVDR, among other things: • strengthens the rules on placing devices on the market and reinforces surveillance once they are available; • establishes explicit provisions on manufacturers’ responsibilities for the follow-up of the quality, performance and safety of devices placed on the market; • improves the traceability of medical devices throughout the supply chain to the end-user or patient through a unique identification number; 41 Table of Contents • establishes a central database to provide patients, healthcare professionals and the public with comprehensive information on products available in the EU; and • strengthens rules for the assessment of certain high-risk devices, such as implants, which may have to undergo an additional check by experts before they are placed on the market.
To the extent that the Section 505(b)(2) sponsor is relying on studies conducted for an already approved product, the sponsor is required to certify to the FDA concerning any patents listed for the approved product in the Orange Book to the same extent that an ANDA sponsor would.
To the extent that the Section 505(b)(2) sponsor is relying on studies conducted for an already approved product, the sponsor is required to certify to the FDA concerning any patents listed for the approved product in the Orange Book to the same extent that an ANDA sponsor would.
Restrictions under applicable federal and state healthcare laws and regulations, including certain laws and regulations applicable only if we have marketed products, include the following: • federal false claims, false statements and civil monetary penalties laws prohibiting, among other things, any person from knowingly presenting, or causing to be presented, a false claim for payment of government funds or knowingly making, or causing to be made, a false statement to get a false claim paid; • federal healthcare program anti-kickback law, which prohibits, among other things, persons from offering, soliciting, receiving or providing remuneration, directly or indirectly, to induce either the referral of an individual for, or the purchasing or ordering of, a good or service for which payment may be made under federal healthcare programs such as Medicare and Medicaid; • the federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), which, in addition to privacy protections applicable to healthcare providers and other entities, prohibits executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters; • federal laws that require pharmaceutical manufacturers to report certain calculated product prices to the government or provide certain discounts or rebates to government authorities or private entities, often as a condition of reimbursement under government healthcare programs; • federal Open Payments (or federal “sunshine” law), which requires pharmaceutical and medical device companies to monitor and report certain financial interactions with certain healthcare providers to the Center for Medicare & Medicaid 34 Table of Contents Services (the “CMS”), within the HHS for re-disclosure to the public, as well as ownership and investment interests held by physicians and their immediate family members; • federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers; • analogous state laws and regulations, including: state anti-kickback and false claims laws; state laws requiring pharmaceutical companies to comply with specific compliance standards, restrict financial interactions between pharmaceutical companies and healthcare providers or require pharmaceutical companies to report information related to payments to health care providers or marketing expenditures; and state laws governing privacy, security and breaches of health information in certain circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts; and • laws and regulations prohibiting bribery and corruption such as the FCPA, which, among other things, prohibits U.S. companies and their employees and agents from authorizing, promising, offering, or providing, directly or indirectly, corrupt or improper payments or anything else of value to foreign government officials, employees of public international organizations or foreign government-owned or affiliated entities, candidates for foreign public office, and foreign political parties or officials thereof.
Restrictions under applicable federal and state healthcare laws and regulations, including certain laws and regulations applicable only if we have marketed products, include the following: • federal false claims, false statements and civil monetary penalties laws prohibiting, among other things, any person from knowingly presenting, or causing to be presented, a false claim for payment of government funds or knowingly making, or causing to be made, a false statement to get a false claim paid; • federal healthcare program anti-kickback law, which prohibits, among other things, persons from offering, soliciting, receiving or providing remuneration, directly or indirectly, to induce either the referral of an individual for, or the purchasing or ordering of, a good or service for which payment may be made under federal healthcare programs such as Medicare and Medicaid; • the federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), which, in addition to privacy protections applicable to healthcare providers and other entities, prohibits executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters; • federal laws that require pharmaceutical manufacturers to report certain calculated product prices to the government or provide certain discounts or rebates to government authorities or private entities, often as a condition of reimbursement under government healthcare programs; • federal Open Payments (or federal “sunshine” law), which requires pharmaceutical and medical device companies to monitor and report certain financial interactions with certain healthcare providers to the Center for Medicare & Medicaid Services (the “CMS”), within the HHS for re-disclosure to the public, as well as ownership and investment interests held by physicians and their immediate family members; • federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers; • analogous state laws and regulations, including: state anti-kickback and false claims laws; state laws requiring pharmaceutical companies to comply with specific compliance standards, restrict financial interactions between pharmaceutical companies and healthcare providers or require pharmaceutical companies to report information related to payments to health care providers or marketing expenditures; and state laws governing privacy, security and breaches of health information in certain circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts; and • laws and regulations prohibiting bribery and corruption such as the FCPA, which, among other things, prohibits U.S. companies and their employees and agents from authorizing, promising, offering, or providing, directly or indirectly, corrupt or improper payments or anything else of value to foreign government officials, employees of public international organizations or foreign government-owned or affiliated entities, candidates for foreign public office, and foreign political parties or officials thereof.
Approval in this indication was based on the results from the BOSTON ( Bo rtezomib, S elinexor and Dexame t has on e) study (the “BOSTON Study”); • In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors (“PIs”), at least two immunomodulatory agents (“IMiDs”), and an anti-CD38 monoclonal antibody (“mAb”).
Approval in this indication was based on the results from the BOSTON ( Bo rtezomib, S elinexor and Dexame t has on e) study (the “BOSTON Study”); • In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (“RRMM”) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors (“PIs”), at least two immunomodulatory agents (“IMiDs”), and an anti-CD38 monoclonal antibody (“mAb”).
Mano served as Counsel, Business Development for Biogen Inc., a public biotechnology company, from January 2018 to December 2020, where he supported Biogen’s global business development platform. Prior to that he was Senior Counsel at Proskauer Rose LLP, an international law firm, from 2013 to January 2018 where he represented clients in a broad range of corporate matters.
Mano served as Counsel, Business Development for Biogen, a public biotechnology company, from January 2018 to December 2020, where he supported Biogen’s global business development platform. Prior to that he was Senior Counsel at Proskauer Rose LLP, an international law firm, from 2013 to 2018 where he represented clients in a broad range of corporate matters.
We believe that selinexor was well tolerated in the SIENDO study with no new safety signals identified, and a discontinuation rate of 10.5% due to adverse events (“AEs”). The most common treatment-emergent AEs in the SIENDO study of any grade were: nausea (84%), vomiting (52%), constipation (37%) and thrombocytopenia (37%).
We believe that selinexor was well tolerated in the SIENDO Study with no new safety signals identified, and a discontinuation rate of 10.5% due to adverse events (“AEs”). The most common treatment-emergent AEs (“TEAEs”) in the SIENDO Study of any grade were: nausea (84%), vomiting (52%), constipation (37%) and thrombocytopenia (37%).
As there is currently no effective treatment for patients who are resistant to JAKi, we believe there is a high unmet need for a treatments with a different mechanism of action to overcome resistance and provide improvement in primary disease management.
As there is currently no effective treatment for patients who are resistant to JAKi, we believe there is a high unmet need for a treatment with a different mechanism of action to overcome resistance and provide improvement in primary disease management.
(“Alnylam”), a public biopharmaceutical company, from 2011 until February 2019, as its Principal Accounting Officer from 2011 to October 2018, and as its Principal Financial Officer from 2011 to 2016 and from January 2017 to May 2017. From 2005 to 2011, Mr. Mason served as Alnylam’s Corporate Controller. From 2000 through 2005, Mr.
(“Alnylam”), a public biopharmaceutical company, from 2011 until February 2019, as its Principal Accounting Officer from 2011 to 2018, and as its Principal Financial Officer from 2011 to 2016 and from January 2017 to May 2017. From 2005 to 2011, Mr. Mason served as Alnylam’s Corporate Controller. From 2000 through 2005, Mr.
The commercialization of XPOVIO and NEXPOVIO ® (selinexor) (the brand name for selinexor in Europe and the United Kingdom) outside of the U.S. is managed by our partners in their respective territories, as described under “ Collaborations ” below.
The commercialization of XPOVIO and NEXPOVIO ® (selinexor) (the brand name for selinexor in Europe and the United Kingdom (“UK”)) outside of the U.S. is managed by our partners in their respective territories, as described under “ Collaborations ” below.
Specifically, the PHSA grants the Secretary of Health and Human Services the authority to issue a notice of noncompliance to a responsible party for failure to submit clinical trial information as required. The responsible party, however, is allowed 30 days to correct the noncompliance and submit the required information.
The PHSA grants the Secretary of Health and Human Services the authority to issue a notice of noncompliance to a responsible party for failure to submit clinical trial information as required. The responsible party, however, is allowed 30 days to correct the noncompliance and submit the required information.
In addition, we granted to Menarini a non-exclusive license to package and label the Product in or outside of the Menarini Territory for all human oncology indications solely to enable Menarini to commercialize the Product within the Menarini Territory.
In addition, we granted to Menarini a non-exclusive license to package and label the Product in or outside of the Expanded Menarini Territory for all human oncology indications solely to enable Menarini to commercialize the Product within the Expanded Menarini Territory.
A sponsor seeking approval to market and distribute a new drug in the U.S. generally must satisfactorily complete each of the following steps before the product candidate will be approved by the FDA: • completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice (“GLP”) regulations, as applicable; • design of a clinical protocol and submission to the FDA of an IND, which must take effect before human clinical trials may begin; • approval by an independent institutional review board (“IRB”) representing each clinical site before each clinical trial may be initiated; • performance of adequate and well-controlled human clinical trials in accordance with good clinical practices (“GCP”) to establish the safety and efficacy of the proposed drug product for each indication; • preparation and submission to the FDA of a marketing application; 21 Table of Contents • review of the product by an FDA advisory committee, where appropriate or if applicable; • satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the product, or components thereof, are produced to assess compliance with current Good Manufacturing Practices (“cGMP”) requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity; • satisfactory completion of FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data; • payment of user fees and securing FDA approval of the New Drug Application (“NDA”); and • compliance with any post-approval requirements, including Risk Evaluation and Mitigation Strategies (“REMS”) and post-approval studies required by the FDA.
A sponsor seeking approval to market and distribute a new drug in the U.S. generally must satisfactorily complete each of the following steps before the product candidate will be approved by the FDA: • completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice (“GLP”) regulations, as applicable; • design of a clinical protocol and submission to the FDA of an IND, which must take effect before human clinical trials may begin; • approval by an independent institutional review board (“IRB”) representing each clinical site before each clinical trial may be initiated; • performance of adequate and well-controlled human clinical trials in accordance with good clinical practices (“GCP”) to establish the safety and effectiveness of the proposed drug product for each indication; • preparation and submission to the FDA of a marketing application; • review of the product by an FDA advisory committee, where appropriate or if applicable; • satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the product, or components thereof, are produced to assess compliance with current Good Manufacturing Practices (“cGMP”) requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity; • satisfactory completion of FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data; • payment of user fees and securing FDA approval of the New Drug Application (“NDA”); and • compliance with any post-approval requirements, including Risk Evaluation and Mitigation Strategies (“REMS”) and post-approval studies required by the FDA.
Under Article 3 of Regulation (EC) 141/2000, a medicinal product may be designated as orphan if (1) it is intended for the diagnosis, prevention or treatment of a life- threatening or chronically debilitating condition, (2) either (a) such condition affects no more than five in 10,000 persons in the EU when the application is made, or (b) the product, without the benefits derived from orphan status, would not generate sufficient return in the EU to justify investment and (3) there exists no satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the EU, or if such a method exists, the product will be of significant benefit to those affected by the condition.
Under Article 3 of Regulation (EC) 141/2000, a medicinal product may be designated as orphan if (1) it is intended for the diagnosis, prevention or treatment of a life- threatening or chronically debilitating condition, (2) either (a) such condition affects no more than five in 10,000 persons in the EU when the application is made, or (b) the product, without the benefits derived from orphan status, would not generate sufficient return in the EU to justify investment and (3) there exists no satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the EU, or if such a method exists, the product will be of significant benefit to 43 Table of Contents those affected by the condition.
We have approximately 70 field-based employees in the U.S. who call on academic and community-based healthcare professionals who treat multiple myeloma and DLBCL, as well as our reimbursement team. We believe that the current size of our sales force is appropriate at this time to effectively reach our target audience in the specialty markets in which we currently operate.
We have approximately 60 field-based employees in the U.S. who call on academic and community-based healthcare professionals who treat multiple myeloma and DLBCL, as well as our reimbursement team. We believe that the current size of our sales force is appropriate at this time to effectively reach our target audience in the specialty markets in which we currently operate.
The ESSENTIAL Study Our evaluation of selinexor to treat MF is supported by data from the ongoing Phase 2 ESSENTIAL Study, an investigator-sponsored open-label, prospective study evaluating single-agent selinexor at a dose of 80 mg, 60 mg or 40 mg once weekly in adult patients with primary or secondary MF with resistance or intolerance to JAKi therapy (NCT03627403).
The ESSENTIAL Study Our evaluation of selinexor to treat MF is supported by data from the ongoing Phase 2 ESSENTIAL study, an investigator-sponsored open-label, prospective study evaluating single-agent selinexor at a dose of 80 mg, 60 mg or 40 mg once weekly in adult patients with primary or secondary MF with resistance or intolerance to JAKi therapy (the “ESSENTIAL Study”; NCT03627403).
The term “substantial evidence” is defined under the FDCA as “evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the product involved, on the basis of which it could fairly and responsibly be concluded by such experts that the product will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.” The FDA has interpreted this evidentiary standard to require at least two adequate and well-controlled clinical investigations to establish effectiveness of a new product.
The term “substantial evidence” is defined under the FDCA as “evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the product involved, on the basis of which it 30 Table of Contents could fairly and responsibly be concluded by such experts that the product will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.” The FDA has interpreted this evidentiary standard to require at least two adequate and well-controlled clinical investigations to establish effectiveness of a new product.
The XPORT-DLBCL-030 Study The XPORT-DLBCL-030 Study, which will serve as the confirmatory study to the accelerated approval of XPOVIO in DLBCL granted by the FDA in June 2020, is a Phase 2/3 multi-center, randomized study evaluating the combination of selinexor and rituximab, gemcitabine and dexamethasone (“R-GDP”) in patients with relapsed or refractory DLBCL (NCT04442022).
The XPORT-DLBCL-030 Study The XPORT-DLBCL-030 study, which will serve as the confirmatory study to the accelerated approval of XPOVIO in DLBCL granted by the FDA in June 2020, is a Phase 2/3 multi-center, randomized study evaluating the combination of selinexor and rituximab, gemcitabine and dexamethasone (“R-GDP”) in patients with relapsed or refractory DLBCL (the “XPORT-DLBCL-030 Study”; NCT04442022).
Unless an exemption applies, diagnostic tests require pre-notification marketing clearance or approval from the FDA prior to commercial distribution. 25 Table of Contents The FDA previously has required in vitro companion diagnostics intended to select the patients who will respond to the product candidate to obtain pre-market approval (“PMA”) simultaneously with approval of the therapeutic product candidate.
Unless an exemption applies, diagnostic tests require pre-notification marketing clearance or approval from the FDA prior to commercial distribution. 26 Table of Contents The FDA previously has required in vitro companion diagnostics intended to select the patients who will respond to the product candidate to obtain pre-market approval (“PMA”) simultaneously with approval of the therapeutic product candidate.
Section 505(b)(2) NDAs NDAs for most new drug products are based on two full clinical studies which must contain substantial evidence of the safety and efficacy of the proposed new product. These applications are submitted under Section 505(b)(1) of the FDCA. The FDA is, however, authorized to approve an alternative type of NDA under Section 505(b)(2) of the FDCA.
Section 505(b)(2) NDAs NDAs for most new drug products are based on two full clinical studies which must contain substantial evidence of the safety and effectiveness of the proposed new product. These applications are submitted under Section 505(b)(1) of the FDCA. The FDA is, however, authorized to approve an alternative type of NDA under Section 505(b)(2) of the FDCA.
The primary endpoint of the Phase 3 portion of the XPORT-DLBCL-030 Study is PFS. The study is currently in the Phase 2 portion of the evaluation. OUR ELTANEXOR PROGRAM Myelodysplastic Neoplasms Overview MDS are a group of hematologic malignancies whereby the bone marrow does not make enough healthy blood cells (white blood cells, red blood cells, and platelets).
The primary endpoint of the Phase 3 portion of the XPORT-DLBCL-030 Study would be PFS. The study is currently in the Phase 2 portion of the evaluation. OUR ELTANEXOR PROGRAM Myelodysplastic Neoplasms Overview MDS are a group of hematologic malignancies whereby the bone marrow does not make enough healthy blood cells (white blood cells, red blood cells, and platelets).
Finally, we are eligible to receive tiered double-digit royalties based on future net sales of selinexor and eltanexor, and tiered single- to double-digit royalties based on future net sales of verdinexor and KPT-9274 in the Antengene Territory. FORUS In December 2020, we entered into an exclusive distribution agreement for the commercialization of XPOVIO in Canada with FORUS Therapeutics Inc.
We are also eligible to receive tiered double-digit royalties based on future net sales of selinexor and eltanexor, and tiered single- to double-digit royalties based on future net sales of verdinexor and KPT-9274 in the Antengene Territory. FORUS In December 2020, we entered into an exclusive distribution agreement for the commercialization of XPOVIO in Canada with FORUS Therapeutics Inc.
There are four types of meetings that occur between sponsors and the FDA. Type A meetings are those that are necessary for an otherwise stalled product development program to proceed or to address an important safety issue. Type B meetings include pre-IND and pre-NDA/pre-BLA meetings, as well as end of phase meetings such as EOP2 meetings.
There are five types of meetings that occur between sponsors and the FDA. Type A meetings are those that are necessary for an otherwise stalled product development program to proceed or to address an important safety issue. Type B meetings include pre-IND and pre-NDA/pre-BLA meetings, as well as end of phase meetings such as EOP2 meetings.
The FDA also maintains a list of diseases that are exempt from PREA requirements due to low prevalence of disease in the pediatric population.
The FDA maintains a list of diseases that are exempt from PREA requirements due to low prevalence of disease in the pediatric population.
Typically, a RTF will be based on administrative incompleteness, such as clear omission of information or sections of required information; scientific incompleteness, such as omission of critical data, information or analyses needed to evaluate safety and efficacy or provide adequate directions for use; or inadequate content, presentation, or organization of information such that substantive and meaningful review is precluded.
Typically, a RTF will be based on administrative incompleteness, such as clear omission of information or sections of required information; scientific incompleteness, such as omission of critical data, information or analyses needed to evaluate safety and effectiveness or provide adequate directions for use; or inadequate content, presentation, or organization of information such that substantive and meaningful review is precluded.
The primary endpoint in the study was PFS from time of randomization until death or disease progression as assessed by an investigator, with the goal of the study demonstrating a HR of 0.6. In the first quarter of 2022, we presented top-line data from the SIENDO study, including exploratory subgroup analyses.
The primary endpoint in the SIENDO Study is PFS from time of randomization until death or disease progression as assessed by an investigator, with the goal of the study demonstrating a HR of 0.6. In the first quarter of 2022, we presented top-line data from the SIENDO Study, including exploratory subgroup analyses.
The KCP-8602-801 Study In September 2021, we initiated a Phase 2 expansion study of an ongoing open-label Phase 1/2 study investigating eltanexor as a single-agent or in combination with approved and investigational agents in patients with several types of hematologic and solid tumor cancers (NCT02649790).
The KCP-8602-801 Study In September 2021, we initiated a Phase 2 expansion study of an ongoing open-label Phase 1/2 study investigating eltanexor as a single-agent or in combination with approved and investigational agents in patients with several types of hematologic and solid tumor cancers (the “KCP-8602-801 Study”; NCT02649790).
Human clinical trials are typically conducted in four sequential phases, which may overlap or be combined: Phase 1 : The drug is initially introduced into a small number of healthy human subjects or patients with the target disease (e.g., cancer) or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early indication of its effectiveness and to determine optimal dosage.
Human clinical trials are typically conducted in four sequential phases, which may overlap or be combined: 24 Table of Contents Phase 1 : The drug is initially introduced into a small number of healthy human subjects or patients with the target disease (e.g., cancer) or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early indication of its effectiveness and to determine optimal dosage.
Similarly, these proteins can also be exported back into the cytoplasm. Proteins move from the nucleus to the cytoplasm through a protein complex embedded in the nuclear membrane called the nuclear pore. The nuclear pore works like a gate through which large molecules, including many other proteins and ribonucleic acids (“RNAs”), enter and exit the nucleus.
Similarly, these proteins can also be exported back into the cytoplasm. Proteins move from the nucleus to the cytoplasm through a protein complex embedded in the nuclear membrane called the nuclear pore. The nuclear pore works like a gate through which large molecules, including many proteins and ribonucleic acids, enter and exit the nucleus.
Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, or at 24 Table of Contents all. The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.
Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, or at all. The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data 25 Table of Contents submitted.
To this end, the marketing authorization holder must provide the EMA or the competent authority with a consolidated version of the file with respect to quality, safety and efficacy, including all variations introduced since the marketing authorization was granted, at least six months before the marketing authorization ceases to be valid.
To this end, the marketing authorization holder must provide the EMA or the competent authority with a consolidated version of the file with respect to quality, safety and effectiveness, including all variations introduced since the marketing authorization was granted, at least six months before the marketing authorization ceases to be valid.
In September 2021, the Court of Appeals for the 11th Circuit held that, for the purpose of determining the scope of market exclusivity, the term “same disease or condition” in the statute means the designated “rare disease or condition” and could not be 33 Table of Contents interpreted by the FDA to mean the “indication or use.” Thus, the court concluded, orphan drug exclusivity applies to the entire designated disease or condition rather than the “indication or use.” It is unclear how this court decision will be addressed by the FDA and Congress.
In September 2021, the Court of Appeals for the 11th Circuit held that, for the purpose of determining the scope of market exclusivity, the term “same disease or condition” in the statute means the designated “rare disease or condition” and could not be interpreted by the FDA to mean the “indication or use.” Thus, the court concluded, orphan drug exclusivity applies to the entire designated disease or condition rather than the “indication or use.” It is unclear how this court decision will be addressed by the FDA and Congress.
Moreover, as noted above, a pivotal trial is a clinical trial that is believed to satisfy FDA requirements for the evaluation of a product candidate’s safety and efficacy such that it can be used, alone or with other pivotal or non-pivotal trials, to support regulatory approval.
Moreover, as noted above, a pivotal trial is a clinical trial that is believed to satisfy FDA requirements for the evaluation of a product candidate’s safety and effectiveness such that it can be used, alone or with other pivotal or non-pivotal trials, to support regulatory approval.
Under this order, federal agencies are directed to re-examine: policies that undermine protections for people with pre-existing conditions, including complications related to COVID 19; demonstrations and waivers under Medicaid and the PPACA that may reduce coverage or undermine the programs, including work requirements; policies that undermine the Health Insurance Marketplace or other markets for health insurance; policies that make it 35 Table of Contents more difficult to enroll in Medicaid and under the PPACA; and policies that reduce affordability of coverage or financial assistance, including for dependents.
Under this order, federal agencies are directed to re-examine: policies that undermine protections for people with pre-existing conditions, including complications related to COVID 19; demonstrations and waivers under Medicaid and the PPACA that may reduce coverage or undermine the programs, including work requirements; policies that undermine the Health Insurance Marketplace or other markets for health insurance; policies that make it more difficult to enroll in Medicaid and under the PPACA; and policies that reduce affordability of coverage or financial assistance, including for dependents.
Cheng spent ten years at Amgen, a public biotechnology company, where she held a variety of sales and marketing leadership roles supporting the commercialization of key oncology brands, including as Executive Director, Head of National Sales Force & Oncology Contracting Strategy from October 2019 to August 2020, Executive Director, Head of Marketing & Sales for their multiple myeloma business from June 2018 to October 2019; and Chief of Staff to General Manager and Strategy & Operations Director for their oncology business from June 2017 to June 2018.
Cheng spent eleven years at Amgen, a public biotechnology company, where she held a variety of sales and marketing leadership roles supporting the commercialization of key oncology brands, including as Executive Director, Head of National Sales Force & Oncology Contracting Strategy from October 2019 to August 2020, Executive Director, Head of Marketing & Sales for their multiple myeloma business from 2018 to October 2019; and Chief of Staff to General Manager and Strategy & Operations Director for their oncology business from 2017 to 2018.
To reach this determination, the FDA must determine that the drug is effective and that its expected benefits outweigh its potential risks to patients. This “benefit-risk” assessment is informed by the extensive body of evidence about the product’s safety and efficacy in the NDA.
To reach this determination, the FDA must determine that the drug is effective and that its expected benefits outweigh its potential risks to patients. This “benefit-risk” assessment is informed by the extensive body of evidence about the product’s safety and effectiveness in the NDA.
District Court judge in the Northern District of Texas ruled that the individual mandate portion of the PPACA is an essential and inseverable feature of the PPACA, and therefore because the mandate was repealed as part of the TCJA, the remaining provisions of the PPACA are invalid as well. The U.S.
District Court judge in the Northern District of Texas ruled that the individual mandate portion of the PPACA is an essential and inseverable feature of the PPACA, and therefore because the mandate was repealed as part of the TCJA, the remaining provisions of the PPACA are invalid as well. In June 2021, the U.S.
The American Cancer Society (the “ACS”) estimates that nearly 36,000 new cases of multiple myeloma will be diagnosed in the U.S. in 2023. Myeloma occurs most commonly in people over age 65 and the risk of developing multiple myeloma increases with age.
The American Cancer Society (the “ACS”) estimates that nearly 36,000 new cases of multiple myeloma will be diagnosed in the U.S. in 2024. Myeloma occurs most commonly in people over age 65 and the risk of developing multiple myeloma increases with age.
When the foreign clinical study is not conducted under an IND, the sponsor must ensure that the study complies with certain FDA regulatory requirements in order to use the study as support for an IND or application for marketing approval.
When a foreign clinical study is not conducted under an IND, the sponsor must ensure that the study complies with certain regulatory requirements of the FDA in order to use the study as support for an IND or application for marketing approval.
Since a significant proportion of the regulatory framework for pharmaceutical products in the U.K. covering the quality, safety, and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales, and distribution of pharmaceutical products is derived from EU directives and regulations, Brexit may have a material impact upon the regulatory regime with respect to the development, manufacture, importation, approval and commercialization of our product candidates in the U.K.
Since a significant proportion of the regulatory framework for pharmaceutical products in the UK covering the quality, safety, and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales, and distribution of pharmaceutical products is derived from EU directives and regulations, Brexit may have a material impact upon the regulatory regime with respect to the development, manufacture, importation, approval and commercialization of our product candidates in the UK.
Menarini will reimburse us for 25% of all documented expenses we incur for the global development of the Product during 2022 through 2025, provided that such reimbursements shall not exceed $15.0 million per calendar year.
Menarini will reimburse us for 25% of all expenses we incur for the development of the Product during 2022 through 2025, provided that such reimbursements shall not exceed $15.0 million per calendar year.
In addition, there are a number of product candidates that plan to file for approval in the next few years in combination with an HMA, primarily azacytidine, in frontline MDS; magrolimab, an anti-CD47-mAb; evorpacept (ALX18), an anti-CD47 fusion protein; lemzoparlimab, another anti-CD47 mAb; venetoclax, a BCL2 inhibitor; ivosidenib, an IDH1 inhibitor; tamibarotene, a RARA agonist; as well as sabatolimab, an anti-TIM-mAb.
In addition, there are a number of product candidates that plan to file for approval in the next few years in combination with an HMA, primarily azacytidine, in frontline MDS; evorpacept (ALX18), an anti-CD47 fusion protein; lemzoparlimab, another anti-CD47 mAb; venetoclax, a BCL2 inhibitor; tamibarotene, a RARA agonist; as well as sabatolimab, an anti-TIM-mAb.
Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), with prices that can be negotiated subject to a cap; imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation (first due in 2023); and replaces the Part D coverage gap discount program with a new discounting program (beginning in 2025).
Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), with prices that can be negotiated subject to a cap; imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation; and replaces the Part D coverage gap discount program with a new discounting program (beginning in 2025).
Higher levels of XPO1 expression in cancer cells has also been correlated with resistance to chemotherapy and poor prognosis in patients. Mechanism of Action of Our SINE Compounds - Inhibition of XPO1 Selinexor and eltanexor are novel therapies that are oral SINE compounds specifically designed to force nuclear accumulation of multiple tumor suppressor proteins that function in the nucleus.
Higher levels of XPO1 expression in cancer cells has also been correlated with resistance to chemotherapy and poor prognosis in patients. 6 Table of Contents Mechanism of Action of Our SINE Compounds - Inhibition of XPO1 Selinexor and eltanexor are novel therapies that are oral SINE compounds specifically designed to force nuclear accumulation of multiple tumor suppressor proteins that function in the nucleus.
Participants in this study with advanced or recurrent disease who had a PR or CR after at least 12 weeks of standard of care taxane-platinum combination chemotherapy were randomized in a 2:1 manner to receive either maintenance therapy of 80 mg of selinexor or placebo taken once per week, until disease progression.
Participants in the SIENDO Study with advanced or recurrent disease who had a PR or CR after at least 12 weeks of standard of care taxane-platinum combination chemotherapy were randomized in a 2:1 manner to receive either maintenance therapy of 80 mg of selinexor or placebo taken once per week, until disease progression.
This provision applies to drug products that have been approved for at least nine years and biologics that have been licensed for 13 years, but it does not apply to drugs and biologics that have been approved for a single rare disease or condition.
This provision applies to drug products that have been approved for at least 9 years and biologics that have been licensed for 13 years, but it does not apply to drugs and biologics that have been approved for a single rare disease or condition.
In addition to the monthly wellness fund, our employees outside of the U.S. receive competitive compensation and benefits that are regularly benchmarked to ensure market norms and reflect our standards. All employees globally have access to complimentary virtual fitness programs, mental and emotional health support services, as well as support programs to assist working parents with childcare and tutoring.
In addition, our employees outside of the U.S. receive competitive compensation and benefits that are regularly benchmarked to ensure market norms and reflect our standards. All employees globally have access to complimentary virtual fitness programs, mental and emotional health support services, as well as support programs to assist working parents with childcare and tutoring.
The PRIority MEdicines (“PRIME”) scheme is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation reviewed under the centralized procedure. Products from small- and medium-sized enterprises may qualify for earlier entry into the PRIME scheme than larger companies.
The PRIority MEdicines (“PRIME”) scheme is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation reviewed under the 42 Table of Contents centralized procedure. Products from small- and medium-sized enterprises may qualify for earlier entry into the PRIME scheme than larger companies.
Proteins called tumor suppressor proteins can monitor DNA for damage, and if damage is detected, the tumor suppressor proteins will direct the cell to attempt to repair it, or if the DNA damage is too severe, the tumor suppressor proteins will direct the cell to die in a process called apoptosis.
Proteins called tumor suppressor proteins can monitor genes encoded in DNA for damage, and if damage is detected, the tumor suppressor proteins will direct the cell to attempt to repair it, or if the DNA damage is too severe, the tumor suppressor proteins will direct the cell to die in a process called apoptosis.
Our sales force is supported by an experienced sales leadership team and professionals in marketing, reimbursement and market access, market research and analytics, commercial operations, finance and human resources. Our sales and marketing organization uses a variety of pharmaceutical marketing strategies to promote XPOVIO, including sales calls, peer-to-peer education, non-personal promotional, and digital content.
Our sales force is supported by an experienced sales leadership team and professionals in marketing, reimbursement and market access, market research and analytics, commercial operations, finance and human resources. Our sales and marketing organization uses a variety of pharmaceutical marketing strategies to promote XPOVIO, including sales calls, peer-to-peer education, non-personal 20 Table of Contents promotional, and digital content.
In addition, companies usually must also develop additional information about the chemistry and physical characteristics of the investigational product and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.
In addition, sponsors usually must also develop additional information about the chemistry and physical characteristics of the investigational product and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.
The FDA strictly regulates the marketing, labeling, advertising and promotion of prescription drug products placed on the market. This regulation includes, among other things, standards and regulations for direct-to-consumer advertising, communications regarding unapproved uses, industry-sponsored scientific and educational activities, and promotional activities involving the Internet 30 Table of Contents and social media.
The FDA strictly regulates the marketing, labeling, advertising and promotion of prescription drug products placed on the market. This regulation includes, among other things, standards and regulations for direct-to-consumer advertising, communications regarding unapproved uses, industry-sponsored scientific and educational activities, and promotional activities involving the Internet and social media.
In addition, we regularly use our website to post information regarding our business, development programs and governance, and we encourage investors to use our website, particularly the information in the section entitled “Investors” as a source of information about us.
In addition, we regularly use our website to post information regarding our business, development programs and governance, and we encourage investors to use our website, particularly the information in the section entitled “ Investors ” as a source of information about us.
With our global partners, we plan to maximize the global opportunity to bring XPOVIO to patients worldwide. • Focus on our Prioritized Clinical Pipeline. Our science enables us to potentially make a big difference in the lives of patients and we are focused on four priority clinical programs: multiple myeloma, endometrial cancer, MF, and MDS.
With our global partners, we plan to maximize the global opportunity to bring XPOVIO to patients worldwide. • Focus on our Prioritized Clinical Pipeline. Our science enables us to potentially make a big difference in the lives of patients and we are focused on three priority clinical programs: multiple myeloma, endometrial cancer, and MF.
We also have agreements with selected consultants, scientific advisors and collaborators requiring assignment of inventions. The 17 Table of Contents confidentiality agreements are designed to protect our proprietary information and, in the case of agreements or clauses requiring invention assignment, to grant us ownership of technologies that are developed through our relationship with a third party.
We also have agreements with selected consultants, scientific advisors and collaborators requiring assignment of inventions. The confidentiality agreements are designed to protect our proprietary information and, in the case of agreements or clauses requiring invention assignment, to grant us ownership of technologies that are developed through our relationship with a third party.
The key competitive factors affecting the success of any approved oncology drug product, including our products and product candidates, if approved, are likely to be their efficacy, safety, tolerability, convenience and price, the availability of alternative cancer therapies and the availability of reimbursement from government and other third-party payors.
The key competitive factors affecting the success of any approved oncology drug product, including our products and product candidates, if approved, are likely to be their actual or perceived efficacy, safety, tolerability, convenience and price, the availability of alternative cancer therapies and the availability of reimbursement from government and other third-party payors.
Unlike five-year NCE exclusivity, an award of three-year exclusivity does not block the FDA from accepting ANDAs seeking approval for generic versions of the drug as of the date of approval of the original drug product. The FDA typically makes decisions about awards of data exclusivity shortly before a product is approved.
Unlike 33 Table of Contents five-year NCE exclusivity, an award of three-year exclusivity does not block the FDA from accepting ANDAs seeking approval for generic versions of the drug as of the date of approval of the original drug product. The FDA typically makes decisions about awards of data exclusivity shortly before a product is approved.
If the sponsor does not challenge the listed patents or indicates that it is 32 Table of Contents not seeking approval of a patented method of use, the ANDA application will not be approved until all the listed patents claiming the referenced product have expired (other than method of use patents involving indications for which the ANDA sponsor is not seeking approval).
If the sponsor does not challenge the listed patents or indicates that it is not seeking approval of a patented method of use, the ANDA application will not be approved until all the listed patents claiming the referenced product have expired (other than method of use patents involving indications for which the ANDA sponsor is not seeking approval).
Our Code of Business Conduct and Ethics, Corporate Governance Guidelines and the charters of the Audit, Compensation, Nominating, Corporate Governance & Compliance and Commercialization and Portfolio Committees of our Board of Directors are all available on our website at http://www.karyopharm.com at the “Investors” section under “Corporate Governance.” Stockholders may request a free copy of any of these documents by writing to Investor Relations, Karyopharm Therapeutics Inc., 85 Wells Avenue, 2 nd floor, Newton, Massachusetts 02459, U.S.A.
Our Code of Business Conduct and Ethics, Corporate Governance Guidelines and the charters of the Audit, Compensation, Nominating, Corporate Governance & Compliance and Commercialization and Portfolio Committees of our Board of Directors are all available on our website at https://www.karyopharm.com at the “Investors” section under “Corporate Governance.” Stockholders may request a free copy of any of these documents by writing to Investor Relations, Karyopharm Therapeutics Inc., 85 Wells Avenue, 2 nd floor, Newton, Massachusetts 02459, U.S.A. 48 Table of Contents
Similar healthcare laws and regulations exist in the EU and other jurisdictions, including reporting requirements detailing interactions with and payments to healthcare providers and laws governing the privacy and security of personal information. Healthcare Reform A primary trend in the U.S. healthcare industry and elsewhere is cost containment.
Similar healthcare laws and regulations exist in the EU and other jurisdictions, including reporting requirements detailing interactions with and payments to healthcare providers and laws governing the privacy and security of personal information. 36 Table of Contents Healthcare Reform A primary trend in the U.S. healthcare industry and elsewhere is cost containment.
This type of application allows the sponsor to rely, in part, on the FDA’s previous findings of safety and efficacy for a similar product, or published literature.
This type of application allows the sponsor to rely, in part, on the FDA’s previous findings of safety and effectiveness for a similar product, or published literature.
At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on 36 Table of Contents certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
This compares favorably with a historical survival of 13 to 14 months in this population. The most common grade ≥3 treatment emergent AEs were anemia (33%) and fatigue (33%). These were manageable with treatment interruption and dose reduction, except in one patient who discontinued treatment.
This compares favorably with a historical survival of 13 to 14 months in this population. The most common grade ≥3 TEAEs were anemia (33%) and fatigue (33%). These were manageable with treatment interruption and dose reduction, except in one patient who discontinued treatment.
The Phase 2 expansion study is designed to evaluate eltanexor monotherapy in 83 patients with HMA-refractory, intermediate or high-risk MDS. The primary endpoint for this Phase 2 expansion study is ORR with PFS and OS, among others, as secondary endpoints.
The KCP-8602-801 Study is designed to evaluate eltanexor monotherapy in 83 patients with HMA-refractory, intermediate or high-risk MDS. The primary endpoint for this Phase 2 expansion study is ORR with PFS and OS, among others, as secondary endpoints.
Further, in November 2020, HHS finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.
Further, the HHS finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.
These programs are referred to as Fast Track 26 Table of Contents designation, Breakthrough Therapy designation, Priority Review designation and Regenerative Advanced Therapy designation. None of these expedited programs change the standards for approval but they may help expedite the development or approval process of product candidates.
These programs are referred to as Fast Track designation, Breakthrough Therapy designation, Priority Review designation and Regenerative Advanced Therapy designation. None of these expedited programs change the standards for approval but they may help expedite the development or approval process of product candidates.
Under the centralized procedure in the EU, the maximum timeframe for the evaluation of an MAA is 210 days, excluding clock stops, when 38 Table of Contents additional information or written or oral explanation is to be provided by the sponsor in response to questions of the CHMP.
Under the centralized procedure in the EU, the maximum timeframe for the evaluation of an MAA is 210 days, excluding clock stops, when additional information or written or oral explanation is to be provided by the sponsor in response to questions of the CHMP.
In addition, regional healthcare organizations and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription pharmaceutical and other healthcare programs. These measures could reduce the ultimate demand for our products, once approved, or put pressure on our product pricing.
In addition, regional healthcare organizations and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription pharmaceutical and 38 Table of Contents other healthcare programs. These measures could reduce the ultimate demand for our products, once approved, or put pressure on our product pricing.
The Phase 3 portion of the study will evaluate the selected dose (as identified in the Phase 2 study) of selinexor or matching placebo given with the standard combination immunochemotherapy R-GDP to patients with at least one prior therapy and who are not intended for stem cell transplant and CAR-T cell therapy.
The Phase 3 portion of the study is currently designed to evaluate the selected dose (as identified in the Phase 2 study) of selinexor or matching placebo given with the standard combination immunochemotherapy R-GDP to patients with at least one prior therapy and who are not intended for stem cell transplant and CAR-T cell therapy.
We are further eligible to receive tiered royalties ranging from the mid-teens to mid-twenties based on future net sales of the Product in the Menarini Territory. The payments owed by Menarini to us are subject to reduction in specified circumstances.
We are also eligible to receive tiered royalties ranging from the mid-teens to mid-twenties based on future net sales of the Product in the Expanded Menarini Territory. The payments owed by Menarini to us are subject to reduction in specified circumstances.
FORUS received the exclusive rights to commercialize XPOVIO in Canada and is responsible for all regulatory filings and obligations required for registering XPOVIO. We have retained the exclusive production rights and will supply finished product to FORUS for commercial use in Canada. Promedico In February 2020, we entered into an exclusive distribution agreement with Promedico Ltd.
FORUS received the exclusive rights to commercialize XPOVIO in Canada and is responsible for all regulatory 15 Table of Contents filings and obligations required for registering XPOVIO. We have retained the exclusive production rights and will supply finished product to FORUS for commercial use in Canada. Promedico In February 2020, we entered into an exclusive distribution agreement with Promedico Ltd.
For products with a new active substance indicated for the treatment of other diseases and products that are highly innovative or for which a centralized process is in the interest of patients, the centralized procedure may be optional.
For products with 40 Table of Contents a new active substance indicated for the treatment of other diseases and products that are highly innovative or for which a centralized process is in the interest of patients, the centralized procedure may be optional.
In addition, in May 2018, the Right to Try Act was signed into law. The law, among other things, provides a federal framework for certain patients to access certain IND products that have completed a Phase I clinical trial and that are undergoing investigation for 23 Table of Contents FDA approval.
In addition, in May 2018, the Right to Try Act was signed into law. The law, among other things, provides a federal framework for certain patients to access certain IND products that have completed a Phase I clinical trial and that are undergoing investigation for FDA approval.
Although SPCs are available throughout the EU, sponsors must apply on a country‑by‑country basis. Similar patent term extension rights exist in certain other foreign jurisdictions outside the EU. 41 Table of Contents Reimbursement and Pricing Decisions for Approved Products In the EU, pricing and reimbursement schemes vary widely from country to country.
Although SPCs are available throughout the EU, sponsors must apply on a country-by-country basis. Similar patent term extension rights exist in certain other foreign jurisdictions outside the EU. Reimbursement and Pricing Decisions for Approved Products In the EU, pricing and reimbursement schemes vary widely from country to country.
NF-κB is found in the nucleus of 6 Table of Contents most cancer cells and plays a role in cancer metastasis and chemotherapy resistance, as well as in many inflammatory and autoimmune diseases. In cancer cells, XPO1 levels are reported to be elevated when compared to their healthy cell counterparts.
NF-κB is found in the nucleus of most cancer cells and plays a role in cancer metastasis and chemotherapy resistance, as well as in many inflammatory and autoimmune diseases. In certain cancer cells, XPO1 levels are reported to be elevated when compared to their healthy cell counterparts.
Oliger 53 Former Senior Vice President of the Oncology Business Unit at Genentech, Inc., a biotechnology company Deepa R.
Oliger 54 Former Senior Vice President of the Oncology Business Unit at Genentech, Inc., a biotechnology company Deepa R.
There is currently no drug therapy that can cure MF. Allogeneic hematopoietic stem cell transplantation (“HSCT”) is currently the only treatment for MF that can provide a clinical cure; patients who are not good candidates for HSCT are treated with a JAK2 inhibitor (“JAKi”), such as ruxolitinib, fedratinib, or pacritinib to reduce spleen volume and improve symptoms.
Allogeneic hematopoietic stem cell transplantation (“HSCT”) is currently the only treatment for MF that can provide a clinical cure; patients who are not good candidates for HSCT are treated with a JAK2 inhibitor (“JAKi”), such as ruxolitinib, fedratinib, pacritinib or momelotinib to reduce spleen volume and improve symptoms.
Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products, or commercialize existing products in new indications, and those products are or are perceived to be safer, more effective, more convenient, less expensive or more tolerable than any products that we have or may develop.
Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products, or commercialize existing 18 Table of Contents products in new indications, and those products are or are perceived to be safer, more effective, more convenient, less expensive or more tolerable than any products that we have or may develop.
A deferral may be granted for several reasons, including a finding that the product or therapeutic candidate is ready for approval for use in adults before pediatric trials are complete or that additional safety or effectiveness data needs to be collected before the pediatric trials begin.
A deferral may be granted for several reasons, including a finding that the product or therapeutic candidate is ready for approval for use in adults before 27 Table of Contents pediatric trials are complete or that additional safety or effectiveness data needs to be collected before the pediatric trials begin.
In the Phase 1a dose escalation portion of the study, we evaluated selinexor at both the 40 mg and 60 mg doses in combination with ruxolitinib in treatment-naïve patients with MF.
In the Phase 1 dose escalation portion of the MF-034 Study, we evaluated selinexor at both the 40 mg and 60 mg doses in combination with ruxolitinib in treatment-naïve patients with MF.
We strive to bring together employees with a wide variety of backgrounds, skills and culture and encourage all our employees to maintain a work environment in which our differences are 43 Table of Contents respected.
We strive to bring together employees with a wide variety of backgrounds, skills and culture and encourage all our employees to maintain a work environment in which our differences are respected.

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Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

195 edited+107 added−40 removed445 unchanged
Biggest changeAny business that we, or our collaborators, conduct outside of the U.S. is subject to additional risks that may materially adversely affect our or their ability to conduct business in international markets, including: • potentially reduced protection of our intellectual property rights; 55 Table of Contents • the potential for so-called parallel importing, which is what happens when a local seller, faced with high or higher local prices, opts to import goods from a foreign market (with low or lower prices) rather than buying them locally; • unexpected changes in tariffs, trade barriers or regulatory requirements; • economic weakness, including the uncertainty associated with current worldwide economic conditions as a result of the COVID-19 pandemic, rising inflation, increasing interest rates, natural disasters and military conflicts, including the conflict between Russia and Ukraine; volatility in currency exchange rates; or political instability in particular foreign economies and markets; • workforce uncertainty in countries where labor unrest is more common than in the U.S.; • production shortages resulting from any events affecting a product candidate and/or finished drug product supply or manufacturing capabilities abroad; • business interruptions resulting from pandemics (including the COVID-19 pandemic), geo-political actions, including war and terrorism, such as the ongoing conflict between Russia and Ukraine, climate change or natural disasters, including earthquakes, hurricanes, typhoons, floods and fires; and • failure to comply with Office of Foreign Asset Control rules and regulations and the Foreign Corrupt Practices Act (“FCPA”).
Biggest changeAny business that we, or our collaborators, conduct outside of the U.S. is subject to additional risks that may materially adversely affect our or their ability to conduct business in international markets, including: • potentially reduced protection of our intellectual property rights; • the potential for so-called parallel importing, which is what happens when a local seller, faced with high or higher local prices, opts to import goods from a foreign market (with low or lower prices) rather than buying them locally; • unexpected changes in tariffs, trade barriers or regulatory requirements; • economic weakness, including the uncertainty associated with worldwide economic conditions as a result of inflation, sustained high interest rates, natural disasters and military conflicts, including the conflict between Russia and Ukraine, the war between Israel and Hamas, the Palestinian group that controls the Gaza Strip, volatility in currency exchange rates, pandemics or other public health emergencies, or political instability in particular foreign economies and markets; • workforce uncertainty in countries where labor unrest is more common than in the U.S.; • production shortages resulting from any events affecting a product candidate and/or finished drug product supply or manufacturing capabilities abroad; • business interruptions resulting from geo-political actions, including war and terrorism, such as the ongoing conflict between Russia and Ukraine, the war between Israel and Hamas, pandemics or other public health emergencies, climate change or natural disasters, including earthquakes, hurricanes, typhoons, floods and fires; and • failure to comply with Office of Foreign Asset Control rules and regulations and the Foreign Corrupt Practices Act (“FCPA”). 57 Table of Contents Risks Related to Regulatory Matters Even if we, or our collaborators, complete the necessary preclinical studies and clinical trials for our product candidates, the regulatory approval process is expensive, time-consuming and uncertain and we or they may not receive approvals for the commercialization of some or all of our or their product candidates in a timely manner, or at all.
If such an event occurs after any of our or our collaborators’ product candidates are approved and/or commercialized, a number of potentially significant negative consequences may result, including: • regulatory authorities may withdraw the approval of such drug; • regulatory authorities may require additional warnings on the label or impose distribution or use restrictions; • patients and/or healthcare providers may elect to utilize other treatment options that have or are perceived to have more tolerable side effects; • regulatory authorities may require one or more post-marketing studies; • we may be required to create a medication guide outlining the risks of such side effects for distribution to patients; • we could be sued and held liable for harm caused to patients; and • our reputation may suffer.
If such an event occurs after any of our or our collaborators’ product candidates are approved and/or commercialized, a number of potentially significant negative consequences may result, including: • regulatory authorities may withdraw the approval of such drug, require additional warnings on the label or impose distribution or use restrictions and/or require one or more post-marketing studies; • patients and/or healthcare providers may elect to utilize other treatment options that have or are perceived to have more tolerable side effects; • we may be required to create a medication guide outlining the risks of such side effects for distribution to patients; • we could be sued and held liable for harm caused to patients; and • our reputation may suffer.
Orphan drug exclusivity may also be lost if the FDA or EMA determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantity of the product to meet the needs of the patients with the rare disease or condition. In 2017, the Congress passed the FDA Reauthorization Act of 2017 (“FDARA”).
Orphan drug exclusivity may also be lost if the FDA or EMA determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantity of the product to meet the needs of the patients with the rare disease or condition. In 2017, the Congress passed the FDA Reauthorization Act of 2017 (the “FDARA”).
FDARA, among other things, codified the FDA’s pre-existing regulatory interpretation, to require that a drug sponsor demonstrate the clinical superiority of an orphan drug that is otherwise the same as a previously approved drug for the same rare disease in order to receive orphan drug exclusivity.
The FDARA, among other things, codified the FDA’s pre-existing regulatory interpretation, to require that a drug sponsor demonstrate the clinical superiority of an orphan drug that is otherwise the same as a previously approved drug for the same rare disease in order to receive orphan drug exclusivity.
Under omnibus legislation signed by former President Trump in December 2020, the requirement for a product to show clinical superiority applies to drugs and biologics that received Orphan Drug Designation before the enactment of FDARA in 2017, but have not yet been approved or licensed by the FDA.
Under omnibus legislation signed by former President Trump in December 2020, the requirement for a product to show clinical superiority applies to drugs and biologics that received Orphan Drug Designation before the enactment of the FDARA in 2017, but have not yet been approved or licensed by the FDA.
Disruptions at the FDA and other agencies may also slow the time necessary for new product candidates to be reviewed and/or approved by necessary government agencies, which would adversely affect our business.
Disruptions at the FDA and other agencies may also slow the time necessary for new product candidates to be reviewed and/or approved by necessary government agencies, which would adversely affect our business.
These laws may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our products or product candidates for which we may obtain regulatory approval or the frequency with which any such product is prescribed or used.
These and other laws may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our products or product candidates for which we may obtain regulatory approval or the frequency with which any such product is prescribed or used.
Drug products on FDA’s drug shortage list are exempt from these new provisions unless the product has been on the list for more than six continuous months or the FDA determines that the supply of the product will help alleviate or prevent a shortage.
Drug products on the FDA’s drug shortage list are exempt from these new provisions unless the product has been on the list for more than six continuous months or the FDA determines that the supply of the product will help alleviate or prevent a shortage.
Collaborations involving our products and product candidates pose the following risks to us: • collaborators have significant discretion in determining the efforts and resources that they will apply to these collaborations; • collaborators may not perform their obligations as expected or in compliance with applicable local and national laws and regulatory requirements; • collaborators may not pursue development, marketing and/or commercialization of our products or product candidates or may elect not to continue or renew development, marketing or commercialization programs based on clinical trial results, changes in the collaborator’s strategic focus or available funding or external factors such as an acquisition that diverts resources or creates competing priorities; • collaborators may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a product candidate, repeat or conduct new clinical trials or require a new formulation of a product candidate for clinical testing; • collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our products or product candidates if the collaborators believe that competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours; • a collaborator with marketing and distribution rights to one or more products or product candidates may not commit sufficient resources to the marketing and distribution of our products or product candidates; • disagreements with collaborators, including disagreements over proprietary rights, contract interpretation or the preferred course of development or commercialization, might cause delays or termination of the research, development or commercialization of products or product candidates, might lead to additional responsibilities for us with respect to our products or product candidates, or might result in litigation or arbitration, any of which would be time-consuming and expensive; • collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential litigation; • collaborators may infringe the intellectual property rights of third parties, which may expose us to litigation and potential liability; • we may lose certain valuable rights under circumstances identified in any collaboration arrangement that we enter into, such as if we undergo a change of control; • collaborations may be terminated and, if terminated, may result in a need for additional capital to pursue further development, marketing and/or commercialization of the applicable products or product candidates or to enter into new collaboration agreements; • collaborators may learn about our discoveries and use this knowledge to compete with us in the future; and • the number and type of our collaborations could adversely affect our attractiveness to other collaborators or acquirers.
Collaborations involving our products and product candidates pose the following risks to us: • collaborators have significant discretion in determining the efforts and resources that they will apply to these collaborations; • collaborators may not perform their obligations as expected or in compliance with applicable local and national laws and regulatory requirements; 81 Table of Contents • collaborators may not pursue development, marketing and/or commercialization of our products or product candidates or may elect not to continue or renew development, marketing or commercialization programs based on clinical trial results, changes in the collaborator’s strategic focus or available funding or external factors such as an acquisition that diverts resources or creates competing priorities; • collaborators may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a product candidate, repeat or conduct new clinical trials or require a new formulation of a product candidate for clinical testing; • collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our products or product candidates if the collaborators believe that competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours; • a collaborator with marketing and distribution rights to one or more products or product candidates may not commit sufficient resources to the marketing and distribution of our products or product candidates; • disagreements with collaborators, including disagreements over proprietary rights, contract interpretation or the preferred course of development or commercialization, might cause delays or termination of the research, development or commercialization of products or product candidates, might lead to additional responsibilities for us with respect to our products or product candidates, or might result in litigation or arbitration, any of which would be time-consuming and expensive; • collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential litigation; • collaborators may infringe the intellectual property rights of third parties, which may expose us to litigation and potential liability; • we may lose certain valuable rights under circumstances identified in any collaboration arrangement that we enter into, such as if we undergo a change of control; • collaborations may be terminated and, if terminated, may result in a need for additional capital to pursue further development, marketing and/or commercialization of the applicable products or product candidates or to enter into new collaboration agreements; • collaborators may learn about our discoveries and use this knowledge to compete with us in the future; and • the number and type of our collaborations could adversely affect our attractiveness to other collaborators or acquirers.
For additional risks related to conducting business outside of the U.S., please see the risk factor above entitled “ The business that we or our collaborators conduct outside of the U.S. may be adversely affected by international risks and uncertainties .” In addition, the FDA and foreign regulatory authorities retain broad discretion in evaluating the results of our clinical trials and in determining whether the results demonstrate that selinexor, eltanexor or any other product candidate is safe and effective.
For additional risks related to conducting business outside of the U.S., please see the risk factor above entitled “ The business that we or our collaborators conduct outside of the U.S. may be adversely affected by international risks and uncertainties .” In addition, the FDA and foreign regulatory authorities retain broad discretion in evaluating the results of our clinical trials and in determining whether the results demonstrate that selinexor or any other product candidate is safe and effective.
If we are required to conduct additional clinical trials of selinexor, eltanexor or other product candidates prior to approval of additional indications, in earlier lines of therapy or in combination with other drugs, including additional earlier phase clinical trials that may be required prior to commencing any later phase clinical trials, or additional clinical trials following completion of our current and planned later phase clinical trials, we may need substantial additional funds, and there is no assurance that the results of any such additional clinical trials will be sufficient for approval.
If we are required to conduct additional clinical trials of selinexor or other product candidates prior to approval of additional indications, in earlier lines of therapy or in combination with other drugs, including additional earlier phase clinical trials that may be required prior to commencing any later phase clinical trials, or additional clinical trials following completion of our current and planned later phase clinical trials, we may need substantial additional funds, and there is no assurance that the results of any such additional clinical trials will be sufficient for approval.
Among other things, these provisions: • establish a classified board of directors such that not all members of the board are elected at one time; • allow the authorized number of our directors to be changed only by resolution of our board of directors; • limit the manner in which stockholders can remove directors from the board; • establish advance notice requirements for stockholder proposals that can be acted on at stockholder meetings and nominations to our board of directors; • require that stockholder actions must be effected at a duly called stockholder meeting and prohibit actions by our stockholders by written consent; • limit who may call stockholder meetings; 85 Table of Contents • authorize our board of directors to issue preferred stock without stockholder approval, which could be used to institute a “poison pill” that would work to dilute the stock ownership of a potential hostile acquirer, effectively preventing acquisitions that have not been approved by our board of directors; and • require the approval of the holders of at least 75% of the votes that all our stockholders would be entitled to cast to amend or repeal certain provisions of our charter or bylaws.
Among other things, these provisions: • establish a classified board of directors such that not all members of the board are elected at one time; • allow the authorized number of our directors to be changed only by resolution of our board of directors; 90 Table of Contents • limit the manner in which stockholders can remove directors from the board; • establish advance notice requirements for stockholder proposals that can be acted on at stockholder meetings and nominations to our board of directors; • require that stockholder actions must be effected at a duly called stockholder meeting and prohibit actions by our stockholders by written consent; • limit who may call stockholder meetings; • authorize our board of directors to issue preferred stock without stockholder approval, which could be used to institute a “poison pill” that would work to dilute the stock ownership of a potential hostile acquirer, effectively preventing acquisitions that have not been approved by our board of directors; and • require the approval of the holders of at least 75% of the votes that all our stockholders would be entitled to cast to amend or repeal certain provisions of our charter or bylaws.
We do not control the design or conduct of the investigator-sponsored trials, and it is possible that the FDA or foreign regulatory authorities will not view these investigator-sponsored trials as providing adequate support for future clinical trials, whether controlled by us or third parties, for any one or more reasons, including elements of the design, execution of the trials, safety concerns or other trial results.
We do not solely control the design or conduct of the investigator-sponsored trials, and it is possible that the FDA or foreign regulatory authorities will not view these investigator-sponsored trials as providing adequate support for future clinical trials, whether controlled by us or third parties, for any one or more reasons, including elements of the design, execution of the trials, safety concerns or other trial results.
Nonetheless, if a prolonged government shutdown occurs, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions, which could have a material adverse effect on our business. Further, future government shutdowns could impact our ability to access the public markets and obtain necessary capital in order to properly capitalize and continue our operations.
If a prolonged government shutdown occurs, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions, which could have a material adverse effect on our business. Further, future government shutdowns could impact our ability to access the public markets and obtain necessary capital in order to properly capitalize and continue our operations.
We have historically financed our operations principally through product sales, private placements of our preferred and common stock, proceeds from our initial public offering and follow-on offerings of common stock, proceeds from the issuance of convertible debt, proceeds from a revenue interest financing agreement, proceeds from sales of common stock under our “at the market offering” program and cash generated from our business development activities.
We have historically financed our operations principally through product sales, private placements of our common stock, proceeds from our initial public offering and follow-on offerings of common stock, proceeds from the issuance of convertible debt, proceeds from a revenue interest financing agreement, proceeds from sales of common stock under our “at the market offering” program and cash generated from our business development activities.
Any delay in obtaining, or an inability to obtain, any marketing approvals, as a result of Brexit or otherwise, may force us to restrict or delay efforts to seek regulatory approval in the UK for our product candidates, which could significantly and materially harm our business.
Any delay in obtaining, or an inability to obtain, any marketing approvals, as a result of Brexit or otherwise, may force us or our collaborators to restrict or delay efforts to seek regulatory approval in the UK for our product candidates, which could significantly and materially harm our business.
The success of XPOVIO and any current or future product candidates, whether alone or in collaboration with third parties, including achieving and maintaining an adequate level of market adoption, depends on several factors, including: • our ability to successfully launch and achieve broad adoption of our approved products in earlier lines of therapy, any future indications for which XPOVIO may be approved, or any product candidates for which we obtain marketing approval; • the competitive landscape for our products, including the timing of new competing products entering the market and the level and speed at which these products achieve market acceptance; • actual or perceived advantages or disadvantages of our products or product candidates as compared to alternative treatments, including their respective safety, tolerability and efficacy profiles, the potential convenience and ease of administration, access or cost effectiveness; • the effectiveness of our sales, marketing, manufacturing and distribution strategies and operations; • the consistency of any new data we collect and analyses we conduct with prior results, whether they support a favorable safety, efficacy and effectiveness profile of XPOVIO and any potential impact on our U.S.
The success of XPOVIO and any current or future product candidates, whether alone or in collaboration with third parties, including achieving and maintaining an adequate level of market adoption, depends on several factors, including: • our ability to achieve broad adoption of XPOVIO in earlier lines of therapy or to successfully launch and achieve broad adoption of any future XPOVIO indications or any product candidates for which we obtain marketing approval; • the competitive landscape for our products, including the timing of new competing products entering the market and the level and speed at which these products achieve market acceptance; • actual or perceived advantages or disadvantages of our products or product candidates as compared to alternative treatments, including their respective safety, tolerability and efficacy profiles, the potential convenience and ease of administration, access or cost effectiveness; • the effectiveness of our sales, marketing, manufacturing and distribution strategies and operations; • the consistency of any new data we collect and analyses we conduct with prior results, whether they support a favorable safety, efficacy and effectiveness profile of XPOVIO and any potential impact on our U.S.
If those collaborations are not successful, or if we are not able to maintain our existing collaborations or establish additional collaborations, we may have to alter our development and commercialization plans and may not be able to capitalize on the market potential of XPOVIO or our product candidates.
If those collaborations are not successful, or if we are not able to maintain our existing collaborations or establish additional collaborations, we may have to alter our development and commercialization plans and may not be able to capitalize on the market potential of XPOVIO or our product candidates, if approved.
Factors that may inhibit our efforts to successfully commercialize XPOVIO or any product candidates, if approved, on our own include: • our inability to recruit, train and retain adequate numbers of effective sales, market access, market analytics, operations and marketing personnel; • the inability of sales personnel to obtain access to physicians or persuade adequate numbers of physicians to prescribe current or future products; • the lack of complementary drugs, which may put us at a competitive disadvantage relative to companies with more extensive drug lines; • unforeseen costs and expenses associated with creating an independent sales, marketing and distribution organization; • our inability to obtain sufficient coverage and reimbursement from third-party payors and governmental agencies; • our ability to supply sufficient inventory of our products for commercial sale; and • existing or new competitors taking share from XPOVIO or any other future product or preventing XPOVIO or any other future product from gaining share in its approved indications.
Factors that may inhibit our efforts to successfully commercialize XPOVIO or any product candidates, if approved, on our own include: • existing or new competitors taking share from XPOVIO or any other future product or preventing XPOVIO or any other future product from gaining share in its approved indications; • our inability to recruit, train and retain adequate numbers of effective sales, market access, market analytics, operations and marketing personnel; • the inability of sales personnel to obtain access to physicians or persuade adequate numbers of physicians to prescribe current or future products; • the lack of complementary drugs, which may put us at a competitive disadvantage relative to companies with more extensive drug lines; • unforeseen costs and expenses associated with creating an independent sales, marketing and distribution organization; • our inability to obtain sufficient coverage and reimbursement from third-party payors and governmental agencies; and 55 Table of Contents • our ability to supply sufficient inventory of our products for commercial sale.
If our collaborators suffer material and adverse effects from such risks and uncertainties, our rights and benefits for our licensed products could be negatively impacted, which could have a material and adverse impact on our revenues. 67 Table of Contents We are subject to stringent privacy laws, information security laws, regulations, policies and contractual obligations related to data privacy and security and changes in such laws, regulations, policies, contractual obligations and failure to comply with such requirements could subject us to significant fines and penalties, which may have a material adverse effect on our business, financial condition or results of operations.
If our collaborators suffer material and adverse effects from such risks and uncertainties, our rights and benefits for our licensed products could be negatively impacted, which could have a material and adverse impact on our revenues. 71 Table of Contents We are subject to stringent privacy laws, information security laws, regulations, policies and contractual obligations related to data privacy and security and changes in such laws, regulations, policies and contractual obligations, and failure to comply with such requirements could subject us to significant fines and penalties, which may have a material adverse effect on our business, financial condition or results of operations.
The amount and timing of our future capital requirements will depend on many factors, including, but not limited to: • the scope, progress, results, timing and costs of our current and planned development efforts and regulatory review of our product candidates; • the amount and timing of revenues from sales of XPOVIO, or any product candidate that we develop or acquire; • the cost of, and our ability to expand and maintain, the commercial infrastructure required to support the commercialization of XPOVIO and any other product for which we receive marketing approval, including medical affairs, manufacturing, marketing and distribution functions; • our ability to establish and maintain collaboration, partnership, licensing, marketing, distribution or other arrangements on favorable terms and the level and timing of success of these arrangements; • the extent to which we acquire or in-license other products, product candidates and technologies; and • the costs and timing of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending intellectual property-related claims.
The amount and timing of our future capital requirements will depend on many factors, including, but not limited to: 77 Table of Contents • the scope, progress, results, timing and costs of our current and planned development efforts and regulatory review of our product candidates; • the amount and timing of revenues from sales of XPOVIO, or any product candidate that we develop or acquire; • the cost of, and our ability to expand and maintain, the commercial infrastructure required to support the commercialization of XPOVIO and any other product for which we receive marketing approval, including medical affairs, manufacturing, marketing and distribution functions; • our ability to establish and maintain collaboration, partnership, licensing, marketing, distribution or other arrangements on favorable terms and the level and timing of success of these arrangements; • the extent to which we acquire or in-license other products, product candidates and technologies; and • the costs and timing of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending intellectual property-related claims.
The FDA or other regulatory authorities may determine that (i) our product candidates are not safe and effective, only moderately effective or have undesirable or unintended side effects, toxicities or other characteristics that preclude our obtaining marketing approval or prevent or limit commercial use; (ii) the dose used in a clinical trial has not been optimized and require us to 56 Table of Contents conduct additional dose optimization studies; or (iii) the comparator arm in a trial is no longer the appropriate comparator due to the evolution of the competitive landscape or subsequent data of the comparator product, even if the FDA or other regulatory authority had previously approved the trial design, and we may be required to amend the trial or we may not receive approval of the indication.
The FDA or other regulatory authorities may determine that (i) our product candidates are not safe and effective, only moderately effective or have undesirable or unintended side effects, toxicities or other characteristics that preclude our obtaining marketing approval or prevent or limit commercial use; (ii) the dose used in a clinical trial has not been optimized and require us to conduct additional dose optimization studies; or (iii) the comparator arm in a trial is no longer the appropriate comparator due to the evolution of the competitive landscape or subsequent data of the comparator product, even if the FDA or other regulatory authority had previously approved the trial design, and we may be required to amend the trial or we may not receive approval of the indication.
Our failure to repurchase the Notes at a time when the repurchase is required by the indenture governing the Notes or to pay cash upon conversion of the Notes as required by the indenture would constitute a default under the indenture.
Our failure to repurchase the Notes at a time when the repurchase is required by the indenture governing the Notes (the “Indenture”) or to pay cash upon conversion of the Notes as required by the Indenture would constitute a default under the Indenture.
The TCJA, among other things, contains significant changes to corporate taxation, including reduction of the corporate tax rate from a top marginal rate of 35% to a flat rate of 21% and limitation of the deduction for net operating losses to 80% of current year taxable income for losses arising in taxable years beginning after December 31, 2017 (though any such net operating losses may be carried forward indefinitely).
The TCJA, among other things, contains significant changes to corporate taxation, including reduction of the corporate tax rate from a top marginal rate of 35% to a flat rate of 21% and limitation of the deduction for net operating losses to 80% of current year taxable income for losses arising in taxable years beginning after December 31, 2017 and the elimination of the carryback of such losses (though any such net operating losses may be carried forward indefinitely).
The use of specialty pharmacies and specialty distributors involves certain risks, including, but not limited to, risks that these organizations will: • not provide us accurate or timely information regarding their inventories, the number of patients who are using XPOVIO or serious adverse reactions, events and/or product complaints regarding XPOVIO; • not effectively sell or support XPOVIO or communicate publicly concerning XPOVIO in a manner that is contrary to FDA rules and regulations; • reduce their efforts or discontinue to sell or support, or otherwise not effectively sell or support, XPOVIO; • not devote the resources necessary to sell XPOVIO in the volumes and within the time frames that we expect; • be unable to satisfy financial obligations to us or others; or • cease operations.
The use of specialty pharmacies and specialty distributors involves certain risks, including, but not limited to, risks that these organizations will: • not provide us accurate or timely information regarding their inventories, the number of patients who are using XPOVIO or serious adverse reactions, events and/or product complaints regarding XPOVIO; • not effectively sell or support XPOVIO or communicate publicly concerning XPOVIO in a manner that is contrary to FDA rules and regulations; 82 Table of Contents • reduce their efforts or discontinue to sell or support, or otherwise not effectively sell or support, XPOVIO; • not devote the resources necessary to sell XPOVIO in the volumes and within the time frames that we expect; • be unable to satisfy financial obligations to us or others; or • cease operations.
We anticipate that our operating expenses will continue to be significant and increase as we continue to: • commercialize XPOVIO in the U.S., including maintaining our commercial infrastructure; • obtain and/or maintain regulatory approval for XPOVIO and our product candidates, including completing any required post-marketing requirements to the satisfaction of the FDA or other regulatory agencies; • expand our research and development programs, identify additional product candidates and initiate and conduct clinical trials, including clinical trials required by the FDA or other regulatory agencies in addition to those that have been or are currently expected to be conducted; • maintain, expand and protect our intellectual property portfolio; 72 Table of Contents • manufacture XPOVIO and our product candidates; and • acquire or in-license other products, product candidates or technologies.
We anticipate that our operating expenses will continue to be significant and increase as we continue to: • commercialize XPOVIO in the U.S., including maintaining our commercial infrastructure; • obtain and/or maintain regulatory approval for XPOVIO and our product candidates, including completing any required post-marketing requirements to the satisfaction of the FDA or other regulatory agencies; • expand our research and development programs, identify additional product candidates and initiate and conduct clinical trials, including clinical trials required by the FDA or other regulatory agencies in addition to those that have been or are currently expected to be conducted; • maintain, expand and protect our intellectual property portfolio; • manufacture XPOVIO and our product candidates; and • acquire or in-license other products, product candidates or technologies.
More recently, on August 16, 2022, the IRA was signed into law by President Biden. The new legislation has implications for Medicare Part D, which is a program available to individuals who are entitled to Medicare Part A or enrolled in Medicare Part B to give them the option of paying a monthly premium for outpatient prescription drug coverage.
On August 16, 2022, the IRA was signed into law by President Biden. The new legislation has implications for Medicare Part D, which is a program available to individuals who are entitled to Medicare Part A or enrolled in Medicare Part B to give them the option of paying a monthly premium for outpatient prescription drug coverage.
We may seek certain designations for our product candidates in or outside of the U.S., including Breakthrough Therapy, Fast Track and Priority Review designations, and PRIME Designation in the EU, but we might not receive such designations, and even if we do, such designations may not lead to a faster development or regulatory review or approval process.
We or our collaborators may seek certain designations for our product candidates in or outside of the U.S., including Breakthrough Therapy, Fast Track and Priority Review designations, and PRIME Designation in the EU, but we, or they, might not receive such designations, and even if we, or they, do, such designations may not lead to a faster development or regulatory review or approval process.
As of December 31, 2022, we believe that our existing cash, cash equivalents and investments will enable us to fund our current operating and capital expenditure plans for at least twelve months from the date of issuance of the financial statements contained in this Annual Report on Form 10-K.
As of December 31, 2023, we believe that our existing cash, cash equivalents and investments will enable us to fund our current operating and capital expenditure plans for at least twelve months from the date of issuance of the financial statements contained in this Annual Report on Form 10-K.
Further, there can be significant variability in safety and/or efficacy results between different trials of the same product candidate due to numerous factors, including changes in trial protocols, differences in size and type of the patient populations, adherence to the dosing regimen and other trial protocols and the dropout rate among clinical trial participants.
Further, there can be significant variability in safety and/or efficacy results between different trials of the same product candidate due to numerous factors, including changes in trial protocols, differences in size and type of the patient populations, starting dose, adherence to the dosing regimen and other trial protocols and the dropout rate among clinical trial participants.
For example, the NCE-1 date for selinexor is July 3, 2023 after which a third party could be positioned to market an ANDA or Section 505(b)(2) product that competes with selinexor prior to the expiry of our patents if the third party successfully challenged the validity of our patents protecting the product.
For example, the NCE-1 date for selinexor was July 3, 2023 after which a third party could be positioned to market an ANDA or Section 505(b)(2) product that competes with selinexor prior to the expiry of our patents if the third party successfully challenged the validity of our patents protecting the product.
Failure by any of our manufacturers to comply with applicable cGMP regulations or other regulatory requirements could result in sanctions being imposed on us or the contract manufacturer, including fines, injunctions, civil penalties, delays, suspensions or withdrawals of approvals, operating restrictions, 79 Table of Contents interruptions in supply and criminal prosecutions, any of which could significantly and adversely affect supplies of our products or product candidates and have a material adverse impact on our business, financial condition and results of operations.
Failure by any of our manufacturers to comply with applicable cGMP regulations or other regulatory requirements could result in sanctions being imposed on us or the contract manufacturer, including fines, injunctions, civil penalties, delays, suspensions or withdrawals of approvals, operating restrictions, interruptions in supply and criminal prosecutions, any of which could significantly and adversely affect supplies of our products or product candidates and have a material adverse impact on our business, financial condition and results of operations.
These requirements include compliance with EU cGMP standards when manufacturing medicinal products and active pharmaceutical ingredients, including the manufacture of active pharmaceutical ingredients outside of the EU with the intention to import the active pharmaceutical ingredients into the EU; and • the marketing and promotion of authorized drugs, including industry-sponsored continuing medical education and advertising directed toward the prescribers of drugs and/or the general public, are strictly regulated in the EU notably 60 Table of Contents under Directive 2001/83/EC, as amended, and are also subject to EU Member State laws.
These requirements include compliance with EU cGMP standards when manufacturing medicinal products and active pharmaceutical ingredients, including the manufacture of active pharmaceutical ingredients outside of the EU with the intention to import the active pharmaceutical ingredients into the EU; and • the marketing and promotion of authorized drugs, including industry-sponsored continuing medical education and advertising directed toward the prescribers of drugs and/or the general public, are strictly regulated in the EU notably under Directive 2001/83/EC, as amended, and are also subject to EU Member State laws.
A failure to obtain accelerated approval or any other form of expedited development, review or approval for our product candidates, or withdrawal of a product candidate, would result in a longer time period until commercialization of such product candidate, could increase the cost of development of such product candidate and could harm our competitive position in the marketplace.
Accordingly, a failure to obtain and maintain accelerated approval or any other form of expedited development, review or approval for our product candidates, or withdrawal of a product candidate, would result in a longer time period until commercialization of such product candidate, could increase the cost of development of such product candidate and could harm our competitive position in the marketplace.
The third parties are allowed to rely on the safety and efficacy data of the innovator’s product, may not need to conduct clinical trials and can market a competing version of a product after the expiration or loss of patent exclusivity or the expiration or loss of regulatory exclusivity and often charge significantly lower prices.
The third parties are allowed to rely on the safety and effectiveness data of the innovator’s product, may not need to conduct clinical trials and can market a competing version of a product after the expiration or loss of patent exclusivity or the expiration or loss of regulatory exclusivity and often charge significantly lower prices.
It is not always possible to identify and deter employee or third-party misconduct, and the precautions we take to detect and prevent these activities may not be effective in 69 Table of Contents controlling unknown or unmanaged risks or losses or in protecting us from significant penalties, governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws, standards, regulations, guidance or codes of conduct.
It is not always possible to identify and deter employee or third-party misconduct, and the precautions we take to detect and prevent these activities may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from significant penalties, governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws, standards, regulations, guidance or codes of conduct.
If we, either alone or with our collaborators, are unable to successfully commercialize current and future indications of XPOVIO or other products or product candidates on a 46 Table of Contents timely basis, including achieving widespread market acceptance by physicians, patients, third-party payors and others in the medical community, our business, financial condition and future profitability will be materially harmed.
If we, either alone or with our collaborators, are unable to successfully commercialize current and future indications of XPOVIO or other products or product candidates on a timely basis, including achieving widespread market acceptance by physicians, patients, third-party payors and others in the medical community, our business, financial condition and future profitability will be materially harmed.
The SEC also may suspend or bar issuers from trading securities on U.S. exchanges for violations of the FCPA’s accounting provisions. 70 Table of Contents Like the FCPA, the UK Bribery Act and other anti-corruption laws throughout the world similarly prohibit offers and payments made to obtain improper business advantages, including offers or payments to healthcare professionals and other government and non-government officials.
The SEC also may suspend or bar issuers from trading securities on U.S. exchanges for violations of the FCPA’s accounting provisions. Like the FCPA, the UK Bribery Act and other anti-corruption laws throughout the world similarly prohibit offers and payments made to obtain improper business advantages, including offers or payments to healthcare professionals and other government and non-government officials.
Further, if investigators or institutions breach their obligations with respect to the clinical development of our product candidates, or if the data proves to be inadequate compared to the first-hand knowledge we might have gained had the investigator-sponsored trials been sponsored and conducted by us, then our ability to design and conduct any future clinical trials ourselves may be adversely affected.
Further, if investigators or institutions breach their obligations with respect to the clinical development of our product candidates, or if the data proves to be inadequate compared to the first-hand knowledge we might have gained had the 83 Table of Contents investigator-sponsored trials been sponsored and conducted by us, then our ability to design and conduct any future clinical trials ourselves may be adversely affected.
If there are patents listed in the Orange Book for the applicable, approved innovator product, a generic or 505(b)(2) sponsor that seeks to market its product before expiration of the patents must include in their applications what is known as a “Paragraph IV” certification, challenging the validity or enforceability, or claiming non-infringement, of the listed patent or patents.
If there are patents listed in the Orange Book for the applicable, approved innovator product, a generic or 505(b)(2) sponsor that seeks to market its product before expiration of the patents must include in their applications what is known as a “Paragraph IV” certification, challenging the validity or enforceability, or 87 Table of Contents claiming non-infringement, of the listed patent or patents.
Adverse events (“AEs”) in our clinical trials to date have been generally predictable and typically manageable, including through prophylactic care or dose reductions, although some patients have experienced more serious AEs.
Adverse events (“AEs”) in our clinical trials for selinexor to date have been generally predictable and typically manageable, including through prophylactic care or dose reductions, although some patients have experienced more serious AEs.
It is also possible that we will fail to identify patentable aspects of our research and development output before it is too late to obtain patent protection. 80 Table of Contents The patent position of biotechnology and pharmaceutical companies generally is highly uncertain, involves complex legal and factual questions and has in recent years been the subject of much litigation.
It is also possible that we will fail to identify patentable aspects of our research and development output before it is too late to obtain patent protection. The patent position of biotechnology and pharmaceutical companies generally is highly uncertain, involves complex legal and factual questions and has in recent years been the subject of much litigation.
If the required post-approval studies fail to verify the clinical benefits of XPOVIO or confirm that the surrogate marker used for accelerated approval of XPOVIO to treat DLBCL showed an adequate correlation with clinical outcomes, if a sufficient number of participants cannot be enrolled, or if we fail to perform the required post-approval studies with due diligence or on a timely basis, the FDA has the authority to withdraw approval of the drug following a hearing conducted under the FDA’s regulations, which could have a material adverse impact on our business.
If required post-approval studies fail to verify the clinical benefits of our products or confirm that the surrogate marker used for accelerated approval of our products showed an adequate correlation with clinical outcomes, if a sufficient number of participants cannot be enrolled, or if we fail to perform the required post-approval studies with due diligence or on a timely basis, the FDA has the authority to withdraw approval of the drug following a hearing conducted under the FDA’s regulations, which could have a material adverse impact on our business.
Our long-term success depends in a large part on our ability to continue to successfully develop new indications of selinexor, our product candidates, including eltanexor, or any new product candidates we may develop or acquire. Clinical testing is expensive, time consuming, difficult to design and implement, inherently uncertain as to outcome and can fail at any stage of testing.
Our long-term success depends in a large part on our ability to continue to successfully develop new indications of selinexor, our product candidates, or any new product candidates we may develop or acquire. Clinical testing is expensive, time consuming, difficult to design, implement and enroll, inherently uncertain as to outcome and can fail at any stage of testing.
If 66 Table of Contents our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, exclusion from government funded healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations.
If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, exclusion from government funded healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations.
In September 2019, we entered into the Revenue Interest Financing Agreement (the “Revenue Interest Agreement”) with HealthCare Royalty Partners III, L.P. and HealthCare Royalty Partners IV, L.P. (“HCR”) and which was amended in June 2021 (the “Amended Revenue Interest Agreement”).
In September 2019, we entered into the Revenue Interest Financing Agreement (the “Revenue Interest Agreement”) with HealthCare Royalty Partners III, L.P. and HealthCare Royalty Partners IV, L.P. (“HCR”) and which was amended in June 2021 and August 2023 (the “Amended Revenue Interest Agreement”).
Our business and our ability to generate product revenue from the sales of drugs that treat cancer and other diseases in humans depend heavily on our and our collaborators’ ability to successfully commercialize our lead drug, XPOVIO ® (selinexor) on a global basis, in currently approved and future indications and the level of market adoption for, and the continued use of, our products and product candidates, if approved.
Our business and our ability to generate product revenue from the sales of drugs that treat cancer depend heavily on our and our collaborators’ ability to successfully commercialize our lead drug, XPOVIO ® (selinexor), on a global basis in currently approved and future indications, and the level of market adoption for, and the continued use of, our products and product candidates, if approved.
Any such failure to comply with data protection and privacy laws could result in government-imposed fines or orders requiring that we change our practices, claims for damages or other liabilities, regulatory investigations and enforcement action, litigation and significant costs for remediation, any of which could adversely affect our business.
Any such failure to comply with data protection and privacy laws could result in government-imposed fines or orders requiring that we change our practices, claims for damages or 73 Table of Contents other liabilities, regulatory investigations and enforcement action, litigation and significant costs for remediation, any of which could adversely affect our business.
If we cannot conclude that we have effective internal control over our financial reporting, or if our independent registered public accounting firm is unable to provide an unqualified opinion regarding the effectiveness of our internal control over financial reporting, 87 Table of Contents investors could lose confidence in the reliability of our financial statements, which could lead to a decline in our stock price.
If we cannot conclude that we have effective internal control over our financial reporting, or if our independent registered public accounting firm is unable to provide an unqualified opinion regarding the effectiveness of our internal control over financial reporting, investors could lose confidence in the reliability of our financial statements, which could lead to a decline in our stock price.
In addition, beginning in 2022, the TCJA eliminates the option to deduct research and development expenditures currently and requires corporations to capitalize and amortize them over five years. 88 Table of Contents In addition to the CARES Act, as part of Congress’ response to the COVID-19 pandemic, economic relief legislation was enacted in 2020 and 2021 containing tax provisions.
In addition, beginning in 2022, the TCJA eliminates the option to deduct research and development expenditures currently and requires corporations to capitalize and amortize them over five years. In addition to the CARES Act, as part of Congress’ response to the COVID-19 pandemic, economic relief legislation was enacted in 2020 and 2021 containing tax provisions.
The approval of these anti-cancer agents, or any others which may receive regulatory approval, may have a significant impact on the therapeutic landscape and our product revenues. See Item 1 under the heading Business - Competition in this Annual Report on Form 10-K for more information on competition.
The approval of these anti-cancer agents, or any others which may receive regulatory approval, have had a significant impact and may continue to have a significant impact on the therapeutic landscape and our product revenues. See Item 1 under the heading Business - Competition in this Annual Report on Form 10-K for more information on competition.
The Order directs the HHS to create a plan within 45 days to combat “excessive pricing of prescription pharmaceuticals and enhance domestic pharmaceutical supply chains, to reduce the prices paid by the federal government for such pharmaceuticals, and to address the recurrent problem of price gouging.” In September 2021, the HHS released its plan to reduce pharmaceutical prices.
The Order directs the HHS to create a plan within 45 days to combat “excessive pricing of prescription pharmaceuticals and enhance domestic pharmaceutical supply chains, to reduce the prices paid by the federal government for such 68 Table of Contents pharmaceuticals, and to address the recurrent problem of price gouging.” In September 2021, the HHS released its plan to reduce pharmaceutical prices.
Under the Hatch-Waxman 82 Table of Contents Amendments, a company may also submit an NDA under section 505(b)(2) of the FDCA that references the FDA’s prior approval of the innovator product or preclinical studies and/or clinical trials that were not conducted by, or for, the sponsor and for which the sponsor has not obtained a right of reference.
Under the Hatch-Waxman Amendments, a company may also submit an NDA under section 505(b)(2) of the FDCA that references the FDA’s prior approval of the innovator product or preclinical studies and/or clinical trials that were not conducted by, or for, the sponsor and for which the sponsor has not obtained a right of reference.
Accordingly, a material weakness increases the risk that the financial information we report contains material errors. We regularly review and update our internal controls, disclosure controls and procedures, and corporate governance policies. In addition, we are required under the Sarbanes-Oxley Act of 2002 to report annually on our internal control over financial reporting.
Accordingly, a material weakness increases the risk that the financial information we report contains material errors. 92 Table of Contents We regularly review and update our internal controls, disclosure controls and procedures, and corporate governance policies. In addition, we are required under the Sarbanes-Oxley Act of 2002 to report annually on our internal control over financial reporting.
Securing marketing approval requires the submission of extensive preclinical and clinical data and supporting information, including manufacturing information, to regulatory authorities for each therapeutic indication to establish the product candidate’s safety and efficacy.
Securing marketing approval requires the submission of extensive preclinical and clinical data and supporting information, including manufacturing information, to regulatory authorities for each therapeutic indication to establish the product candidate’s safety and effectiveness.
If our or our partners’ or service providers’ privacy or data security measures fail to comply with the GDPR requirements, we may be subject to litigation, regulatory 68 Table of Contents investigations, enforcement notices requiring us to change the way we use personal data and/or fines of up to 20 million Euros or up to 4% of the total worldwide annual turnover of the preceding financial year, whichever is higher, as well as compensation claims by affected individuals, negative publicity, reputational harm and a potential loss of business and goodwill.
If our or our partners’ or service providers’ privacy or data security measures fail to comply with the GDPR requirements, we may be subject to litigation, regulatory investigations, enforcement notices requiring us to change the way we use personal data and/or fines of up to 20 million Euros or up to 4% of the total worldwide annual turnover of the group of companies of the preceding financial year, whichever is higher, as well as compensation claims by affected individuals, negative publicity, reputational harm and a potential loss of business and goodwill.
If any of these events occurs, the market potential of our products and product candidates, if approved, could be reduced, and our business could be materially harmed. 77 Table of Contents If we are unable to establish and maintain our agreements with third parties to distribute XPOVIO to patients, our results of operations and business could be adversely affected.
If any of these events occurs, the market potential of our products and product candidates, if approved, could be reduced, and our business could be materially harmed. If we are unable to establish and maintain our agreements with third parties to distribute XPOVIO to patients, our results of operations and business could be adversely affected.
An adverse determination in any such submission, proceeding or litigation could reduce the scope of, or invalidate, our patent rights, allow third parties to commercialize our discoveries or drugs and compete directly with us, without payment to us, or result in our inability to manufacture or commercialize drugs without infringing third-party patent rights.
An adverse determination in any such submission, proceeding or litigation could reduce the scope of, or invalidate, our patent rights, allow third 85 Table of Contents parties to commercialize our discoveries or drugs and compete directly with us, without payment to us, or result in our inability to manufacture or commercialize drugs without infringing third-party patent rights.
For any of our product candidates for which we are seeking regulatory approval in the U.S. or the EU, we cannot guarantee that we will be able to obtain a waiver or alternatively complete any required studies and other requirements in a timely manner, or at all, which could result in in issuance and publication of a PREA Non-Compliance letter and associated reputational harm, our product candidate being considered misbranded and subject to relevant enforcement action, invalidation of the marketing application, and/or financial penalties.
For any of our product candidates for which we 58 Table of Contents or our collaborators are seeking regulatory approval in the U.S. or the EU, we cannot guarantee that we will be able to obtain a waiver or alternatively complete any required studies and other requirements in a timely manner, or at all, which could result in an issuance and publication of a PREA Non-Compliance letter and associated reputational harm, our product candidate being considered misbranded and subject to relevant enforcement action, invalidation of the marketing application, and/or financial penalties.
For example, the July 2022 marketing authorization from the European Commission (“EC”) for NEXPOVIO to treat adult patients with multiple myeloma after at least one prior therapy satisfied the conditional approval obligation for NEXPOVIO for patients with multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy.
For example, the July 2022 marketing authorization from the EC for NEXPOVIO to treat adult patients with multiple myeloma after at least one prior therapy satisfied the conditional approval obligation for NEXPOVIO for patients with multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy.
While we began to generate revenue from the sales of XPOVIO in July 2019 and have received revenue from our license arrangements, such as the partnership we have with Antengene Therapeutics Limited (“Antengene”) for our programs across most of the Asia-Pacific region, and with Menarini for our programs in Europe, Latin America and other key countries, there can be no assurance as to the amount or timing of future product or license and other revenues, and we may not achieve profitability for several years, if at all.
While we began to generate revenue from the sales of XPOVIO in July 2019 and have received revenue from our license arrangements, such as the partnership we have with Antengene Therapeutics Limited (“Antengene”) for our programs across most of the Asia-Pacific region, and with Menarini for our programs in Europe, Latin America, certain Middle East and Africa regions and other key countries, there can be no assurance as to the amount or timing of future product or license and other revenues, and we may not achieve profitability for several years, if at all.
Risks Related to Employee Matters and Managing Growth Our future success depends on our ability to retain key members of our management team and to attract, retain and motivate qualified personnel. We are highly dependent on the management, technical and scientific expertise of principal members of our management and scientific teams, including our President and Chief Executive Officer.
Risks Related to Our Operations and Employee Matters Our future success depends on our ability to retain key members of our management team and to attract, retain and motivate qualified personnel. We are highly dependent on the management, technical and scientific expertise of principal members of our management and scientific teams, including our President and Chief Executive Officer.
A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted 63 Table of Contents deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs.
A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs.
Although we have no knowledge of any such claims being alleged to date, if such claims were to arise, litigation may be necessary to defend against any such claims. If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel.
Although we have no knowledge of any such claims being alleged to date, if such claims were to arise, litigation may be necessary to 86 Table of Contents defend against any such claims. If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel.
We also have pending applications in the U.S. to register KARYOPHARM alone, and our logo in greyscale, for pharmaceuticals. Outside of the U.S., XPOVIO is registered or pending in 46 additional jurisdictions, and is registered in Katakana in Japan, Hangul in South Korea, and Chinese characters in Taiwan.
We also have pending applications in the U.S. to register KARYOPHARM alone, and our logo in greyscale, for pharmaceuticals. Outside of the U.S., XPOVIO is registered or pending in 46 additional jurisdictions, 88 Table of Contents and is registered in Katakana in Japan, Hangul in South Korea, and Chinese characters in Taiwan.
Although we intend to comply fully with the terms of these new statutory provisions, we are still exposed to potential litigation and damages by competitors who may claim that we are not providing sufficient quantities of our approved products on commercially reasonable, market-based terms for testing in support of ANDAs and 505(b)(2) applications.
Although we intend to comply fully with the terms of these statutory provisions, we are still exposed to potential litigation and damages by competitors who may claim that we are not providing sufficient quantities of our approved products on commercially 75 Table of Contents reasonable, market-based terms for testing in support of ANDAs and 505(b)(2) applications.
As XPOVIO is used over longer periods of time by a wider group of patients taking numerous other medicines or by patients with additional underlying conditions, the likelihood of adverse drug reactions or unintended side effects, including death, may increase.
As XPOVIO is used over longer periods of time by a wider group of patients taking numerous other medicines or by patients with additional underlying conditions, the likelihood of adverse drug 56 Table of Contents reactions or unintended side effects, including death, may increase.
Serious AEs generally refer to AEs that result in death, are life threatening, require 50 Table of Contents hospitalization or prolonging of hospitalization, or cause a significant and permanent disruption of normal life functions, congenital anomalies or birth defects, or require intervention to prevent such an outcome.
Serious AEs generally refer to AEs that result in death, are life threatening, require hospitalization or prolonging of hospitalization, or cause a significant and permanent disruption of normal life functions, congenital anomalies or birth defects, or require intervention to prevent such an outcome.
In addition, changes in our products or changes in applicable export or import laws and regulations may create delays in the introduction, provision, or sale of our products in international markets, prevent customers from using our products or, in some cases, 71 Table of Contents prevent the export or import of our products to certain countries, governments or persons altogether.
In addition, changes in our products or changes in applicable export or import laws and regulations may create delays in the introduction, provision, or sale of our products in international markets, prevent customers from using our products or, in some cases, prevent the export or import of our products to certain countries, governments or persons altogether.
If the commercial launch of any of our product candidates is delayed or does not occur for any reason, including if we do 53 Table of Contents not receive marketing approval in the timeframe we expect, we may have prematurely or unnecessarily incurred commercialization expenses.
If the commercial launch of any of our product candidates is delayed or does not occur for any reason, including if we do not receive marketing approval in the timeframe we expect, we may have prematurely or unnecessarily incurred commercialization expenses.
In such an event, our financial results and the commercial prospects for our products or product candidates, if approved, could be harmed, our costs could increase and our ability to generate revenues could be delayed, impaired or foreclosed. 78 Table of Contents We also expect to rely on other third parties to store and distribute drug supplies for our clinical trials.
In such an event, our financial results and the commercial prospects for our products or product candidates, if approved, could be harmed, our costs could increase and our ability to generate revenues could be delayed, impaired or foreclosed. We also expect to rely on other third parties to store and distribute drug supplies for our clinical trials.
Our company has completed several financings since its inception which resulted in an ownership change under Sections 382 and 383 of the Code. In addition, future changes in our stock ownership, some of which are outside of our control, could result in ownership changes in the future.
Our company has completed several financings since its inception which resulted in an ownership change under Sections 382 and 383 of the Code. In addition, future changes in our stock ownership, some of which are outside of our control, could result in ownership 93 Table of Contents changes in the future.
XPOVIO and any of our product candidates for which we, or our collaborators, obtain marketing approval in the future are subject to post-marketing regulatory requirements and could be subject to post-marketing restrictions or withdrawal from the market, and we, and our collaborators, may be subject to substantial penalties if we, or they, fail to comply with regulatory requirements or if we, or they, experience unanticipated problems with our products following approval.
XPOVIO and any of our product candidates for which we, or our collaborators, obtain marketing approval in the future are subject to post-marketing regulatory requirements, including following accelerated or conditional approvals of our product candidates, and could be subject to post-marketing restrictions or withdrawal from the market, and we, and our collaborators, may be subject to substantial penalties if we, or they, fail to comply with regulatory requirements or if we, or they, experience unanticipated problems with our products following approval.
Our products are priced at a significant premium over competitive generic drugs, which may make it difficult for us to achieve our business strategy of using our products in combination with existing therapies or replacing existing therapies with our products.
Our products are priced at a significant premium over 50 Table of Contents competitive generic drugs, which may make it difficult for us to achieve our business strategy of using our products in combination with existing therapies or replacing existing therapies with our products.
Furthermore, the failure of any product candidates to demonstrate safety and efficacy in any clinical trial could negatively impact the perception of selinexor, eltanexor or our other product candidates and/or cause the FDA or other regulatory authorities to require additional testing before any of our product candidates are approved.
Furthermore, the failure of any product candidates to demonstrate safety and effectiveness in any clinical trial could negatively impact the perception of selinexor or our other product candidates and/or cause the FDA or other regulatory authorities to require additional testing before any of our product candidates are approved.
The accelerated approval pathway may be used in cases in which the advantage of a new drug over available therapy may not be a direct therapeutic advantage, but is a clinically important improvement from a patient and public health perspective.
The accelerated approval pathway may be used in cases in which the advantage of a new drug over available 60 Table of Contents therapy may not be a direct therapeutic advantage, but is a clinically important improvement from a patient and public health perspective.
The approval of our and our collaborators’ current or future product candidates for commercial sale could be delayed, limited or denied or we or they may be required to conduct additional studies for a number of reasons, including, but not limited to, the following: • regulatory authorities may determine that our or our collaborators’ product candidates do not demonstrate safety and effectiveness in accordance with regulatory agency standards based on a number of considerations, including AEs that are reported during clinical trials; • regulatory authorities could analyze and/or interpret data from clinical trials and preclinical testing in different ways than we, or our collaborators, interpret them and determine that our data is insufficient for approval; • regulatory authorities may require more information, including additional preclinical or clinical data or trials, to support approval, as in the case of our new trial for selinexor in endometrial cancer following discussions with the FDA in early 2022 on our SIENDO Study; • regulatory authorities could determine that our manufacturing processes are not properly designed, are not conducted in accordance with federal or other laws or otherwise not properly managed and we may be unable to obtain regulatory approval for a commercially viable manufacturing process for our product candidates in a timely manner, or at all; • the supply or quality of our or our collaborators’ product candidates for our clinical trials may be insufficient, inadequate or delayed; • the size of the patient population required to establish the efficacy of our or our collaborators’ product candidates to the satisfaction of regulatory agencies may be larger than we or they anticipated; • our failure or the failure of clinical investigational sites and the records kept at the respective locations, including clinical trial data, to be in compliance with the FDA’s current good clinical practices regulations (“GCP”) or comparable regulations outside of the U.S., including the failure to pass inspections of our corporate site or our clinical trial sites; • regulatory authorities may change their approval policies or adopt new regulations; • regulatory authorities may not be able to undertake reviews, applicable inspections or approval processes in a timely manner; • the results of our earlier clinical trials may not be representative of our future, larger trials; • regulatory authorities may not agree with our or our collaborators’ regulatory approval strategies or components of our or their regulatory filings, such as the design or implementation of the relevant clinical trials; or • a product may not be approved for the indications that we, or our collaborators, request or may be limited or subject to restrictions or post-approval commitments that render the approved drug not commercially viable. 57 Table of Contents Further, we could face heightened risks with respect to seeking marketing approval in the UK as a result of the withdrawal of the UK from the EU, commonly referred to as Brexit.
The approval of our and our collaborators’ current or future product candidates for commercial sale could be delayed, limited or denied or we or they may be required to conduct additional studies for a number of reasons, including, but not limited to, the following: • regulatory authorities may determine that our or our collaborators’ product candidates do not demonstrate safety and effectiveness in accordance with regulatory agency standards based on a number of considerations, including AEs that are reported during clinical trials; • regulatory authorities could analyze and/or interpret data from clinical trials and preclinical testing in different ways than we, or our collaborators, interpret them and determine that our data is insufficient for approval; • regulatory authorities may require more information, including additional preclinical or clinical data or trials, to support approval, as in the case of our new trial for selinexor in endometrial cancer following discussions with the FDA in early 2022 on our SIENDO Study; • regulatory authorities could determine that our manufacturing processes are not properly designed, are not conducted in accordance with federal or other laws or otherwise not properly managed, and we may be unable to obtain regulatory approval for a commercially viable manufacturing process for our product candidates in a timely manner, or at all; • the supply or quality of our or our collaborators’ product candidates for our clinical trials may be insufficient, inadequate or delayed; • the size of the patient population required to establish the efficacy of our or our collaborators’ product candidates to the satisfaction of regulatory agencies may be larger than we or they anticipated; • our failure or the failure of clinical investigational sites and the records kept at the respective locations, including clinical trial data, to be in compliance with the FDA’s current good clinical practices regulations (“GCP”) or comparable regulations outside of the U.S., including the failure to pass inspections of our corporate site or our clinical trial sites; • regulatory authorities may change their approval policies or adopt new regulations; 59 Table of Contents • regulatory authorities may not be able to undertake reviews, applicable inspections or approval processes in a timely manner; • the results of our earlier clinical trials may not be representative of our future, larger trials; • regulatory authorities may not agree with our or our collaborators’ regulatory approval strategies or components of our or their regulatory filings, such as the design or implementation of the relevant clinical trials; or • a product may not be approved for the indications that we, or our collaborators, request or may be limited or subject to restrictions or post-approval commitments that render the approved drug not commercially viable.
Many of the CCPA’s requirements are similar to those found in the European General Data Protection Regulation (the “GDPR”), including requiring businesses to provide notice to data subjects regarding the information collected about them and how such information is used and shared, and providing data subjects the right to request access to such personal information and, in certain cases, request the erasure of such personal information.
Many of the CCPA’s requirements are similar to those found in the European General Data Protection Regulation (the “GDPR”), which is further described below, including requiring businesses to provide notice to data subjects regarding the information collected about them and how such information is used and shared, and providing data subjects the right to request access to such personal information and, in certain cases, request the erasure of such personal information.
The most common drug-related AEs in our clinical trials for XPOVIO include fatigue, nausea, anorexia, diarrhea, peripheral neuropathy, upper respiratory tract infection, vomiting, cytopenias, hyponatremia, weight loss, decreased appetite, cataract, dizziness, syncope, depressed level of consciousness, and mental status changes. These side effects were generally mild or moderate in severity.
The most 52 Table of Contents common drug-related AEs in our clinical trials for selinexor include fatigue, nausea, anorexia, diarrhea, peripheral neuropathy, upper respiratory tract infection, vomiting, cytopenias, hyponatremia, weight loss, decreased appetite, cataract, dizziness, syncope, depressed level of consciousness, and mental status changes. These side effects were generally mild or moderate in severity.
Investors may not agree with what we determine is the material or otherwise appropriate information to include in our 52 Table of Contents disclosure, and any information we determine not to disclose may ultimately be deemed significant with respect to future decisions, conclusions, views, activities or otherwise regarding a particular product, product candidate or our business.
Investors may not agree with what we determine is the material or otherwise appropriate information to include in our disclosure, and any information we determine not to disclose may ultimately be deemed significant with respect to future decisions, conclusions, views, activities or otherwise regarding a particular product, product candidate or our business.

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Item 3. Legal Proceedings

Legal Proceedings — active lawsuits and investigations

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Biggest changeItem 3. Legal Proceedings The information required by this Item is provided under “Litigation” in Note 11 “ Commitments and Contingencies” of the Consolidated Financial Statements included in Part II, Item 8 of this Annual Report on Form 10-K. Item 4. Mine Safety Disclosures Not applicable. 90 Table of Contents PART II
Biggest changeItem 3. Legal Proceedings The information required by this Item is provided under “ Litigation ” in Note 11 “ Commitments and Contingencies” of the Consolidated Financial Statements included in Part II, Item 8 of this Annual Report on Form 10-K. Item 4. Mine Safety Disclosures Not applicable. 96 Table of Contents PART II

Item 4. Mine Safety Disclosures

Mine Safety Disclosures — required of mining issuers

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Biggest changeItem 4. Mine Safety Disclosures 90 PART II 91 Item 5. Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities 91 Item 6. [Reserved] 92 Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations 93 Item 7A. Quantitative and Qualitative Disclosures about Market Risk 101 Item 8.
Biggest changeItem 4. Mine Safety Disclosures 96 PART II 97 Item 5. Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities 97 Item 6. [Reserved] 98 Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations 99 Item 7A. Quantitative and Qualitative Disclosures about Market Risk 106 Item 8.
Financial Statements and Supplementary Data 101 Item 9A. Controls and Procedures 101 Item 9B. Other Information 104
Financial Statements and Supplementary Data 106 Item 9A. Controls and Procedures 106 Item 9B. Other Information 109

Item 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

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Biggest changeData for the NASDAQ Composite Index and NASDAQ Biotechnology Index assume reinvestment of dividends. 91 Table of Contents Cumulative Total Return Comparison 12/31/17 12/31/18 12/31/19 12/31/20 12/31/21 12/31/22 Karyopharm Therapeutics Inc. 100.00 97.60 199.69 161.25 66.98 35.42 NASDAQ Composite 100.00 97.16 132.81 192.47 235.15 158.65 NASDAQ Biotechnology 100.00 91.14 114.02 144.15 144.18 129.59 The performance graph in this Item 5 is not deemed to be “soliciting material” or to be “filed” with the SEC for purposes of Section 18 of the Exchange Act, or otherwise subject to the liabilities under that Section, and shall not be deemed incorporated by reference into any filing of Karyopharm Therapeutics Inc. under the Securities Act or the Exchange Act, except to the extent we specifically incorporate it by reference into such a filing.
Biggest changeData for the NASDAQ Composite Index and NASDAQ Biotechnology Index assume reinvestment of dividends. 97 Table of Contents Cumulative Total Return Comparison 12/31/18 12/31/19 12/31/20 12/31/21 12/31/22 12/31/23 Karyopharm Therapeutics Inc. 100.00 204.59 165.21 68.62 36.29 9.23 NASDAQ Composite 100.00 136.69 198.10 242.03 163.28 236.17 NASDAQ Biotechnology 100.00 125.11 158.17 158.20 142.19 148.72 The performance graph in this Item 5 is not deemed to be “soliciting material” or to be “filed” with the SEC for purposes of Section 18 of the Exchange Act, or otherwise subject to the liabilities under that Section, and shall not be deemed incorporated by reference into any filing of Karyopharm Therapeutics Inc. under the Securities Act or the Exchange Act, except to the extent we specifically incorporate it by reference into such a filing.
Stock Performance Graph The following graph shows a comparison from December 31, 2017 through December 31, 2022, of the cumulative total return on an assumed investment of $100.00 in cash in our common stock as compared to the same investment in the NASDAQ Composite Index and the NASDAQ Biotechnology Index.
Stock Performance Graph The following graph shows a comparison from December 31, 2018 through December 31, 2023, of the cumulative total return on an assumed investment of $100.00 in cash in our common stock as compared to the same investment in the NASDAQ Composite Index and the NASDAQ Biotechnology Index.
Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities Market Information Our common stock, $0.0001 par value per share, began trading on the Nasdaq Global Select Market on November 6, 2013, where its prices are quoted under the symbol “KPTI.” Holders As of February 10, 2023, there were 18 holders of record of our common stock.
Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities Market Information Our common stock, $0.0001 par value per share, began trading on the Nasdaq Global Select Market on November 6, 2013, where its prices are quoted under the symbol “KPTI.” Holders As of February 23, 2024, there were seven holders of record of our common stock.

Item 7. Management's Discussion & Analysis

Management's Discussion & Analysis (MD&A) — revenue / margin commentary

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Biggest changeWe expect our research and development expenses to remain relatively consistent in 2023 as compared to 2022, primarily due to increased mid- and late-stage programs within our prioritized core development programs, offset by the cost saving measures we initiated in 2022, which included an overall headcount reduction and continued focus on our prioritized pipeline. 97 Table of Contents Selling, General and Administrative Expenses (in thousands, except for percentages) For the Years Ended December 31, 2022 vs. 2021 2021 vs. 2020 2022 2021 2020 $ Change % Change $ Change % Change Personnel costs $ 68,167 $ 66,465 $ 58,568 $ 1,702 3 % $ 7,897 13 % Consulting, professional and other costs 56,412 59,594 53,783 (3,182 ) (5 )% 5,811 11 % Stock-based compensation 20,822 17,787 14,066 3,035 17 % 3,721 26 % Total selling, general and administrative expenses $ 145,401 $ 143,846 $ 126,417 $ 1,555 1 % $ 17,429 14 % Selling, general and administrative expenses for the year ended December 31, 2022 increased by $1.6 million as compared to the year ended December 31, 2021 due to an increase in personnel costs and stock-based compensation, which was primarily attributable to $5.7 million of severance-related expenses incurred in 2022, largely in connection with the departure of our former Chief Executive Officer.
Biggest changeSelling, General and Administrative Expenses (in thousands, except for percentages) For the Years Ended December 31, 2023 vs. 2022 2022 vs. 2021 2023 2022 2021 $ Change % Change $ Change % Change Personnel costs $ 66,465 $ 68,167 $ 66,465 $ (1,702 ) (2 )% $ 1,702 3 % Consulting, professional and other costs 50,606 56,412 59,594 (5,806 ) (10 )% (3,182 ) (5 )% Stock-based compensation 14,810 20,822 17,787 (6,012 ) (29 )% 3,035 17 % Total selling, general and administrative expenses $ 131,881 $ 145,401 $ 143,846 $ (13,520 ) (9 )% $ 1,555 1 % Selling, general and administrative expenses for the year ended December 31, 2023 decreased by $13.5 million as compared to the year ended December 31, 2022, primarily due to a decrease in stock-based compensation and a decrease in consulting, professional and other costs.
We currently expect that cash, cash equivalents and investments at December 31, 2022 will be sufficient to fund our current operating plans and capital expenditure requirements for at least twelve months from the date of issuance of the financial statements contained in this Annual Report on Form 10-K while we continue to commercialize XPOVIO in the U.S. and continue the clinical trials of our product candidates.
We currently expect that cash, cash equivalents and investments at December 31, 2023 will be sufficient to fund our current operating plans and capital expenditure requirements for at least twelve months from the date of issuance of the financial statements contained in this Annual Report on Form 10-K while we continue to commercialize XPOVIO in the U.S. and continue the clinical trials of our product candidates.
We expect that our cash, cash equivalents and investments at December 31, 2022 will be sufficient to fund our current operating plans and capital expenditure requirements for at least twelve months from the date of issuance of the financial statements contained in this Annual Report on Form 10-K.
We expect that our cash, cash equivalents and investments at December 31, 2023 will be sufficient to fund our current operating plans and capital expenditure requirements for at least twelve months from the date of issuance of the financial statements contained in this Annual Report on Form 10-K.
You should review the section titled “ Risk Factors ” in Part I - Item 1A of this report for a discussion of important factors that could cause actual results to differ materially from the results described in or implied by the forward-looking statements contained in the following discussion and analysis.
You should review the section entitled “ Risk Factors ” in Part I - Item 1A of this report for a discussion of important factors that could cause actual results to differ materially from the results described in or implied by the forward-looking statements contained in the following discussion and analysis.
A 10% increase or decrease in these estimates would impact net product revenue by a corresponding increase or decrease of less than $2.0 million. License and Asset Purchase Agreements We generate revenue from license or similar agreements with pharmaceutical companies for the development and commercialization of certain of our products and product candidates.
A 10% increase or decrease in these estimates would impact net product revenue by a corresponding increase or decrease of less than $3.0 million. License and Asset Purchase Agreements We generate revenue from license or similar agreements with pharmaceutical companies for the development and commercialization of certain of our products and product candidates.
Results of Operations - Years Ended December 31, 2021 and 2020 Discussion and analysis of the results of operations for the year ended December 31, 2021 as compared to the results of operations for the year ended December 31, 2020 is included under the heading “ Item 7.
Results of Operations - Years Ended December 31, 2022 and 2021 Discussion and analysis of the results of operations for the year ended December 31, 2022 as compared to the results of operations for the year ended December 31, 2021 is included under the heading “ Item 7.
The commercialization of XPOVIO in the U.S., for both the multiple myeloma and DLBCL indications, is currently supported by sales representatives, nurse liaisons, and a market access team, as well as KaryForward™, an extensive patient and healthcare provider support program. Our commercial efforts are also supplemented by patient support initiatives coordinated by our dedicated network of participating specialty pharmacy providers.
The commercialization of XPOVIO in the U.S. is currently supported by sales representatives, nurse liaisons, and a market access team, as well as KaryForward™, an extensive patient and healthcare provider support program. Our commercial efforts are also supplemented by patient support initiatives coordinated by our dedicated network of participating specialty pharmacy providers.
If we are unable to raise capital when needed or on attractive terms, we would be forced to delay, reduce or eliminate our research and development programs or commercialization efforts.
If we are unable to 105 Table of Contents raise capital when needed or on attractive terms, we would be forced to delay, reduce or eliminate our research and development programs or commercialization efforts.
Management’s Discussion and Analysis of Financial Condition and Results of Operations ” in our Annual Report on Form 10-K for the year ended December 31, 2021 as filed with the SEC on March 1, 2022 (“2021 Form 10-K”). 98 Table of Contents Liquidity and Capital Resources Cash flows To date, we have financed our operations through a combination of product revenue sales, private placements of our common and preferred stock, proceeds from public offerings of our common stock, proceeds from the issuance of convertible debt, proceeds pursuant to the deferred royalty obligation, and cash generated from our business development activities.
Management’s Discussion and Analysis of Financial Condition and Results of Operations ” in our Annual Report on Form 10-K for the year ended December 31, 2022 as filed with the SEC on February 17, 2023 (“2022 Form 10-K”). 103 Table of Contents Liquidity and Capital Resources Cash flows To date, we have financed our operations primarily through a combination of product revenue sales, private placements of our common stock, proceeds from public offerings of our common stock, proceeds from the issuance of convertible debt, proceeds pursuant to the deferred royalty obligation, and cash generated from our business development activities.
As of December 31, 2022, $64.0 million of Open Market Shares remained available for issuance under the 2018 Open Market Sale Agreement. During the year ended December 31, 2022, we sold an aggregate of 3,991,652 Open Market Shares under the 2018 Open Market Sale Agreement, for net proceeds of approximately $35.1 million.
During the year ended December 31, 2022, we sold an aggregate of 3,991,652 Open Market Shares under the 2018 Open Market Sale Agreement, for net proceeds of approximately $35.1 million.
During the year ended December 31, 2022, we received $3.6 million in milestone payments under our license and distribution arrangements pursuant to which we are entitled to receive additional milestone payments, if certain development goals and sales 99 Table of Contents milestones are achieved, as well as royalties on future net sales of the licensed and sold products in the territories under such arrangements.
During the year ended December 31, 2023, we received $32.0 million in milestone and upfront payments under our license and distribution arrangements pursuant to which we are entitled to receive additional milestone payments, if certain development goals and sales milestones are achieved, as well as royalties on future net sales of the licensed and sold products in the territories under such arrangements.
We received $15.0 million of reimbursements for development related expenses under the Menarini Agreement during the year ended December 31, 2022. In September 2019, we entered into the Revenue Interest Financing Agreement (the “Revenue Interest Agreement”) with HealthCare Royalty Partners III, L.P. and HealthCare Royalty Partners IV, L.P.
We received $15.0 million of reimbursements for development related expenses under the Menarini Agreement during the year ended December 31, 2023. In September 2019, we entered into the Revenue Interest Financing Agreement (the “Revenue Interest Agreement”) with HealthCare Royalty Partners III, L.P. and HealthCare Royalty Partners IV, L.P. (“HCR”) which was amended in June 2021 (the “Amended Revenue Interest Agreement”).
(“HCR”) and which was amended in June 2021 (the “Amended Revenue Interest Agreement”). Pursuant to the Revenue Interest Agreement, HCR paid us $75.0 million, less certain transaction expenses, on September 27, 2019 and pursuant to the Amended Revenue Interest Agreement, HCR paid us $60.0 million on June 23, 2021.
Pursuant to the Revenue Interest Agreement, HCR paid us $75.0 million, less certain transaction expenses, on September 27, 2019 and pursuant to the Amended Revenue Interest Agreement, HCR paid us $60.0 million on June 23, 2021.
Net Cash Provided by Financing Activities The $120.1 million increase in net cash provided by financing activities during the year ended December 31, 2022 as compared to the year ended December 31, 2021 was primarily driven by net proceeds of approximately $154.7 million from a private placement offering of our common stock in 2022 and a $25.2 million increase in proceeds received from the sale of common stock under our “at the market offering” program.
Net Cash Provided by Financing Activities The $192.6 million decrease in net cash provided by financing activities during the year ended December 31, 2023 as compared to the year ended December 31, 2022 was primarily driven by net proceeds of approximately $154.7 million from a private placement offering of our common stock in 2022 and $35.1 million in net proceeds received from the sale of common stock under our “at the market offering” program in 2022.
In addition, under the Menarini Agreement, Menarini will reimburse us for 25% of all documented expenses we incur for the global development of selinexor during 2022 through 2025, provided that such reimbursements shall not exceed $15.0 million per calendar year.
In addition, under the Menarini Agreement, Menarini will reimburse us for 25% of all development related expenses we 104 Table of Contents incur for selinexor from 2022 through 2025, provided that such reimbursements shall not exceed $15.0 million per calendar year.
These reserves reflect our best estimates of the variable consideration based on the terms of the respective underlying contracts. 94 Table of Contents The estimates for our product revenue allowances and accruals are most significantly affected by chargebacks, which are contractual commitments to provide products to qualified healthcare entities at prices lower than the list prices charged to our customers who purchase XPOVIO directly from us, and rebates that represent discount obligations under government programs, including Medicaid, Medicare, the Department of Veterans Affairs, the Department of Defense, and others.
The estimates for our product revenue allowances and accruals are most significantly affected by chargebacks, which are contractual commitments to provide products to qualified healthcare entities at prices lower than the list prices charged to our customers who purchase XPOVIO directly from us, and rebates that represent discount obligations under government programs, including Medicaid, Medicare, the Department of Veterans Affairs, the Department of Defense, and others.
Under the 2023 Open Market Sale Agreement, we may issue and sell shares of our common stock having an aggregate offering price of up to $100.0 million from time to time through Jefferies. Upon entry into the 2023 Open Market Sale Agreement, the 2018 Open Market Sale Agreement was terminated.
Under the 2023 Open Market Sale Agreement, we may issue and sell shares of our common stock having an aggregate offering price of up to $100.0 million (the “Shares”) from time to time through Jefferies (the “2023 Open Market Offering”).
In addition to the expenses required to fund our operations described above, our funding requirements also include the following: • Lease costs for our headquarters in Newton, Massachusetts with a term through September 30, 2025, which totaled $3.4 million in 2022 and increase annually; we expect total future lease costs to be approximately $10.5 million; 100 Table of Contents • Future long-term debt obligations related to the Notes of $188.0 million over the next three years; and • Future royalty obligations to HCR under our Revenue Interest Financing Agreement of approximately $204.2 million.
In addition to the expenses required to fund our operations described above, our funding requirements also include the following: • Lease costs for our headquarters in Newton, Massachusetts with a term through September 30, 2025, which totaled $3.7 million in 2023 and increase annually; we expect total future lease costs to be approximately $6.7 million; • Future long-term debt obligations related to the 3.00% Convertible Senior Notes due 2025 of $182.9 million over the next three years; and • Future royalty obligations to HCR under our Revenue Interest Financing Agreement of approximately $201.6 million.
As of December 31, 2022, our principal source of liquidity was $278.0 million of cash, cash equivalents and investments. We have had recurring losses since inception and incurred a loss of $165.3 million for the year ended December 31, 2022.
As of December 31, 2023, our principal source of liquidity was $191.4 million of cash, cash equivalents and investments. We have had recurring losses since inception and incurred a loss of $143.1 million for the year ended December 31, 2023.
We plan to continue to conduct clinical trials and to seek additional approvals for the use of selinexor and eltanexor as single agents or in combination with other oncology therapies to expand the patient populations that are eligible for treatment with selinexor or eltanexor. As of December 31, 2022, we had an accumulated deficit of $1.3 billion.
We plan to continue to conduct clinical trials and to seek additional approvals for the use of selinexor as a single agent or in combination with other oncology therapies to expand the patient populations that are eligible for treatment with selinexor.
The license agreements with Menarini (“the Menarini Agreement”) and Antengene are each defined and described in Note 5 “ License and Asset Purchase Agreements ”, to the consolidated financial statements included under Part II, Item 8 of this Annual Report on Form 10-K.
The license agreements with Menarini and Antengene are each defined and described in Note 5 “ License and Asset Purchase Agreements ”, to the consolidated financial statements included under Part II, Item 8 of this Annual Report on Form 10-K. We expect license and other revenue to increase in 2024 as compared to 2023 primarily due to expected milestone achievements.
We had net losses of $165.3 million, $124.1 million, and $196.3 million for the years ended December 31, 2022, 2021 and 2020, respectively. We recognized total revenue of $157.1 million in 2022, including $120.4 million of XPOVIO net product revenue and $36.6 million of license revenue.
We had net losses of $143.1 million, $165.3 million, and $124.1 million for the years ended December 31, 2023, 2022 and 2021, respectively. We recognized total revenue of $146.0 million in 2023, including $112.0 million of XPOVIO net product revenue and $34.0 million of license revenue.
Critical Accounting Estimates Our discussion and analysis of our financial condition and results of operations are based on our consolidated financial statements, which we have prepared in accordance with U.S. generally accepted accounting principles.
As of December 31, 2023, we had $191.4 million in cash, cash equivalents and investments. 99 Table of Contents Critical Accounting Estimates Our discussion and analysis of our financial condition and results of operations are based on our consolidated financial statements, which we have prepared in accordance with U.S. generally accepted accounting principles.
At the end of each reporting period, we re-evaluate our estimate of the transaction price including the probability of achieving milestone payments that may not be subject to a material reversal and adjust the transaction price if necessary. Any such adjustments are recorded on a cumulative catch-up basis, which would affect license and other revenue in the period of adjustment.
At the end of each reporting period, we re-evaluate our estimate of the transaction price including the probability of achieving milestone payments that may not be subject to a material reversal and adjust the transaction price if necessary.
For additional information on the Amended Revenue Interest Agreement, see Note 10, “ Long-Term Obligations ”, to the consolidated financial statements included under Part II, Item 8 of this Annual Report on Form 10-K.
For additional information on the Amended Revenue Interest Agreement, see Note 10, “ Long-Term Obligations ”, to the consolidated financial statements included under Part II, Item 8 of this Annual Report on Form 10-K. On February 17, 2023, we entered into an Open Market Sale Agreement (the “2023 Open Market Sale Agreement”) with Jefferies LLC, as agent (“Jefferies”).
Relevant factors used in the expected value method include: current contractual and statutory requirements, specific known market events and trends, industry data, and forecasted customer buying and payment patterns.
Relevant factors used in the expected value method include: current contractual and statutory requirements, specific known market events and trends, industry data, and forecasted customer buying and payment patterns. These reserves reflect our best estimates of the variable consideration based on the terms of the respective underlying contracts.
Accrued Research and Development Costs We estimate our accrued research and development costs by reviewing quotes and contracts, identifying services that have been performed on our behalf, and estimating the associated cost incurred for services performed when we have not yet been invoiced or otherwise notified of the actual cost.
Any such adjustments are recorded on a cumulative catch-up basis, which would affect license and other revenue in the period of adjustment. 100 Table of Contents Accrued Research and Development Costs We estimate our accrued research and development costs by reviewing quotes and contracts, identifying services that have been performed on our behalf, and estimating the associated cost incurred for services performed when we have not yet been invoiced or otherwise notified of the actual cost.
License and Other Revenue (in thousands, except for percentages) For the Years Ended December 31, 2022 vs. 2021 2021 vs. 2020 2022 2021 2020 $ Change % Change $ Change % Change Antengene $ 13,353 $ 30,429 $ 23,749 $ (17,076 ) (56 )% $ 6,680 28 % Menarini 15,672 75,000 — (59,328 ) (79 )% 75,000 100 % Other 7,604 5,954 8,126 1,650 28 % (2,172 ) (27 )% Total license and other revenue $ 36,629 $ 111,383 $ 31,875 $ (74,754 ) (67 )% $ 79,508 249 % License and other revenue for the year ended December 31, 2022 decreased by $74.8 million as compared to the year ended December 31, 2021 primarily due to the $75.0 million one-time upfront payment from Menarini recognized in 2021 and a $21.5 million decrease year over year in development/regulatory milestone revenue from Antengene.
License and Other Revenue (in thousands, except for percentages) For the Years Ended December 31, 2023 vs. 2022 2022 vs. 2021 2023 2022 2021 $ Change % Change $ Change % Change Menarini $ 24,360 $ 15,672 $ 75,000 $ 8,688 55 % $ (59,328 ) (79 )% Antengene 2,713 13,353 30,429 (10,640 ) (80 )% (17,076 ) (56 )% Other 6,949 7,604 5,954 (655 ) (9 )% 1,650 28 % Total license and other revenue $ 34,022 $ 36,629 $ 111,383 $ (2,607 ) (7 )% $ (74,754 ) (67 )% License and other revenue for the year ended December 31, 2023 decreased by $2.6 million as compared to the year ended December 31, 2022 primarily due to a decrease in milestone-related revenue and royalty revenue from Antengene Therapeutics Limited (“Antengene”), partially offset by an increase in milestone-related revenue, license-related revenue, and royalty revenue from Menarini.
Net Cash (Used in) Provided by Investing Activities The $246.1 million increase in net cash used in investing activities during the year ended December 31, 2022 as compared to the year ended December 31, 2021 was primarily driven by a $180.8 million increase in purchases of investments and a $70.9 million decrease in proceeds from the sales and maturities of investments, partially offset by the use of $5.5 million in 2021 to acquire in-process research and development as a result of our acquisition of assets from Neumedicines.
Net Cash Provided by (Used in) Investing Activities The $112.2 million increase in net cash provided by investing activities during the year ended December 31, 2023 as compared to the year ended December 31, 2022 was primarily driven by a $66.9 million decrease in purchases of investments and a $45.2 million increase in proceeds from the sales and maturities of investments.
Funding Requirements We expect our expenses to increase in 2023 as compared to 2022. We expect to continue to incur significant commercialization expenses related to sales, marketing, manufacturing and distribution of any of our products, to the extent that these functions are not the responsibility of our collaborators.
We expect to continue to incur costs related to our clinical development programs as we rapidly advance three pivotal Phase 3 trials, as well as commercialization expenses related to sales, marketing, manufacturing and distribution of any of our products, to the extent that these functions are not the responsibility of our collaborators.
To date, our estimates have not been materially different than amounts actually incurred. 95 Table of Contents Results of Operations The following table summarizes our results of operations (in thousands): For the Years Ended December 31, 2022 2021 2020 Product revenue, net $ 120,445 $ 98,436 $ 76,210 License and other revenue 36,629 111,383 31,875 Total revenue 157,074 209,819 108,085 Operating expenses: Cost of sales 5,213 3,402 2,705 Research and development 148,662 160,842 150,813 Selling, general and administrative 145,401 143,846 126,417 Loss from operations (142,202 ) (98,271 ) (171,850 ) Other expense, net (22,720 ) (25,549 ) (24,114 ) Loss before income taxes (164,922 ) (123,820 ) (195,964 ) Income tax provision (369 ) (268 ) (309 ) Net loss $ (165,291 ) $ (124,088 ) $ (196,273 ) Product Revenue, net (in thousands, except for percentages) For the Years Ended December 31, 2022 vs. 2021 2021 vs. 2020 2022 2021 2020 $ Change % Change $ Change % Change Product revenue, net $ 120,445 $ 98,436 $ 76,210 $ 22,009 22 % $ 22,226 29 % Net product revenue from U.S. commercial sales of XPOVIO for the year ended December 31, 2022 increased 22% as compared to the year ended December 31, 2021 due to an increasing number of patients treated in earlier lines of therapy and improved net price.
Results of Operations The following table summarizes our results of operations (in thousands): For the Years Ended December 31, 2023 2022 2021 Product revenue, net $ 112,011 $ 120,445 $ 98,436 License and other revenue 34,022 36,629 111,383 Total revenue 146,033 157,074 209,819 Operating expenses: Cost of sales 4,942 5,213 3,402 Research and development 138,750 148,662 160,842 Selling, general and administrative 131,881 145,401 143,846 Loss from operations (129,540 ) (142,202 ) (98,271 ) Other expense, net (13,236 ) (22,720 ) (25,549 ) Loss before income taxes (142,776 ) (164,922 ) (123,820 ) Income tax provision (323 ) (369 ) (268 ) Net loss $ (143,099 ) $ (165,291 ) $ (124,088 ) Product Revenue, net (in thousands, except for percentages) For the Years Ended December 31, 2023 vs. 2022 2022 vs. 2021 2023 2022 2021 $ Change % Change $ Change % Change Product revenue, net $ 112,011 $ 120,445 $ 98,436 $ (8,434 ) (7 )% $ 22,009 22 % Net product revenue from U.S. commercial sales of XPOVIO for the year ended December 31, 2023 decreased 7% as compared to the year ended December 31, 2022.
On May 5, 2020, we entered into Amendment No. 1 to the Open Market Sale Agreement, dated August 17, 2018 (the “2018 Open Market Sale Agreement”), with Jefferies LLC, as agent (“Jefferies”), pursuant to which we increased the maximum aggregate offering price of shares of our common stock that we may issue and sell from time to time through Jefferies, by $100.0 million from $75.0 million to up to $175.0 million (the “Open Market Shares”).
Upon entry into the 2023 Open Market Sale Agreement, we terminated our previous Open Market Sale Agreement with Jefferies, as agent, which we had entered into in August 2018 (the “2018 Open Market Sale Agreement”), pursuant to which we could issue and sell shares of our common stock having an aggregate offering price of up to $175.0 million (the “Open Market Shares”).
We plan to continue to educate physicians, other healthcare providers and patients about XPOVIO’s clinical profile and unique mechanism of action as we continue to expand XPOVIO use. The commercialization of XPOVIO and NEXPOVIO ® (selinexor) (the brand name for selinexor in Europe and the United Kingdom) outside of the U.S. is managed by our partners in their respective territories.
The commercialization of XPOVIO and NEXPOVIO ® (selinexor) (the brand name for selinexor in Europe and the United Kingdom (“UK”)) outside of the U.S. is managed by our partners in their respective territories.
Research and Development Expenses (in thousands, except for percentages) For the Years Ended December 31, 2022 vs. 2021 2021 vs. 2020 2022 2021 2020 $ Change % Change $ Change % Change Personnel costs $ 59,095 $ 52,001 $ 47,107 $ 7,094 14 % $ 4,894 10 % Clinical trial and related costs 56,502 68,473 72,029 (11,971 ) (17 )% (3,556 ) (5 )% Consulting, professional and other costs 18,714 21,171 21,462 (2,457 ) (12 )% (291 ) (1 )% Stock-based compensation 14,351 11,842 10,215 2,509 21 % 1,627 16 % In-process research and development — 7,355 — (7,355 ) (100 )% 7,355 100 % Total research and development expenses $ 148,662 $ 160,842 $ 150,813 $ (12,180 ) (8 )% $ 10,029 7 % Research and development expenses for the year ended December 31, 2022 decreased by $12.2 million as compared to the year ended December 31, 2021 primarily due to a $12.0 million decrease in clinical trial and related costs due to our prioritization of the core programs in our clinical pipeline and the timing of the purchases of comparator drugs used in clinical trials, coupled with a $7.4 million decrease in in-process research and development costs related to the acquisition of certain assets from Neumedicines Inc.
Research and Development Expenses (in thousands, except for percentages) For the Years Ended December 31, 2023 vs. 2022 2022 vs. 2021 2023 2022 2021 $ Change % Change $ Change % Change Clinical trial and related costs $ 65,693 $ 56,502 $ 68,473 $ 9,191 16 % $ (11,971 ) (17 )% Personnel costs 49,907 59,095 52,001 (9,188 ) (16 )% 7,094 14 % Consulting, professional and other costs 16,621 18,714 21,171 (2,093 ) (11 )% (2,457 ) (12 )% Stock-based compensation 6,529 14,351 11,842 (7,822 ) (55 )% 2,509 21 % In-process research and development — — 7,355 — — (7,355 ) (100 )% Total research and development expenses $ 138,750 $ 148,662 $ 160,842 $ (9,912 ) (7 )% $ (12,180 ) (8 )% Research and development expenses for the year ended December 31, 2023 decreased by $9.9 million as compared to the year ended December 31, 2022, primarily due to a decrease in personnel costs of $9.2 million and a decrease in stock-based compensation of $7.8 million, which was primarily because of a reduction in headcount and contractors, including severance-related expenses 102 Table of Contents incurred in 2022.
License revenue included $15.0 million of revenue related to the reimbursement of documented expenses for global development of the selinexor from Menarini and $7.8 million of milestone-related revenue from Antengene Therapeutics Limited (“Antengene”).
License revenue included $15.0 million of revenue for the reimbursement of development related expenses from the Menarini Group (“Menarini”).
The following table provides information regarding our cash flows (in thousands): For the Years Ended December 31, 2022 2021 2020 Net cash used in operating activities $ (149,554 ) $ (107,116 ) $ (160,234 ) Net cash (used in) provided by investing activities (104,256 ) 141,840 (53,685 ) Net cash provided by financing activities 193,738 73,648 172,083 Effect of foreign exchange rates (488 ) (48 ) 268 Net (decrease) increase in cash, cash equivalents and restricted cash $ (60,560 ) $ 108,324 $ (41,568 ) Net Cash Used in Operating Activities The $42.4 million increase in net cash used in operating activities during the year ended December 31, 2022 as compared to the year ended December 31, 2021 was primarily driven by 2021 activity including the $75.0 million upfront payment we received from Menarini.
The following table provides information regarding our cash flows (in thousands): For the Years Ended December 31, 2023 vs. 2022 2022 vs. 2021 2023 2022 2021 $ Change % Change $ Change % Change Net cash used in operating activities $ (92,723 ) $ (149,554 ) $ (107,116 ) $ 56,831 (38 )% $ (42,438 ) 40 % Net cash provided by (used in) investing activities 7,940 (104,256 ) 141,840 112,196 (108 )% (246,096 ) (174 )% Net cash provided by financing activities 1,124 193,738 73,648 (192,614 ) (99 )% 120,090 163 % Effect of foreign exchange rates (34 ) (488 ) (48 ) 454 (93 )% (440 ) 917 % Net (decrease) increase in cash, cash equivalents and restricted cash $ (83,693 ) $ (60,560 ) $ 108,324 $ (23,133 ) 38 % $ (168,884 ) (156 )% Net Cash Used in Operating Activities The $56.8 million decrease in net cash used in operating activities during the year ended December 31, 2023 as compared to the year ended December 31, 2022 was primarily driven by a decrease in expenses and $27.3 million of milestone payments we received from Antengene in 2023.
Other Expense, net (in thousands, except for percentages) For the Years Ended December 31, 2022 vs. 2021 2021 vs. 2020 2022 2021 2020 $ Change % Change $ Change % Change Interest expense $ (24,996 ) $ (26,046 ) $ (27,140 ) $ 1,050 (4 )% $ 1,094 (4 )% Interest income 2,359 582 2,820 1,777 305 % (2,238 ) (79 )% Other income (expense): Change in fair value of embedded derivative 280 90 500 190 211 % (410 ) (82 )% Foreign currency remeasurement (376 ) (216 ) (404 ) (160 ) 74 % 188 (47 )% Other 13 41 110 (28 ) (68 )% (69 ) (63 )% Total other expense, net $ (22,720 ) $ (25,549 ) $ (24,114 ) $ 2,829 (11 )% $ (1,435 ) 6 % Other expense, net for the year ended December 31, 2022 decreased by $2.8 million as compared to the year ended December 31, 2021, primarily due to an increase in interest income resulting from higher interest rates on our investments.
Other Expense, net (in thousands, except for percentages) For the Years Ended December 31, 2023 vs. 2022 2022 vs. 2021 2023 2022 2021 $ Change % Change $ Change % Change Interest expense $ (23,823 ) $ (24,996 ) $ (26,046 ) $ 1,173 (5 )% $ 1,050 (4 )% Interest income 10,943 2,359 582 8,584 364 % 1,777 305 % Other expense, net (356 ) (83 ) (85 ) (273 ) 329 % 2 (2 )% Total other expense, net $ (13,236 ) $ (22,720 ) $ (25,549 ) $ 9,484 (42 )% $ 2,829 (11 )% Other expense, net for the year ended December 31, 2023 decreased by $9.5 million as compared to the year ended December 31, 2022, primarily due to an increase in interest income resulting from higher interest rates on our investments.
This increase was partially offset by a decrease in consulting, professional and other costs due to one-time commercial-related activities incurred in 2021. We expect our selling, general and administrative expenses to increase slightly in 2023 as compared to 2022 due to increased personnel costs.
The decrease in stock-based compensation of $6.0 million was primarily due to severance-related expenses incurred during 2022. The decrease in consulting, professional and other costs was primarily due to lower commercial-related activities. We expect our selling, general and administrative expenses to decrease slightly in 2024 as compared to 2023 due to cost optimization efforts.
This was partially offset by $60.0 million in proceeds received from the Amended Revenue Interest Agreement (as defined below) in 2021. A discussion of changes in our financial condition for the year ended December 31, 2021 as compared to the year ended December 31, 2020 is included under the heading “ Item 7.
A discussion of changes in our financial condition for the year ended December 31, 2022 as compared to the year ended December 31, 2021 is included under the heading “ Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations ” in the 2022 Form 10-K.
XPOVIO/ NEXPOVIO has received regulatory approval in various indications in approximately 40 countries outside the U.S., including the European Union (“EU”), United Kingdom, Singapore, Mainland China, South Korea, Australia, Canada, Taiwan and Israel and is commercially available in a growing number of countries.
XPOVIO/NEXPOVIO has received regulatory approval in various indications in over 40 countries outside the U.S. and is commercially available in a growing number of countries as our partners continue to secure reimbursement approvals.
We expect license and other revenue to remain consistent in 2023 as compared to 2022 primarily due to increased royalties related to the commercialization of selinexor outside the U.S., offset by a decrease in development/regulatory milestone revenue. 96 Table of Contents Operating Costs and Expenses (in thousands, except for percentages) For the Years Ended December 31, 2022 vs. 2021 2021 vs. 2020 2022 2021 2020 $ Change % Change $ Change % Change Cost of sales $ 5,213 $ 3,402 $ 2,705 $ 1,811 53 % $ 697 26 % Research and development 148,662 160,842 150,813 (12,180 ) (8 )% 10,029 7 % Selling, general and administrative 145,401 143,846 126,417 1,555 1 % 17,429 14 % Total operating expenses $ 299,276 $ 308,090 $ 279,935 $ (8,814 ) (3 )% $ 28,155 10 % Cost of Sales We began capitalizing XPOVIO inventory costs during the third quarter of 2019 subsequent to FDA approval as such costs are recoverable through the commercialization of XPOVIO.
Operating Costs and Expenses (in thousands, except for percentages) For the Years Ended December 31, 2023 vs. 2022 2022 vs. 2021 2023 2022 2021 $ Change % Change $ Change % Change Cost of sales $ 4,942 $ 5,213 $ 3,402 $ (271 ) (5 )% $ 1,811 53 % Research and development 138,750 148,662 160,842 (9,912 ) (7 )% (12,180 ) (8 )% Selling, general and administrative 131,881 145,401 143,846 (13,520 ) (9 )% 1,555 1 % Total operating expenses $ 275,573 $ 299,276 $ 308,090 $ (23,703 ) (8 )% $ (8,814 ) (3 )% Cost of Sales We expect cost of sales to remain relatively consistent in 2024 as compared to 2023.
This indication is based on the results from the Phase 3 BOSTON Study, which evaluated once-weekly administration of selinexor in combination with once-weekly administration of Velcade ® and low-dose dexamethasone compared to standard twice-weekly administration of Velcade ® plus low-dose dexamethasone in patients with multiple myeloma who have received one to three prior lines of therapy. 93 Table of Contents Our primary focus is on marketing XPOVIO in its currently approved indications as well as developing and seeking the regulatory approval of selinexor as an oral agent in multiple myeloma, endometrial cancer, and myelofibrosis; eltanexor as an oral agent in myelodysplastic neoplasms; and in additional cancer indications with significant unmet medical need.
Our primary focus is on marketing XPOVIO in its currently approved indications as well as developing and seeking the regulatory approval of selinexor as an oral agent targeting multiple high unmet need cancer indications, including our core programs in endometrial cancer, multiple myeloma, and myelofibrosis.
We expect other expense, net to decrease in 2023 as compared to 2022 primarily due to an increase in interest income from our investments.
We expect other expense, net to remain relatively consistent in 2024 as compared to 2023.
Removed
In July 2022, the European Commission granted full marketing authorisation for NEXPOVIO in combination with once-weekly Velcade ® (bortezomib) and low-dose dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
Added
We plan to continue to educate physicians, other healthcare providers and patients about XPOVIO’s clinical profile and unique mechanism of action as we continue to expand XPOVIO use.
Removed
This approval for the extension of NEXPOVIO's indication in the EU converted the previously received conditional marketing authorisation to a full approval. The marketing authorisation, which marks the second indication for NEXPOVIO, is valid in all 27 member states of the EU as well as Iceland, Liechtenstein, Norway, and Northern Ireland.
Added
In January 2024, we announced that further clinical development of our eltanexor program is on hold in an effort to focus our resources on our prioritized late-stage programs. As of December 31, 2023, we had an accumulated deficit of $1.5 billion.
Removed
Stemline Therapeutics B.V., a wholly owned subsidiary of the Menarini Group (“Menarini”), is responsible for all commercialization activities relating to NEXPOVIO in Europe.
Added
To date, our estimates have not been materially different than amounts actually incurred.
Removed
On December 5, 2022, we entered into a securities purchase agreement with certain institutional investors pursuant to which we issued and sold, in a private placement offering of securities, an aggregate of (i) 31,791,908 shares of common stock and (ii) accompanying warrants to purchase up to 9,537,563 shares of common stock at an exercise price of $6.3578 per share.
Added
A number of myeloma foundations that help support Medicare Part D patients with their out-of-pocket costs for multiple myeloma oral oncolytics, including XPOVIO, closed during the first quarter of 2023 and some remained closed throughout 2023.
Removed
We received aggregate net proceeds of approximately $154.7 million. As of December 31, 2022, we had $278.0 million in cash, cash equivalents and investments. Uncertainty Relating to the COVID-19 Pandemic The COVID-19 pandemic has and will continue to affect economies, healthcare systems, and businesses around the world.
Added
During the foundation closures, we provided XPOVIO to these patients at no charge through our Patient Assistance Program (“PAP”), which adversely impacted our 2023 revenues by approximately $5.8 million as patients who entered our PAP earlier in the year remained in the program through the calendar year and received their refills during the course of their treatment.
Removed
We continue to closely monitor the impact of the COVID-19 pandemic on all aspects of our business, including the impact on our employees, patients and business operations. We have experienced and may continue to experience disruptions that could impact clinical trial enrollment and/or our results of operations, including product revenue and our financial condition.
Added
We believe this trend will be mainly limited to 2023 since, beginning in 2024, changes in the design of Medicare Part D 101 Table of Contents under the Inflation Reduction Act eliminated the patient burden of the 5% Beneficiary Coinsurance requirement and we expect less need for Medicare Part D patients to utilize PAP for co-pay assistance in 2024 compared to 2023.
Removed
Uncertainties relating to the COVID-19 pandemic include the availability, administration rates and effectiveness of vaccines and therapeutics against any variants as new strains of the virus evolve, the continued duration and severity of the pandemic, governmental, business or other actions, and changes to our operations, among others.
Added
These decreases were partially offset by an increase in clinical trial and related costs of $9.2 million, primarily due to the advancement of our three pivotal Phase 3 trials and the timing of purchases of comparator drug used in our clinical trials.
Removed
We will continue to monitor the COVID-19 situation closely and intend to follow health and safety guidelines as they evolve. Further, the impacts of a potential worsening of global economic conditions and the continued disruptions to, and volatility in, the credit and financial markets, as well as other unanticipated consequences, remain unknown.
Added
We expect our research and development expenses to increase slightly in 2024 as compared to 2023 as we continue to advance our three pivotal Phase 3 trials.
Removed
The situation surrounding the COVID-19 pandemic remains fluid and we are actively managing our response and assessing potential impacts to our operating results and financial condition, as well as adverse developments in our business. For further information regarding the impact of the COVID-19 pandemic on us, see Item 1A - Risk Factors included in this Annual Report on Form 10-K.
Added
We did not sell any Open Market Shares under the 2018 Open Market Sale Agreement nor any Shares under the 2023 Open Market Sales Agreement during the year ended December 31, 2023. As of December 31, 2023, $100.0 million of Shares was available for issuance and sale under the 2023 Open Market Sale Agreement.
Removed
We expect these trends to continue in 2023, resulting in an increase in net product revenue when compared to 2022.
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Commitments, Contingencies and Contractual Obligations Operating Leases We are party to an operating lease of 98,502 square feet of office and research space in Newton, Massachusetts with a term through September 30, 2025 (the “Newton, MA Lease”).
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These decreases were partially offset by $15.0 million in revenue earned from Menarini in 2022 for the reimbursement of selinexor development related expenses.
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Pursuant to the Newton, MA Lease, we have provided a security deposit in the form of a cash-collateralized letter of credit in the amount of $0.3 million which is classified in long-term restricted cash on our consolidated balance sheets. We expect to incur total lease costs of $6.7 million from December 31, 2023 to September 30, 2025.
Removed
Prior to the capitalization of XPOVIO inventory costs, such costs were recorded as research and development expenses in the period incurred.
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In addition, we are party to certain short-term leases having a term of twelve months or less at the commencement date. We recognize short-term lease expense on a straight-line basis and do not record a related right-of use asset or lease liability for such leases. These costs were insignificant for the years ended December 31, 2023, 2022 and 2021.
Removed
Therefore, cost of sales recorded during the years ended December 31, 2022, 2021 and 2020 only reflect a portion of the costs related to the manufacturing of XPOVIO and related materials, since, prior to FDA approval, these costs were expensed. The manufacturing costs of XPOVIO on-hand upon approval were approximately $2.8 million.
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Contractual Obligations We have contractual obligations under our 3.00% Convertible Senior Notes due 2025 and under our Revenue Interest Financing Agreement as disclosed in Note 10, “ Long-Term Obligations ”, to the consolidated financial statements included under Part II, Item 8 of this Annual Report on Form 10-K.
Removed
At December 31, 2022, we had $0.3 million of this previously expensed XPOVIO and related material on-hand. We expect cost of sales to slightly increase in 2023 as compared to 2022 due primarily to an expected increase in net product sales.
Added
Funding Requirements We expect our expenses to remain relatively consistent in 2024 as compared to 2023.
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(“Neumedicines”) in the third quarter of 2021, for which there were no similar costs in 2022.
Removed
These decreases were partially offset by an increase in personnel costs and stock-based compensation, which was largely attributable to $7.5 million of severance-related expenses incurred during 2022 driven primarily by the departures of our former Chief Scientific Officer, Chief Medical Officer and Chief Development Officer.
Removed
This was partially offset by increased cash receipts from increased net product sales in 2022 compared to 2021.
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Management’s Discussion and Analysis of Financial Condition and Results of Operations ” in the 2021 Form 10-K.
Removed
During the year ended December 31, 2021, we sold an aggregate of 638,341 Open Market Shares under the Open Market Sale Agreement, for net proceeds of approximately $9.9 million. On February 17, 2023, we entered into a new Open Market Sale Agreement (the “2023 Open Market Sale Agreement”) with Jefferies, as agent.

Item 7A. Quantitative and Qualitative Disclosures About Market Risk

Market Risk — interest-rate, FX, commodity exposure

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Biggest changeWe also contract with a number of clinical trial sites outside of the U.S., and our budgets for those studies are frequently denominated in foreign currencies. We are subject to fluctuations in foreign currency rates in connection with these agreements. We do not currently hedge our foreign currency exchange rate risk.
Biggest changeWe are subject to fluctuations in foreign currency rates in connection with these agreements. We do not currently hedge our foreign currency exchange rate risk.
Item 7A. Quantitative and Qualitative Disclosures about Market Risk We are exposed to market risk related to changes in interest rates. We had cash, cash equivalents and investments of $278.0 million as of December 31, 2022. Our primary exposure to market risk is interest rate sensitivity, which is affected by changes in the general level of U.S. interest rates.
Item 7A. Quantitative and Qualitative Disclosures about Market Risk We are exposed to market risk related to changes in interest rates. We had cash, cash equivalents and investments of $191.4 million as of December 31, 2023. Our primary exposure to market risk is interest rate sensitivity, which is affected by changes in the general level of U.S. interest rates.
Given the potential instability of financial institutions, we cannot provide assurance that we will not experience losses on these deposits and investments. We are also exposed to market risk related to changes in foreign currency exchange rates. We contract with contract research organizations and contract manufacturing organizations that are located in Canada and Europe, which are denominated in foreign currencies.
Given the potential instability of financial institutions, we cannot provide assurance that we will not experience losses on these deposits and investments. We are also exposed to market risk related to changes in foreign currency exchange rates.
Added
We contract with contract research organizations and contract manufacturing organizations that are located in Canada, the United Kingdom and Europe, which are denominated in foreign currencies. We also contract with a number of clinical trial sites outside of the U.S., and our budgets for those studies are frequently denominated in foreign currencies.

Other KPTI 10-K year-over-year comparisons