10q10k10q10k.net

What changed in IONIS PHARMACEUTICALS INC's 10-K — 2022 vs 2023

vs

Paragraph-level year-over-year comparison of IONIS PHARMACEUTICALS 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.

+645 added−606 removedSource: 10-K (2024-02-21) vs 10-K (2023-02-22)

Top changes in IONIS PHARMACEUTICALS INC's 2023 10-K

645 paragraphs added · 606 removed · 447 edited across 6 sections

Item 1. Business

Business — how the company describes what it does

264 edited+140 added−100 removed104 unchanged
Biggest changeTitle Expiration Description of Claims United States 7,750,131 5’-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS 2027 Oligonucleotides having 5’-methyl BNA nucleosides Europe 2092065 ANTISENSE COMPOUNDS 2027 Gapmer oligonucleotides having 2’-modifed and LNA nucleosides Europe 2410053 ANTISENSE COMPOUNDS 2027 Gapmer oligonucleotides having wings comprised of 2’-MOE and bicyclic nucleosides Europe 2410054 ANTISENSE COMPOUNDS 2027 Gapmer oligonucleotides having a 2’-modifed nucleoside in the 5’-wing and a bicyclic nucleoside in the 3’-wing Japan 5665317 ANTISENSE COMPOUNDS 2027 Gapmer oligonucleotides having wings comprised of 2’-MOE and bicyclic nucleosides United States 9,550,988 ANTISENSE COMPOUNDS 2028 Gapmer oligonucleotides having BNA nucleosides and 2’-MOE nucleosides United States 10,493,092 ANTISENSE COMPOUNDS 2028 Gapmer oligonucleotides having BNA nucleosides and 2’-MOE nucleosides and/or 2’-OMe nucleosides Europe 3067421 OLIGOMERIC COMPOUNDS COMPRISING BICYCLIC NUCLEOTIDES AND USES THEREOF 2032 Gapmer oligonucleotides having at least one bicyclic, one 2’-modified nucleoside and one 2’-deoxynucleoside 28 LIgand-Conjugated Antisense (LICA) Technology We also have patent claims to new chemistries created to enhance targeting of antisense medicines to specific tissues and cells to improve a drug’s properties.
Biggest changeTitle Expiration Description of Claims United States 7,399,845 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS 2027 cEt nucleosides and oligonucleotides containing these nucleoside analogs United States 7,741,457 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS 2027 cEt nucleosides and oligonucleotides containing these nucleoside analogs United States 8,022,193 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS 2027 Oligonucleotides containing cEt nucleoside analogs Europe 1984381 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS 2027 cEt nucleosides and oligonucleotides containing these nucleoside analogs Europe 2314594 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS 2027 Oligonucleotides containing cEt nucleoside analogs and methods of use United States 7,569,686 COMPOUNDS AND METHODS FOR SYNTHESIS OF BICYCLIC NUCLEIC ACID ANALOGS 2027 Methods of synthesizing cEt nucleosides Europe 2092065 ANTISENSE COMPOUNDS 2027 Gapmer oligonucleotides having 2’-modifed and LNA nucleosides Europe 2410053 ANTISENSE COMPOUNDS 2027 Gapmer oligonucleotides having wings comprised of 2’-MOE and bicyclic nucleosides Europe 2410054 ANTISENSE COMPOUNDS 2027 Gapmer oligonucleotides having a 2’-modifed nucleoside in the 5’-wing and a bicyclic nucleoside in the 3’-wing United States 9,550,988 ANTISENSE COMPOUNDS 2028 Gapmer oligonucleotides having BNA nucleosides and 2’-MOE nucleosides United States 10,493,092 ANTISENSE COMPOUNDS 2028 Gapmer oligonucleotides having BNA nucleosides and 2’-MOE nucleosides and/or 2’-OMe nucleosides Europe 3067421 OLIGOMERIC COMPOUNDS COMPRISING BICYCLIC NUCLEOTIDES AND USES THEREOF 2032 Gapmer oligonucleotides having at least one bicyclic, one 2’-modified nucleoside and one 2’-deoxynucleoside United States 11,629,348 LINKAGE MODIFIED OLIGONUCLEOTIDES AND USES THEREOF 2040 Gapmer oligonucleotides having 2-4 mesyl phosphoramidate internucleoside linkages at specified positions in the gap 36 Table of Contents LIgand-Conjugated Antisense (LICA) Technology We also have patent claims to new chemistries created to enhance targeting of antisense medicines to specific tissues and cells to improve a drug’s properties.
Marketed Medicines SPINRAZA is the global market leader for the treatment of patients with spinal muscular atrophy, or SMA, a progressive, debilitating and often fatal genetic disease. Biogen is our partner responsible for commercializing SPINRAZA worldwide.
Marketed Medicines SPINRAZA is the global market leader for the treatment of patients with spinal muscular atrophy, or SMA, a progressive, debilitating and often fatal genetic disease. Our partner, Biogen, is responsible for commercializing SPINRAZA worldwide.
As a result, Roche is responsible for global development, regulatory and commercialization activities, and costs for IONIS-FB-L Rx , except for the open label Phase 2 study in patients with IgAN and the Phase 2 study in patients with GA, both of which we are conducting and funding.
As a result, Roche is responsible for global development, regulatory and commercialization activities, and costs for IONIS-FB-L Rx , except for the open label Phase 2 study in patients with IgAN and the Phase 2 study in patients with GA, both of which we are conducting and funding.
All of our trainings from new hire through senior leader, are focused on the Ionis culture and core principles and learning what we mean when we say: “Working the Ionis Way.” 40 We empower our employees to build rewarding careers at Ionis, driven by a culture of having a bias to act that encourages personal and professional employee growth.
All of our trainings from new hire through senior leader, are focused on the Ionis culture and core principles and learning what we mean when we say: “Working the Ionis Way.” We empower our employees to build rewarding careers at Ionis, driven by a culture of having a bias to act that encourages personal and professional employee growth.
Due to the breadth of the statutory provisions, limited statutory exceptions and regulatory safe harbors, and the absence of guidance in the form of regulations and very few court decisions addressing industry practices, it is possible that our practices might be challenged under anti-kickback or similar laws. Moreover, recent healthcare reform legislation has strengthened these laws.
Due to the breadth of the statutory provisions, limited statutory exceptions and regulatory safe harbors, and the absence of guidance in the form of regulations and very few court decisions addressing industry practices, it is possible that our practices might be challenged under anti-kickback or similar laws. Moreover, healthcare reform legislation has strengthened these laws.
Approximately 98 percent of patients who received the highest dose in the study demonstrated a reduction in Lp(a) levels to below the recommended threshold for CVD events ( In February 2019, Novartis exercised its option to license pelacarsen. As a result, Novartis is responsible for global development, regulatory and commercialization activities, and costs for pelacarsen.
Approximately 98% of patients who received the highest dose in the study demonstrated a reduction in Lp(a) levels to below the recommended threshold for CVD events ( In February 2019, Novartis exercised its option to license pelacarsen. As a result, Novartis is responsible for global development, regulatory and commercialization activities, and costs for pelacarsen.
The process for determining whether a payer will provide coverage for a product may be separate from the process for setting the reimbursement rate that the payer will pay for the product, or procedures which utilize such product. Private health plans may seek to manage cost and use of our medicines by implementing coverage and reimbursement limitations.
The process for determining whether a payer will provide coverage for a product may be separate from the process for setting the reimbursement rate that the payer will pay for the product, or procedures that utilize such product. Private health plans may seek to manage cost and use of our medicines by implementing coverage and reimbursement limitations.
It is believed that decreasing the production of the alpha-synuclein protein will reduce the toxic effects of gain-of-function mutations. 14 In July 2020, we initiated a Phase 1/2 study evaluating ION464 in patients with MSA.
It is believed that decreasing the production of the alpha-synuclein protein will reduce the toxic effects of gain-of-function mutations. In July 2020, we initiated a Phase 1/2 study evaluating ION464 in patients with MSA.
New antisense medicines for the treatment of SMA In December 2017, we entered into a collaboration agreement with Biogen to identify new antisense medicines for the treatment of SMA. Biogen has the option to license therapies arising out of this collaboration following the completion of preclinical studies.
New antisense medicines for the treatment of SMA In 2017, we entered into a collaboration agreement with Biogen to identify new antisense medicines for the treatment of SMA. Biogen has the option to license therapies arising out of this collaboration following the completion of preclinical studies.
In addition to salary and bonus programs, we also offer: ● Comprehensive medical, dental and vision insurance; ● 401(k) matching; ● Stock options, RSUs and an Employee Stock Purchase Plan, or ESPP; ● Vacation, holiday, sick time and paid time off for volunteering; ● Wellness programs; ● Flexible spending accounts for health and dependent day care needs; ● Life, AD&D insurance and long-term disability insurance coverage options; and ● Employee Assistance Program, or EAP.
In addition to salary and bonus programs, we also offer: ● Comprehensive medical, dental and vision insurance; ● 401(k) matching; ● Stock options, RSUs and an Employee Stock Purchase Plan, or ESPP; ● Vacation, holiday, sick time and paid time off for volunteering; ● Wellness programs; ● Flexible spending accounts for health and dependent day care needs; ● Family care benefits; ● Life, AD&D insurance and long-term disability insurance coverage options; and ● Employee Assistance Program, or EAP.
The reduction of ATXN2 has been shown to decrease aggregation of TDP-43, a toxic RNA binding protein found in most patients with ALS, including the approximately 90 percent of the ALS population with no known family history of ALS. In October 2020, Biogen initiated a Phase 1/2 clinical study evaluating ION541 in patients with ALS.
The reduction of ATXN2 has been shown to decrease toxic aggregation of TDP-43, an RNA binding protein found in most patients with ALS, including the approximately 90% of the ALS population with no known family history of ALS. In October 2020, Biogen initiated a Phase 1/2 clinical study evaluating ION541 in patients with ALS.
Additionally, in November 2022, we initiated ESSENCE, a global, multi-center, randomized, double-blind, placebo-controlled study enrolling approximately 1,300 patients to provide a robust safety database. The primary endpoint of the study is the percent change in fasting triglycerides from baseline at week six.
Additionally, in November 2022, we initiated ESSENCE, a global, multi-center, randomized, double-blind, placebo-controlled study enrolling approximately 1,300 patients to provide a robust safety database. The primary endpoint of the study is the percent change in fasting triglycerides from baseline at month six.
NASH is a common liver disease characterized by liver steatosis, inflammation and scarring and can lead to increased risk of cardiovascular disease, liver cancer, need for liver transplantation and early death. DGAT2 is an enzyme that catalyzes the final step in triglyceride synthesis in the liver. Reducing the production of DGAT2 should therefore decrease triglyceride synthesis in the liver.
NASH is a common liver disease characterized by liver steatosis, inflammation and scarring and can lead to increased risk of CVD, liver cancer, need for liver transplantation and early death. DGAT2 is an enzyme that catalyzes the final step in triglyceride synthesis in the liver. Reducing the production of DGAT2 should therefore decrease triglyceride synthesis in the liver.
Given the significant penalties and fines that can be imposed on companies and individuals if convicted, allegations of such violations often result in settlements even if the company or individual being investigated admits no wrongdoing. Settlements often include significant civil sanctions, including fines and civil monetary penalties, and corporate integrity agreements.
Given the significant penalties and fines that can be imposed on companies and individuals if convicted, allegations of such violations often result in settlements even if the company or individual being investigated admits no wrongdoing. Settlements often include significant civil sanctions, including fines and civil monetary penalties, corporate integrity agreements, and could include criminal penalties.
The Phase 1/2 study was a blinded, randomized, placebo-controlled, dose-escalation study of IONIS-MAPT Rx to evaluate the safety and activity of once-monthly intrathecal injections of IONIS-MAPT Rx in patients with mild AD. The study showed that IONIS-MAPT Rx met its primary objective of safety and tolerability in patients with mild Alzheimer’s disease.
The Phase 1/2 study was a blinded, randomized, placebo-controlled, dose-escalation study of IONIS-MAPT Rx to evaluate the safety and activity of once-monthly intrathecal injections of IONIS-MAPT Rx in patients with mild AD. The study showed that IONIS-MAPT Rx met its primary objective of safety and tolerability in patients with mild AD.
In addition, we are eligible to receive tiered royalties from the mid-teens to mid-20 percent range on net sales from any product that Biogen successfully commercializes under this collaboration. From inception through December 31, 2022, we have generated $85 million in payments under this collaboration.
In addition, we are eligible to receive tiered royalties from the mid-teens to mid-20 percent range on net sales from any product that Biogen successfully commercializes under this collaboration. From inception through December 31, 2023, we have generated $85 million in payments under this collaboration.
Results from Part A, an open-label safety evaluation period in children and teens with later-onset SMA, suggest that the higher dosing regimen of SPINRAZA leads to higher levels of the drug in the cerebrospinal fluid, supporting further development of a higher dose of SPINRAZA.
Results from Part A, an open-label safety evaluation period in children and teens with later-onset SMA, suggest that the higher dosing regimen of SPINRAZA leads to higher levels of the drug in the cerebrospinal fluid, or CSF, supporting further development of a higher dose of SPINRAZA.
We also could experience a disruption in supply from our current CMO partners. CMOs are subject to the FDA’s cGMP requirements and other rules and regulations prescribed by foreign regulatory authorities. We depend on our CMO partners for continued compliance with cGMP requirements and applicable foreign standards.
We also could experience a disruption in supply from our current CMOs. CMOs are subject to the FDA’s cGMP requirements and other rules and regulations prescribed by foreign regulatory authorities. We depend on our CMOs for continued compliance with cGMP requirements and applicable foreign standards.
Even in those countries where we may not be directly responsible for the promotion and marketing of our medicines, if our potential international distribution partners engage in inappropriate activity, it can have adverse implications for us. The U.S.
Even in those countries where we may not be directly responsible for the promotion and marketing of our medicines, if our potential international distribution partners engage in inappropriate activity, it can have adverse implications for us.
The 12-month integrated data show that earlier initiation of tofersen, compared to delayed initiation, slowed declines in clinical function, respiratory function, muscle strength and quality of life and build on the results previously observed in the initial readout.
The 12-month integrated data show that earlier initiation of QALSODY, compared to delayed initiation, slowed declines in clinical function, respiratory function, muscle strength and quality of life and build on the results previously observed in the initial readout.
We recognize achievements with salary increases, equity awards, promotions, and bonus opportunities. Pay Equity We are committed to paying our employees fairly, regardless of their gender, race, or other personal characteristics.
We recognize achievements with salary increases, equity awards, promotions, and bonus opportunities. Pay Equity We are committed to paying our employees fairly, regardless of their gender, ethnicity, race, age or other personal characteristics.
The study demonstrated robust time and dose dependent lowering of tau protein in cerebrospinal fluid over the three-month treatment period and sustained reductions during the six-month post-treatment period. IONIS-MAPT Rx had a favorable safety and tolerability profile supportive of continued development. In December 2019, Biogen exercised its option to license IONIS-MAPT Rx .
The study demonstrated robust time and dose dependent lowering of tau protein in CSF over the three-month treatment period and sustained reductions during the six-month post-treatment period. IONIS-MAPT Rx had a favorable safety and tolerability profile supportive of continued development. In December 2019, Biogen exercised its option to license IONIS-MAPT Rx .
Currently available therapies, although effective in reducing circulating HBV in the blood, do not effectively inhibit HBV antigen production and secretion, which are associated with poor prognosis and increased risk of liver cancer. In January 2023, GSK initiated the Phase 3 program of bepirovirsen, B-Well, in patients with chronic HBV.
Currently available therapies, although effective in reducing circulating HBV in the blood, do not effectively inhibit HBV antigen production and secretion, which are associated with poor prognosis and increased risk of liver cancer. 13 Table of Contents In January 2023, GSK initiated the Phase 3 program of bepirovirsen, B-Well, in patients with chronic HBV.
Title Expiration Description of Claims United States 9,163,239 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION 2034 Composition of olezarsen Europe 2991656 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION 2034 Composition of olezarsen Donidalorsen and PKK We believe donidalorsen is protected from generic competition in the U.S. and Europe until at least 2035.
Title Expiration Description of Claims United States 9,163,239 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION 2034 Composition of olezarsen Europe 2991656 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION 2034 Composition of olezarsen 33 Table of Contents Donidalorsen and PKK We believe donidalorsen is protected from generic competition in the U.S. and Europe until at least 2035.
The tofersen NDA and MAA included results from a Phase 1 study in healthy volunteers, a Phase 1/2 study evaluating ascending dose levels, the Phase 3 VALOR study, and the Phase 3 OLE study, as well as 12-month integrated results from VALOR and the Phase 3 OLE study.
The QALSODY NDA and MAA included results from a Phase 1 study in healthy volunteers, a Phase 1/2 study evaluating ascending dose levels, the Phase 3 VALOR study, and the Phase 3 OLE study, as well as 12-month integrated results from the Phase 3 VALOR study and the Phase 3 OLE study.
Additional patent applications to protect eplontersen in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting eplontersen in the U.S. and Europe: Jurisdiction Patent No.
Additional patent applications to protect WAINUA in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting WAINUA in the U.S. and Europe: Jurisdiction Patent No.
The end of study results showed that treatment with bepirovirsen resulted in sustained clearance of HBsAg and HBV DNA for 24 weeks after end of bepirovirsen treatment in people with chronic HBV infection.
The end of study results showed that treatment with bepirovirsen in some patients resulted in sustained clearance of HBsAg and HBV DNA for 24 weeks after end of bepirovirsen treatment in people with chronic HBV infection.
We have several employee-led resource groups dedicated to different aspects of diversity and a diverse management team and board of directors. Training and Development We designed our training and development programs to help employees gain important Ionis knowledge and develop the skills to be successful at Ionis.
We have several employee-led resource groups dedicated to different aspects of diversity and a diverse management team and board of directors. 46 Table of Contents Training and Development We designed our training and development programs to help employees gain important Ionis knowledge and develop the skills to be successful at Ionis.
Previously, Dr. Swayze was Vice President of Chemistry and Neuroscience Drug Discovery at Ionis, overseeing the advancement of multiple programs to clinical development. He joined Ionis in 1994 and has contributed to key technology advancements, including Ionis’ Generation 2.5 chemistry and LICA technology. 42
Swayze was Vice President of Chemistry and Neuroscience Drug Discovery at Ionis, overseeing the advancement of multiple programs to clinical development. He joined Ionis in 1994 and has contributed to key technology advancements, including Ionis’ Generation 2.5 chemistry and LICA technology.
However, the SMN2 gene can only produce approximately 10 percent of the SMN protein critical for motor neurons, resulting in severe and progressive loss of motor function and strength. The rate and severity of degeneration varies depending on the amount of functional SMN protein a patient can produce.
However, in untreated people the SMN2 gene can only produce approximately 10% of the SMN protein critical for motor neurons, resulting in severe and progressive loss of motor function and strength. The rate and severity of degeneration varies depending on the amount of functional SMN protein a patient can produce.
The Phase 2/3 study of zilganersen is a multi-center, double-blind, placebo-controlled, multiple-ascending dose study in approximately 55 patients with AxD designed to assess the efficacy, safety and tolerability of zilganersen. Patients will receive zilganersen or placebo for a 60-week period, after which all patients in the study will receive zilganersen for a 60-week open-label treatment period.
The pivotal study of zilganersen is a multi-center, double-blind, placebo-controlled, multiple-ascending dose study in approximately 55 patients with AxD designed to assess the efficacy, safety and tolerability of zilganersen. Patients will receive zilganersen or placebo for a 60-week period, after which all patients in the study will receive zilganersen for a 60-week open-label treatment period.
Patents issued from these applications would have terms until at least 2040. The table below lists some key pending patent applications designed to protect ION363 in the U.S. and Europe: Jurisdiction Patent No.
Patents issued from these applications would have terms until at least 2040. The table below lists some key pending patent applications designed to protect ulefnersen in the U.S. and Europe: Jurisdiction Patent Application No.
As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for these diseases for 10 years. We are responsible for the identification of antisense drug candidates based on selected targets. Biogen will usually be responsible for conducting IND-enabling toxicology studies for the selected medicine.
As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for these diseases for 10 years. We are responsible for the identification of antisense drug candidates based on selected targets. In most cases, Biogen will be responsible for conducting IND-enabling toxicology studies for the selected medicine.
Additional patent applications designed to protect tofersen in other foreign jurisdictions are being pursued. With Biogen’s license of tofersen, we assigned our interest in these patents to Biogen. The table below lists some key issued patents protecting t ofersen in the U.S. and Europe: Jurisdiction Patent No.
Additional patent applications designed to protect QALSODY in other foreign jurisdictions are being pursued. With Biogen’s license of QALSODY, we assigned our interest in these patents to Biogen. The table below lists some key issued patents protecting QALSODY in the U.S. and Europe: Jurisdiction Patent No.
We manufacture process performance qualification batches and pre-approval inspection batches of our Phase 3 medicines that may be used for regulatory submissions and, pending regulatory approval, commercial sale. We believe our current network of CMO partners are capable of providing sufficient quantities to meet anticipated commercial demands.
We and/or our CMOs manufacture process performance qualification batches and pre-approval inspection batches of our Phase 3 medicines that may be used for regulatory submissions and, pending regulatory approval, commercial sale. We believe our current network of CMOs are capable of providing sufficient quantities to meet anticipated commercial demands.
These companies include biopharmaceutical companies and large pharmaceutical companies acting either independently or together. Our medicines are differentiated from traditional small molecule medicines by their chemistry, how they move in the body, how they act in the body, delivery technology, and formulations. 36 Our approved medicines and our medicines under development address numerous markets.
These companies include biopharmaceutical companies and large pharmaceutical companies acting either independently or together. Our medicines are differentiated from traditional small molecule medicines by their chemistry, how they move in the body, how they act in the body, delivery technology, and formulations. Our commercial medicines and our medicines in development address numerous markets.
The safety of SPINRAZA over this extended follow-up period was consistent with previously reported findings. 6 The approval of SPINRAZA was based on efficacy and safety data from multiple clinical studies, including two randomized, placebo-controlled Phase 3 studies, ENDEAR, in patients with infantile-onset SMA, and CHERISH, in patients with later-onset SMA as well as from SHINE, an open-label extension, or OLE, study for patients with SMA who participated in prior SPINRAZA studies.
The safety of SPINRAZA over this extended follow-up period was consistent with previously reported findings. 6 Table of Contents The approval of SPINRAZA was based on efficacy and safety data from multiple clinical studies, including two randomized, placebo-controlled Phase 3 studies, ENDEAR, in patients with infantile-onset SMA, and CHERISH, in patients with later-onset SMA as well as from SHINE, an OLE study for patients with SMA who participated in prior SPINRAZA studies.
The primary endpoint is the change from baseline as measured by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, or ALSFRS-R, Total Score, time of rescue or discontinuation from Part 1 and entering Part 2 due to a deterioration in function, and Ventilation Assistance-free survival, or VAFS.
The primary endpoint is the change from baseline as measured by joint rank analysis of the combined assessment of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, or ALSFRS-R, Total Score, time of rescue or discontinuation from Part 1 and entering Part 2 due to a deterioration in function, and Ventilation Assistance-free survival, or VAFS.
In the study, eplontersen achieved an 81.2% (p In January 2020, we initiated the CARDIO-TTRansform Phase 3 cardiovascular outcome study of eplontersen in patients with ATTR-CM. CARDIO-TTRansform i s a global, multi-center, randomized, double-blind, placebo-controlled study in approximately 1,400 patients with ATTR-CM. We designed the study to evaluate the efficacy, safety and tolerability of eplontersen in patients with ATTR-CM.
In January 2020, we initiated the CARDIO-TTRansform Phase 3 cardiovascular outcome study of eplontersen in patients with ATTR-CM. CARDIO-TTRansform i s a global, multi-center, randomized, double-blind, placebo-controlled study in approximately 1,400 patients with ATTR-CM. We designed the study to evaluate the efficacy, safety and tolerability of eplontersen in patients with ATTR-CM.
O’Neil, Esq. 49 Chief Legal Officer, General Counsel and Corporate Secretary Eugene Schneider, M.D. 50 Executive Vice President, Chief Clinical Development Officer Eric E. Swayze, Ph.D. 57 Executive Vice President, Research BRETT P. MONIA, Ph.D. Chief Executive Officer Dr. Monia was promoted to Chief Executive Officer in January 2020. From January 2018 to December 2019, Dr.
O’Neil, Esq. 50 Chief Legal Officer, General Counsel and Corporate Secretary Eugene Schneider, M.D. 51 Executive Vice President, Chief Clinical Development and Operations Officer Eric E. Swayze, Ph.D. 58 Executive Vice President, Research BRETT P. MONIA, Ph.D. Chief Executive Officer Dr. Monia was promoted to Chief Executive Officer in January 2020. From January 2018 to December 2019, Dr.
These issued patents include: (i) patents licensed from the University of Massachusetts drawn to antisense compounds having the sequence of SPINRAZA, independent of chemical modification and uses of such compounds for treating SMA, and (ii) joint patents with Cold Spring Harbor Laboratory claiming fully modified 2’MOE compositions targeting SMN2, including the precise composition of matter of SPINRAZA and methods of using such compositions.
These issued patents include: (i) patents licensed from the University of Massachusetts drawn to antisense compounds having the sequence of SPINRAZA, independent of chemical modification, and uses of such compounds for treating SMA, (ii) joint patents with Cold Spring Harbor Laboratory claiming fully modified 2’-MOE compounds targeting SMN2, including the precise composition of matter of SPINRAZA and methods of using such compositions; and (iii) dosing and therapeutic methods of using such compounds and compositions.
From inception through December 31, 2022, we have generated nearly $1.1 billion in payments under this collaboration. 2013 Strategic Neurology In September 2013, we and Biogen entered into a long-term strategic relationship focused on applying antisense technology to advance the treatment of neurodegenerative diseases.
From inception through December 31, 2023, we have generated nearly $1.1 billion in payments under this collaboration. 2013 Strategic Neurology In 2013, we and Biogen entered into a strategic relationship focused on applying antisense technology to advance the treatment of neurodegenerative diseases.
Fesomersen had a favorable safety and tolerability profile supportive of continued development. In November 2022, we regained all rights to fesomersen, which we had previously licensed to Bayer in February 2017. IONIS-AGT-L Rx – IONIS-AGT-L Rx is an investigational LICA medicine we designed to inhibit the production of angiotensinogen to decrease blood pressure in people with uncontrolled hypertension.
Fesomersen had a favorable safety and tolerability profile supportive of continued development. In November 2022, we regained all rights to fesomersen, which we had previously licensed to Bayer in February 2017. ION904 (AGT) – ION904 is an investigational next-generation LICA medicine designed to inhibit the production of angiotensinogen to decrease blood pressure in people with uncontrolled hypertension.
IONIS-FB-L Rx – IONIS-FB-L Rx (RG6299) is an investigational LICA medicine we designed to inhibit the production of complement factor B, or FB, and the alternative complement pathway.
IONIS-FB-L Rx – IONIS-FB-L Rx (RG6299) is an investigational LICA medicine we designed to inhibit the production of FB, and the alternative complement pathway.
We have also diversified the approaches we can use in designing our medicines in order to reach more patients with severe diseases. Today our medicines and those entering our pipeline utilize our key technology advances, including our LICA technology and mesyl phosphoramidate, or MsPA, backbone chemistry.
We have also diversified the approaches we can use in designing our medicines in order to reach more patients with severe diseases. Today our medicines and those entering our pipeline utilize our key technology advances, including our Bicycle LICA technology, siRNA technology and MsPA backbone chemistry.
O’Neil served as our Senior Vice President, Legal and General Counsel. From September 2010 to January 2013, Mr. O’Neil served as our Vice President, Legal and General Counsel and from January 2009 to September 2010, he served as our Vice President, Legal and Senior Transactions Counsel. From October 2001 to January 2009 he held various positions within our Legal department.
O’Neil served as our Vice President, Legal and General Counsel and from January 2009 to September 2010, he served as our Vice President, Legal and Senior Transactions Counsel. From October 2001 to January 2009 he held various positions within our Legal department. Prior to joining Ionis, Mr.
Treatment with bepirovirsen, with a loading dose at day four and 11, and at a dose of 300 mg per week for 24 weeks (treatment arm 1), resulted in 9% of patients on NA treatment and 10% of patients not on NA treatment achieving the primary outcome of HBsAg levels below the LLOQ and HBV DNA levels, both below the LLOQ, respectively.
Treatment with bepirovirsen that was administered weekly at a dose of 300 mg per week for 24 weeks, with loading doses administered on day four and 11 (treatment arm 1), resulted in 9% of patients on NA treatment and 10% of patients not on NA treatment both achieving the primary outcome of HBsAg levels and HBV DNA levels below the LLOQ.
SPINRAZA is an example of an antisense medicine that modulates RNA splicing to increase protein production of the SMN protein, which is critical to the health and survival of nerve cells in the spinal cord that are responsible for neuro-muscular function. The SMN protein is deficient in people with SMA.
Examples of these include WAINUA, olezarsen and donidalorsen. SPINRAZA is an example of an antisense medicine that modulates RNA splicing to increase protein production of the SMN protein, which is critical to the health and survival of nerve cells in the spinal cord that are responsible for neuro-muscular function. The SMN protein is deficient in people with SMA.
Other healthcare laws that may affect our ability to operate include, for example, the following: ● The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, which governs the conduct of certain electronic healthcare transactions and protects the security and privacy of protected health information; ● Foreign and state laws governing the privacy and security of health information, such as the General Data Protection Regulation, or GDPR, in the EU; and the California Consumer Privacy Act, or CCPA, in California, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect; and ● The Physician Payments Sunshine Act, which requires manufacturers of medicines, devices, biologics, and medical supplies to report annually to the HHS information related to payments and other transfers of value to physicians (defined to include doctors, dentists, optometrists, podiatrists, and chiropractors), other healthcare providers (such as physician assistants and nurse practitioners), and teaching hospitals, and ownership and investment interests held by physicians and their immediate family members.
Other healthcare laws that may affect our ability to operate include, for example, the following: ● The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, which governs the conduct of certain electronic healthcare transactions and protects the security and privacy of protected health information; ● Foreign and state laws governing the privacy and security of health information, such as the General Data Protection Regulation, or GDPR, in the EU; and the California Consumer Privacy Act, or CCPA, in California, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect; and ● The Physician Payments Sunshine Act, which requires manufacturers of medicines, devices, biologics, and medical supplies to report annually to the HHS information related to payments and other transfers of value to physicians (defined to include doctors, dentists, optometrists, podiatrists, and chiropractors), other healthcare providers (such as physician assistants and nurse practitioners), and teaching hospitals, and ownership and investment interests held by physicians and their immediate family members. 39 Table of Contents Sales and Marketing Numerous regulatory authorities in addition to the FDA, including, in the U.S., the Centers for Medicare and Medicaid Services, other divisions of the HHS, the U.S.
In August 2019, GSK exercised its option to license our HBV program following the positive results of the Phase 2a study of bepirovirsen in patients with chronic HBV infection. As a result, GSK is responsible for global development, regulatory and commercialization activities, and costs for the HBV program.
Bepirovirsen had a favorable safety and tolerability profile supportive of continued development. In August 2019, GSK exercised its option to license our HBV program following the positive results of the Phase 2a study of bepirovirsen in patients with chronic HBV infection. As a result, GSK is responsible for global development, regulatory and commercialization activities, and costs for the HBV program.
Under the terms of the agreement, we received an upfront payment of $100 million and are eligible to receive milestone payments, license fees and royalty payments for all medicines developed under this collaboration, with the specific amounts dependent upon the modality of the molecule advanced by Biogen.
Under the terms of the agreement, we are eligible to receive milestone payments, license fees and royalty payments for all medicines developed under this collaboration, with the specific amounts dependent upon the modality of the molecule advanced by Biogen.
Metagenomi In November 2022, we entered into a collaboration and license agreement with Metagenomi to research, develop and commercialize investigational medicines for up to four initial genetic targets, and, upon the achievement of certain development milestones, four additional genetic targets using gene editing technologies. As a result, we paid $80 million to license Metagenomi’s technologies.
Metagenomi In 2022, we entered into a collaboration and license agreement with Metagenomi to research, develop and commercialize investigational medicines for up to four initial genetic targets, and, upon the achievement of certain development milestones, four additional genetic targets using gene editing technologies.
In Latin America, PTC is commercializing WAYLIVRA in Brazil for two indications, FCS and familial partial lipodystrophy, or FPL, and is pursuing access in additional Latin American countries through its exclusive license agreement with us.
We sell WAYLIVRA in Europe through our distribution agreement with Sobi. In Latin America, PTC is commercializing WAYLIVRA in Brazil for two indications, FCS and familial partial lipodystrophy, or FPL, and is pursuing access in additional Latin American countries through its exclusive license agreement with us.
Frank Bennett, Ph.D. 66 Executive Vice President, Chief Scientific Officer Onaiza Cadoret-Manier 58 Executive Vice President, Chief Global Product Strategy and Operations Officer Richard S. Geary, Ph.D. 65 Executive Vice President, Chief Development Officer Elizabeth L. Hougen 61 Executive Vice President, Finance and Chief Financial Officer Patrick R.
Frank Bennett, Ph.D. 67 Executive Vice President, Chief Scientific Officer Onaiza Cadoret-Manier 59 Executive Vice President, Chief Global Product Strategy and Operations Officer Richard S. Geary, Ph.D. 66 Executive Vice President, Chief Development Officer Elizabeth L. Hougen 62 Executive Vice President, Finance and Chief Financial Officer Patrick R.
In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any product that Biogen successfully commercializes under this collaboration.
In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement.
For additional details, including other financial information, refer to Part IV, Item 15, Note 7, Collaborative Arrangements and Licensing Agreements, in the Notes to the Consolidated Financial Statements. 20 Strategic Partnership Biogen We have several strategic collaborations with Biogen focused on using our technology to advance the treatment of neurological disorders.
Below, we include the significant terms of our collaboration agreements. For additional details, including other financial information, refer to Part IV, Item 15, Note 4, Collaborative Arrangements and Licensing Agreements, in the Notes to the Consolidated Financial Statements. Strategic Partnership Biogen We have several strategic collaborations with Biogen focused on using antisense technology to advance the treatment of neurological disorders.
Tofersen reduced total cerebrospinal fluid, or CSF, SOD1 protein and plasma neurofilament levels in both early- and delayed-start groups as follows: • 33% and 21% reduction in SOD1 protein, the intended target for tofersen, respectively • 51% and 41% reduction in plasma neurofilament, a marker of neuron injury, respectively Tofersen had a favorable safety and tolerability profile supportive of continued development.
QALSODY reduced total CSF SOD1 protein and plasma neurofilament levels in both early- and delayed-start groups as follows: • 33% and 21% reduction in SOD1 protein, the intended target for QALSODY, respectively • 51% and 41% reduction in plasma neurofilament, a marker of neuron injury, respectively QALSODY had a favorable safety and tolerability profile.
Patients experience ongoing debilitating heart damage resulting in progressive heart failure, which results in death within three to five years from disease onset. ATTR-CM includes both the genetic and wild-type form of the disease. There are an estimated 300,000 to 500,000 patients with ATTR-CM worldwide.
ATTR-CM is caused by the accumulation of misfolded TTR protein in the cardiac muscle. Patients experience ongoing debilitating heart damage resulting in progressive heart failure, which results in death within three to five years from disease onset. ATTR-CM includes both the genetic and wild-type form of the disease. There are an estimated 300,000 to 500,000 patients with ATTR-CM worldwide.
Our partners include the following companies, among others: AstraZeneca, Biogen, GSK, Novartis and Roche. Through our partnerships, we have earned both commercial revenue and a broad and sustaining base of R&D revenue in the form of license fees, upfront payments and milestone payments.
Our partners include the following companies, among others: AstraZeneca, Biogen, GSK, Novartis, Otsuka and Roche. Through our partnerships, we have earned both commercial revenue and a broad and sustaining base of R&D revenue in the form of license fees, upfront payments and milestone payments. In addition, we are eligible to receive royalties under our partnerships.
Gene Editing and Metagenomi Collaboration In November 2022, we entered into a collaboration with Metagenomi that leverages our extensive expertise in RNA-targeted therapeutics and Metagenomi’s versatile next-generation gene editing systems to pursue a mix of validated and novel genetic targets with the goal of discovering and developing new drugs. These targets have the potential to expand therapeutic options for patients.
Gene Editing and Metagenomi Collaboration In 2022, we entered into a collaboration with Metagenomi that leverages our extensive expertise in RNA-targeted therapeutics and Metagenomi’s versatile next-generation gene editing systems to pursue a mix of validated and novel genetic targets with the goal of discovering and developing new drugs.
If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. We are currently advancing five investigational medicines in development under this collaboration, including a medicine for Parkinson’s disease, two medicines for ALS, a medicine for multiple system atrophy and a medicine for an undisclosed target.
If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. We are currently advancing four investigational medicines in development under this collaboration, including a medicine for Parkinson’s disease (ION859), two medicines for ALS (QALSODY and ION541) and a medicine for multiple system atrophy (ION464).
We have dedicated significant resources to develop ways to improve manufacturing efficiency and capacity. Since we can use variants of the same nucleotide building blocks and the same type of equipment to produce our oligonucleotide medicines, we found that the same techniques we used to efficiently manufacture one oligonucleotide medicine could help improve the manufacturing processes for our other medicines.
Since we can use variants of the same nucleotide building blocks and the same type of equipment to produce our oligonucleotide medicines, we found that the same techniques we used to efficiently manufacture one oligonucleotide medicine could help improve the manufacturing processes for our other medicines.
We currently have an integrated assessment of data from multiple LICA medicines and clinical programs which demonstrates that our LICA technology for liver targets can increase potency by 20-30-fold over our non-LICA antisense medicines. Our LICA medicines have also demonstrated consistently favorable safety and tolerability in clinical trials.
We currently have an integrated assessment of data from multiple LICA medicines and clinical programs which demonstrates that our LICA technology for liver targets can increase potency by 20-30-fold over our non-LICA antisense medicines.
We will usually be responsible for drug discovery and early development of antisense medicines and Biogen will have the option to license antisense medicines after Phase 2 proof-of-concept. In October 2016, we expanded our collaboration to include additional research activities we will perform.
In most cases, we are responsible for drug discovery and early development of antisense medicines and Biogen has the option to license antisense medicines after Phase 2 proof-of-concept. In 2016, we expanded our collaboration to include additional research activities we will perform.
Both platforms rely on the same nucleic acid hybridization principals to precisely target nucleases to either RNA, in the case of RNase H and siRNA drugs, or to DNA in the case of Clustered Regularly Interspaced Short Palindromic Repeats, or CRISPR-Cas systems.
Gene editing is highly complementary and synergistic with RNA-targeted therapeutics. Both platforms rely on the same nucleic acid hybridization principals to precisely target nucleases to either RNA, in the case of RNase H and siRNA drugs, or to DNA in the case of Clustered Regularly Interspaced Short Palindromic Repeats, or CRISPR-Cas systems.
Because antisense-mediated reduction of mutant FUS protein in a FUS-ALS mouse model demonstrated the ability to prevent motor neuron loss, it is hypothesized that reduction of FUS protein will reverse or prevent disease progression in FUS-ALS patients.
Because antisense-mediated reduction of mutant FUS protein in a FUS-ALS mouse model demonstrated the ability to prevent motor neuron loss, it is hypothesized that reduction of FUS protein will reverse or prevent disease progression in FUS-ALS patients. It is estimated that there are approximately 350 patients with FUS-ALS in G7 countries.
In January 2020, we reported positive results from a Phase 2 clinical study in patients with hypertriglyceridemia and at high risk of or with established CVD. Olezarsen achieved statistically significant, dose-dependent reductions in fasting triglycerides compared to placebo at all dose levels.
In January 2020, we reported positive results from a Phase 2 clinical study in patients with hypertriglyceridemia and at high risk of or with established CVD. Olezarsen achieved statistically significant, dose-dependent reductions in fasting triglycerides compared to placebo at all dose levels. Olezarsen also achieved statistical significance in numerous key secondary endpoints, including significant reductions in apoC-III.
After receiving positive data from the Phase 2 clinical study of IONIS-FB-L Rx in patients with IgAN, Roche licensed IONIS-FB-L Rx in July 2022.
After positive data from a Phase 2 clinical study in patients with IgAN, Roche licensed IONIS-FB-L Rx in 2022.
The Phase 2 study is a multi-center, randomized, double-blind, placebo-controlled clinical study in approximately 160 patients designed to assess the efficacy, safety and tolerability of multiple subcutaneous doses of ION224 on NASH histologic improvement.
In June 2021, we initiated a Phase 2 study of ION224 in patients with confirmed non-alcoholic steatohepatitis. The Phase 2 study is a multi-center, randomized, double-blind, placebo-controlled clinical study in approximately 160 patients designed to assess the efficacy, safety and tolerability of multiple subcutaneous doses of ION224 on NASH histologic improvement.
In 2021, we began selling TEGSEDI in the U.S., Canada and Europe through our distribution agreement with Sobi. In Latin America, PTC is commercializing TEGSEDI in Brazil and is pursuing access in additional Latin American countries through its exclusive license agreement with us.
In 2021, we began selling TEGSEDI in the U.S., Canada and Europe through our distribution agreement with Sobi. Refer to the section titled, Overview , for further details on our distribution agreement with Sobi. In Latin America, PTC is commercializing TEGSEDI in Brazil and is pursuing access in additional Latin American countries through its exclusive license agreement with us.
Title Expiration Description of Claims United States 10,266,822 SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES 2025 Methods of increasing exon-7 containing SMN2 mRNA in a cell using an oligonucleotide having the sequence of SPINRAZA United States 8,110,560 SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES 2025 Methods of using antisense oligonucleotides having sequence of SPINRAZA to alter splicing of SMN2 and/or to treat SMA Europe 1910395 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING 2026 Sequence and chemistry (full 2’-MOE) of SPINRAZA Europe 3308788 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING 2026 Pharmaceutical compositions that include SPINRAZA United States 7,838,657 SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES 2027 Oligonucleotides having sequence of SPINRAZA United States 8,361,977 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING 2030 Sequence and chemistry (full 2’-MOE) of SPINRAZA United States 8,980,853 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2030 Methods of administering SPINRAZA United States 9,717,750 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2030 Methods of administering SPINRAZA to a patient Europe 3449926 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2030 Pharmaceutical compositions that include SPINRAZA for treating SMA Europe 3305302 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2030 Antisense compounds including SPINRAZA for treating SMA United States 9,926,559 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2034 SPINRAZA doses for treating SMA United States 10,436,802 METHODS FOR TREATING SPINAL MUSCULAR ATROPHY 2035 SPINRAZA dosing regimen for treating SMA 30 TEGSEDI and Transthyretin We believe TEGSEDI is protected from generic competition in the U.S. and Europe until at least 2031.
Title Expiration Description of Claims United States 10,266,822 SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES 2025 Methods of increasing exon-7 containing SMN2 mRNA in a cell using an oligonucleotide having the sequence of SPINRAZA United States 8,110,560 SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES 2025 Methods of using antisense oligonucleotides having sequence of SPINRAZA to alter splicing of SMN2 and/or to treat SMA Europe 1910395 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING 2026 Sequence and chemistry (full 2’-MOE) of SPINRAZA Europe 3308788 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING 2026 Pharmaceutical compositions that include SPINRAZA United States 7,838,657 SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES 2027 Oligonucleotides having sequence of SPINRAZA United States 8,361,977 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING 2030 Sequence and chemistry (full 2’-MOE) of SPINRAZA United States 8,980,853 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2030 Methods of administering SPINRAZA United States 9,717,750 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2030 Methods of administering SPINRAZA to a patient Europe 3449926 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2030 Pharmaceutical compositions that include SPINRAZA for treating SMA Europe 3305302 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2030 Antisense compounds including SPINRAZA for treating SMA United States 9,926,559 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2034 SPINRAZA doses for treating SMA United States 10,436,802 METHODS FOR TREATING SPINAL MUSCULAR ATROPHY 2035 SPINRAZA dosing regimen for treating SMA 30 Table of Contents Trademarks The name “SPINRAZA” is protected throughout the world by trademarks owned by our commercial partner Biogen.
Tominersen (HTT) ( RG6042 ) – Tominersen (formerly IONIS-HTT Rx ) is an investigational antisense medicine we designed to target the underlying cause of Huntington’s disease, or HD, by reducing the production of all forms of the huntingtin protein, or HTT, including its mutated variant, or mHTT.
ION582 is being developed under our 2012 Neurology collaboration with Biogen. Tominersen (HTT) ( RG6042 ) – Tominersen (formerly IONIS-HTT Rx ) is an investigational antisense medicine we designed to target the underlying cause of Huntington’s disease, or HD, by reducing the production of all forms of the huntingtin protein, or HTT, including its mutated variant, or mHTT.
Our multiple sources of revenue and strong balance sheet enable us to continue investing in our commercial readiness efforts for multiple late-stage programs and our innovative pipeline. By continuing to focus on these priorities, we believe we are well positioned to drive future growth and to deliver increasing value for patients and shareholders.
Our multiple sources of revenue and capital structure enable us to continue investing in our commercial readiness efforts for multiple late-stage programs, our innovative pipeline and our technology. By continuing to focus on these priorities, we believe we are well positioned to drive future growth and to bring next-level value to patients and shareholders.
AstraZeneca is currently responsible for 55 percent of the costs associated with the ongoing global Phase 3 development program. AstraZeneca is responsible for the majority of the commercial and medical affairs costs in the U.S. and all costs associated with bringing eplontersen to market outside the U.S.
The collaboration includes territory-specific development, commercial and medical affairs cost-sharing provisions. AstraZeneca is currently responsible for 55 percent of the costs associated with the ongoing global Phase 3 development program. AstraZeneca is responsible for the majority of the commercial and medical affairs costs in the U.S. and all costs associated with bringing WAINUA to market outside the U.S.
We have filed for patent term extension, to potentially extend the term beyond 2030. With Biogen’s license of SPINRAZA, we assigned our interest in these patents to Biogen. The table below lists some key issued patents protecting SPINRAZA in the U.S. and Europe: Jurisdiction Patent No.
With Biogen’s license of SPINRAZA, we assigned our interest in these patents to Biogen. The table below lists some key issued patents protecting SPINRAZA in the U.S. and Europe: Jurisdiction Patent No.
In Latin America, PTC Therapeutics International Limited, or PTC, is commercializing TEGSEDI in Brazil and is pursuing access in additional Latin American countries through its exclusive license agreement with us. 4 WAYLIVRA is a once weekly, self-administered, subcutaneous medicine that received conditional marketing authorization in May 2019 from the European Commission, or EC, as an adjunct to diet in adult patients with genetically confirmed familial chylomicronemia syndrome, or FCS, and at high risk for pancreatitis.
In Latin America, PTC Therapeutics International Limited, or PTC, is commercializing TEGSEDI in Brazil and is pursuing access in additional Latin American countries through its exclusive license agreement with us. 4 Table of Contents WAYLIVRA is a once weekly, self-administered, subcutaneous medicine approved in Europe and Brazil as an adjunct to diet in adult patients with genetically confirmed familial chylomicronemia syndrome, or FCS, and at high risk for pancreatitis.
The first patient was treated in the ASCEND study in the first quarter of 2022. Additionally, Biogen continues to conduct the Phase 2 NURTURE study, an open-label study investigating the benefit of SPINRAZA when administered before symptom onset in patients genetically diagnosed with SMA, and likely to develop Type 1 or Type 2 SMA.
Additionally, Biogen continues to conduct the Phase 2 NURTURE study, an open-label study investigating the benefit of SPINRAZA when administered before symptom onset in patients genetically diagnosed with SMA, and likely to develop Type 1 or Type 2 SMA. NURTURE was the first study to investigate the potential to slow or stop SMA disease progression in presymptomatic SMA patients.
The Phase 3 trial of ION363 is a global, multi-center, randomized, double-blind, placebo-controlled study in approximately 75 patients designed to assess the efficacy, safety and tolerability of ION363.
In April 2021, we initiated a Phase 3 study of ulefnersen in patients with FUS-ALS. The Phase 3 trial of ulefnersen is a global, multi-center, randomized, double-blind, placebo-controlled study in approximately 75 patients designed to assess the efficacy, safety and tolerability of ulefnersen.
In 2019, following positive Phase 2 results, GSK licensed our HBV program. GSK is responsible for all global development, regulatory and commercialization activities and costs for the HBV program.
Under our collaboration, GSK is developing bepirovirsen for the treatment of chronic HBV infection. In 2019, following positive Phase 2 results, GSK licensed our HBV program. GSK is responsible for all global development, regulatory and commercialization activities and costs for the HBV program.
We are also eligible to receive tiered royalties in the mid-teens to low 20 percent range on net sales of pelacarsen. From inception through December 31, 2022, w e have generated nearly $275 million in payments under this collaboration. In conjunction with this collaboration, we entered into a SPA with Novartis.
We are also eligible to receive tiered royalties in the mid-teens to low 20 percent range on net sales of pelacarsen . From inception through December 31, 2023, w e have generated more than $275 million in payments under this collaboration.

… 424 more changes not shown on this page.

Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

122 edited+31 added−32 removed95 unchanged
Biggest changeThe failure of these third parties to carry out their obligations, including as a result of delays or disruptions caused by the COVID-19 pandemic, or a termination of our relationship with such third parties, could delay or prevent the development, marketing authorization and commercialization of our medicines or additional marketing authorizations for TEGSEDI and WAYLIVRA. 49 In addition, while we do not have any clinical trial sites in Ukraine, we do have a limited number of clinical trial sites in Russia and surrounding countries that may be impacted by the ongoing war between Russia and Ukraine and could result in difficulties enrolling or completing our clinical trials in such areas on schedule.
Biggest changeIn addition, while we do not have any clinical trial sites in Ukraine or Gaza, we do have a limited number of clinical trial sites in Russia and Israel that may be materially impacted by the ongoing wars between Russia and Ukraine and military conflicts in Israel and the surrounding areas, as well as related political or economic responses and counter-responses by various global actors, or collectively, conflicts in Eastern Europe and the Middle East, and could result in difficulties enrolling or completing our clinical trials in such areas on schedule.
For example, a collaborator such as AstraZeneca, Biogen, GSK, Novartis, or Roche, could determine that it is in its financial interest to: ● pursue alternative technologies or develop alternative products that may be competitive with the medicine that is part of the collaboration with us; ● pursue higher-priority programs or change the focus of its own development programs; or ● choose to devote fewer resources to our medicines than it does to its own medicines.
For example, a collaborator such as AstraZeneca, Biogen, GSK, Novartis, Otsuka or Roche, could determine that it is in its financial interest to: ● pursue alternative technologies or develop alternative products that may be competitive with the medicine that is part of the collaboration with us; ● pursue higher-priority programs or change the focus of its own development programs; or ● choose to devote fewer resources to our medicines than it does to its own medicines.
Once we have secured a collaborative arrangement to further develop and commercialize one of our drug development programs, such as our collaborations with AstraZeneca, Biogen, GSK, Novartis, and Roche, these collaborations may not continue or result in commercialized medicines, or may not progress as quickly as we anticipated.
Once we have secured a collaborative arrangement to further develop and commercialize one of our drug development programs, such as our collaborations with AstraZeneca, Biogen, GSK, Novartis, Otsuka and Roche, these collaborations may not continue or result in commercialized medicines, or may not progress as quickly as we anticipated.
We currently rely on third parties for the commercialization of our marketed medicines, have limited experience as a company in commercializing medicines and we will have to invest significant financial and management resources to develop the infrastructure required to successfully commercialize our medicines.
We currently rely on third parties for the commercialization of our marketed medicines, have limited experience as a company in commercializing medicines and will have to continue to invest significant financial and management resources to develop the infrastructure required to successfully commercialize our medicines.
In December 2019, we entered into privately negotiated exchange and/or subscription agreements with certain new investors and certain holders of our existing 1% Notes to exchange $375.6 million of our 1% Notes for $439.3 million of our 0.125% Notes, and to issue $109.5 million of our 0.125% Notes.
In 2019, we entered into privately negotiated exchange and/or subscription agreements with certain new investors and certain holders of our existing 1% Notes to exchange $375.6 million of our 1% Notes for $439.3 million of our 0.125% Notes, and to issue $109.5 million of our 0.125% Notes.
Provisions in our certificate of incorporation, convertible notes documents, call spread hedge transaction documents and Delaware law may prevent stockholders from receiving a premium for their shares. Our certificate of incorporation provides for classified terms for the members of our board of directors.
Provisions in our certificate of incorporation, bylaws, convertible notes documents, call spread hedge transaction documents and Delaware law may prevent stockholders from receiving a premium for their shares. Our certificate of incorporation provides for classified terms for the members of our board of directors.
In April 2021, we completed a $632.5 million offering of 0% Notes and used a portion of the net proceeds from the issuance of the 0% Notes to repurchase $247.9 million of our 1% Notes for $257.0 million.
In 2021, we completed a $632.5 million offering of 0% Notes and used a portion of the net proceeds from the issuance of the 0% Notes to repurchase $247.9 million of our 1% Notes for $257.0 million.
If we or others identify side effects after any of our medicines are on the market, or if manufacturing problems occur subsequent to regulatory approval, or if we, our manufacturers or our partners fail to comply with regulatory requirements, we or our partners may, among other things, lose regulatory approval and be forced to withdraw products from the market, need to conduct additional clinical studies, incur restrictions on the marketing, distribution or manufacturing of the product, and/or change the labeling of our medicines.
If we or others identify side effects after any of our medicines are on the market, or if manufacturing problems occur subsequent to regulatory approval, or if we, our CMOs or our partners fail to comply with regulatory requirements, we or our partners may, among other things, lose regulatory approval and be forced to withdraw products from the market, need to conduct additional clinical studies, incur restrictions on the marketing, distribution or manufacturing of the product, and/or change the labeling of our medicines.
Our facilities or those of our partners or contract manufacturers may be harmed by natural disasters or other events outside our control, such as earthquakes, war, civil or political unrest, deliberate acts of sabotage, terrorism or industrial accidents such as fire and explosion, whether due to human or equipment error, and if such facilities are affected by a disaster or other event, our development and commercialization efforts would be delayed.
Our facilities or those of our partners or contract manufacturers may be harmed by natural disasters or other events outside our control, such as earthquakes, wars, civil or political unrest, deliberate acts of sabotage, terrorism or industrial accidents such as fire and explosion, whether due to human or equipment error, and if such facilities are affected by a disaster or other event, our development and commercialization efforts would be delayed.
Risks Related to the Commercialization of our Medicines We have limited experience as a company in commercializing medicines and we will have to invest significant resources to develop our capabilities.
Risks Related to the Commercialization of our Medicines We have limited experience as a company in commercializing medicines and we will have to continue to invest significant resources to develop our capabilities.
In addition, only our board of directors, chairman of the board or chief executive officer can call special meetings of our stockholders. We have in the past, and may in the future, implement a stockholders’ rights plan, also called a poison pill, which could make it uneconomical for a third party to acquire our company on a hostile basis.
In addition, only our board of directors, chairperson of the board or chief executive officer can call special meetings of our stockholders. We have in the past, and may in the future, implement a stockholders’ rights plan, also called a poison pill, which could make it uneconomical for a third party to acquire our company on a hostile basis.
Future sales of substantial amounts of our common stock in the public market, or the perception that such sales could occur, could adversely affect trading prices of our securities.
Future sales of our common stock in the public market could adversely affect the trading price of our securities. Future sales of substantial amounts of our common stock in the public market, or the perception that such sales could occur, could adversely affect trading prices of our securities.
We will also need to scale-up existing internal support functions to aid our commercialization efforts, in particular, regulatory affairs and medical affairs.
We will also need to continue to scale-up existing internal support functions to aid our commercialization efforts, in particular, regulatory affairs and medical affairs.
However, the warrant transactions could separately have a dilutive effect to the extent that the market value per share of our common stock exceeds the applicable strike price of the warrants. Negative conditions in the global credit markets and financial services and other industries may adversely affect our business.
However, the warrant transactions could separately have a dilutive effect to the extent that the market value per share of our common stock exceeds the applicable strike price of the warrants. Negative conditions in the global credit markets and financial services and other industries may adversely affect our business, financial condition or stock price.
We also do not have control over the amount and timing of resources that AstraZeneca devotes to our collaboration, particularly outside of the U.S. If the co-commercialization arrangement for eplontersen is not successful for any reason, eplontersen may not meet our commercial objectives and our revenues for eplontersen may be limited.
We also do not have control over the amount and timing of resources that AstraZeneca devotes to our collaboration, particularly outside of the U.S. If the co-commercialization arrangement for WAINUA is not successful for any reason, WAINUA may not meet our commercial objectives and our revenues for WAINUA may be limited.
For example, in October 2021, Biogen reported that tofersen did not meet the primary clinical endpoint in the Phase 3 VALOR study; however, trends favoring tofersen were seen across multiple secondary and exploratory measures of disease activity and clinical function.
For example, in October 2021, Biogen reported that QALSODY did not meet the primary clinical endpoint in the Phase 3 VALOR study; however, trends favoring QALSODY were seen across multiple secondary and exploratory measures of disease activity and clinical function.
In addition, a Joint Steering Committee, or JSC, having equal membership from us and AstraZeneca, and various subcommittees oversee and coordinate the development, manufacturing, commercialization and other exploitation activities for eplontersen in the U.S. by mutual agreement.
In addition, a Joint Steering Committee, or JSC, having equal membership from us and AstraZeneca, and various subcommittees oversee and coordinate the development, manufacturing, commercialization and other exploitation activities for WAINUA in the U.S. by mutual agreement.
Thus, whether or not we are insured, a product liability claim or product recall may result in losses that could be material. Risks related to our personnel The loss of key personnel, or the inability to attract and retain highly skilled personnel, could make it more difficult to run our business and reduce our likelihood of success.
Thus, whether or not we are insured, a product liability claim or product recall may result in losses that could be material. 59 Table of Contents Risks related to our personnel The loss of key personnel, or the inability to attract and retain highly skilled personnel, could make it more difficult to run our business and reduce our likelihood of success.
If we lose orphan drug exclusivity on any of our medicines, we may face increased competition and lose market share for such medicine. Risks Associated with our Businesses as a Whole Risks related to our financial condition If we fail to obtain timely funding, we may need to curtail or abandon some of our programs.
If we lose orphan drug exclusivity on any of our medicines, we may face increased competition and lose market share for such medicine. 57 Table of Contents Risks Associated with our Businesses as a Whole Risks related to our financial condition If we fail to obtain timely funding, we may need to curtail or abandon some of our programs.
A security breach or privacy violation that leads to disclosure or modification of or prevents access to patient information, including personally identifiable information or protected health information, could harm our reputation, compel us to comply with federal and state breach notification laws and foreign law equivalents, subject us to financial penalties and mandatory and costly corrective action, require us to verify the correctness of database contents and otherwise subject us to litigation or other liability under laws and regulations that protect personal data, any of which could disrupt our business and result in increased costs or loss of revenue.
A security breach or privacy violation that leads to disclosure or modification of or prevents access to patient information, including personally identifiable information or protected health information, could harm our reputation, delay progress on the development of our medicines, compel us to comply with federal and state breach notification laws and foreign law equivalents, subject us to financial penalties and mandatory and costly corrective action, require us to verify the correctness of database contents and otherwise subject us to litigation or other liability under laws and regulations that protect personal data, any of which could disrupt our business and result in increased costs or loss of revenue.
Because we have international operations, we are subject to numerous risks associated with international business activities, including: ● compliance with differing or unexpected regulatory requirements for our medicines and foreign employees; ● complexities associated with managing multiple payer reimbursement regimes, government payers or patient self-pay systems; ● difficulties in staffing and managing foreign operations; ● in certain circumstances, increased dependence on the commercialization efforts and regulatory compliance of third-party distributors or strategic partners; ● foreign government taxes, regulations and permit requirements; ● U.S. and foreign government tariffs, trade restrictions, price and exchange controls and other regulatory requirements; ● anti-corruption laws, including the Foreign Corrupt Practices Act, or the FCPA, and its equivalent in foreign jurisdictions; ● economic weakness, including inflation, natural disasters, war, events of terrorism, political instability or public health issues or pandemics, such as the COVID-19 pandemic, in particular foreign countries or globally; ● fluctuations in currency exchange rates, which could result in increased operating expenses and reduced revenue, and other obligations related to doing business in another country; ● compliance with tax, employment, privacy, immigration and labor laws, regulations and restrictions for employees living or traveling abroad; ● workforce uncertainty in countries where labor unrest is more common than in the U.S.; and ● changes in diplomatic and trade relationships. 56 Our business activities outside of the U.S. are subject to the FCPA and similar anti-bribery or anti-corruption laws, regulations or rules of other countries in which we operate, including the United Kingdom’s Bribery Act 2010.
Because we have international operations, we are subject to numerous risks associated with international business activities, including : ● compliance with differing or unexpected regulatory requirements for our medicines and foreign employees; ● complexities associated with managing multiple payer reimbursement regimes, government payers or patient self-pay systems; ● difficulties in staffing and managing foreign operations; ● in certain circumstances, increased dependence on the commercialization efforts and regulatory compliance of third-party distributors or strategic partners; ● foreign government taxes, regulations and permit requirements; ● U.S. and foreign government tariffs, trade and export restrictions, price and exchange controls and other regulatory requirements; ● anti-corruption laws, including the Foreign Corrupt Practices Act, or the FCPA, and its equivalent in foreign jurisdictions; ● economic weakness, including inflation, natural disasters, war, events of terrorism, political instability or public health issues or pandemics, in particular foreign countries or globally; ● fluctuations in currency exchange rates, which could result in increased operating expenses and reduced revenue, and other obligations related to doing business in another country; ● compliance with tax, employment, privacy, immigration and labor laws, regulations and restrictions for employees living or traveling abroad; ● workforce uncertainty in countries where labor unrest is more common than in the U.S.; and ● changes in diplomatic and trade relationships. 63 Table of Contents Our business activities outside of the U.S. are subject to the FCPA and similar anti-bribery or anti-corruption laws, regulations or rules of other countries in which we operate, including the United Kingdom’s Bribery Act 2010.
Under the Internal Revenue Code of 1986, as amended, or the Code, a corporation is generally allowed a deduction for net operating losses, or NOLs, carried over from a prior taxable year. Under the Code, we can carryforward our NOLs to offset our future taxable income, if any, until such NOLs are used or expire.
Under the Internal Revenue Code of 1986, as amended, or the Code, a corporation is generally allowed a deduction for net operating losses, or NOLs, carried over from a prior taxable year. Under the Code, we can carry forward our NOLs to offset our future taxable income, if any, until such NOLs are used or expire.
From time to time, we have to defend our intellectual property rights. If we are involved in an intellectual property dispute, we may need to litigate to defend our rights or assert them against others. Disputes can involve arbitration, litigation or proceedings declared by the U.S. PTO or the International Trade Commission or foreign patent authorities.
If we are involved in an intellectual property dispute, we may need to litigate to defend our rights or assert them against others. Disputes can involve arbitration, litigation or proceedings declared by the U.S. PTO or the International Trade Commission or foreign patent authorities.
Stockholder activism, the current political environment and the current high level of government intervention and regulatory reform may lead to substantial new regulations and disclosure obligations, which has and may in the future lead to additional compliance costs and impact the manner in which we operate our business. 57 Risks related to taxes Our ability to use our net operating loss carryovers and certain other tax attributes may be limited.
Stockholder activism, the current political environment and the current high level of government intervention and regulatory reform may lead to substantial new regulations and disclosure obligations, which has and may in the future lead to additional compliance costs and impact the manner in which we operate our business. 64 Table of Contents Risks related to taxes Our ability to use our net operating loss carryovers and certain other tax attributes may be limited.
Our business exposes us to potential product liability risks that are inherent in the testing, manufacturing, marketing and sale of therapeutic products, including potential product liability claims related to SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in development. We have clinical study insurance coverage and commercial product liability insurance coverage.
Our business exposes us to potential product liability risks that are inherent in the testing, manufacturing, marketing and sale of therapeutic products, including potential product liability claims related to our commercial medicines and our medicines in development. We have clinical study insurance coverage and commercial product liability insurance coverage.
Additionally, our insurance carriers and insurance policies covering all aspects of our business may become financially unstable or may not be sufficient to cover any or all of our losses and may not continue to be available to us on acceptable terms, or at all.
In addition, our insurance carriers and insurance policies covering all aspects of our business may become financially unstable or may not be sufficient to cover any or all of our losses and may not continue to be available to us on acceptable terms, or at all.
In addition, pursuant to the call spread transactions we entered into in connection with the pricing of our 0% Notes and 0.125% Notes, the counterparties are likely to modify their hedge positions from time to time at or prior to the conversion or maturity of the notes by purchasing and selling shares of our common stock, other of our securities, or other instruments, including over-the-counter derivative instruments, that they may wish to use in connection with such hedging, which may have a negative effect on the conversion value of those notes and an adverse impact on the trading price of our common stock.
The addition of any of these shares into the public market may have an adverse effect on the price of our securities. 62 Table of Contents In addition, pursuant to the call spread transactions we entered into in connection with the pricing of our 0% Notes and 0.125% Notes, the counterparties are likely to modify their hedge positions from time to time at or prior to the conversion or maturity of the notes by purchasing and selling shares of our common stock, other of our securities, or other instruments, including over-the-counter derivative instruments, that they may wish to use in connection with such hedging, which may have a negative effect on the conversion value of those notes and an adverse impact on the trading price of our common stock.
Biogen has disclosed that SPINRAZA revenue has decreased primarily due to a reduction in demand as a result of increased competition and that future sales of SPINRAZA may be adversely affected by competing products.
Biogen has in the past disclosed that SPINRAZA revenue decreased due to a reduction in demand as a result of increased competition and that future sales of SPINRAZA may be adversely affected by competing products.
The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.
The FDA and other regulatory authorities actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.
For example: ● in the U.S., TEGSEDI’s label contains a boxed warning for thrombocytopenia and glomerulonephritis; ● TEGSEDI requires periodic blood and urine monitoring; and ● in the U.S., TEGSEDI is available only through a REMS program. Prescription medicines may be promoted only for the approved indication(s) in accordance with the approved label.
For example: ● in the U.S., TEGSEDI’s label contains a boxed warning for thrombocytopenia and glomerulonephritis; ● TEGSEDI requires periodic blood and urine monitoring; and ● in the U.S., TEGSEDI is available only through a REMS program. 52 Table of Contents Prescription medicines may be promoted only for the approved indication(s) in accordance with the approved label.
Failure to receive marketing authorization for our medicines, or failure to receive additional marketing authorizations for SPINRAZA, TEGSEDI or WAYLIVRA, or delays in these authorizations, could prevent or delay commercial introduction of the medicine, and, as a result, could negatively impact our ability to generate revenue from product sales.
Failure to receive marketing authorization for our medicines in development, or failure to receive additional marketing authorizations for our commercial medicines, or delays in these authorizations, could prevent or delay commercial introduction of the medicine, and, as a result, could negatively impact our ability to generate revenue from product sales.
The degree of market acceptance for our medicines, including SPINRAZA, TEGSEDI, WAYLIVRA, eplontersen and tofersen, and our medicines in development, depends upon a number of factors, including the: ● receipt and scope of marketing authorizations; ● establishment and demonstration in the medical and patient community of the efficacy and safety of our medicines and their potential advantages over competing products; ● cost and effectiveness of our medicines compared to other available therapies; ● patient convenience of the dosing regimen for our medicines; and ● reimbursement policies of government and third-party payers.
The degree of market acceptance for our medicines, including our commercial medicines and our medicines in development, depends upon a number of factors, including the: ● receipt and scope of marketing authorizations; ● establishment and demonstration in the medical and patient community of the efficacy and safety of our medicines and their potential advantages over competing products; ● cost and effectiveness of our medicines compared to other available therapies; ● patient convenience of the dosing regimen for our medicines; and ● reimbursement policies of government and third-party payers.
We are relying on Biogen to obtain additional regulatory approvals for SPINRAZA, generate additional clinical data for SPINRAZA, manufacture, and continue to successfully commercialize SPINRAZA. In general, we cannot control the amount and timing of resources that Biogen devotes to our collaboration.
We are relying on Biogen to obtain additional regulatory approvals for SPINRAZA and QALSODY, generate additional clinical data for SPINRAZA and QALSODY, manufacture SPINRAZA and QALSODY, and successfully commercialize SPINRAZA and QALSODY. In general, we cannot control the amount and timing of resources that Biogen devotes to our collaborations.
Third-party coverage and reimbursement for medicines may not be available or adequate in either the U.S. or international markets, which would negatively affect the potential commercial success of our products, our revenue and our profits. 44 If we or our partners fail to compete effectively, our medicines, including SPINRAZA, TEGSEDI, WAYLIVRA, eplontersen and tofersen, and our medicines in development, will not generate significant revenues.
Third-party coverage and reimbursement for medicines may not be available or adequate in either the U.S. or international markets, which would negatively affect the potential commercial success of our products, our revenue and our profits. If we or our partners fail to compete effectively, our medicines, including our commercial medicines and our medicines in development, will not generate significant revenues.
We or our partners may need to conduct post-marketing studies to demonstrate the cost-effectiveness of any future products to satisfy third-party payers. These studies might require us to commit a significant amount of management time and financial and other resources. Third-party payers may never consider our future products as cost-effective.
Furthermore, we or our partners may need to conduct post-marketing studies to demonstrate the cost-effectiveness of any future products to satisfy third-party payers. These studies might require us to commit a significant amount of management time and financial and other resources.
We may not be able to attract and retain skilled and experienced scientific personnel on acceptable terms because of intense competition for experienced scientists among many pharmaceutical and health care companies, universities and non-profit research institutions. In addition, failure to succeed in clinical studies may make it more challenging to recruit and retain qualified scientific personnel .
We may not be able to attract and retain skilled and experienced personnel on acceptable terms because of intense competition for experienced personnel among many pharmaceutical and health care companies, universities and non-profit research institutions. In addition, failure to succeed in clinical studies or in commercializing our medicines may make it more challenging to recruit and retain qualified personnel .
We cannot guarantee that any of our medicines will be considered safe and effective or will be approved for commercialization. In addition, it is possible that SPINRAZA, TEGSEDI and WAYLIVRA may not be approved in additional markets or for additional indications.
We cannot guarantee that any of our medicines will be considered safe and effective or will be approved for commercialization. In addition, it is possible that our commercial medicines may not be approved in additional markets or for additional indications.
Risks related to cybersecurity We are dependent on information technology systems, infrastructure and data, which exposes us to data security risks. We are dependent upon our own and third-party information technology systems, infrastructure and data, including mobile technologies, to operate our business.
Risks related to cybersecurity, social media and artificial intelligence We are dependent on information technology systems, infrastructure and data, which exposes us to data security risks. We are dependent upon our own and third-party information technology systems, infrastructure and data, including mobile technologies, to operate our business.
If the JSC cannot come to a mutual agreement on any particular matter, this could delay our ability to develop or commercialize eplontersen. 46 If we are not successful in expanding our manufacturing capabilities or cannot manufacture our medicines or contract with a third party to manufacture our medicines at costs that allow us to charge competitive prices to buyers, we cannot market our products profitably.
If the JSC cannot come to a mutual agreement on any particular matter, this could delay our ability to develop or commercialize WAINUA. 53 Table of Contents If we are not successful in expanding our manufacturing capabilities or cannot manufacture our medicines or contract with a third party to manufacture our medicines at costs that allow us to charge competitive prices to buyers, we cannot market our products profitably.
If the FDA or another regulatory agency believes that we or our partners have not sufficiently demonstrated the safety or efficacy of any of our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, or our medicines in development, the agency will not approve the specific medicine or will require additional studies, which could be time consuming and expensive and delay or harm commercialization of the medicine.
If the FDA or another regulatory authority believes that we or our partners have not sufficiently demonstrated the safety or efficacy of any of our medicines, including our commercial medicines or our medicines in development, the authority will not approve the specific medicine or will require additional studies, which could be time consuming and expensive and delay or harm commercialization of the medicine.
Our future capital requirements will depend on many factors such as: ● successful commercialization of SPINRAZA, TEGSEDI and WAYLIVRA; ● the profile and launch timing of our medicines, including donidalorsen, eplontersen, ION363, olezarsen, pelacarsen and tofersen; ● changes in existing collaborative relationships and our ability to establish and maintain additional collaborative arrangements; ● continued scientific progress in our research, drug discovery and development programs; ● the size of our programs and progress with preclinical and clinical studies; ● the time and costs involved in obtaining marketing authorizations; ● competing technological and market developments, including the introduction by others of new therapies that address our markets; and ● our manufacturing requirements and capacity to fulfill such requirements.
Our future capital requirements will depend on many factors such as: ● successful commercialization of our commercial medicines; ● the profile and launch timing of our medicines in development; ● changes in existing collaborative relationships and our ability to establish and maintain additional collaborative arrangements; ● continued scientific progress in our research, drug discovery and development programs; ● the size of our programs and progress with preclinical and clinical studies; ● the time and costs involved in obtaining marketing authorizations; ● competing technological and market developments, including the introduction by others of new therapies that address our markets; and ● our manufacturing requirements and capacity to fulfill such requirements.
Risks Related to the Development and Regulatory Approval of our Medicines If we or our partners fail to obtain regulatory approval for our medicines and additional approvals for SPINRAZA, TEGSEDI and WAYLIVRA, we or our partners cannot sell them in the applicable markets.
Risks Related to the Development and Regulatory Approval of our Medicines If we or our partners fail to obtain regulatory approval for our medicines and additional approvals for our commercial medicines, we or our partners cannot sell them in the applicable markets.
Although we believe our tax estimates are reasonable, the final determination of any tax audits or litigation could be materially different from our historical tax provisions and accruals, which could have a material adverse effect on our operating results or cash flows in the period for which a determination is made.
Although we believe our tax estimates are reasonable, the final determination of any tax audits or litigation could be materially different from our historical tax provisions and accruals, which could have a material adverse effect on our operating results or cash flows in the period for which a determination is made . Item 1B. Unresolved Staff Comments Not applicable.
Non-compliance could significantly delay or prevent receipt of marketing authorizations for our medicines, including authorizations for SPINRAZA, TEGSEDI, WAYLIVRA, eplontersen and tofersen, and our medicines in development, or could result in enforcement action after authorization that might limit the commercial success of our medicines, including SPINRAZA, TEGSEDI, WAYLIVRA, eplontersen and tofersen, and our medicines in development.
Non-compliance could significantly delay or prevent receipt of marketing authorizations for our medicines, including authorizations for our commercial medicines and our medicines in development, or could result in enforcement action after authorization that might limit the commercial success of our medicines, including our commercial medicines and our medicines in development.
We or our partners may not obtain the labeling claims necessary or desirable to successfully commercialize our medicines, including SPINRAZA, TEGSEDI, WAYLIVRA, eplontersen and tofersen, and our medicines in development. 45 The FDA and foreign regulatory bodies have the authority to impose significant restrictions on an approved medicine through the product label and on advertising, promotional and distribution activities.
We or our partners may not obtain the labeling claims necessary or desirable to successfully commercialize our medicines, including our commercial medicines and our medicines in development. The FDA and foreign regulatory bodies have the authority to impose significant restrictions on an approved medicine through the product label and on advertising, promotional and distribution activities.
If any of our medicines in Phase 3 clinical studies, including the studies of donidalorsen, eplontersen , ION363, olezarsen, pelacarsen and tofersen, do not show sufficient efficacy in patients with the targeted indication, or if such studies are discontinued for any other reason, it could negatively impact our development and commercialization goals for these medicines and our stock price could decline.
If any of our medicines in Phase 3 clinical studies do not show sufficient efficacy in patients with the targeted indication, or if such studies are discontinued for any other reason, it could negatively impact our development and commercialization goals for these medicines and our stock price could decline.
There is no certainty that all employees and third-party business partners (including our distributors, wholesalers, agents, contractors and other partners) will comply with anti-bribery laws. In particular, we do not control the actions of manufacturers and other third-party agents, although we may be liable for their actions.
There is no certainty that all employees and third-party business partners (including our contract research organizations, contract manufacturing organizations, distributors, wholesalers, agents, contractors and other partners) will comply with anti-bribery laws. Importantly, we do not control the actions of manufacturers and other third-party agents, although we may be liable for their actions.
Even if favorable coverage status and adequate reimbursement rates are attained, less favorable coverage policies and reimbursement rates may be implemented in the future. Accordingly, SPINRAZA, TEGSEDI, WAYLIVRA, eplontersen and tofersen, and our medicines in development, will face competition from other therapies and medicines for limited financial resources.
Even if favorable coverage status and adequate reimbursement rates are attained, less favorable coverage policies and reimbursement rates may be implemented in the future. Accordingly, our commercial medicines and our medicines in development will face competition from other therapies and medicines for limited financial resources.
If Biogen fails to further develop SPINRAZA, obtain additional regulatory approvals for SPINRAZA, manufacture or continue to successfully commercialize SPINRAZA, or if Biogen’s efforts in any of these respects are ineffective, revenues for SPINRAZA would be negatively affected. In addition, our collaboration with Biogen may not continue for various reasons. Biogen can terminate our collaboration at any time.
If Biogen fails to further develop SPINRAZA or QALSODY, obtain additional regulatory approvals for SPINRAZA or QALSODY, manufacture SPINRAZA or QALSODY, or successfully commercialize SPINRAZA or QALSODY, or if Biogen’s efforts in any of these respects are ineffective, revenues for SPINRAZA or QALSODY would be negatively affected. In addition, our collaborations with Biogen may not continue for various reasons.
We cannot be certain that the U.S. Patent and Trademark Office, or U.S. PTO, and courts in the U.S. or the patent offices and courts in foreign countries will consider the claims in our patents and applications covering SPINRAZA, TEGSEDI, WAYLIVRA, eplontersen and tofersen, or any of our medicines in development as patentable.
We cannot be certain that the U.S. Patent and Trademark Office, or U.S. PTO, and courts in the U.S. or the patent offices and courts in foreign countries will consider the claims in our patents and applications covering our commercial medicines, or any of our medicines in development, as patentable.
As of December 31, 2022, we had cash, cash equivalents and short-term investments equal to $2.0 billion. If we or our partners do not meet our goals to successfully commercialize our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, or to license certain medicines and proprietary technologies, we will need additional funding in the future.
As of December 31, 2023, we had cash, cash equivalents and short-term investments equal to $2.3 billion. If we or our partners do not meet our goals to successfully commercialize our medicines, including our commercial medicines, or to license certain medicines and proprietary technologies, we will need additional funding in the future.
Many factors can affect the market price of our securities, including, for example, fluctuations in our operating results, announcements of collaborations, clinical study results, technological innovations or new products being developed by us or our competitors, the commercial success of our approved medicines, governmental regulation, marketing authorizations, changes in payers’ reimbursement policies, developments in patent or other proprietary rights and public concern regarding the safety of our medicines.
Many factors can affect the market price of our securities, including, for example, fluctuations in our operating results, announcements of collaborations, clinical study results, technological innovations or new products being developed by us or our competitors, the commercial success of our approved medicines, governmental regulation, marketing authorizations, changes in payers’ reimbursement policies, developments in patent or other proprietary rights and public concern regarding the safety of our medicines. 61 Table of Contents Broad market factors may materially harm the market price of our common stock irrespective of our operating performance.
This happened in connection with the conditional marketing approval for WAYLIVRA in the EU, as the EC is requiring us to conduct a post-authorization safety study to evaluate the safety of WAYLIVRA on thrombocytopenia and bleeding in FCS patients taking WAYLIVRA. We have ongoing post-marketing studies for WAYLIVRA and TEGSEDI and an EAP for WAYLIVRA.
This happened in connection with the conditional marketing approval for WAYLIVRA in the EU, as the EC is requiring us to conduct a post-authorization safety study to evaluate the safety of WAYLIVRA on thrombocytopenia and bleeding in FCS patients taking WAYLIVRA.
Competition may negatively impact a partner’s focus on and commitment to our medicines and, as a result, could delay or otherwise negatively affect the commercialization of our medicines, including SPINRAZA, TEGSEDI, WAYLIVRA, eplontersen and tofersen. Many of our competitors have substantially greater financial, technical and human resources than we do.
Competition may negatively impact a partner’s focus on and commitment to our medicines and, as a result, could delay or otherwise negatively affect the commercialization of our medicines, including our commercial medicines and our medicines in development. Many of our competitors have substantially greater financial, technical and human resources than we do.
In addition, as we commercialize more medicines on our own, we will need to invest significant financial resources to continue developing the infrastructure required to successfully commercialize our medicines, including the build-out of a new manufacturing facility. All of these activities will require significant cash.
In addition, as we commercialize more medicines on our own, we will need to invest significant financial resources to continue developing the infrastructure required to successfully commercialize our medicines, including the expansion of our manufacturing capabilities. All of these activities will require significant cash.
Additionally, in many of the markets where we or our partners may sell our medicines in the future, if we or our partners cannot agree with the government or other third-party payers regarding the price we can charge for our medicines, we may not be able to sell our medicines in that market.
Furthermore, we and our partners may not successfully commercialize additional medicines. 49 Table of Contents Additionally, in many of the markets where we or our partners may sell our medicines in the future, if we or our partners cannot agree with the government or other third-party payers regarding the price we can charge for our medicines, we may not be able to sell our medicines in that market.
These competitive developments could make our medicines, including SPINRAZA, TEGSEDI, WAYLIVRA, eplontersen and tofersen, and our medicines in development, obsolete or non-competitive. Certain of our partners are pursuing other technologies or developing other medicines either on their own or in collaboration with others, including our competitors, to treat some of the same diseases our own collaborative programs target.
These competitive developments could make our medicines, including our commercial medicines and our medicines in development, obsolete or non-competitive. 51 Table of Contents Certain of our partners are pursuing other technologies or developing other medicines either on their own or in collaboration with others, including our competitors, to treat some of the same diseases our own collaborative programs target.
Similar results could occur in clinical studies for our other medicines, including the studies of donidalorsen, eplontersen , ION363, olezarsen, pelacarsen and tofersen. 48 There are a number of factors that could cause a clinical study to fail or be delayed, including: ● the clinical study may produce negative or inconclusive results; ● regulators may require that we hold, suspend or terminate clinical research for noncompliance with regulatory requirements; ● we, our partners, the FDA or foreign regulatory authorities could suspend or terminate a clinical study due to adverse side effects of a medicine on subjects or lack of efficacy in the trial; ● we or our partners may decide, or regulators may require us, to conduct additional preclinical testing or clinical studies; ● enrollment in our clinical studies may be slower than we anticipate; ● we or our partners, including our independent clinical investigators, contract research organizations and other third-party service providers on which we rely, may not identify, recruit and train suitable clinical investigators at a sufficient number of study sites or timely enroll a sufficient number of study subjects in the clinical study; ● the institutional review board for a prospective site might withhold or delay its approval for the study; ● people who enroll in the clinical study may later drop out due to adverse events, a perception they are not benefiting from participating in the study, fatigue with the clinical study process or personal issues; ● a clinical study site may deviate from the protocol for the study; ● the cost of our clinical studies may be greater than we anticipate; ● our partners may decide not to exercise any existing options to license and conduct additional clinical studies for our medicines; and ● the supply or quality of our medicines or other materials necessary to conduct our clinical studies may be insufficient, inadequate or delayed.
There are a number of factors that could cause a clinical study to fail or be delayed, including: ● the clinical study may produce negative or inconclusive results; ● regulators may require that we hold, suspend or terminate clinical research for noncompliance with regulatory requirements; ● we, our partners, the FDA or foreign regulatory authorities could suspend or terminate a clinical study due to adverse side effects of a medicine on subjects or lack of efficacy in the trial; ● we or our partners may decide, or regulators may require us, to conduct additional preclinical testing or clinical studies; ● enrollment in our clinical studies may be slower than we anticipate; ● we or our partners, including our independent clinical investigators, contract research organizations and other third-party service providers on which we rely, may not identify, recruit or train suitable clinical investigators at a sufficient number of study sites or timely enroll a sufficient number of study subjects in the clinical study; ● the institutional review board for a prospective site might withhold or delay its approval for the study; ● people who enroll in the clinical study may later drop out due to adverse events, a perception they are not benefiting from participating in the study, fatigue with the clinical study process or personal issues; ● a clinical study site may deviate from the protocol for the study; ● the cost of our clinical studies may be greater than we anticipate; ● our partners may decide not to exercise any existing options to license and conduct additional clinical studies for our medicines; and ● the supply or quality of our medicines or other materials necessary to conduct our clinical studies may be insufficient, inadequate or delayed. 55 Table of Contents Further, the FDA or other regulatory authorities could request, among other things, additional information or commitments before we can start or continue a clinical study, protocol amendments, increased safety monitoring, additional product labeling information, and post-approval commitments.
In addition, in March 2021, Roche decided to discontinue dosing in the Phase 3 GENERATION HD1 study of tominersen in patients with manifest Huntington’s disease based on the results of a pre-planned review of data from the Phase 3 study conducted by an unblinded Independent Data Monitoring Committee.
In addition, in March 2021, Roche decided to discontinue dosing in the Phase 3 GENERATION HD1 study of tominersen in patients with manifest Huntington’s disease based on the results of a pre-planned review of data from the Phase 3 study conducted by an unblinded Independent Data Monitoring Committee. Similar results could occur in clinical studies for our other medicines.
The FDA or other comparable foreign regulatory authorities can delay, limit or deny approval of a medicine for many reasons, including: ● such authorities may disagree with the design or implementation of our clinical studies; ● we or our partners may be unable to demonstrate to the satisfaction of the FDA or other regulatory authorities that a medicine is safe and effective for any indication; ● such authorities may not accept clinical data from studies conducted at clinical facilities that have deficient clinical practices or that are in countries where the standard of care is potentially different from the U.S.; ● we or our partners may be unable to demonstrate that our medicine’s clinical and other benefits outweigh its safety risks to support approval; ● such authorities may disagree with the interpretation of data from preclinical or clinical studies; ● such authorities may find deficiencies in the manufacturing processes or facilities of third-party manufacturers who manufacture clinical and commercial supplies for our medicines, or may delay the inspection of such facilities due to restrictions related to the COVID-19 pandemic; and ● the approval policies or regulations of such authorities or their prior guidance to us or our partners during clinical development may significantly change in a manner rendering our clinical data insufficient for approval.
We also received a Notice of Non-Compliance Withdrawal Letter, or Non-W, from Health Canada for WAYLIVRA in November 2018. 54 Table of Contents The FDA or other comparable foreign regulatory authorities can delay, limit or deny approval of a medicine for many reasons, including: ● such authorities may disagree with the design or implementation of our clinical studies; ● we or our partners may be unable to demonstrate to the satisfaction of the FDA or other regulatory authorities that a medicine is safe and effective for any indication; ● such authorities may not accept clinical data from studies conducted at clinical facilities that have deficient clinical practices or that are in countries where the standard of care is potentially different from the U.S.; ● we or our partners may be unable to demonstrate that our medicine’s clinical and other benefits outweigh its safety risks to support approval; ● such authorities may disagree with the interpretation of data from preclinical or clinical studies; ● such authorities may find deficiencies in the manufacturing processes or facilities of third-party manufacturers who manufacture clinical and commercial supplies for our medicines; and ● the approval policies or regulations of such authorities or their prior guidance to us or our partners during clinical development may significantly change in a manner rendering our clinical data insufficient for approval.
Adequate third-party coverage and reimbursement might not be available to enable us to maintain price levels sufficient to realize an appropriate return on investment in product development. Third-party payers, whether foreign or domestic, or governmental or commercial, are developing increasingly sophisticated methods of controlling healthcare costs.
In addition, third-party payers may never consider our future products as cost-effective and adequate third-party coverage and reimbursement might not be available to enable us to maintain price levels sufficient to realize an appropriate return on investment in product development. Third-party payers, whether foreign or domestic, or governmental or commercial, are developing increasingly sophisticated methods of controlling healthcare costs.
Risks related to the COVID-19 pandemic and other events Our business may be adversely affected by pandemics, climate change, extreme weather events, earthquakes, war, civil or political unrest, terrorism or other catastrophic events.
Risks related to pandemics, climate change and other events Our business may be adversely affected by pandemics, climate change, extreme weather events, earthquakes, wars, civil or political unrest, terrorism or other catastrophic events.
Third parties may not complete activities on schedule or may not conduct our clinical studies in accordance with regulatory requirements or our stated protocols. For example, some of our key vendors are experiencing labor shortages, which could impact their ability to perform services for us for certain of our clinical trials.
Third parties may not complete activities on schedule or may not conduct our clinical studies in accordance with regulatory requirements or our stated protocols. For example, some of our key vendors have in the past experienced labor shortages, which impacted their ability to perform services for us for certain of our clinical trials.
These provisions, as well as Delaware law, including Section 203 of the Delaware General Corporation Law, and other of our agreements, may discourage certain types of transactions in which our stockholders might otherwise receive a premium for their shares over then-current market prices, and may limit the ability of our stockholders to approve transactions that they think may be in their best interests. 55 Future sales of our common stock in the public market could adversely affect the trading price of our securities.
These provisions, as well as Delaware law, including Section 203 of the Delaware General Corporation Law, and other of our agreements, may discourage certain types of transactions in which our stockholders might otherwise receive a premium for their shares over then-current market prices, and may limit the ability of our stockholders to approve transactions that they think may be in their best interests.
If we or any licensor partner loses or cannot obtain patent protection for SPINRAZA, TEGSEDI, WAYLIVRA, eplontersen and tofersen, or any of our medicines in development, it could have a material adverse impact on our business. Intellectual property litigation could be expensive and prevent us from pursuing our programs.
If we or any licensor partner loses or cannot obtain patent protection for our commercial medicines or any of our medicines in development, it could have a material adverse impact on our business. Intellectual property litigation could be expensive and prevent us from pursuing our programs. From time to time, we have to defend our intellectual property rights.
Violation of these laws may result in civil or criminal sanctions, which could include monetary fines, criminal penalties, and disgorgement of past profits, which could have an adverse impact on our business and financial condition . Risks related to compliance with laws Our operations are subject to additional healthcare laws.
Violation of these laws may result in civil or criminal sanctions, which could include monetary fines, criminal penalties, and disgorgement of past profits, which could have an adverse impact on our business and financial condition. Risks related to compliance with laws Our operations are subject to extensive legal and regulatory requirements affecting the health care industry.
We and our partners must conduct time-consuming, extensive and costly clinical studies to demonstrate the safety and efficacy of each of our medicines before they can be approved or receive additional approvals for sale.
We and our partners must conduct time-consuming, extensive and costly clinical studies to demonstrate the safety and efficacy of each of our medicines before they can be approved or receive additional approvals for sale. We and our partners must conduct these studies in compliance with FDA regulations and with comparable regulations in other countries.
If any of these occur, it could affect our partner’s commitment to the collaboration with us and could delay or otherwise negatively affect the commercialization of our medicines, including SPINRAZA, eplontersen, pelacarsen and tofersen . 50 We may not be able to benefit from orphan drug designation for our medicines.
If any of these occur, it could affect our partner’s commitment to the collaboration with us and could delay or otherwise negatively affect the commercialization of our medicines, including QALSODY, SPINRAZA, WAINUA, bepirovirsen, donidalorsen, IONIS-FB-L Rx and pelacarsen. We may not be able to benefit from orphan drug designation for our medicines.
Based on the profile of our medicines, physicians, patients, patient advocates, payers or the medical community in general may not accept or use any of the medicines that we may develop. 43 For example, TEGSEDI requires periodic blood and urine monitoring, is available in the U.S. only through a REMS program, and the product label in the U.S. has a boxed warning for thrombocytopenia and glomerulonephritis.
Based on the profile of our medicines, physicians, patients, patient advocates, payers or the medical community in general may not accept or use any of the medicines that we or our partners may develop. For example, TEGSEDI requires periodic blood and urine monitoring and is available in the U.S. only through a risk evaluation and mitigation strategy, or REMS program.
Our operations are subject to additional healthcare laws, including federal and state anti-kickback laws, false claims laws, transparency laws, such as the federal Sunshine Act, and health information privacy and security laws, which are subject to change at any time.
Our operations are subject to extensive legal and regulatory requirements affecting the health care industry, including federal and state anti-kickback laws, false claims laws, transparency laws, such as the federal Sunshine Act, and health information privacy and security laws, which are subject to change at any time.
For example, we use clinical research organizations, such as Icon Clinical Research Limited, Medpace, Inc., Parexel International Corporation, Syneos Health, Inc. and Thermo Fisher Scientific Inc. for the clinical studies for our medicines, including donidalorsen, eplontersen, ION363, olezarsen, pelacarsen and tofersen.
For example, we use clinical research organizations, such as Icon Clinical Research Limited, Medpace, Inc., Parexel International Corporation, Syneos Health, Inc. and Thermo Fisher Scientific Inc. for the clinical studies for our medicines, including WAINUA for the treatment of ATTR-CM, donidalorsen, olezarsen, ulefnersen and zilganersen.
Our main competitors in the U.S. market for TEGSEDI are patisiran and vutrisiran, both marketed by Alnylam Pharmaceuticals, Inc. Neither patisiran nor vutrisiran has a boxed warning nor does either require use of a REMS program. Additionally, the product label for WAYLIVRA in the European Union, or EU, requires regular blood monitoring.
In addition, the product label for TEGSEDI in the U.S. has a boxed warning for thrombocytopenia and glomerulonephritis. Our main external competitors in the U.S. market for TEGSEDI are patisiran and vutrisiran, both marketed by Alnylam Pharmaceuticals, Inc. Neither patisiran nor vutrisiran has a boxed warning nor does either require use of a REMS program.
This could cause the FDA or other regulators to ask questions or take actions that could harm or delay our ability to develop and commercialize our medicines or increase our costs.
This could cause the FDA or other regulators to ask questions or take actions that could harm or delay our ability to develop and commercialize our medicines or increase our costs. Any failure or delay in our clinical studies could reduce the commercial potential or viability of our medicines.
For example, in 2022, Pfizer and Bayer decided to discontinue the clinical development programs for vupanorsen and fesomersen, respectively. Even with funding from corporate partners, if our partners do not effectively perform their obligations under our agreements with them, it would delay or stop the progress of our drug development and commercial programs.
Even with funding from corporate partners, if our partners do not effectively perform their obligations under our agreements with them, it would delay or stop the progress of our drug development and commercial programs.
Congressional inquiries, legislation and executive orders designed to, among other things, reduce drug prices, increase competition, lower out-of-pocket drug costs for patients, and foster scientific innovation to promote better health care and improved health.
Congressional inquiries, legislation and executive orders designed to, among other things, reduce drug prices, increase competition (including by enhancing support for generic and biosimilar drugs), lower out-of-pocket drug costs for patients, curtail spread pricing practices by pharmacy benefit managers, and foster scientific innovation to promote better health care and improved health.
Significant judgment is required in evaluating our tax positions and our worldwide provision for taxes. During the ordinary course of business, there are many activities and transactions for which the ultimate tax determination is uncertain.
We are subject to U.S. federal, state, local and foreign income taxes, sales taxes in the U.S., withholding taxes and transaction taxes in foreign jurisdictions. Significant judgment is required in evaluating our tax positions and our worldwide provision for taxes. During the ordinary course of business, there are many activities and transactions for which the ultimate tax determination is uncertain.
If the pricing of any of our medicines decreases for any reason, it will reduce our revenue for such medicine. For example, Biogen has disclosed that SPINRAZA revenue has decreased in part due to lower pricing in the U.S. and certain rest of world markets.
For example, Biogen has in the past disclosed that SPINRAZA revenue decreased in part due to lower pricing in the U.S. and certain rest-of-world markets.
Our future product sales may be subject to additional discounts from list price in the form of rebates and discounts provided to 340B covered entities. Changes to the 340B program or to Medicare or Medicaid programs at the federal or state level, including outcomes of ongoing litigation in our industry, may impact our product prices and rebate liability.
Changes to the 340B program or to Medicare or Medicaid programs at the federal or state level, including outcomes of ongoing litigation in our industry, may impact our product prices and rebate liability.
Should we not satisfy such conditions by the applicable deadlines, or if we fail to meet our obligations or default under this agreement, the actual amount of additional payments to us could be substantially less than the maximum amounts available thereunder.
Should we not satisfy such conditions by the applicable deadlines, or if we fail to meet our obligations or default under this agreement, the actual amount of additional payments to us could be substantially less than the maximum amounts available thereunder. 58 Table of Contents Risks related to our intellectual property If we cannot protect our patent rights or our other proprietary rights, others may compete more effectively against us.
The FDA has granted orphan drug designation to eplontersen for the treatment of patients with transthyretin-mediated amyloidosis and to ION582 for the treatment of patients with Angelman syndrome.
The FDA has granted orphan drug designation to olezarsen for the treatment of patients with FCS, to ulefnersen for the treatment of patients with FUS-ALS, and to ION582 for the treatment of patients with Angelman syndrome.

… 105 more changes not shown on this page.

Item 2. Properties

Properties — owned and leased real estate

1 edited+1 added−7 removed0 unchanged
Biggest changeProperties As of February 16, 2023, the following are the primary facilities in which we operate: Property Description Location Square Footage Owned or Leased Initial Lease Term End Date Lease Extension Options Laboratory and office space facility Carlsbad, CA 176,300 Leased 2037 Two, five-year options to extend Office and meeting space facility Carlsbad, CA 74,000 Leased 2037 Two, five-year options to extend Manufacturing facility Carlsbad, CA 26,800 Owned Manufacturing support facility Carlsbad, CA 25,800 Leased 2026 One, five-year option to extend Office and storage space facility Carlsbad, CA 18,700 Leased 2023 None Office space facility Boston, MA 14,300 Leased 2029 One, five-year option to extend Office space facility Carlsbad, CA 5,800 Leased 2027 None 341,700 In October 2022, we concurrently entered into two purchase and sale agreements with a real estate investor.
Biggest changeProperties As of February 15, 2024, the following are the primary facilities in which we operate: Property Description Location Square Footage Owned or Leased Initial Lease Term End Date Lease Extension Options Laboratory and office space facility Carlsbad, CA 176,300 Leased 2037 Two, five-year options to extend Office and meeting space facility Carlsbad, CA 74,000 Leased 2037 Two, five-year options to extend Manufacturing facility Carlsbad, CA 26,800 Owned Manufacturing support facility Carlsbad, CA 25,800 Leased 2026 One, five-year option to extend Office space facility Boston, MA 14,300 Leased 2029 One, five-year option to extend Office space facility Carlsbad, CA 5,800 Leased 2027 None Warehouse facility Carlsbad, CA 4,200 Leased 2028 None Office space facility Dublin, Ireland 3,900 Leased 2025 None 331,100 We believe that our current and future facilities will be adequate for the foreseeable future.
Removed
Under the agreements, we sold and leased back the facilities at our headquarters location in Carlsbad, California and will sell, subject to meeting certain closing conditions, two lots of undeveloped land adjacent to our headquarters.
Added
Refer to Part IV, Section 15, Note 7, Long-Term Obligations and Commitments , in the Notes to the Consolidated Financial Statements for details on real estate transactions.
Removed
We sold the facilities at our headquarters for net proceeds of approximately $200 million , with the potential to receive additional payments of up to $40 million plus funding to expand our R&D campus . We used a portion of the sale proceeds to extinguish our mortgage debt on our headquarters facilities of $51 million.
Removed
The initial lease term for our headquarters facilities is 15 years with options to extend the lease for two additional terms of five years each. In connection with the sale of our two undeveloped lots, we will enter into a build-to-suit lease agreement with the same real estate investor to lease a new R&D facility.
Removed
The lessor will develop and construct a new building composed of research and development space and office space. We will design and construct tenant improvements to customize the facility’s interior space. Once this new facility is completed, our lease will commence.
Removed
In October 2022, we entered into a build-to-suit lease agreement to lease a development chemistry and manufacturing facility in Oceanside, California. The lessor will develop and construct a 217,000-square-foot building, composed of manufacturing space, office space, research and development space and warehouse space. We will design and construct tenant improvements to customize the facility’s interior space.
Removed
We will lease the facility for an initial term of 20 years and 3 months with options to extend the lease for two additional terms of 10 years each. The lease will commence when the lessor’s construction is complete and we are able to begin constructing tenant improvements.
Removed
We believe that our current and future facilities will be adequate for the foreseeable future.

Item 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

4 edited+0 added−0 removed1 unchanged
Biggest changeFiscal year ending December 31. 60 COMPARISON OF 5 YEAR CUMULATIVE TOTAL RETURN Among Ionis Pharmaceuticals, Inc., the Nasdaq Composite Index, and the Nasdaq Biotechnology Index Dec-17 Dec-18 Dec-19 Dec-20 Dec-21 Dec-22 Ionis Pharmaceuticals, Inc. $ 100.00 $ 107.48 $ 120.10 $ 112.41 $ 60.50 $ 75.09 Nasdaq Composite Index $ 100.00 $ 97.16 $ 132.81 $ 192.47 $ 235.15 $ 158.65 Nasdaq Biotechnology Index $ 100.00 $ 91.14 $ 114.02 $ 144.15 $ 144.18 $ 129.59 ________________ (1) This section is not “soliciting material,” is not deemed “filed” with the SEC, is not subject to the liabilities of Section 18 of the Exchange Act and is not to be incorporated by reference in any of our filings under the Securities Act or the Exchange Act, whether made before or after the date hereof and irrespective of any general incorporation language in any such filing.
Biggest changeFiscal year ending December 31. 68 Table of Contents COMPARISON OF 5 YEAR CUMULATIVE TOTAL RETURN Among Ionis Pharmaceuticals, Inc., the Nasdaq Composite Index, and the Nasdaq Biotechnology Index Dec-18 Dec-19 Dec-20 Dec-21 Dec-22 Dec-23 Ionis Pharmaceuticals, Inc. $ 100.00 $ 111.75 $ 104.59 $ 56.29 $ 69.87 $ 93.58 Nasdaq Composite Index $ 100.00 $ 136.69 $ 198.10 $ 242.03 $ 163.28 $ 236.17 Nasdaq Biotechnology Index $ 100.00 $ 125.11 $ 158.17 $ 158.20 $ 142.19 $ 148.72 ___________ (1) This section is not “soliciting material,” is not deemed “filed” with the SEC, is not subject to the liabilities of Section 18 of the Exchange Act and is not to be incorporated by reference in any of our filings under the Securities Act or the Exchange Act, whether made before or after the date hereof and irrespective of any general incorporation language in any such filing.
Performance Graph (1) Set forth below is a table and chart comparing the total return on an indexed basis of $100 invested on December 31, 2017 in our common stock, the Nasdaq Composite Index (total return) and the Nasdaq Biotechnology Index.
Performance Graph (1) Set forth below is a table and chart comparing the total return on an indexed basis of $100 invested on December 31, 2018 in our common stock, the Nasdaq Composite Index (total return) and the Nasdaq Biotechnology Index.
The total return assumes reinvestment of dividends. * $100 invested on December 31, 2017 in stock or index, including reinvestment of dividends.
The total return assumes reinvestment of dividends. * $100 invested on December 31, 2018 in stock or index, including reinvestment of dividends.
Item 5. Market for Registrant ’ s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities Market Information and Dividends Our common stock is traded publicly through The Nasdaq Global Select Market under the symbol “IONS.” As of February 16, 2023, there were approximately 483 stockholders of record of our common stock.
Item 5. Market for Registrant ’ s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities Market Information and Dividends Our common stock is traded publicly through The Nasdaq Global Select Market under the symbol “IONS.” As of February 15, 2024, there were approximately 476 stockholders of record of our common stock.

Item 7. Management's Discussion & Analysis

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

55 edited+26 added−20 removed30 unchanged
Biggest changeThe following is a summary of the financial impacts on our statement of operations for the year ended December 31, 2022 of the joint development activities under our eplontersen collaboration with AstraZeneca: 62 Operating Expenses Our operating expenses were as follows (in millions): Year Ended December 31, 2022 2021 Operating expenses, excluding non-cash compensation expense related to equity awards $ 897.3 $ 696.0 Restructuring expenses — 23.9 Total operating expenses, excluding non-cash compensation expense related to equity awards 897.3 719.9 Non-cash compensation expense related to equity awards 100.3 120.7 Total operating expenses $ 997.6 $ 840.6 Our operating expenses, excluding non-cash compensation expense related to equity awards, increased in 2022 compared to 2021.
Biggest changeOperating Expenses The following table sets forth information on operating expenses (in millions): Year Ended December 31, 2023 2022 Operating expenses, excluding non-cash compensation expense related to equity awards $ 1,035.7 $ 897.3 Non-cash compensation expense related to equity awards 105.7 100.3 Total operating expenses $ 1,141.4 $ 997.6 Our operating expenses, excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2022, primarily due to certain one-time costs, including a non-cash charge associated with a lease exit and the license fee we paid to Vect-Horus.
However, such fluctuations are not indicative of a shift in our emphasis from one medicine to another and cannot be used to accurately predict future costs for each medicine. And, because we always have numerous medicines in preclinical and varying stages of clinical research, the fluctuations in expenses from medicine to medicine, in large part, offset one another.
However, such fluctuations are not indicative of a shift in our emphasis from one medicine to another and cannot be used to accurately predict future costs for each medicine. Because we always have numerous medicines in preclinical and varying stages of clinical research, the fluctuations in expenses from medicine to medicine, in large part, offset one another.
Milestone Payments When recognizing revenue related to milestone payments we typically make the following judgements and estimates: ● Whether the milestone payment is probable (discussed in detail above under “Determining the transaction price, including any variable consideration” ); and ● Whether the milestone payment relates to services we are performing or if our partner is performing the services: ● If we are performing services, we recognize revenue over our estimated period of performance in a similar manner to the amortization of upfront payments (discussed above under “R&D Services with Upfront Payments”). ● Conversely, we recognize in full those milestone payments that we earn based on our partners’ activities when our partner achieves the milestone event and we do not have a performance obligation.
Milestone Payments When recognizing revenue related to milestone payments, we typically make the following judgements and estimates: ● Whether a milestone payment is probable (discussed in detail above under “Determining the transaction price, including any variable consideration” ); ● Whether a milestone payment relates to services we are performing or if our partner is performing the services; ● If we are performing services, we recognize revenue over our estimated period of performance in a similar manner to the amortization of upfront payments (discussed above under “R&D Services with Upfront Payments”); and ● Conversely, we recognize in full those milestone payments that we earn based on our partners’ activities when our partner achieves the milestone event and we do not have a performance obligation.
The increase was primarily related to increased occupancy and personnel costs to support advancing our pipeline and our technology. In October 2022, we executed a sale and leaseback transaction for our headquarters in Carlsbad, California. As a result, beginning in the fourth quarter of 2022, our occupancy costs increased because we began incurring rent expense for these facilities.
The increase was primarily related to increased occupancy, personnel and consulting costs to support advancing our pipeline and our technology. In October 2022, we executed a sale and leaseback transaction for our headquarters in Carlsbad, California. As a result, beginning in the fourth quarter of 2022, our occupancy costs increased because we began incurring rent expense for these facilities.
Selling, General and Administrative Expenses Selling, general and administrative, or SG&A, expenses include personnel and outside costs associated with the pre-commercialization and commercialization activities for our medicines and costs to support our company, our employees and our stockholders including, legal, human resources, investor relations and finance.
Selling, General and Administrative Expenses SG&A expenses include personnel and outside costs associated with the pre-commercialization and commercialization activities for our medicines and costs to support our company, our employees and our stockholders including, legal, human resources, investor relations and finance.
As AstraZeneca is responsible for the majority of the medical affairs and commercial costs in the U.S. and all costs associated with bringing eplontersen to market outside the U.S., we are recognizing cost-share funding we receive from AstraZeneca related to these activities as a reduction of our medical affairs and commercialization expenses, which we classify as R&D and selling, general and administrative, or SG&A, expenses, respectively.
As AstraZeneca is responsible for the majority of the medical affairs and commercial costs in the U.S. and all costs associated with bringing WAINUA to market outside the U.S., we are recognizing cost-share funding we receive from AstraZeneca related to these activities as a reduction of our medical affairs and commercialization expenses, which we classify as R&D and selling, general and administrative, or SG&A, expenses, respectively.
Item 7. Management ’ s Discussion and Analysis of Financial Condition and Results of Operations This financial review presents our operating results for each of the two years in the period ended December 31, 2022, and our financial condition as of December 31, 2022. Refer to our 2021 Form 10-K for our results of operations for 2021 compared to 2020.
Item 7. Management ’ s Discussion and Analysis of Financial Condition and Results of Operations This financial review presents our operating results for each of the two years in the period ended December 31, 2023, and our financial condition as of December 31, 2023. Refer to our 2022 Form 10-K for our results of operations for 2022 compared to 2021.
We may enter into additional collaborations with partners that could provide for additional revenue to us and we may incur additional cash expenditures related to our obligations under any of the new agreements we may enter into. We currently intend to use our cash, cash equivalents and short-term investments to finance our activities.
We may enter into additional collaborations with partners which could provide for additional revenue to us and we may incur additional cash expenditures related to our obligations under any of the new agreements we may enter into. We currently intend to use our cash, cash equivalents and short-term investments to finance our activities.
Convertible Debt and Call Spread Refer to our Convertible Debt and Call Spread accounting policies in Part IV, Item 15, Note 1, Organization and Significant Accounting Policies , and Note 4, Long-Term Obligations and Commitments , in the Notes to our consolidated financial statements for the significant terms of each convertible debt instrument.
Convertible Debt and Call Spread Refer to our Convertible Debt and Call Spread accounting policies in Part IV, Item 15, Note 1, Organization and Significant Accounting Policies , and Note 7, Long-Term Obligations and Commitments , in the Notes to the Consolidated Financial Statements for the significant terms of each convertible debt instrument.
Other Obligations In addition to contractual obligations, we had outstanding purchase orders as of December 31, 2022 for the purchase of services, capital equipment and materials as part of our normal course of business.
Other Obligations In addition to contractual obligations, we had outstanding purchase orders as of December 31, 2023 for the purchase of services, capital equipment and materials as part of our normal course of business.
Operating Facilities Refer to Part IV, Item 15, Note 4, Long-Term Obligations and Commitments , in the Notes to our consolidated financial statements for further details on our operating facilities.
Operating Facilities Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments , in the Notes to the Consolidated Financial Statements for further details on our operating facilities.
R&D Support In our research, development and patent expenses, we include support costs such as rent, repair and maintenance for buildings and equipment, utilities, depreciation of laboratory equipment and facilities, amortization of our intellectual property, informatics costs, procurement costs and waste disposal costs. We call these costs R&D support expenses.
R&D Support In our research, development and patent expenses, we include support costs such as rent, repair and maintenance for buildings and equipment, utilities, depreciation of laboratory equipment and facilities, amortization of our intellectual property, information technology costs, procurement costs and waste disposal costs. We call these costs R&D support expenses.
We discuss the estimates we make related to the relative stand-alone selling price of a license in detail above under “Allocating the transaction price to each of our performance obligations.” 70 Estimated Liability for Clinical Development Costs We have numerous medicines in preclinical studies and/or clinical trials at clinical sites throughout the world.
We discuss the estimates we make related to the relative stand-alone selling price of a license in detail above under “Allocating the transaction price to each of our performance obligations.” 78 Table of Contents Estimated Liability for Clinical Development Costs We have numerous medicines in preclinical studies and/or clinical trials at clinical sites throughout the world.
As of December 31, 2022, a hypothetical 10 percent increase in our liability for preclinical and clinical development costs would have resulted in an increase in our loss before income tax benefit and accrued liabilities of approximately $11.6 million.
As of December 31, 2023, a hypothetical 10 percent increase in our liability for preclinical and clinical development costs would have resulted in an increase in our loss before income tax benefit and accrued liabilities of approximately $10.6 million.
If we partner a medicine, it may affect the size of a trial, its timing, its total cost and the timing of the related costs. Medical Affairs Our medical affairs function is responsible for managing publications planning, funding and coordinating investigator-sponsored trials and communicating scientific and clinical information to healthcare providers, medical professionals and patients .
If we partner a medicine, it may affect the size of a trial, its timing, its total cost and the timing of the related costs. 72 Table of Contents Medical Affairs Our medical affairs function is responsible for funding and coordinating investigator-sponsored trials, communicating scientific and clinical information to healthcare providers, medical professionals and patients, and managing publications.
The following is a summary of the critical accounting estimates we make with respect to our revenue. 69 Research and development revenue under collaborative agreements We recognize R&D revenue from numerous collaboration agreements. Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, R&D services, and manufacturing services.
The following is a summary of the critical accounting estimates we make with respect to our revenue. 77 Table of Contents Research and development revenue under collaborative agreements We recognize R&D revenue from numerous collaboration agreements. Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, R&D services, and manufacturing services.
Operating Leases Refer to Part IV, Item 15, Note 4, Long-Term Obligations and Commitments , in the Notes to our consolidated financial statements for further details on our operating leases . 68 Royalty Revenue Monetization In January 2023, we entered into a royalty purchase agreement with Royalty Pharma to monetize a portion of our future SPINRAZA and pelacarsen royalties we are entitled to under our agreements with Biogen and Novartis, respectively.
Operating Leases Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments , in the Notes to the Consolidated Financial Statements for further details on our operating leases . 76 Table of Contents Royalty Revenue Monetization In January 2023, we entered into a royalty purchase agreement with Royalty Pharma to monetize a portion of our future SPINRAZA and pelacarsen royalties we are entitled to under our agreements with Biogen and Novartis, respectively.
Results of Operations Below we have included our results of operations for 2022 compared to 2021. Refer to our 2021 Form 10-K for our results of operations for 2021 compared to 2020.
Results of Operations Below we have included our results of operations for 2023 compared to 2022. Refer to our 2022 Form 10-K for our results of operations for 2022 compared to 2021.
Refer to Part IV, Item 15, Note 4, Long-Term Obligations and Commitments , in the Notes to our consolidated financial statements for further details on this agreement.
Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments , in the Notes to the Consolidated Financial Statements for further details on this agreement.
This method requires us to make estimates of the total costs we expect to incur to complete our R&D services performance obligation or the total length of time it will take us to complete our R&D services performance obligation. If we change our estimates, we may have to adjust our revenue.
This method requires us to make estimates of the total costs we expect to incur to complete our R&D services performance obligation or the total amount of effort it will take us to complete our R&D services performance obligation. If we change our estimates, we may have to adjust our revenue.
However, we may also pursue other financing alternatives, like issuing additional shares of our common stock, issuing debt instruments, refinancing our existing debt, or securing lines of credit.
However, we may also pursue other financing alternatives, like issuing additional shares of our common stock, issuing debt instruments, refinancing our existing debt, securing lines of credit or executing royalty monetization agreements.
Additionally, we include in selling, general and administrative expenses such costs as rent, repair and maintenance of buildings and equipment, depreciation and utilities costs that we need to support the corporate functions listed above. We also include fees we owe under our in-licensing agreements related to SPINRAZA.
Additionally, we include in SG&A expenses such costs as rent, repair and maintenance of buildings and equipment, depreciation and utilities costs that we need to support the corporate functions listed above. We also include fees we owe under our in-licensing agreements related to SPINRAZA and QALSODY.
The following are our significant accounting estimates, which we believe are the most critical to aid in fully understanding and evaluating our reported financial results: ● Assessing the propriety of revenue recognition and associated deferred revenue; and ● Determining the appropriate cost estimates for unbilled preclinical studies and clinical development activities The following are descriptions of our critical accounting estimates.
The following are our significant accounting estimates, which we believe are the most critical to aid in fully understanding and evaluating our reported financial results: ● Assessing the propriety of revenue recognition and associated deferred revenue; ● Determining the appropriate cost estimates for unbilled preclinical studies and clinical development activities; and ● Assessing the appropriate estimate of anticipated future royalty payments under our royalty purchase agreement The following are descriptions of our critical accounting estimates.
Our significant accounting policies are outlined in Note 1, Organization and Significant Accounting Policies , in the Notes to the Consolidated Financial Statements.
Our significant accounting policies are outlined in Part IV, Item 15, Note 1, Organization and Significant Accounting Policies , in the Notes to the Consolidated Financial Statements.
The following table sets forth information on research, development and patent expenses (in millions): Year Ended December 31, 2022 2021 Research, development and patent expenses, excluding non-cash compensation expense related to equity awards $ 759.4 $ 547.4 Restructuring expenses — 8.5 Total research, development and patent expenses, excluding non-cash compensation expense related to equity awards 759.4 555.9 Non-cash compensation expense related to equity awards 73.7 87.6 Total research, development and patent expenses $ 833.1 $ 643.5 Drug Discovery We use our proprietary technologies to generate information about the function of genes and to determine the value of genes as drug discovery targets.
The following table sets forth information on research, development and patent expenses (in millions): Year Ended December 31, 2023 2022 Research, development and patent expenses, excluding non-cash compensation expense related to equity awards $ 821.7 $ 759.4 Non-cash compensation expense related to equity awards 77.9 73.7 Total research, development and patent expenses $ 899.6 $ 833.1 71 Table of Contents Drug Discovery We use our proprietary technologies to generate information about the function of genes and to determine the value of genes as drug discovery targets.
The following table sets forth information on R&D support expenses (in millions): Year Ended December 31, 2022 2021 Personnel costs $ 21.2 $ 17.7 Occupancy 19.2 13.1 Patent expenses 4.7 5.3 Insurance 3.8 3.2 Computer software and licenses 1.9 1.8 Other 9.0 7.3 Restructuring expenses — 0.1 Total R&D support expenses, excluding non-cash compensation expense related to equity awards 59.8 48.5 Non-cash compensation expense related to equity awards 14.1 15.5 Total R&D support expenses $ 73.9 $ 64.0 R&D support expenses, excluding non-cash compensation expense related to equity awards, increased in 2022 compared to 2021.
The following table sets forth information on R&D support expenses (in millions): Year Ended December 31, 2023 2022 Personnel costs $ 27.2 $ 21.2 Occupancy 28.7 19.2 Consulting 4.8 0.8 Patent expenses 4.3 4.7 Insurance 3.6 3.8 Computer software and licenses 2.7 1.9 Other 9.7 8.2 Total R&D support expenses, excluding non-cash compensation expense related to equity awards 81.0 59.8 Non-cash compensation expense related to equity awards 15.0 14.1 Total R&D support expenses $ 96.0 $ 73.9 73 Table of Contents R&D support expenses, excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2022.
Contractual Obligations Payments Due by Period (in millions) (selected balances described below) Total Less than 1 year More than 1 year 0% Notes (principal payable) $ 632.5 $ — $ 632.5 0.125% Notes (principal and interest payable) 550.2 0.7 549.5 Building mortgage payments (principal and interest payable) 10.7 0.5 10.2 Operating leases 299.6 20.1 279.5 Other obligations (principal and interest payable) 0.9 0.1 0.8 Total $ 1,493.9 $ 21.4 $ 1,472.5 Our contractual obligations consist primarily of our convertible debt.
Contractual Obligations Payments Due by Period (in millions) (selected balances described below) Total Less than 1 year More than 1 year 1.75% Notes (principal and interest payable) $ 620.3 $ 10.1 $ 610.2 0% Notes (principal payable) 632.5 — 632.5 0.125% Notes (principal and interest payable) 44.6 44.6 — Building mortgage payments (principal and interest payable) 10.2 0.5 9.7 Operating leases 279.5 20.4 259.1 Other obligations (principal and interest payable) 0.8 0.1 0.7 Total $ 1,587.9 $ 75.7 $ 1,512.2 Our contractual obligations consist primarily of our convertible debt.
Refer to Part IV, Item 15, Note 1, Organization and Significant Accounting Policies , for our revenue recognition policy.
Refer to Part IV, Item 15, Note 1, Organization and Significant Accounting Policies , in the Notes to the Consolidated Financial Statements for our revenue recognition policy.
Our cost of sales were as follows (in millions): Year Ended December 31, 2022 2021 Cost of sales, excluding non-cash compensation expense related to equity awards $ 13.4 $ 10.4 Non-cash compensation expense related to equity awards 0.7 0.4 Total cost of sales $ 14.1 $ 10.8 63 Research, Development and Patent Expenses Our research, development and patent expenses consist of expenses for drug discovery, drug development, manufacturing and development chemistry and R&D support expenses.
The following table sets forth information on cost of sales (in millions): Year Ended December 31, 2023 2022 Cost of sales, excluding non-cash compensation expense related to equity awards $ 8.7 $ 13.4 Non-cash compensation expense related to equity awards 0.4 0.7 Total cost of sales $ 9.1 $ 14.1 Research, Development and Patent Expenses Our research, development and patent expenses consist of expenses for drug discovery, drug development, medical affairs, manufacturing and development chemistry and R&D support expenses.
Manufacturing and Development Chemistry Expenditures in our manufacturing and development chemistry function consist primarily of personnel costs, specialized chemicals for oligonucleotide manufacturing, laboratory supplies and outside services. Our manufacturing and development chemistry function is responsible for providing drug supplies to drug development and our collaboration partners. Our manufacturing procedures include testing to satisfy good laboratory and good manufacturing practice requirements.
Manufacturing and Development Chemistry Expenditures in our manufacturing and development chemistry function consist primarily of personnel costs, specialized chemicals for oligonucleotide manufacturing, validation batches to support regulatory approvals, laboratory supplies and outside services. Our manufacturing and development chemistry function is responsible for providing drug supplies to drug development and our collaboration partners.
Interest Expense The following table sets forth information on interest expense (in millions): Year Ended December 31, 2022 2021 Convertible senior notes: Non-cash amortization of the debt discounts and debt issuance costs $ 5.3 $ 4.9 Interest expense payable in cash 0.7 1.9 Interest on mortgage for primary R&D and manufacturing facilities 2.1 2.5 Total interest expense $ 8.1 $ 9.3 Gain (Loss) on Investments We recorded a $7.3 million loss on investments for 2022 compared to a $10.1 million gain on investments for 2021.
Interest Expense The following table sets forth information on interest expense (in millions): Year Ended December 31, 2023 2022 Convertible senior notes: Non-cash amortization of debt issuance costs $ 5.9 $ 5.3 Interest expense payable in cash 6.4 0.7 Interest on mortgage for primary R&D and manufacturing facilities 0.4 2.1 Total interest expense $ 12.7 $ 8.1 In 2023, we completed a $575.0 million offering of our 1.75% Notes and repurchased $504.4 million in principal of our 0.125% Notes.
Refer to the section titled, Manufacturing , in Part I, Item 1, Business , for further details on the activities and types of costs we incur in our manufacturing process.
In 2022, we manufactured higher quantities of API to support launch preparation activities for WAINUA, olezarsen and donidalorsen. Refer to the section titled, Manufacturing , in Part I, Item 1, Business , for further details on the activities and types of costs we incur in our manufacturing process.
We discuss such risks, uncertainties and other factors throughout this report and specifically under Item 1A of Part I of this report, “Risk Factors.” In addition, the following review should be read in conjunction with the information presented in our consolidated financial statements and the related notes to our consolidated financial statements included in Item 8 of Part II of this report.
In addition, the following review should be read in conjunction with the information presented in our consolidated financial statements and the related notes to our consolidated financial statements included in Item 8 of Part II of this report.
Drug Development The following table sets forth drug development expenses, including expenses for our marketed medicines and those in Phase 3 development for which we have incurred significant costs (in millions): Year Ended December 31, 2022 2021 TEGSEDI and WAYLIVRA $ 10.6 $ 8.3 Eplontersen 103.9 79.1 Olezarsen 68.1 22.0 Donidalorsen 14.1 6.7 ION363 8.4 7.7 Other development projects 129.1 104.5 Development overhead expenses 92.0 75.2 Restructuring expenses — 7.7 Total drug development, excluding non-cash compensation expense related to equity awards 426.2 311.2 Non-cash compensation expense related to equity awards 31.5 37.8 Total drug development expenses $ 457.7 $ 349.0 64 Our development expenses, excluding non-cash compensation expense related to equity awards, increased in 2022 compared to 2021 primarily due to our advancing late-stage pipeline, including the expanded number of Phase 3 studies we are conducting, which doubled over the course of 2021 from three to six studies.
Drug Development The following table sets forth drug development expenses, including expenses for our marketed medicines and those in Phase 3 development for which we have incurred significant costs (in millions): Year Ended December 31, 2023 2022 WAINUA $ 115.5 $ 103.9 TEGSEDI and WAYLIVRA 8.1 10.6 Olezarsen 138.3 68.1 Donidalorsen 24.9 14.1 Zilganersen 8.4 5.6 Ulefnersen 10.8 8.4 Other development projects 101.0 123.5 Development overhead expenses 123.3 92.0 Total drug development, excluding non-cash compensation expense related to equity awards 530.3 426.2 Non-cash compensation expense related to equity awards 34.5 31.5 Total drug development expenses $ 564.8 $ 457.7 Our development expenses, excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2022 primarily due to our advancing late-stage pipeline and full or nearly full enrollment of many of our Phase 3 studies.
From our inception through December 31, 2022, we have earned approximately $6.4 billion in revenue. We have also financed our operations through the sale of our equity securities and the issuance of long-term debt.
In addition, we expect to receive commercial revenue from WAINUA royalties beginning in 2024. From our inception through December 31, 2023, we have earned approximately $7.2 billion in revenue. We have also financed our operations through the sale of our equity securities, the issuance of long-term debt and the sale of future royalties.
Basic and diluted net loss per share for 2021 were each $0.20. 67 Liquidity and Capital Resources We have financed our operations primarily from research and development collaborative agreements. We also finance our operations from commercial revenue from SPINRAZA royalties and TEGSEDI and WAYLIVRA commercial revenue.
Basic and diluted net loss per share for 2023 were $2.56 compared to $1.90 for 2022. 75 Table of Contents Liquidity and Capital Resources We have financed our operations primarily from research and development collaborative agreements. We also financed our operations from commercial revenue from SPINRAZA and QALSODY royalties and TEGSEDI and WAYLIVRA commercial revenue.
The following table provides selected summary information from our consolidated statements of operations for 2022 and 2021 (in millions): Year Ended December 31, 2022 2021 Total revenue $ 587.4 $ 810.5 Total operating expenses $ 997.6 $ 840.6 Loss from operations $ (410.2 ) $ (30.2 ) Net loss $ (269.7 ) $ (28.6 ) Cash, cash equivalents and short-term investments $ 1,986.9 $ 2,115.0 61 Revenue Total revenue for 2022 was $587.4 million compared to $810.5 million in 2021 and was comprised of the following (in millions): Year Ended December 31, 2022 2021 Revenue: Commercial revenue: SPINRAZA royalties $ 242.3 $ 267.8 TEGSEDI and WAYLIVRA revenue, net 30.1 55.5 Licensing and other royalty revenue 31.0 19.1 Total commercial revenue 303.4 342.4 R&D revenue: Amortization from upfront payments 68.6 77.5 Milestone payments 74.0 88.3 License fees 37.0 291.3 Other services 27.6 11.0 Collaborative agreement revenue 207.2 468.1 Eplontersen joint development revenue 76.8 — Total R&D revenue 284.0 468.1 Total revenue $ 587.4 $ 810.5 Our 2022 revenue continued to be derived from diverse sources, with just over half coming from commercial products and the balance from numerous partnered programs.
The following table provides selected summary information from our consolidated statements of operations for 2023 and 2022 (in millions): Year Ended December 31, 2023 2022 Total revenue $ 787.6 $ 587.4 Total operating expenses $ 1,141.4 $ 997.6 Loss from operations $ (353.7 ) $ (410.2 ) Net loss $ (366.3 ) $ (269.7 ) Cash, cash equivalents and short-term investments $ 2,331.2 $ 1,986.9 69 Table of Contents Revenue Total revenue for 2023 was $787.6 million compared to $587.4 million in 2022 and was comprised of the following (in millions): Year Ended December 31, 2023 2022 Revenue: Commercial revenue: SPINRAZA royalties $ 240.4 $ 242.3 Other commercial revenue: TEGSEDI and WAYLIVRA revenue, net 34.9 30.1 Licensing and other royalty revenue 33.3 31.0 Total other commercial revenue 68.2 61.1 Total commercial revenue 308.6 303.4 R&D revenue: Amortization from upfront payments 125.3 68.6 Milestone payments 100.5 74.0 License fees 116.8 37.0 Other services 10.0 27.6 Collaborative agreement revenue 352.6 207.2 WAINUA joint development revenue 126.4 76.8 Total R&D revenue 479.0 284.0 Total revenue $ 787.6 $ 587.4 Commercial revenues in 2023 were relatively consistent compared to 2022.
Therefore, we have excluded our gross unrecognized tax benefits from our contractual obligations table above. We have not entered into, nor do we currently have, any off-balance sheet arrangements (as defined under SEC rules ).
We have not entered into, nor do we currently have, any off-balance sheet arrangements (as defined under SEC rules).
The following table summarizes our contractual obligations as of December 31, 2022. The table provides a breakdown of when obligations become due. We provide a more detailed description of the major components of our debt in Note 4, Long-Term Obligations and Commitments .
The table provides a breakdown of when obligations become due. We provide a more detailed description of the major components of our debt in Part IV, Item 15, Note 7, Long-Term Obligations and Commitments , in the Notes to the Consolidated Financial Statements .
The following table sets forth information on SG&A expenses (in millions): Year Ended December 31, 2022 2021 Selling, general and administrative expenses, excluding non-cash compensation expense related to equity awards $ 124.4 $ 138.1 Restructuring expenses — 15.4 Total selling, general and administrative expenses, excluding non-cash compensation related to equity awards 124.4 153.5 Non-cash compensation expense related to equity awards 25.9 32.8 Total selling, general and administrative expenses $ 150.3 $ 186.3 SG&A expenses, excluding non-cash compensation expense related to equity awards, decreased in 2022 compared to 2021 due to operating efficiencies achieved from restructuring our commercial operations for TEGSEDI and WAYLIVRA, partially offset by increased expenses for our go-to-market preparations for our near-term commercial opportunities.
The following table sets forth information on SG&A expenses (in millions): Year Ended December 31, 2023 2022 Selling, general and administrative expenses, excluding non-cash compensation expense related to equity awards $ 205.1 $ 124.4 Non-cash compensation expense related to equity awards 27.5 25.9 Total selling, general and administrative expenses $ 232.6 $ 150.3 SG&A expenses, excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2022 primarily due to increased expenses related to our go-to-market activities for WAINUA, olezarsen and donidalorsen.
In addition to our commercial medicines and medicines under regulatory review, we have a rich innovative late- and mid-stage pipeline primarily focused on our leading cardiovascular and neurology franchises. We currently have seven medicines in Phase 3 development. Refer to Part I, Item 1, Business , for further details on our business and key developments in our medicines.
We also have a rich innovative late- and mid-stage pipeline in neurology, cardiology and other areas of high patient need. We currently have nine medicines in Phase 3 development and multiple additional medicines in early and mid-stage development . Refer to Part I, Item 1, Business , for further details on our business and key developments in our medicines.
Our medical affairs expenses were as follows (in millions): Year Ended December 31, 2022 2021 Medical affairs expenses, excluding non-cash compensation expense related to equity awards $ 15.9 $ 11.6 Non-cash compensation expense related to equity awards 2.0 1.4 Total medical affairs expenses $ 17.9 $ 13.0 Medical affairs expenses, excluding non-cash compensation expense related to equity awards, increased in 2022 compared to 2021 due to increased costs we incurred as we built our medical affairs function to support our late-stage pipeline .
The following table sets forth information on medical affairs expenses (in millions): Year Ended December 31, 2023 2022 Medical affairs expenses, excluding non-cash compensation expense related to equity awards $ 19.5 $ 15.9 Non-cash compensation expense related to equity awards 3.4 2.0 Total medical affairs expenses $ 22.9 $ 17.9 Medical affairs expenses, excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2022 as we continued advancing our late-stage pipeline .
Eplontersen Collaboration with AstraZeneca Our financial results for the year ended December 31, 2022 reflected the cost-sharing provisions related to our collaboration with AstraZeneca to develop and commercialize eplontersen for the treatment of ATTR. Under the terms of the collaboration agreement, AstraZeneca is currently paying 55 percent of the costs associated with the ongoing global Phase 3 development program.
WAINUA (Eplontersen) Collaboration with AstraZeneca Our financial results for the years ended December 31, 2023 and 2022 reflected the cost-sharing provisions related to our collaboration with AstraZeneca to develop and commercialize WAINUA for the treatment of ATTR.
The period-over-period fluctuation in our gain (loss) on investments was primarily driven by changes in fair value of our investments in publicly traded biotechnology companies . Gain on Sale of Real Estate In October 2022, we concurrently entered into two purchase and sale agreements with a real estate investor.
The period-over-period fluctuation in our loss on investments was primarily driven by changes in the fair value of our investments in publicly traded and privately held biotechnology companies.
From the time we were founded through December 31, 2022 , we have raised net proceeds of approximately $ 2.0 billion from the sale of our equity securities. Additionally, we borrowed approximately $ 2.1 billion under long-term debt arrangements to finance a portion of our operations over the same time period.
From the time we were founded through December 31, 2023 , we have raised net proceeds of approximately $ 2.1 billion from the sale of our equity securities.
We sold the facilities at our headquarters for a total purchase price of $263.4 million and recorded a gain of $150.1 million in the fourth quarter of 2022, resulting in income tax expense of $8.8 million. Other Expense In 2022, we recorded a $7.7 million net expense to settle a litigation claim.
Gain on Sale of Real Estate In 2022, we closed a purchase and sale agreement with a real estate investor in which we sold and leased back the facilities at our headquarters location in Carlsbad, California for a total purchase price of $263.4 million and recorded a gain of $150.1 million in 2022, resulting in income tax expense of $8.8 million.
Our R&D expenses also increased in 2022 compared to 2021 due to $80 million that we recognized in 2022 for licensing Metagenomi’s gene editing technologies.
In 2022, we recognized $80 million for licensing Metagenomi’s gene editing technologies.
In the year ended December 31, 2022, we recognized $2.0 million and $2.6 million of medical affairs expenses and commercialization expenses for eplontersen, respectively, net of cost-share funding from AstraZeneca. We expect our medical affairs and commercialization expenses to increase as eplontersen advances toward the market under our collaboration with AstraZeneca.
We expect our medical affairs and commercialization expenses to increase as WAINUA advances toward the market under our collaboration with AstraZeneca.
The increase in investment income was primarily due to an increase in interest rates during 2022 compared to 2021.
Investment Income Investment income for 2023 was $89.0 million compared to $25.3 million for 2022. The increase in investment income was primarily due to an increase in interest rates associated with our investments in debt securities and an increase in our cash available for investment during 2023 compared to 2022.
The loss on the early retirement of our debt is the difference between the amount we paid to retire our 1% Notes and the net carrying balance of the liability at the time that we retired the debt.
As a result of these repurchases, we recorded a $13.4 million gain on early retirement of debt in 2023, which reflects the difference between the amounts we paid to repurchase portions of our 0.125% Notes and the net carrying balance of the liability at the time that we repurchased the debt.
Our drug discovery expenses were as follows (in millions): Year Ended December 31, 2022 2021 Drug discovery expenses, excluding non-cash compensation expense related to equity awards $ 181.3 $ 136.6 Non-cash compensation expense related to equity awards 16.2 21.4 Total drug discovery expenses $ 197.5 $ 158.0 Drug discovery expenses, excluding non-cash compensation expense related to equity awards, increased in 2022 compared to 2021 primarily due to $80 million that we recognized in 2022 for licensing Metagenomi’s gene editing technologies.
The following table sets forth information on drug discovery expenses (in millions): Year Ended December 31, 2023 2022 Drug discovery expenses, excluding non-cash compensation expense related to equity awards $ 125.6 $ 181.3 Non-cash compensation expense related to equity awards 16.2 16.2 Total drug discovery expenses $ 141.8 $ 197.5 Drug discovery expenses, excluding non-cash compensation expense related to equity awards, decreased in 2023 compared to 2022.
Our manufacturing and development chemistry expenses were as follows (in millions): Year Ended December 31, 2022 2021 Manufacturing and development chemistry expenses, excluding non-cash compensation expense related to equity awards $ 76.2 $ 47.2 Restructuring expenses — 0.8 Total manufacturing and development chemistry expenses, excluding non-cash compensation expense related to equity awards 76.2 48.0 Non-cash compensation expense related to equity awards 9.9 11.5 Total manufacturing and development chemistry expenses $ 86.1 $ 59.5 65 Manufacturing and development chemistry expenses, excluding non-cash compensation expense related to equity awards, increased in 2022 compared to 2021 due to increased R&D-related manufacturing costs we incurred in preparation for our near-term commercial launches of eplontersen, olezarsen and donidalorsen.
The following table sets forth information on manufacturing and development chemistry expenses (in millions): Year Ended December 31, 2023 2022 Manufacturing and development chemistry expenses, excluding non-cash compensation expense related to equity awards $ 65.3 $ 76.2 Non-cash compensation expense related to equity awards 8.8 9.9 Total manufacturing and development chemistry expenses $ 74.1 $ 86.1 Manufacturing and development chemistry expenses, excluding non-cash compensation expense related to equity awards, decreased in 2023 compared to 2022.
Our 2022 tax expense relates primarily to the impact of this new law and to federal and state tax on the gain from the sale of our headquarters facilities that closed in October 2022. Net Loss and Net Loss per Share We generated a net loss of $269.7 million for 2022 compared to $28.6 million for 2021.
Net Loss and Net Loss per Share We generated a net loss of $366.3 million for 2023 compared to $269.7 million for 2022. Our net loss increased for 2023 compared to 2022 primarily due to factors discussed in the sections above .
Income Tax Expense (Benefit) We recorded an income tax expense of $11.7 million for 2022 compared to an income tax benefit of $0.6 million for 2021. Beginning in 2022, the Tax Cuts and Jobs Act of 2017, or TCJA, requires taxpayers to capitalize and amortize research and development expenditures pursuant to Internal Revenue Code, or IRC, Section 174.
The primary drivers of our income tax expense despite our full year pretax loss relate to the requirement for taxpayers to amortize research and development expenditures over five years pursuant to Internal Revenue Code, or IRC, Section 174 beginning in 2022 under the Tax Cuts and Jobs Act of 2017, or TCJA, and the impact of the royalty purchase agreement with Royalty Pharma, which we reflected as a taxable sale which required us to include the proceeds from the sale, net of currently deductible issuance costs, as taxable income in 2023.
Our cash, cash equivalents and short-term investments, debt obligations and working capital decreased from 2021 to 2022. In 2021, we issued $632.5 million of 0% Notes (due in April 2026) and we used a portion of the proceeds to repurchase $247.9 million of our 1% Notes in April 2021.
Additionally, from our inception through December 31, 2023 , we have borrowed approximately $ 2.7 billion under long-term debt arrangements and received proceeds of $0.5 billion from the sale of future royalties to finance a portion of our operations. Our cash, cash equivalents and short-term investments, working capital and long-term obligations increased from 2022 to 2023.
Removed
Overview As noted in our Business Overview in Part I of this report, we were founded over 30 years ago to deliver innovative new medicines for diseases with great medical need. Today, we are building on our advancements in RNA-targeted therapeutics with a vision to be the leader in genetic medicines.
Added
We discuss such risks, uncertainties and other factors throughout this report and specifically under Item 1A of Part I of this report, Risk Factors .
Removed
We believe our genetic medicines have the potential to pioneer new markets, change standards of care and transform the lives of people with devastating diseases. We currently have three marketed medicines: SPINRAZA, TEGSEDI and WAYLIVRA. We also have two medicines, eplontersen and tofersen, that will add to our commercial portfolio this year, assuming positive regulatory outcomes.
Added
Overview As noted in our Business Overview in Part I of this report, for three decades, we have invented medicines that we believe bring better futures to people with serious diseases. Today, as a pioneer in RNA-targeted medicines, we continue to drive innovation in RNA therapies. We currently have five marketed medicines: SPINRAZA, QALSODY, WAINUA, TEGSEDI and WAYLIVRA.
Removed
SPINRAZA royalties, the largest contributor to our commercial revenue, increased each quarter in 2022. Total SPINRAZA product sales increased six percent in the fourth quarter of 2022 compared to the third quarter of 2022 and also increased four percent compared to the same quarter in 2021.
Added
Commercial revenue for 2023 included $240 million from SPINRAZA royalties, which were relatively consistent compared to 2022. Our commercial revenue in 2023 also included royalties from QALSODY U.S. product sales. Our R&D revenue increased in 2023 compared to 2022 primarily due to continued success with our pipeline and technology.
Removed
The increases were driven by stabilization in the U.S. and growth in Asian markets, partially offset by competition in Europe. Total SPINRAZA product sales decreased six percent year-over-year driven by foreign currency exchange and competition in Europe, partially offset stabilization in the U.S. and growth in Asian markets.
Added
As a result, we earned significant partner payments, including $50 million from AstraZeneca for the FDA approval of WAINUA for ATTRv-PN in the U.S., $36 million from AstraZeneca for licensing ION826 and payments from our new collaborations with Otsuka, Roche and Novartis.
Removed
Our TEGSEDI and WAYLIVRA revenue was also lower year-over-year due to the shift to distribution fees in 2021.
Added
Under the terms of the collaboration agreement, AstraZeneca is currently paying 55 percent of the costs associated with the ongoing global Phase 3 development program.
Removed
Our R&D revenue for 2022 included $112 million from Biogen for advancing several neurology disease programs, $77 million from AstraZeneca for its share of the global Phase 3 development costs for eplontersen and $64 million from Roche for licensing and advancing IONIS-FB-L Rx , among other partnered payments.
Added
The following table sets forth information on revenue and expenses under this collaboration (in millions): Year Ended December 31, 2023 2022 WAINUA joint development revenue $ 126.4 $ 76.8 Research and development expenses related to Phase 3 development expenses for WAINUA 150.8 147.1 Medical affairs expenses for WAINUA 4.1 2.0 Commercialization expenses for WAINUA 15.6 2.6 70 Table of Contents Our WAINUA joint development revenue in 2023 includes a $50 million milestone payment from AstraZeneca that we earned when the FDA approved WAINUA for ATTRv-PN in the U.S.
Removed
R&D revenue was higher in 2021 compared to 2022 driven primarily by the $200 million we earned in the fourth quarter of 2021 from AstraZeneca to jointly develop and commercialize eplontersen.
Added
Our R&D expenses increased as we advanced our pipeline, which included an increase in the costs associated with our clinical studies as most of our Phase 3 studies were either fully enrolled or approaching full enrollment at the end of 2023. Our SG&A expenses increased due to expenses related to our launch preparation activities for WAINUA, olezarsen and donidalorsen.
Removed
In the year ended December 31, 2022, we earned $77 million in joint development revenue and recorded $147M of R&D expenses related to Phase 3 development expenses under this collaboration.
Added
Our manufacturing procedures include testing to satisfy good laboratory and good manufacturing practice requirements.
Removed
Our R&D expenses increased in 2022 compared to 2021 due to our investments in advancing our late-stage pipeline, including the expanded number of Phase 3 studies we are conducting, which doubled from three to six studies in 2021.
Added
In addition, we recorded a one-time expense of $20 million when we terminated a build-to-suit lease agreement in August 2023. Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments , in the Notes to the Consolidated Financial Statements for further details on the lease termination .
Removed
Our SG&A expenses decreased in 2022 compared to 2021 as a result of savings we realized from integrating Akcea and restructuring our commercial operations for TEGSEDI and WAYLIVRA, partially offset by the increase in expenses related to our go-to-market activities for eplontersen, donidalorsen and olezarsen.
Added
Our cash balance increased due to the $500.0 million upfront payment we received in January 2023 from our royalty purchase agreement with Royalty Pharma Investments, or Royalty Pharma, net proceeds we received from the debt offering in June 2023 and payments from partners.
Removed
Our non-cash compensation expense related to equity awards decreased in 2022 compared to 2021 as a result of the decrease in our stock price in 2022 compared to 2021 and reduced headcount due to restructuring our commercial operations in 2021.
Added
These increases were partially offset by the repurchase of $504.4 million in principal of our 0.125% Notes during 2023.
Removed
We anticipate our non-cash compensation expense related to equity awards to increase in 2023 due to increased headcount and an increase in our stock price when we granted annual equity awards to our employees in January 2023 compared to January 2022.
Added
As a result, beginning in the second quarter of 2023, our interest expense related to our convertible notes increased because we began incurring interest expense for our 1.75% Notes. 74 Table of Contents Interest Expense Related to Sale of Future Royalties We recorded $ 68.8 million of interest expense related to the sale of future royalties in 2023 as a result of the Royalty Pharma transaction, in which we sold a minority interest in our future SPINRAZA and pelacarsen royalties to Royalty Pharma for a $500 million upfront payment and $625 million of potential future payments.
Removed
In 2021, we incurred certain licensing expenses, including $35 million for licensing Bicycle Therapeutics’ peptide technology.

… 21 more changes not shown on this page.

Item 7A. Quantitative and Qualitative Disclosures About Market Risk

Market Risk — interest-rate, FX, commodity exposure

1 edited+0 added−0 removed2 unchanged
Biggest changeAccordingly, we believe that, while the securities we hold are subject to changes in the financial standing of the issuer of such securities, we were not subject to any material risks arising from changes in interest rates, foreign currency exchange rates, commodity prices, equity prices or other market changes that affect market risk sensitive instruments as of December 31, 2022 and will not be subject to any material risks arising from these changes in the foreseeable future .
Biggest changeAccordingly, we believe that, while the securities we hold are subject to changes in the financial standing of the issuer of such securities, we were not subject to any material risks arising from changes in interest rates, foreign currency exchange rates, commodity prices, equity prices or other market changes that affect market risk sensitive instruments as of December 31, 2023 and will not be subject to any material risks arising from these changes in the foreseeable future .

Other IONS 10-K year-over-year comparisons