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What changed in PROTHENA CORP PUBLIC LTD CO's 10-K — 2023 vs 2024

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Paragraph-level year-over-year comparison of PROTHENA CORP PUBLIC LTD CO's 2023 and 2024 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 2024 report.

+342 added−316 removedSource: 10-K (2025-02-27) vs 10-K (2024-02-22)

Top changes in PROTHENA CORP PUBLIC LTD CO's 2024 10-K

342 paragraphs added · 316 removed · 266 edited across 8 sections

Item 1. Business

Business — how the company describes what it does

96 edited+62 added−34 removed202 unchanged
Biggest changeIf our operations are found to be in violation of any of such laws or any other governmental regulations that apply to us, we may be subject to penalties, including, without limitation, civil and criminal penalties, damages, fines, the curtailment or restructuring of our operations, exclusion from participation in federal and state healthcare programs and imprisonment, any of which could adversely affect our ability to operate our business and our financial results.
Biggest changeIf any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of civil, criminal and administrative penalties, damages, disgorgement, monetary fines, individual imprisonment, additional reporting obligations and oversight if we become subject to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with these laws, possible exclusion from participation in federal healthcare programs, contractual damages, reputational harm, diminished profits and future earnings, and curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.
Instead, our internally discovered pipeline has generated multiple proof points that our molecules have successfully influenced biology in a manner that translates into clinical benefit. We’ve most recently demonstrated this in AL amyloidosis, ATTR amyloidosis, and Parkinson’s disease where preclinical findings in our programs have translated to positive clinical data. 2 • Focus on diseases that lack effective therapies.
Instead, our internally discovered pipeline has generated multiple proof points that our molecules have successfully influenced biology in a manner that translates into clinical benefit. We’ve most recently 2 demonstrated this in AL amyloidosis, ATTR amyloidosis, and Parkinson’s disease where preclinical findings in our programs have translated to positive clinical data. • Focus on diseases that lack effective therapies.
Confirmatory Phase 3 AFFIRM-AL Clinical Trial Design under SPA Agreement with the FDA Based on further analyses of data from the VITAL clinical trial and multiple in-depth discussions with the FDA, Prothena announced plans in February 2021, to advance birtamimab into the confirmatory Phase 3 AFFIRM-AL clinical trial in patients with Mayo Stage IV AL amyloidosis.
Confirmatory Phase 3 AFFIRM-AL Clinical Trial Design under SPA Agreement with FDA Based on further analyses of data from the VITAL clinical trial and multiple in-depth discussions with the FDA, Prothena announced plans in February 2021, to advance birtamimab into the confirmatory Phase 3 AFFIRM-AL clinical trial in patients with Mayo Stage IV AL amyloidosis.
In addition to the $30.0 million upfront payment and clinical milestone payment of $15.0 million (both in 2014), the clinical milestone payment of $30.0 million in 2017, and the clinical milestone payment of $60 million in 2021, Roche is also obligated to pay: • up to $290.0 million upon the achievement of additional development, regulatory and various first commercial sales milestones; • up to $155.0 million upon the achievement of U.S. commercial sales milestones; • up to $175.0 million upon achievement of ex-U.S. commercial sales milestones; and • tiered, high single-digit to high double-digit royalties in the teens based on U.S. and ex-U.S. annual net sales, subject to certain adjustments, with respect to the applicable Licensed Product.
In addition to the $ $30.0 million upfront payment and clinical milestone payment of $15.0 million (both in 2014), the clinical milestone payment of $30.0 million in 2017, and the clinical milestone payment of $60.0 million in 2021, Roche is also obligated to pay: 8 • up to $290.0 million upon the achievement of additional development, regulatory and various first commercial sales milestones; • up to $155.0 million upon the achievement of U.S. commercial sales milestones; • up to $175.0 million upon achievement of ex-U.S. commercial sales milestones; and • tiered, high single-digit to high double-digit royalties in the teens based on U.S. and ex-U.S. annual net sales, subject to certain adjustments, with respect to the applicable Licensed Product.
Prasinezumab also delayed time to clinically meaningful worsening of motor progression in prasinezumab-treated patients vs. 7 placebo over 52 weeks as demonstrated by site rating of time to at least a 5-point progression in MDS-UPDRS Part III (pooled dose levels: HR=0.82, 80% CI=0.64 to 0.99, p=0.17; low dose level: HR=0.77, 80% CI=0.63 to 0.96; and high dose level: HR=0.87, CI=0.70 to 1.07).
Prasinezumab also delayed time to clinically meaningful worsening of motor progression in prasinezumab-treated patients vs. placebo over 52 weeks as demonstrated by site rating of time to at least a 5-point progression in MDS-UPDRS Part III (pooled dose levels: HR=0.82, 80% CI=0.64 to 0.99, p=0.17; low dose level: HR=0.77, 80% CI=0.63 to 0.96; and high dose level: HR=0.87, CI=0.70 to 1.07).
During the seven-year exclusivity period, the FDA may not approve any other applications to market the same drug for the same orphan indication, except in limited circumstances, such as demonstration of clinical superiority to the product with orphan exclusivity or if FDA finds that the holder of the orphan drug exclusivity has not shown 17 that it can assure the availability of sufficient quantities of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated.
During the seven-year exclusivity period, the FDA may not approve any other applications to market the same drug for the same orphan indication, except in limited circumstances, such as demonstration of clinical superiority to the product with orphan exclusivity or if FDA finds that the holder of the orphan drug exclusivity has not shown that it can assure the availability of sufficient quantities of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated.
This may include activities such as testing and characterizing our potential therapeutic candidates and gaining feedback and guidance on our programs through advisory boards. 3 • Pursue commercialization strategies to maximize the value of our product candidates or future potential products. As we move our drug candidates through development toward regulatory approval, we will evaluate several strategic options for commercialization.
This may include activities such as testing and characterizing our potential therapeutic candidates and gaining feedback and guidance on our programs through advisory boards. • Pursue commercialization strategies to maximize the value of our product candidates or future potential products. As we move our drug candidates through development toward regulatory approval, we will evaluate several strategic options for commercialization.
The published data demonstrate that in a post hoc analysis of patients with Mayo Stage IV AL amyloidosis, a statistically significant survival benefit of 74 percent was observed for those treated with birtamimab plus standard of care (SOC) versus 49 percent in patients on placebo plus SOC at 9 months (HR 0.413, p=0.021).
The published data demonstrate that in a post hoc analysis of patients with Mayo Stage IV AL amyloidosis, a statistically significant survival benefit of 74 percent was observed for those treated with birtamimab plus standard of care (“SOC”) versus 49 percent in patients on placebo plus SOC at 9 months (HR 0.413, p=0.021).
You can also obtain copies of these documents free of charge by writing or telephoning us at: Prothena Corporation plc, 77 Sir John Rogerson’s Quay, Block C, Grand Canal Docklands, Dublin 2, D02 VK60, Ireland, +353-1-236-2500, or through the Investors page of our website.
You can also obtain copies of these documents free of charge by writing or telephoning us at: Prothena Corporation plc, 77 Sir John Rogerson’s Quay, Block C, Grand Canal Docklands, Dublin 2, D02 VK60, Ireland, +353-1-236-2500, or through the Investors page of our website. 23
Additionally, any significant change in the approved product or in how it is manufactured, including changes in formulation or the site of manufacture, generally 16 require prior FDA approval of a supplemental BLA. The packaging and labeling of all products developed by us are also subject to FDA approval and ongoing regulation and oversight.
Additionally, any significant change in the approved product or in how it is manufactured, including changes in formulation or the site of manufacture, generally require prior FDA approval of a supplemental BLA. The packaging and labeling of all products developed by us are also subject to FDA approval and ongoing regulation and oversight.
Those licenses are worldwide, fully paid, royalty-free, perpetual and irrevocable, and relate to our program targeting α - synuclein. Subsequent to entering into this Agreement, Elan was acquired by Perrigo Company plc. Competition 19 The pharmaceutical industry is highly competitive.
Those licenses are worldwide, fully paid, royalty-free, perpetual and irrevocable, and relate to our program targeting α - synuclein. Subsequent to entering into this Agreement, Elan was acquired by Perrigo Company plc. Competition The pharmaceutical industry is highly competitive.
In addition, administrative remedies can involve requests to recall violative products, the refusal of the government to enter into supply contracts; or the refusal to approve pending applications for product approvals until manufacturing or other alleged deficiencies are brought into compliance.
In addition, administrative remedies can involve requests to recall violative products, the refusal of the government to enter into supply contracts; or the refusal to approve pending 12 applications for product approvals until manufacturing or other alleged deficiencies are brought into compliance.
Bribery Act prohibit companies and their representatives from offering, promising, authorizing or making payments to governmental officials (and certain private individuals under the Irish Corruption Act and the U.K. Bribery Act) for the purpose of obtaining or retaining business abroad.
Bribery Act prohibit companies and their representatives from offering, promising, authorizing or making payments to governmental officials (and certain private individuals under the Irish Corruption Act and 16 the U.K. Bribery Act) for the purpose of obtaining or retaining business abroad.
We engage and collaborate with consultants and advisors with certain scientific, clinical or other functional and/or disease area expertise to help us execute specific activities related to our programs.
We engage and collaborate with consultants and advisors with certain scientific, clinical or other functional and/or disease area expertise to 3 help us execute specific activities related to our programs.
Parkinson’s disease is a progressive degenerative disorder of the central nervous system (CNS) that affects approximately one in 100 people over the age of 60, with incidence increasing based on an aging population. With an estimated 10 million people living with Parkinson’s disease worldwide today, it is the most common neurodegenerative movement disorder and fastest growing neurological disorder.
Parkinson’s disease is a progressive degenerative disorder of the central nervous system (“CNS”) that affects approximately one in 100 people over the age of 60, with incidence increasing based on an aging population. With an estimated 10 million people living with Parkinson’s disease worldwide today, it is the most common neurodegenerative movement disorder and fastest growing neurological disorder.
Birtamimab binds to both soluble and insoluble amyloid aggregates in multiple organs and promotes the clearance of amyloid deposits via phagocytosis. This depleter mechanism of action broadly targets misfolded kappa and lambda light chain to clear deposited amyloid that causes organ dysfunction and failure in patients with AL amyloidosis.
Birtamimab binds to both soluble and insoluble amyloid aggregates in multiple organs and promotes the clearance of amyloid deposits via phagocytosis. This anti-amyloid mechanism of action broadly targets misfolded kappa and lambda light chain to clear deposited amyloid that causes organ dysfunction and failure in patients with AL amyloidosis.
Roche is responsible for the clinical and commercial 8 manufacture and supply of Licensed Products within a defined time period following the effective date of the License Agreement. We have so far earned $135 million of a total $755 million in potential clinical, regulatory and sales milestones.
Roche is responsible for the clinical and commercial manufacture and supply of Licensed Products within a defined time period following the effective date of the License Agreement. We have so far earned $135.0 million of a total $755.0 million in potential clinical, regulatory and sales milestones.
MDS-UPDRS Part III is a clinical examination of motor function that assesses motor symptoms associated with Parkinson’s disease.
MDS- 7 UPDRS Part III is a clinical examination of motor function that assesses motor symptoms associated with Parkinson’s disease.
NNC6019 (formerly PRX004) for the Potential Treatment of ATTR Amyloidosis NNC6019 (formerly PRX004) is an investigational antibody designed to deplete amyloid associated with disease pathology in hereditary and wild type ATTR amyloidosis, without affecting the native, normal tetrameric form of the protein.
Coramitug (formerly PRX004) for the Potential Treatment of ATTR Amyloidosis Coramitug is an investigational antibody designed to deplete amyloid associated with disease pathology in hereditary and wild type ATTR amyloidosis, without affecting the native, normal tetrameric form of the protein.
The therapeutic approaches we are developing with birtamimab for AL amyloidosis and NNC6019 (formerly PRX004) for ATTR amyloidosis, are investigational monoclonal antibodies designed to clear the pathogenic amyloid deposits. Birtamimab and NNC6019 are designed to target and clear amyloid deposited in organs in order to improve organ function.
The therapeutic approaches we are developing with birtamimab for AL amyloidosis and coramitug (formerly PRX004) for ATTR amyloidosis, are investigational monoclonal antibodies designed to clear the pathogenic amyloid deposits. Birtamimab and coramitug are designed to target and clear amyloid deposited in organs in order to improve organ function.
No clinically relevant changes were observed in other safety parameters. BMS-986446 also met key pharmacokinetic (PK) and immunogenicity secondary endpoints. Plasma drug concentrations of BMS-986446 increased in a dose-proportional manner.
No clinically relevant changes were observed in other safety parameters. BMS-986446 also met key pharmacokinetic (“PK”) and immunogenicity secondary endpoints. Plasma drug concentrations of BMS-986446 increased in a dose-proportional manner.
Furthermore, BMS-986446 exposure in cerebrospinal fluid (CSF) was measured in the high dose cohort and based on the robust exposure of BMS-986446 in the CSF (day 29 CSF:Plasma ratio=0.2%), substantial target engagement is expected in the CNS. BMS-986446 had a desirable immunogenicity profile with no persistent BMS-986446-induced antidrug antibodies (ADAs) observed.
Furthermore, BMS-986446 exposure in cerebrospinal fluid (“CSF”) was measured in the high dose cohort and based on the robust exposure of BMS-986446 in the CSF (day 29 CSF:Plasma ratio=0.2%), substantial target engagement is expected in the CNS. BMS-986446 had a desirable immunogenicity profile with no persistent BMS-986446-induced antidrug antibodies (“ADA”s) observed.
There are currently no approved treatments for AL amyloidosis that have demonstrated a survival benefit, and there is an urgent unmet medical need for therapies that improve survival in patients at risk for early mortality due to amyloid deposition.
There are currently no approved treatments for AL amyloidosis that have demonstrated a survival benefit in a randomized clinical trial, and there is an urgent unmet medical need for therapies that improve survival in patients at risk for early mortality due to amyloid deposition.
Trial participants received a single dose of BMS-986446 or placebo intravenously (IV) and were followed for up to two months. The results of the trial found all three dose level cohorts of BMS-986446 to be generally safe and well tolerated, meeting the Phase 1 SAD trial primary objective. None of the treatment emergent adverse events (TEAE) were serious.
Trial participants received a single dose of BMS-986446 or placebo intravenously (“IV”) and were followed for up to two months. The results of the trial found all three dose level cohorts of BMS-986446 to be generally safe and well tolerated, meeting the Phase 1 SAD trial primary objective. None of the treatment emergent adverse events (“TEAE”) were serious.
Birtamimab is the only investigational therapeutic that has demonstrated a significant survival benefit in patients with Mayo Stage IV AL amyloidosis. Birtamimab has been granted Fast Track Designation by the U.S.
Birtamimab is the only investigational therapeutic that has demonstrated a significant survival benefit in a randomized clinical trial in patients with Mayo Stage IV AL amyloidosis. Birtamimab has been granted Fast Track Designation by the U.S.
The FDA and other comparable regulatory authorities also have the authority to cause the withdrawal of approval of a marketed product or to impose additional labeling or distribution restrictions. 13 The pricing of pharmaceutical and biological products is regulated in many countries and the mechanism of price regulation varies.
The FDA, the EMA and comparable regulatory authorities in other countries also have the authority to cause the revocation of approval of a marketed product or to impose additional labeling or distribution restrictions. The pricing of pharmaceutical and biological products is regulated in many countries and the mechanism of price regulation varies.
We are also entitled to certain potential milestone payments pursuant to our share purchase agreement with Novo Nordisk pertaining to our ATTR amyloidosis business (NNC6019, formerly PRX004). We were formed on September 26, 2012, under the laws of Ireland and re-registered as an Irish public limited company on October 25, 2012.
We are also entitled to certain potential milestone payments pursuant to the Company’s share purchase agreement with Novo Nordisk pertaining to the Company’s ATTR amyloidosis business (inclusive of coramitug, formerly PRX004). We were formed on September 26, 2012, under the laws of Ireland and re-registered as an Irish public limited company on October 25, 2012.
ATTR Amyloidosis Business Acquired by Novo Nordisk In July 2021, we announced that we and Novo Nordisk entered into a definitive purchase agreement under which Novo Nordisk acquired our clinical stage antibody NNC6019 (formerly PRX004) and broader ATTR amyloidosis business.
ATTR Amyloidosis Business Acquired by Novo Nordisk In July 2021, we announced that we and Novo Nordisk entered into a definitive purchase agreement under which Novo Nordisk acquired our clinical stage antibody coramitug and broader ATTR amyloidosis business.
ITEM 1. BUSINESS Overview Prothena is a late-stage clinical biotechnology company with expertise in protein dysregulation and a pipeline of investigational therapeutics with the potential to change the course of devastating neurodegenerative and rare peripheral amyloid diseases.
ITEM 1. BUSINESS Overview Prothena Corporation plc (“Prothena” or the “Company”) is a late-stage clinical biotechnology company with expertise in protein dysregulation and a pipeline of investigational therapeutics with the potential to change the course of devastating neurodegenerative and rare peripheral amyloid diseases.
A marketing application approved by the EC is valid in all EU member states.
A marketing application approved by the EC is valid in all EEA member states.
Our Research and Development Pipeline Our clinical research and development pipeline includes five therapeutic antibody programs currently in clinical development: birtamimab for the potential treatment of AL amyloidosis; prasinezumab, in collaboration with Roche, for the potential treatment of Parkinson’s disease and other related synucleinopathies; NNC6019, which is being developed by Novo Nordisk, for the potential treatment of ATTR amyloidosis; PRX012 for the potential treatment of Alzheimer’s disease; and BMS-986446, in collaboration with BMS, for the potential treatment of Alzheimer’s disease.
Our Research and Development Pipeline Our clinical research and development pipeline includes six therapeutic antibody programs currently in clinical development: birtamimab for the potential treatment of AL amyloidosis; prasinezumab, in collaboration with Roche, for the potential treatment of Parkinson’s disease and other related synucleinopathies; coramitug, which is being developed by Novo Nordisk, for the potential treatment of ATTR amyloidosis; PRX012 for the potential treatment of Alzheimer’s disease; and BMS-986446 and PRX019, in collaboration with BMS, for the potential treatment of Alzheimer’s disease and neurodegenerative diseases respectively.
For more information, see “Management’s Discussion and Analysis of Financial Condition and Results of Operations.” 20 Employees and Human Capital Management As of December 31, 2023, we had 173 employees, including 42 holding M.D. and/or Ph.D. degrees. Of our employees, 127 were engaged in research and development activities and the remainder were working in general and administrative areas.
For more information, see “Management’s Discussion and Analysis of Financial Condition and Results of Operations.” Employees and Human Capital Management As of December 31, 2024 , we had 163 employees, including 27 holding M.D. and/or Ph.D. degrees. Of our employees, 116 were engaged in research and development activities and the remainder were working in general and administrative areas.
Key elements of our biology-directed discovery engine include: • A focus on pathophysiology-directed targeting focused on targeting proteins with the greatest effect on disease; • Expert epitope mapping with deep expertise in determining optimal epitopes to be targeted for maximal efficacy; and • Disease driven antibody engineering for therapeutics engineered to optimally eliminate pathogenic proteins while preserving normal biology Once we formulate a novel hypothesis or approach, we determine how to optimally intervene against a known target.
Key elements of our biology-directed discovery engine include: • A focus on pathophysiology-directed targeting focused on targeting proteins with the greatest effect on disease; • Expert epitope mapping with deep expertise in determining optimal epitopes to be targeted for maximal efficacy; and • Disease driven antibody engineering for therapeutics engineered to optimally eliminate pathogenic proteins while preserving normal biology.
As of December 31, 2023, our patent portfolio included the following families of patents or patent applications that we own or have exclusively licensed from other parties: • Approximately 8 patent families related to AL or AA amyloidosis, including our birtamimab program, including a composition of matter patent anticipated to expire 2029 (subject to potential adjustments in patent term as described below); • Approximately 16 patent families related to passive immunotherapy for Parkinson’s disease and other synucleinopathies, including our prasinezumab program, including a composition of matter patent anticipated to expire in 2032 (subject to potential adjustments in patent term as described below); • Approximately 12 patent families related to passive immunotherapy for Alzheimer's disease, including our PRX005 and PRX012 programs; and • Approximately 24 patent families related to other potential targets of intervention and diseases and other product candidates, including PRX019 and vaccines. 18 The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained.
As of December 31, 2024, our patent portfolio included the following families of patents or patent applications that we own or have exclusively licensed from other parties: • Approximately 9 patent families related to AL or AA amyloidosis, including our birtamimab program, including a composition of matter patent anticipated to expire 2029 (subject to potential adjustments in patent term as described below); • Approximately 16 patent families related to passive immunotherapy for Parkinson’s disease and other synucleinopathies, including our prasinezumab program, including a composition of matter patent anticipated to expire in 2032 (subject to potential adjustments in patent term as described below); 20 • Approximately 14 patent families related to passive immunotherapy for Alzheimer's disease, including our PRX005 and PRX012 programs; and • Approximately 20 patent families related to other potential targets of intervention and diseases and other product candidates, including PRX019 and vaccines.
In July 2023, we entered into 10 the Tau Global License Agreement, which as discussed above supersedes and replaces the Tau US License Agreement in its entirety. We received the associated option exercise fee of $55 million in August 2023.
In July 2023, we entered into an exclusive global license agreement for BMS-986446, which as discussed above supersedes and replaces the US license agreement in its entirety and we received an associated option exercise fee of $55 million.
In January 2024, we announced that topline Phase 1 data from the single-ascending dose (SAD) trial and the initial multiple-ascending dose (MAD) 12 cohort (70 mg) supports once-monthly subcutaneous treatment and dose escalation. The ongoing Phase 1 trial continues as planned.
In January 2024, we announced that topline Phase 1 data from the single ascending dose trial and the initial multiple dose cohort (70 mg) supports single-injection once-monthly subcutaneous treatment and dose escalation.
Under the centralized procedure, a sponsor submits a single application to the EMA. The marketing application is similar to the BLA submitted to FDA in the U.S. and is evaluated by the Committee for Medicinal Products for Human Use (the “CHMP”), the expert scientific committee of the EMA.
The marketing application is similar to the BLA submitted to the FDA in the U.S. and is evaluated by the Committee for Medicinal Products for Human Use (the 15 “CHMP”), the expert scientific committee of the EMA.
In January 2024, we announced that the FDA has cleared the IND application for PRX123 and granted PRX123 Fast Track designation. PRX019, a potential treatment for neurodegenerative diseases In December 2023, the FDA cleared the IND application for PRX019, a potential treatment of neurodegenerative diseases with an undisclosed target.
In January 2024, we announced that the FDA has cleared the IND application for PRX123 and granted PRX123 Fast Track designation. PRX019 for the Potential Treatment of Neurodegenerative Diseases PRX019 is an investigational antibody for the potential treatment of neurodegenerative diseases in development in collaboration with BMS. In December 2023, the FDA cleared the IND application for PRX019.
In addition to the centralized procedure, the EU also has: (i) national authorization procedures, which requires a separate application in and approval determination by each country; (ii) a decentralized procedure, whereby applicants submit identical applications to several countries and receive simultaneous approval; and (iii) a mutual recognition procedure, where applicants submit an application to one country for review and approval, and other countries may accept or reject the decision in the initial country.
National marketing authorization are available for product candidates not falling within the mandatory scope of the centralized procedure, namely: (i) national authorization procedures, which requires a separate application in and approval determination by each country; (ii) a decentralized procedure, whereby applicants submit identical applications to several countries and receive simultaneous approval; and (iii) a mutual recognition procedure, where applicants submit an application to one country for review and approval, and other countries may accept or reject the decision in the initial country.
Furthermore, the FDA can waive orphan exclusivity if we are unable to manufacture sufficient supply of our product. Pharmaceutical Coverage, Pricing and Reimbursement Sales of our products will depend, in part, on the extent to which our products will be covered by third-party payors, such as federal, state and other government health care programs, commercial insurance and managed healthcare organizations.
Pharmaceutical Coverage, Pricing and Reimbursement Sales of our products will depend, in part, on the extent to which our products will be covered by third-party payors, such as federal, state and other government health care programs, commercial insurance and managed healthcare organizations.
Additionally, approval must also be obtained from each clinical trial site’s Institutional Review Board (“IRB”) before the trials may be initiated, and the IRB must provide oversight of the trials until completed. There are also requirements governing the reporting of ongoing clinical trials and clinical trial results to public registries.
Additionally, approval must also be obtained from each clinical trial site’s Institutional Review Board (“IRB”) before the trials may be initiated, and the IRB must provide oversight of the trials until completed.
Prasinezumab is the first anti-alpha synuclein antibody to advance into late-stage development. In March 2022, results from the analysis of part 2 of the Phase 2 PASADENA trial of prasinezumab were presented in an oral presentation by Roche at the International Conference on Alzheimer’s and Parkinson’s Diseases (“AD/PD 2022”).
In March 2022, results from the analysis of part 2 of the Phase 2 PASADENA trial of prasinezumab were presented in an oral presentation by Roche at the International Conference on Alzheimer’s and Parkinson’s Diseases (“AD/PD 2022”).
Phase 1 clinical trials are typically more closely monitored and may be conducted in patients with the target disease or condition or in healthy volunteers.
Phase 1 includes the initial introduction of an investigational product into humans. Phase 1 clinical trials are typically more closely monitored and may be conducted in patients with the target disease or condition or in healthy volunteers.
We employ a combination of our understanding of normal protein structure, computational antibody design technologies, and an empirical and unbiased screening process to determine the optimal epitope to target on a pathogenic protein.
Once we formulate a novel hypothesis or approach, we determine how to optimally intervene against a known target. We employ a combination of our understanding of normal protein structure, computational antibody design technologies, and an empirical and unbiased screening process to determine the optimal epitope to target on a pathogenic protein.
We have earned approximately $100 million to date, including a $40 million clinical milestone payment that we announced in November 2022. A Phase 2 clinical trial of NNC6019 in patients with ATTR cardiomyopathy is being conducted by Novo Nordisk (NCT05442047).
We have earned approximately $100 million to date. A Phase 2 clinical trial of coramitug in approximately 99 patients with ATTR amyloidosis with cardiomyopathy is being conducted by Novo Nordisk (NCT05442047).
AFFIRM-AL is a registration-enabling Phase 3 clinical trial that is being conducted with a primary endpoint of all-cause mortality at p 0.10 under a Special Protocol Assessment (SPA) agreement with the FDA.
AFFIRM-AL is a registration-enabling Phase 3 clinical trial that is being conducted with a primary endpoint of time to all-cause mortality at p 0.10 under a Special Protocol Assessment (SPA) agreement with the FDA. Patient enrollment is on track in the AFFIRM-AL trial and topline trial results are expected in the second quarter of 2025.
For this reason, the laws and regulations discussed below focus on the requirements applicable to biologic products in the U.S. Government Regulation Governmental authorities, including the FDA, the EMA and comparable regulatory authorities in other countries, regulate the development, testing, use, labeling, manufacturing, storage, recordkeeping, reporting, marketing, advertising, promotion, tracking and tracing of pharmaceutical and biological products.
Government Regulation Governmental authorities, including the FDA, the EMA and comparable regulatory authorities in other countries, regulate the development, testing, use, labeling, manufacturing, storage, recordkeeping, reporting, marketing, advertising, promotion, tracking and tracing of pharmaceutical and biological products. The FDA does so under the U.S.
Elan License Agreement: Under an Amended and Restated Intellectual Property License and Contribution Agreement with Elan and certain of its affiliates, we have exclusively licensed from Elan and those affiliates certain patents and patent applications owned by them, and exclusively sublicensed from Elan and those affiliates certain patents and patent applications owned by Janssen Alzheimer Immunotherapy.
We may terminate the agreement prior to the end of its term upon a 90 day written notice to the University of California. 21 Elan License Agreement: Under an Amended and Restated Intellectual Property License and Contribution Agreement with Elan and certain of its affiliates, we have exclusively licensed from Elan and those affiliates certain patents and patent applications owned by them, and exclusively sublicensed from Elan and those affiliates certain patents and patent applications owned by Janssen Alzheimer Immunotherapy.
Information about Segment and Geographic Revenue Information about segment and geographic revenue is set forth in Note 2 to the Consolidated Financial Statements included in this report. Available information Our principal executive office is at 77 Sir John Rogerson’s Quay, Block C, Grand Canal Docklands, Dublin 2, D02 VK60, Ireland, and our telephone number at that address is +353-1-236-2500.
Available information Our principal executive office is at 77 Sir John Rogerson’s Quay, Block C, Grand Canal Docklands, Dublin 2, D02 VK60, Ireland, and our telephone number at that address is +353-1-236-2500.
PASADENA is a two-part Phase 2 clinical trial in early Parkinson's disease patients that is being conducted by Roche. Part 1 was a randomized, double-blind, placebo-controlled, three-arm trial and enrolled 316 patients to evaluate the efficacy and safety of prasinezumab in patients over 52 weeks.
Part 1 was a randomized, double-blind, placebo-controlled, three-arm trial and enrolled 316 patients to evaluate the efficacy and safety of prasinezumab in patients over 52 weeks.
New target discovery will focus on areas where we can bring potential new therapies to patients expeditiously through our internal expertise and resources. Existing late discovery-stage or preclinical-stage programs may be partnered or out-licensed. Regulation We anticipate that if we commercialize any products, the U.S. market will ultimately be our most important market.
If promising, we expect to advance our discovery programs into preclinical development. New target discovery will focus on areas where we can bring potential new therapies to patients expeditiously through our internal expertise and resources. Existing late discovery-stage or preclinical-stage programs may be partnered or out-licensed.
TDP-43 is one of the three programs that are the focus of our collaboration with BMS. While we are modality agnostic, we have deep expertise in antibody targeting and have developed a diverse pipeline that includes antibody as well as small molecule and vaccine approaches.
While we are modality agnostic, we have deep expertise in antibody targeting and have developed a diverse pipeline that includes antibody as well as small molecule and vaccine approaches.
In addition to our clinical development pipeline, we have recently received clearance by the FDA for two investigational new drug (IND) applications including PRX123 and PRX019. PRX123 is our Alzheimer’s disease vaccine program and was also granted Fast Track designation from the FDA.
In addition to our clinical development pipeline, we have recently received clearance by the FDA for an investigational new drug (IND) application for PRX123. PRX123 is our Alzheimer’s disease vaccine program and was also granted Fast Track designation from the FDA. We also have a number of discovery- and late-preclinical-stage programs targeting proteins implicated in neurological diseases.
As of December 31, 2023, we employed approximately 65% women and 35% men, and approximately 44% of our employees are racially or ethnically diverse. Our executive team, including employees at or above the vice president level, includes approximately 39% women, and approximately 26% who are racially or ethnically diverse. These figures were estimated by our human resources department.
Our executive team, including employees at or above the vice president level, includes approximately 44% women, and approximately 26% who are racially or ethnically diverse. These figures were estimated by our human resources department. The well-being, health, and safety of our employees are integral to the success of our business.
Noncompliance with applicable requirements can result in warning and untitled letters, civil and criminal fines and other judicially imposed sanctions, including product seizures, import restrictions, injunctive actions and criminal prosecutions of both companies and individuals.
Federal Food, Drug, and Cosmetic Act and its implementing regulations and guidance for industry, and the U.S. Public Health Service Act and its implementing regulations. Noncompliance with applicable requirements can result in warning and untitled letters, civil and criminal fines and other judicially imposed sanctions, including product seizures, import restrictions, injunctive actions and criminal prosecutions of both companies and individuals.
Improving survival for these patients is an area of urgent need which directly aligns with birtamimab and NNC6019’s differentiated depleter mechanism that targets the amyloid that causes organ dysfunction and failure and puts patients at risk for early mortality. Moving forward, we intend to advance new discovery-stage therapeutics for other diseases of protein dysregulation with unmet medical needs.
Improving survival for these patients is an area of urgent need which directly aligns with birtamimab and coramitug’s differentiated depleter mechanism that targets the amyloid that causes organ dysfunction and failure and puts patients at risk for early mortality.
A multiple ascending dose (MAD) portion of the Phase 1 clinical trial is ongoing. In September 2023, BMS reported that Phase 1 data supports moving BMS-986446 into a Phase 2 clinical trial. All program updates going forward, including results from ongoing and any future BMS-986446 clinical trials, will be reported by BMS.
A multiple ascending dose (MAD) portion of the Phase 1 clinical trial was ongoing at the time BMS acquired the global rights to the program and control of the Phase 1 trial. All program updates going forward, including results from ongoing and any future BMS-986446 clinical trials, will be reported by BMS.
We completed a Phase 1 clinical trial with NNC6019 in patients with hereditary forms of ATTR amyloidosis, in which NNC6019 was demonstrated to be safe and well tolerated.
We completed a Phase 1 clinical trial with coramitug in patients with hereditary forms of ATTR amyloidosis, in which coramitug was demonstrated to be safe and well tolerated. In October 2024, these Phase 1 results were published in Amyloid , the official journal of the International Society of Amyloidosis.
We are advancing our lead candidate, PRX012, as a next-generation approach for subcutaneous administration to improve access for patients with Alzheimer’s disease.
We are advancing our lead candidate, PRX012, as a next-generation approach for subcutaneous administration to address the unmet need of millions of patients with presymptomatic or early symptomatic Alzheimer's disease.
NNC6019’s proposed mechanism of action is to deplete both circulating non-native TTR to prevent further deposition and deposited amyloid to improve organ function. NNC6019 has been shown in preclinical studies to inhibit amyloid fibril formation, neutralize soluble aggregate forms of non-native TTR, and promote clearance of insoluble amyloid fibrils through antibody-mediated phagocytosis.
Coramitug has been shown in preclinical studies to inhibit amyloid fibril formation, neutralize soluble aggregate forms of non-native TTR, and promote clearance of insoluble amyloid fibrils through antibody-mediated phagocytosis.
AFFIRM-AL is an ongoing global, multi-center, double-blind, placebo-controlled, 2:1 randomized, time-to-event trial expected to enroll approximately 150 newly diagnosed, treatment naïve patients with AL amyloidosis categorized as Mayo Stage IV. It has been designed to evaluate the primary endpoint of all-cause mortality with a significance level of p 0.10.
AFFIRM-AL is an ongoing global, multi-center, double-blind, placebo-controlled, 2:1 randomized, time-to-event trial expected to enroll up to 220 newly diagnosed, treatment naïve patients with AL amyloidosis categorized as Mayo Stage IV.
Decreases in third-party reimbursement for our drug candidates or a decision by a third-party payor to not cover our drug candidates could reduce physician usage of our products once approved and have a material adverse effect on our sales, results of operations and financial condition.
A decision by a third-party payor to limit or not cover a product candidate could reduce physician utilization once the product is approved and have an adverse effect on sales, results of operations and financial condition.
Phase 1 Clinical T rials In this first-in-human, randomized, placebo controlled, single ascending dose (SAD) clinical trial, healthy volunteers (n=19) were enrolled into three BMS-986446 dose level cohorts (low, medium or high dose) and randomized in a 3:1 drug to placebo ratio.
We are eligible to receive regulatory and sales milestone payments of up to $563 million, as well as tiered royalties on annual, worldwide net sales. 10 Phase 1 Clinical Trial In this first-in-human, randomized, placebo controlled, single ascending dose (“SAD”) clinical trial, healthy volunteers (n=19) were enrolled into three BMS-986446 dose level cohorts (low, medium or high dose) and randomized in a 3:1 drug to placebo ratio.
The clinical investigation of a pharmaceutical, including a biologic, is generally divided into three phases. Although the phases are usually conducted sequentially, they may overlap or be combined. The three phases of an investigation are as follows: 14 • Phase 1. Phase 1 includes the initial introduction of an investigational product into humans.
There are also requirements governing the reporting of ongoing clinical trials and clinical trial results to public registries. 13 The clinical investigation of a pharmaceutical, including a biologic, is generally divided into three phases. Although the phases are usually conducted sequentially, they may overlap or be combined. The three phases of an investigation are as follows: • Phase 1.
A rolling review allows for completed portions of the application to be submitted and reviewed by the FDA prior to submission of the complete application.
The Fast Track designation provides pharmaceutical manufacturers with opportunities for frequent interactions with FDA during the product’s development and for a rolling review of the BLA. A rolling review allows for completed portions of the application to be submitted and reviewed by the FDA prior to submission of the complete application.
Three late-stage programs in our pipeline are ongoing, including AFFIRM-AL, a registration-enabling Phase 3 clinical trial of birtamimab in Mayo Stage IV patients with AL amyloidosis being conducted under a Special Protocol Assessment (SPA) agreement with FDA with significance level of p≤0.10, a Phase 2b PADOVA clinical trial of prasinezumab in patients with early Parkinson’s disease being conducted by Roche, and a Phase 2 clinical trial of NNC6019 (formerly PRX004) in patients with ATTR cardiomyopathy being conducted by Novo Nordisk.
We are currently conducting the registration-enabling confirmatory Phase 3 AFFIRM-AL clinical trial evaluating birtamimab in Mayo Stage IV patients with AL amyloidosis being conducted under a Special Protocol Assessment (SPA) agreement with FDA with significance level of p≤0.10., In December 2024, our partner Roche announced topline results from the Phase 2b PADOVA clinical trial of prasinezumab in patients with early Parkinson’s disease.
An SPA does not indicate FDA concurrence on every detail in a particular trial protocol, and final marketing approval depends upon factors including the efficacy and safety results from the trial, the overall safety profile and an evaluation of the benefit/risk profile for the product candidate as demonstrated across clinical trials for the target patient population.
An SPA does not indicate FDA concurrence on every detail in a particular trial protocol, and final marketing approval depends upon factors including the efficacy and safety results from the trial, the overall safety profile and an evaluation of the benefit/risk profile for the product candidate as demonstrated across clinical trials for the target patient population. 14 The FDA has four expedited program designations for serious conditions - Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review - to facilitate and expedite development and review of new drugs to address unmet medical needs or provide substantial improvements in the treatment of serious or life-threatening conditions.
Other Healthcare Laws Although we currently do not have any products on the market, if our drug candidates are approved and we begin commercialization, we may be subject to additional healthcare regulation and enforcement by the federal government and by authorities in the states and other jurisdictions in which we conduct our business.
It is likely that additional state and federal healthcare reform measures will continue to be adopted in the future, which could limit the amounts that federal and state governments will pay for healthcare products and services, potentially reducing demand for a pharmaceutical manufacturer’s products or adding additional pricing pressure. 18 Other Healthcare Laws Although we currently do not have any products on the market, if our drug candidates are approved and we begin commercialization, we may be subject to additional healthcare regulation and enforcement by the federal government and by authorities in the states and other jurisdictions in which we conduct our business.
Patent and Trademark Office in granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier-filed patent.
In the U.S., a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the U.S. Patent and Trademark Office in granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier-filed patent.
Prasinezumab - BI manufactured clinical supplies of our drug candidate prasinezumab for our completed Phase 1a single ascending dose and Phase 1b multiple ascending dose clinical trials. Roche, with whom we are collaborating on development of prasinezumab, is manufacturing clinical supplies for the ongoing Phase 2 and any subsequent clinical trials for prasinezumab.
We are dependent on Catalent Pharma and Sharp Sterile to manufacture clinical supplies for our Phase 1 clinical trials and any subsequent clinical trials for PRX012. Prasinezumab - BI manufactured clinical supplies of our drug candidate prasinezumab for our completed Phase 1a single ascending dose and Phase 1b multiple ascending dose clinical trials.
BMS-986446 (formerly PRX005) - Catalent Pharma was our third-party manufacturer of drug substance and Berkshire was our third-party manufacturer for drug product for our drug candidate BMS-986446 for our Phase 1 clinical trial. BMS, with whom we are collaborating on development of BMS-986446, is responsible for manufacturing clinical supplies for any subsequent clinical trials for BMS-986446.
BMS, with whom we are collaborating on development of BMS-986446, is responsible for manufacturing clinical supplies for any subsequent clinical trials for BMS-986446. We are dependent on BMS, and its third-party manufacturers if applicable, to manufacture these clinical supplies. 22 PRX019 - Lonza Ltd (“Lonza”) is our third-party manufacturer for drug substance and drug product for our drug candidate PRX019.
These programs include PRX012, an anti-Aβ antibody designed to be best-in-class and dosed subcutaneously; BMS-986446 (formerly PRX005), an investigational antibody that specifically targets a key epitope within the microtubule binding region (MTBR) of tau, and a potential best-in-class treatment, which is partnered with BMS; and PRX123, a dual Aβ-tau vaccine for the treatment and prevention of Alzheimer’s disease. 1 Key elements of our strategy to achieve our goal are to: • Concentrate our discovery and development efforts in areas where we have decades of scientific expertise and experience.
These programs include PRX012, an anti-Aβ antibody designed to be best-in-class and dosed single-injection once-monthly subcutaneously currently in the ongoing Phase 1 ASCENT clinical trials; BMS-986446 (formerly PRX005), an investigational antibody that specifically targets a key epitope within the microtubule binding region (MTBR) of tau, and a potential best-in-class treatment, currently in an ongoing Phase 2 clinical trial being conducted by our partner BMS; and PRX123, a dual Aβ-tau 1 vaccine for the treatment and prevention of Alzheimer’s disease.
Prasinezumab was found to be generally safe and well tolerated, with the majority of adverse events reported as mild or moderate and similar across placebo and both treatment arms. In October 2020, we announced that Roche and Prothena will advance prasinezumab into a late-stage Phase 2b clinical trial in patients with early Parkinson’s disease.
Prasinezumab was found to be generally safe and well tolerated, with the majority of adverse events reported as mild or moderate and similar across placebo and both treatment arms. Phase 1 Clinical Trials During 2014, together with Roche, we advanced prasinezumab into clinical development with the initiation of two Phase 1 clinical trials.
Additionally, because we have a geographically diverse workforce, including remote working arrangements, we have efforts focused on engagement and integration of our existing and new employees.
We utilize numerous policies and strategies to ensure a safe workplace and laboratory environment, and also provide programs for employee wellness. Additionally, because we have a geographically-dispersed workforce, including remote working arrangements, we have efforts focused on engagement and integration of our existing and new employees.
PRX123, a Dual Aβ-Tau Vaccine for the Potential Treatment and Prevention of Alzheimer’s Disease We are developing a dual vaccine, PRX123, which concomitantly targets key epitopes within both the Aβ and tau proteins.
The ongoing Phase 1 trial continues as planned and we expect to report multiple clinical readouts starting in mid-2025 and continuing throughout the year. 11 PRX123, a Dual Aβ-Tau Vaccine for the Potential Treatment and Prevention of Alzheimer’s Disease We are developing a dual vaccine, PRX123, which concomitantly targets key epitopes within both the Aβ and tau proteins.
In August 2022, Roche presented data at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) from the open-label extension of the PASADENA trial which compared the prasinezumab population with a propensity score-balanced cohort of real-world data (RWD) Parkinson’s Progression Markers Initiative (PPMI).
In October 2024, Roche published results in Nature Medicine from the long term open-label extension of the PASADENA trial, which compared the prasinezumab population with a propensity score-balanced cohort of real-world data (“RWD”) Parkinson’s Progression Markers Initiative (“PPMI”).
We are dependent on Roche, and its third-party manufacturers if applicable, to manufacture these clinical supplies. NNC6019 (formerly PRX004) - Rentschler manufactured clinical supplies of our drug candidate NNC6019 for our completed Phase 1 clinical trial. In July 2021, we sold shares of one of our wholly-owned subsidiaries to Novo Nordisk.
Coramitug (formerly PRX004) - Rentschler manufactured clinical supplies of our drug candidate coramitug for our completed Phase 1 clinical trial. In July 2021, we sold shares of one of our wholly-owned subsidiaries to Novo Nordisk. In connection with the transaction, Novo Nordisk acquired our ATTR amyloidosis business, including our drug candidate coramitug.
We are dependent on SBM, and its third-party manufacturers if applicable, to manufacture these clinical supplies. Research and Development Our research and development expenses totaled $220.6 million, $135.6 million, and $82.3 million in 2023, 2022, and 2021, respectively.
We are dependent on Lonza to manufacture clinical supplies for our Phase 1 clinical trial. Research and Development Our research and development expenses totaled $222.5 million, $220.6 million, and $135.6 million in 2024, 2023, and 2022, respectively.
Our discovery effort targeting TDP-43 for the potential treatm ent of amyotropic lateral sclerosis (ALS) is an example of this. • Pursue strategic business development opportunities and collaborations and leverage external resources. We capitalize on a foundation of internal discovery efforts augmented by collaborations with academic and industry partners and business development activities to build upon our internally generated pipeline.
Moving forward, we intend to advance new discovery-stage therapeutics for other diseases of protein dysregulation with unmet medical needs. • Pursue strategic business development opportunities and collaborations and leverage external resources. We capitalize on a foundation of internal discovery efforts augmented by collaborations with academic and industry partners and business development activities to build upon our internally generated pipeline.
It is generally accepted that, at the time of diagnosis, affected organs in ATTR amyloidosis patients (both hATTR and wtATTR amyloidosis) contain extracellular amyloid deposits. These deposits, together with prefibrillar species, are believed to cause organ dysfunction and failure.
It is estimated that there are approximately 50,000 patients with hATTR worldwide, with approximately 10,000 characterized as hATTR-PN and 40,000 characterized as hATTR-CM. 9 It is generally accepted that, at the time of diagnosis, affected organs in ATTR amyloidosis patients (both hATTR and wtATTR amyloidosis) contain extracellular amyloid deposits.

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Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

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Biggest changeCMS has recently taken steps to implement the IRA, including: on June 30, 2023, issuing guidance detailing the requirements and parameters of the first round of price negotiations, to take place during 2023 and 2024, for products subject to the “maximum fair price” provision that would become effective in 2026; on August 29, 2023, releasing the initial list of ten drugs subject to price negotiations; on November 17, 2023, releasing guidance outlining the methodology for identifying certain manufacturers eligible to participate in a phase-in period where discounts on applicable products will be lower than those required by the Medicare Part D Manufacturer Discount Program; and on December 14, 2023, releasing a list of 48 Medicare Part B products that had an adjusted coinsurance rate based on the inflationary rebate provisions of the IRA for the time period of January 1, 2024 to March 31, 2024.
Biggest changeCMS has also taken steps to implement the IRA, including: on October 2, 2024, releasing final guidance outlining the process for the second round of price negotiations for products subject to the “maximum fair price” provision; on December 20, 2024, releasing a list of 64 Medicare Part B products that had an adjusted coinsurance rate based on the inflationary rebate provisions of the IRA for the time period of January 1, 2025 to March 31, 2025; and on January 17, 2025, releasing a list of fifteen additional drugs covered under Medicare Part D subject to price negotiations during 2025.
In addition, our right to co-promote prasinezumab and other Licensed Products will terminate if we commence a Phase 3 study for a competitive product that treats Parkinson’s disease.
In addition, our right to co-promote prasinezumab and other Licensed Products will terminate if we commence a Phase 3 study for a competitive product that treats Parkinson’s disease.
For example: • others may be able to make drug candidates that are similar to ours but that are not covered by the claims of the patents that we own or have exclusively licensed; • we or our licensors or future collaborators might not have been the first to make the inventions covered by the issued patent or pending patent application that we own or have exclusively licensed; • we or our licensors or future collaborators might not have been the first to file patent applications covering certain of our inventions; • others may independently develop similar or alternative technologies or duplicate any of our technologies without infringing our intellectual property rights; • it is possible that our pending patent applications will not lead to issued patents; • issued patents that we own or have exclusively licensed may be held invalid or unenforceable, as a result of legal challenges by our competitors; • our competitors might conduct research and development activities in countries where we do not have patent rights and then use the information learned from such activities to develop competitive products for sale in our major commercial markets; • we may not develop additional proprietary technologies that are patentable; • we cannot predict the scope of protection of any patent issuing based on our patent applications, including whether the patent applications that we own or in-license will result in issued patents with claims that cover our drug candidates or uses thereof in the United States or in other foreign countries; • the claims of any patent issuing based on our patent applications may not provide protection against competitors or any competitive advantages, or may be challenged by third parties; • if enforced, a court may not hold that our patents are valid, enforceable and infringed; • we may need to initiate litigation or administrative proceedings to enforce and/or defend our patent rights which will be costly whether we win or lose; • we may choose not to file a patent in order to maintain certain trade secrets or know-how, and a third party may subsequently file a patent covering such intellectual property; • we may fail to adequately protect and police our trademarks and trade secrets; and • the patents of others may have an adverse effect on our business, including if others obtain patents claiming subject matter similar to or improving that covered by our patents and patent applications.
For example: • others may be able to make drug candidates that are similar to ours but that are not covered by the claims of the patents that we own or have exclusively licensed; • we or our licensors or future collaborators might not have been the first to make the inventions covered by the issued patent or pending patent application that we own or have exclusively licensed; • we or our licensors or future collaborators might not have been the first to file patent applications covering certain of our inventions; • others may independently develop similar or alternative technologies or duplicate any of our technologies without infringing our intellectual property rights; • it is possible that our pending patent applications will not lead to issued patents; • issued patents that we own or have exclusively licensed may be held invalid or unenforceable, as a result of legal challenges by our competitors; • our competitors might conduct research and development activities in countries where we do not have patent rights and then use the information learned from such activities to develop competitive products for sale in our major commercial markets; • we may not develop additional proprietary technologies that are patentable; • we cannot predict the scope of protection of any patent issuing based on our patent applications, including whether the patent applications that we own or in-license will result in issued patents with claims that cover our drug candidates or uses thereof in the United States or in other foreign countries; • the claims of any patent issuing based on our patent applications may not provide protection against competitors or any competitive advantages, or may be challenged by third parties; • if enforced, a court may not hold that our patents are valid, enforceable and infringed; • we may need to initiate litigation or administrative proceedings to enforce and/or defend our patent rights which will be costly whether we win or lose; 55 • we may choose not to file a patent in order to maintain certain trade secrets or know-how, and a third party may subsequently file a patent covering such intellectual property; • we may fail to adequately protect and police our trademarks and trade secrets; and • the patents of others may have an adverse effect on our business, including if others obtain patents claiming subject matter similar to or improving that covered by our patents and patent applications.
Research, development, commercialization and/or strategic collaborations, including those that we have with Roche and BMS, are subject to numerous risks, which include the following: • collaborators may have significant control or discretion in determining the efforts and resources that they will apply to a collaboration, and might not commit sufficient efforts and resources or might misapply those efforts and resources; • we may have limited influence or control over the approaches to research, development, and/or commercialization of products candidates in the territories in which our collaboration partners lead research, development, and/or commercialization; • collaborators might not pursue research, development, and/or commercialization of collaboration drug candidates or might elect not to continue or renew research, development, and/or commercialization programs based on nonclinical and/or clinical trial results, changes in their strategic focus due to the acquisition of competing products, availability of funding, or other factors, such as a business combination that diverts resources or creates competing priorities; • collaborators might delay, provide insufficient resources to, or modify or stop research or clinical development for collaboration drug candidates or require a new formulation of a drug candidate for clinical testing; • collaborators could develop or acquire products outside of the collaboration that compete directly or indirectly with our drug candidates or require a new formulation of a drug candidate for nonclinical and/or clinical testing; • collaborators with sales, marketing, and distribution rights to one or more drug candidates might not commit sufficient resources to sales, marketing, and distribution or might otherwise fail to successfully commercialize those drug candidates; • collaborators might not properly maintain or defend our intellectual property rights or might use our intellectual property improperly or in a way that jeopardizes our intellectual property or exposes us to potential liability; • collaboration activities might result in the collaborator having intellectual property covering our activities or drug candidates, which could limit our rights or ability to research, develop, and/or commercialize our drug candidates; • collaborators might not be in compliance with laws applicable to their activities under the collaboration, which could impact the collaboration or us; • disputes might arise between us and a collaborator that could cause a delay or termination of the collaboration or result in costly litigation that diverts management attention and resources; and • collaborations might be terminated, which could result in a need for additional capital to pursue further research, development, and/or commercialization of our drug candidates.
Research, development, commercialization and/or strategic collaborations, including those that we have with Roche and BMS, are subject to numerous risks, which include the following: • collaborators may have significant control or discretion in determining the efforts and resources that they will apply to a collaboration, and might not commit sufficient efforts and resources or might misapply those efforts and resources; • we may have limited influence or control over the approaches to research, development, and/or commercialization of products candidates in the territories in which our collaboration partners lead research, development, and/or commercialization; • collaborators might not pursue research, development, and/or commercialization of collaboration drug candidates or might elect not to continue or renew research, development, and/or commercialization programs based on nonclinical and/or clinical trial results, changes in their strategic focus due to the acquisition of competing products, availability of funding, or other factors, such as a business combination that diverts resources or creates competing priorities; • collaborators might delay, provide insufficient resources to, or modify or stop research or clinical development for collaboration drug candidates or require a new formulation of a drug candidate for clinical testing; • collaborators could develop or acquire products outside of the collaboration that compete directly or indirectly with our drug candidates or require a new formulation of a drug candidate for nonclinical and/or clinical testing; 30 • collaborators with sales, marketing, and distribution rights to one or more drug candidates might not commit sufficient resources to sales, marketing, and distribution or might otherwise fail to successfully commercialize those drug candidates; • collaborators might not properly maintain or defend our intellectual property rights or might use our intellectual property improperly or in a way that jeopardizes our intellectual property or exposes us to potential liability; • collaboration activities might result in the collaborator having intellectual property covering our activities or drug candidates, which could limit our rights or ability to research, develop, and/or commercialize our drug candidates; • collaborators might not be in compliance with laws applicable to their activities under the collaboration, which could impact the collaboration or us; • disputes might arise between us and a collaborator that could cause a delay or termination of the collaboration or result in costly litigation that diverts management attention and resources; and • collaborations might be terminated, which could result in a need for additional capital to pursue further research, development, and/or commercialization of our drug candidates.
A number of events, including any of the following, could delay the completion of our ongoing or planned clinical trials and negatively impact our ability to obtain regulatory approval for, and to market and sell, a particular drug candidate: • conditions imposed on us by the FDA, the EMA, or other comparable regulatory authorities regarding the scope or design of our clinical trials; • delays in obtaining, or our inability to obtain, required approvals from institutional review boards (“IRBs”) or other reviewing entities at clinical sites selected for participation in our clinical trials; • insufficient supply or deficient quality of our drug candidates or other materials necessary to conduct our clinical trials; • delays in obtaining regulatory authority authorization for the conduct of our clinical trials; • lower than anticipated enrollment and/or retention rate of subjects in our clinical trials, which can be impacted by a number of factors, including size of patient population, design of trial protocol, trial length, eligibility criteria, perceived risks and benefits of the drug candidate, patient proximity to trial sites, patient referral practices of physicians, availability of other treatments for the relevant disease, and competition from other clinical trials; • slower than expected rates of events in trials with a primary endpoint that is event-based; • serious and unexpected drug-related side effects experienced by subjects in clinical trials; or • failure of our third-party contractors and collaborators to meet their contractual obligations to us or otherwise meet their development or other objectives in a timely manner.
A number of events, including any of the following, could delay the completion of our ongoing or planned clinical trials and negatively impact our ability to obtain regulatory approval for, and to market and sell, a particular drug candidate: • conditions imposed on us by the FDA, the EMA, or other comparable regulatory authorities regarding the scope or design of our clinical trials; • delays in obtaining, or our inability to obtain, required approvals from institutional review boards (“IRBs”) or other reviewing entities at clinical sites selected for participation in our clinical trials; • insufficient supply or deficient quality of our drug candidates or other materials necessary to conduct our clinical trials; • delays in obtaining regulatory authority authorization for the conduct of our clinical trials; • lower than anticipated enrollment and/or retention rate of subjects in our clinical trials, which can be impacted by a number of factors, including size of patient population, design of trial protocol, trial length, eligibility criteria, perceived risks and benefits of the drug candidate, patient proximity to trial sites, patient referral practices of physicians, availability of other treatments for the relevant disease, and competition from other clinical trials; 31 • slower than expected rates of events in trials with a primary endpoint that is event-based; • serious and unexpected drug-related side effects experienced by subjects in clinical trials; or • failure of our third-party contractors and collaborators to meet their contractual obligations to us or otherwise meet their development or other objectives in a timely manner.
Our drug candidates could fail to receive regulatory approval for many reasons, including the following: • the FDA, the EMA, or comparable regulatory authorities may disagree with the design, implementation, or conduct of our clinical trials; • we may be unable to demonstrate to the satisfaction of the FDA, the EMA, or comparable regulatory authorities that a drug candidate is safe and effective for its proposed indication; • the results of clinical trials may not meet the level of statistical significance required by the FDA, the EMA, or comparable regulatory authorities for approval; • we may be unable to demonstrate that a drug candidate’s clinical and other benefits outweigh its safety risks; • the FDA, the EMA, or comparable regulatory authorities may disagree with our interpretation of data from nonclinical studies or clinical trials; • the data collected from clinical trials of our drug candidates may not be sufficient to support the submission of an NDA or a BLA to the FDA, a Marketing Authorization Application (“MAA”) to the EMA, or similar applications to comparable regulatory authorities; • the FDA, the EMA, or comparable regulatory authorities may fail to approve the manufacturing processes or facilities of third-party manufacturers with which we contract for clinical and commercial supplies; or 30 • the approval policies or regulations of the FDA, the EMA, or comparable regulatory authorities may significantly change in a manner rendering our clinical data insufficient for approval.
Our drug candidates could fail to receive regulatory approval for many reasons, including the following: • the FDA, the EMA, or comparable regulatory authorities may disagree with the design, implementation, or conduct of our clinical trials; • we may be unable to demonstrate to the satisfaction of the FDA, the EMA, or comparable regulatory authorities that a drug candidate is safe and effective for its proposed indication; • the results of clinical trials may not meet the level of statistical significance required by the FDA, the EMA, or comparable regulatory authorities for approval; • we may be unable to demonstrate that a drug candidate’s clinical and other benefits outweigh its safety risks; • the FDA, the EMA, or comparable regulatory authorities may disagree with our interpretation of data from nonclinical studies or clinical trials; • the data collected from clinical trials of our drug candidates may not be sufficient to support the submission of an NDA or a BLA to the FDA, a Marketing Authorization Application (“MAA”) to the EMA, or similar applications to comparable regulatory authorities; • the FDA, the EMA, or comparable regulatory authorities may fail to approve the manufacturing processes or facilities of third-party manufacturers with which we contract for clinical and commercial supplies; or • the approval policies or regulations of the FDA, the EMA, or comparable regulatory authorities may significantly change in a manner rendering our clinical data insufficient for approval.
Even if any of our drug candidates receives marketing approval, as greater numbers of patients use a drug following its approval, an increase in the incidence or severity of side effects or the incidence of other post-approval problems that were not seen or anticipated during pre-approval clinical trials could result in a number of potentially significant negative consequences, including: • regulatory authorities may withdraw their approval of the product; • regulatory authorities may require the addition of labeling statements, such as contraindications, warnings, or precautions; or impose additional safety monitoring or reporting requirements; • we may be required to change the way the product is administered, or to conduct additional clinical trials; • we could be sued and held liable for harm caused to patients; and • our reputation may suffer.
Even if any of our drug candidates receives marketing approval, as greater numbers of patients use a drug following its approval, an increase in the incidence or severity of side effects or the incidence of other post-approval problems that were not seen or anticipated during pre-approval clinical trials could result in a number of potentially significant negative consequences, including: • regulatory authorities may withdraw their approval of the product; • regulatory authorities may require the addition of labeling statements, such as contraindications, warnings, or precautions; or impose additional safety monitoring or reporting requirements; • we may be required to change the way the product is administered, or to conduct additional clinical trials; 35 • we could be sued and held liable for harm caused to patients; and • our reputation may suffer.
In July 2020, the Court of Justice of the EU limited how organizations could lawfully transfer personal data from the EEA to the United States by invalidating the EU-US Privacy Shield Framework for purposes of international transfers and imposing further restrictions on the use of standard contractual clauses (“EU SCCs”) including, a requirement for companies to carry out a transfer privacy impact assessment (“TIA”), which, among other things, assesses the laws governing access to personal data in the recipient country and considers whether supplementary measures that provide privacy protections additional to those provided under the EU SCCs will need to be implemented to ensure an “essentially equivalent” level of data protection to that afforded in the EEA.
In July 2020, the Court of Justice of the EU limited how organizations could lawfully transfer personal data from the EEA to the United States by invalidating the EU-US Privacy Shield Framework for purposes of international transfers and imposing further restrictions on the use of standard contractual clauses (“EU SCCs”) including, a requirement for companies to carry out a transfer privacy impact assessment (“TIA”), which, among other things, assesses the laws governing access to personal data in the recipient 28 country and considers whether supplementary measures that provide privacy protections additional to those provided under the EU SCCs will need to be implemented to ensure an “essentially equivalent” level of data protection to that afforded in the EEA.
The market price of our ordinary shares may fluctuate widely, depending upon many factors, some of which may be beyond our control, including: • our ability to obtain financing as needed; • progress in and results from our ongoing or future nonclinical research and clinical trials; • the execution of our agreements with third parties, including with Roche, BMS, and Novo Nordisk; • failure or delays in advancing our nonclinical drug candidates or other drug candidates we may develop in the future into clinical trials; • results of clinical trials conducted by others, including on drugs that would compete with our drug candidates; 52 • issues in manufacturing our drug candidates; • regulatory developments or enforcement in the U.S. and other countries; • developments or disputes concerning patents or other proprietary rights; • introduction of technological innovations or new commercial products by our competitors; • changes in estimates or recommendations by securities analysts, if any, who cover our company; • public concern over our drug candidates; • litigation; • future sales of our ordinary shares by us or by existing shareholders; • general market conditions; • changes in the structure of healthcare payment systems; • failure of any of our drug candidates, if approved, to achieve commercial success; • economic and other external factors or other disasters or crises; • period-to-period fluctuations in our financial results; • overall fluctuations in U.S. equity markets; • our quarterly or annual results, or those of other companies in our industry; • announcements by us or our competitors of significant acquisitions or dispositions; • the operating and ordinary share price performance of other comparable companies; • investor perception of our company and the drug development industry; • natural or environmental disasters that investors believe may affect us; • changes in tax laws or regulations applicable to our business or the interpretations of those tax laws and regulations by taxing authorities; or • fluctuations in the budgets of federal, state and local governmental entities around the world.
The market price of our ordinary shares may fluctuate widely, depending upon many factors, some of which may be beyond our control, including: • our ability to obtain financing as needed; • progress in and results from our ongoing or future nonclinical research and clinical trials; • the execution of our agreements with third parties, including with Roche, BMS, and Novo Nordisk; • failure or delays in advancing our nonclinical drug candidates or other drug candidates we may develop in the future into clinical trials; • results of clinical trials conducted by others, including on drugs that would compete with our drug candidates; • issues in manufacturing our drug candidates; • regulatory developments or enforcement in the U.S. and other countries; • developments or disputes concerning patents or other proprietary rights; • introduction of technological innovations or new commercial products by our competitors; • changes in estimates or recommendations by securities analysts, if any, who cover our company; • public concern over our drug candidates; • litigation; • future sales of our ordinary shares by us or by existing shareholders; • general market conditions; • changes in the structure of healthcare payment systems; • failure of any of our drug candidates, if approved, to achieve commercial success; • economic and other external factors or other disasters or crises; • period-to-period fluctuations in our financial results; • overall fluctuations in U.S. equity markets; • our quarterly or annual results, or those of other companies in our industry; 56 • announcements by us or our competitors of significant acquisitions or dispositions; • the operating and ordinary share price performance of other comparable companies; • investor perception of our company and the drug development industry; • natural or environmental disasters that investors believe may affect us; • changes in tax laws or regulations applicable to our business or the interpretations of those tax laws and regulations by taxing authorities; or • fluctuations in the budgets of federal, state and local governmental entities around the world.
For example, the Phase 3 clinical trial for birtamimab has clinical trial sites located globally, including in Israel and Eastern Europe, and operations at such clinical trial sites may be disrupted by ongoing conflicts and/or new conflicts, which could result in (i) the inability or unwillingness of study participants, site investigators or other study personnel to travel to such clinical trial sites or otherwise follow study protocols, (ii) the diversion of healthcare resources away from the conduct of clinical trials, or (iii) the complete or partial cessation of operations at such clinical trial sites. • Our key research facility and a significant portion of our operations are in the San Francisco Bay Area of Northern California, which in the past has experienced severe earthquakes.
For example, the Phase 3 clinical trial for birtamimab has clinical trial sites located globally, including in Israel and Eastern Europe, and operations at such clinical trial sites may be disrupted by ongoing conflicts and/or new conflicts, which could result in (i) the inability or unwillingness of study participants, site investigators or other study personnel to travel to such clinical trial sites or otherwise follow study protocols, (ii) the diversion of healthcare resources away from the conduct of clinical trials, or (iii) the complete or partial cessation of operations at such clinical trial sites. 26 • Our key research facility and a significant portion of our operations are in the San Francisco Bay Area of Northern California, which in the past has experienced severe earthquakes.
In addition, a clinical trial may be delayed, suspended or terminated by us, the FDA, the EMA or other comparable regulatory authorities, the 29 IRBs for the sites where the IRBs are overseeing a trial, or the safety oversight committee overseeing the clinical trial at issue due to a number of factors, including: • failure to conduct the clinical trial in accordance with regulatory requirements or our clinical protocols; • inspection of the clinical trial operations or trial sites by the FDA, the EMA, or other regulatory authorities resulting in the imposition of a clinical hold on or imposition of additional conditions for the conduct of the trial; • interpretation of data by the FDA, the EMA, or other regulatory authorities; • requirement by the FDA, the EMA, or other regulatory authorities to perform additional studies; • failure to achieve primary or secondary endpoints or other failure to demonstrate efficacy or adequate safety; • unforeseen safety issues; or • lack of adequate funding to continue the clinical trial.
In addition, a clinical trial may be delayed, suspended or terminated by us, the FDA, the EMA or other comparable regulatory authorities, the IRBs for the sites where the IRBs are overseeing a trial, or the safety oversight committee overseeing the clinical trial at issue due to a number of factors, including: • failure to conduct the clinical trial in accordance with regulatory requirements or our clinical protocols; • inspection of the clinical trial operations or trial sites by the FDA, the EMA, or other regulatory authorities resulting in the imposition of a clinical hold on or imposition of additional conditions for the conduct of the trial; • interpretation of data by the FDA, the EMA, or other regulatory authorities; • requirement by the FDA, the EMA, or other regulatory authorities to perform additional studies; • failure to achieve primary or secondary endpoints or other failure to demonstrate efficacy or adequate safety; • unforeseen safety issues; or • lack of adequate funding to continue the clinical trial.
These laws include: • the U.S. federal Anti-Kickback Statute, an intent-based federal criminal statute which prohibits, among other things, persons and entities from knowingly and willfully soliciting, receiving, offering, providing, or paying remuneration, directly or indirectly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, lease, order or arrangement for, or recommendation of an item or service for which payment may be made, in whole or in part, by a federal healthcare program, such as the Medicare and Medicaid programs.
These laws include: • the U.S. federal Anti-Kickback Statute, an intent-based federal criminal statute which prohibits, among other things, persons and entities from knowingly and willfully soliciting, receiving, offering, providing, or paying remuneration, directly or indirectly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or 42 the purchase, lease, order or arrangement for, or recommendation of an item or service for which payment may be made, in whole or in part, by a federal healthcare program, such as the Medicare and Medicaid programs.
Anti-Kickback Statute, new government investigative powers and enhanced penalties for non-compliance; • extension of manufacturers’ Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations; • expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional individuals and by adding new mandatory eligibility categories for certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability; • a licensure framework for follow-on biologic products; • expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program; 36 • implementation of the federal Physician Payments Sunshine Act, which requires pharmaceutical manufacturers, among others, to annually track and report all payments and other transfers of value they make to certain healthcare providers, as well as physician ownership held in the company; • a requirement for manufacturers and distributors to annually report drug samples that they provide to physicians; and • establishment of the Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research.
Anti-Kickback Statute, new government investigative powers and enhanced penalties for non-compliance; • extension of manufacturers’ Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations; • expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional individuals and by adding new mandatory eligibility categories for certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability; • a licensure framework for follow-on biologic products; • expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program; • implementation of the federal Physician Payments Sunshine Act, which requires pharmaceutical manufacturers, among others, to annually track and report all payments and other transfers of value they make to certain healthcare providers, as well as physician ownership held in the company; • a requirement for manufacturers and distributors to annually report drug samples that they provide to physicians; and 39 • establishment of the Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research.
The degree of market acceptance for any approved drug candidate will depend on a number of factors, including: • the indication and label for the product and the timing of introduction of competitive products; • demonstration of clinical safety and efficacy compared to other products; • prevalence, frequency, and severity of adverse side effects; • availability of coverage and adequate reimbursement from managed care plans and other third-party payers; • convenience and ease of administration; • cost-effectiveness; • other potential advantages of alternative treatment methods; and 33 • the effectiveness of marketing and distribution support of the product.
The degree of market acceptance for any approved drug candidate will depend on a number of factors, including: • the indication and label for the product and the timing of introduction of competitive products; • demonstration of clinical safety and efficacy compared to other products; • prevalence, frequency, and severity of adverse side effects; • availability of coverage and adequate reimbursement from managed care plans and other third-party payers; • convenience and ease of administration; • cost-effectiveness; • other potential advantages of alternative treatment methods; and • the effectiveness of marketing and distribution support of the product.
If side effects are identified during the time our drug candidates are in development, or, if they are approved by applicable regulatory authorities, after they are on the market, we may choose to or be required to perform lengthy additional clinical 32 trials, discontinue development of the affected drug candidate, change the labeling of any such products, or withdraw any such products from the market, any of which would hinder or preclude our ability to generate revenues.
If side effects are identified during the time our drug candidates are in development, or, if they are approved by applicable regulatory authorities, after they are on the market, we may choose to or be required to perform lengthy additional clinical trials, discontinue development of the affected drug candidate, change the labeling of any such products, or withdraw any such products from the market, any of which would hinder or preclude our ability to generate revenues.
If material, these adjustments could require us to restate previously reported financial results, which could have a negative effect on our stock price. 34 Our ability to receive any significant revenue from prasinezumab will be dependent on Roche’s efforts and may result in lower levels of income than if we marketed or developed our drug candidates entirely on our own.
If material, these adjustments could require us to restate previously reported financial results, which could have a negative effect on our stock price. Our ability to receive any significant revenue from prasinezumab will be dependent on Roche’s efforts and may result in lower levels of income than if we marketed or developed our drug candidates entirely on our own.
Our operations and activities are directly, or indirectly through our service providers and collaborators, subject to numerous healthcare and other laws and regulations, including, without limitation, those relating to anti-bribery, anti-kickback, 39 fraud and abuse, false claims, physician payment transparency, and health information privacy and security, in the U.S., the EU, and other countries and jurisdictions in which we conduct our business.
Our operations and activities are directly, or indirectly through our service providers and collaborators, subject to numerous healthcare and other laws and regulations, including, without limitation, those relating to anti-bribery, anti-kickback, fraud and abuse, false claims, physician payment transparency, and health information privacy and security, in the U.S., the EU, and other countries and jurisdictions in which we conduct our business.
The law is complex and is still being interpreted and implemented by the FDA. Any processes adopted by the FDA to implement the BPCIA could have a material adverse effect on the future commercial prospects for our biologic products. In 38 addition, there has been discussion of whether Congress should reduce the 12-year reference product exclusivity period.
The law is complex and is still being interpreted and implemented by the FDA. Any processes adopted by the FDA to implement the BPCIA could have a material adverse effect on the future commercial prospects for our biologic products. In addition, there has been discussion of whether Congress should reduce the 12-year reference product exclusivity period.
The resolution of any contract interpretation disagreement that may arise could narrow what we believe to be the scope of our rights to the relevant intellectual property or technology or increase what we believe to be our financial or other obligations under the relevant agreement, either of which could have a material adverse effect on our business, financial condition, results of operations, and/or growth prospects.
The resolution of any contract interpretation disagreement that may arise could narrow what we believe to be the scope of our rights to the relevant intellectual property or technology or increase what we believe to be our financial or other obligations under the relevant 50 agreement, either of which could have a material adverse effect on our business, financial condition, results of operations, and/or growth prospects.
Inventorship disputes may arise from conflicting views regarding the contributions of different individuals named as inventors, the effects of foreign laws where foreign nationals are involved in the development of the subject matter of the patent, conflicting obligations of third parties involved in developing our drug candidates or as a result of questions regarding co-ownership of potential joint inventions.
Inventorship disputes may arise from conflicting views regarding the 49 contributions of different individuals named as inventors, the effects of foreign laws where foreign nationals are involved in the development of the subject matter of the patent, conflicting obligations of third parties involved in developing our drug candidates or as a result of questions regarding co-ownership of potential joint inventions.
However, the Leahy-Smith Act and its implementation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents, all of which could have a material adverse effect on our business, financial condition, results of operations, and/or growth prospects. Recent U.S.
However, the Leahy-Smith Act and its implementation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued 48 patents, all of which could have a material adverse effect on our business, financial condition, results of operations, and/or growth prospects. Recent U.S.
Proceedings involving our patents or patent applications or those of others could result in adverse decisions regarding: • the patentability of our inventions relating to our drug candidates; and/or • the enforceability, validity or scope of protection offered by our patents relating to our drug candidates; and/or 49 • findings that our drug candidates, products, or activities infringe third-party patents or other intellectual property rights.
Proceedings involving our patents or patent applications or those of others could result in adverse decisions regarding: • the patentability of our inventions relating to our drug candidates; and/or • the enforceability, validity or scope of protection offered by our patents relating to our drug candidates; and/or • findings that our drug candidates, products, or activities infringe third-party patents or other intellectual property rights.
Therefore, the success of an investment in our ordinary shares will depend upon appreciation in their value and in order to receive any income or realize a return on your investment, you will need to sell 56 your Prothena ordinary shares. There can be no assurance that our ordinary shares will maintain their price or appreciate in value.
Therefore, the success of an investment in our ordinary shares will depend upon appreciation in their value and in order to receive any income or realize a return on your investment, you will need to sell your Prothena ordinary shares. There can be no assurance that our ordinary shares will maintain their price or appreciate in value.
Coverage and reimbursement may not be available for any drug that we or our collaborators commercialize and, even if these are available, the level of reimbursement may not be 35 satisfactory. Third-party payers often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement policies.
Coverage and reimbursement may not be available for any drug that we or our collaborators commercialize and, even if these are available, the level of reimbursement may not be satisfactory. Third-party payers often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement policies.
Depending on decisions by Congress, the federal courts, the USPTO and the relevant law-making bodies in other 45 countries, the laws and regulations governing patents could change in unpredictable ways that would weaken our ability to obtain new patents or to enforce our existing patents and patents that we might obtain in the future.
Depending on decisions by Congress, the federal courts, the USPTO and the relevant law-making bodies in other countries, the laws and regulations governing patents could change in unpredictable ways that would weaken our ability to obtain new patents or to enforce our existing patents and patents that we might obtain in the future.
Accordingly, the application of the Irish Takeover Rules may restrict the ability of certain of our shareholders and directors to acquire our ordinary shares. 55 Irish law differs from the laws in effect in the United States with respect to defending unwanted takeover proposals and may give our board of directors less ability to control negotiations with hostile offerors.
Accordingly, the application of the Irish Takeover Rules may restrict the ability of certain of our shareholders and directors to acquire our ordinary shares. Irish law differs from the laws in effect in the United States with respect to defending unwanted takeover proposals and may give our board of directors less ability to control negotiations with hostile offerors.
Shareholders entitled to an exemption from Irish dividend withholding tax on any dividends received from us will not be subject to Irish income tax in respect of those dividends, unless they have some connection with Ireland other than their shareholding (for example, they are resident in Ireland).
Shareholders entitled to an exemption from Irish dividend withholding tax on any dividends received from us will not be subject to Irish income tax in respect of those dividends, unless they have some connection with Ireland other than their 60 shareholding (for example, they are resident in Ireland).
Other parties may hold or obtain patents in the future and allege that the use of our technologies infringes these patent claims or that we are employing their proprietary technology without authorization. Furthermore, patent reform and changes to patent laws add uncertainty to the possibility of challenge to our patents in the future.
Other parties may hold or obtain patents in the future and allege that the use of our technologies infringes these patent claims or that we are employing their proprietary technology without authorization. Furthermore, patent reform and changes to patent laws add uncertainty to the possibility of 52 challenge to our patents in the future.
Additional risks and uncertainties not presently known to us or that we currently deem immaterial also may impair our business operations. 21 Risks Relating to Our Financial Position, Our Need for Additional Capital, and Our Business We anticipate that we will incur losses for the foreseeable future and we may never sustain profitability.
Additional risks and uncertainties not presently known to us or that we currently deem immaterial also may impair our business operations. Risks Relating to Our Financial Position, Our Need for Additional Capital, and Our Business We anticipate that we will incur losses for the foreseeable future and we may never sustain profitability.
In addition, such foreign trials would be subject to the applicable local laws of the foreign jurisdictions where the trials are conducted. There can be no assurance that the FDA or any other comparable foreign regulatory authority will accept data from trials conducted outside of its applicable jurisdiction.
In addition, such foreign trials would be subject to the applicable local laws of 33 the foreign jurisdictions where the trials are conducted. There can be no assurance that the FDA or any other comparable foreign regulatory authority will accept data from trials conducted outside of its applicable jurisdiction.
Any reduction in reimbursement from Medicare or other government healthcare programs may result in a similar reduction in payments from 37 private payers. The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability or commercialize our drugs.
Any reduction in reimbursement from Medicare or other government healthcare programs may result in a similar reduction in payments from private payers. The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability or commercialize our drugs.
However, there is a risk that this exclusivity could be shortened due to congressional action or otherwise, or that the FDA will not consider our drug candidates to be reference products for competing products, potentially creating the opportunity for generic competition sooner than anticipated.
However, there is a risk that this exclusivity could be shortened due to congressional action or otherwise, 41 or that the FDA will not consider our drug candidates to be reference products for competing products, potentially creating the opportunity for generic competition sooner than anticipated.
If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights, such as exclusive ownership of, or right to use, valuable intellectual property. Such an outcome could have a material adverse effect on our 46 business.
If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights, such as exclusive ownership of, or right to use, valuable intellectual property. Such an outcome could have a material adverse effect on our business.
A material weakness in internal control over financial reporting is a deficiency, or a combination of deficiencies, in internal control over financial reporting, such that there is a reasonable possibility that a material misstatement of a company’s annual or interim consolidated financial statements will not be prevented or detected on a timely basis by the company’s internal controls.
A material weakness in internal control over financial reporting is a deficiency, 57 or a combination of deficiencies, in internal control over financial reporting, such that there is a reasonable possibility that a material misstatement of a company’s annual or interim consolidated financial statements will not be prevented or detected on a timely basis by the company’s internal controls.
A number of exemptions from dividend withholding tax exist such that shareholders resident in the U.S. and shareholders resident in other countries that have entered into a double taxation treaty with Ireland may be entitled to exemptions from dividend withholding tax subject to the completion of certain dividend withholding tax declaration forms.
A number of exemptions from Irish dividend withholding tax exist such that shareholders resident in the U.S. and shareholders resident in other countries that have entered into a double taxation treaty with Ireland may be entitled to exemptions from Irish dividend withholding tax subject to the completion of certain dividend withholding tax declaration forms.
Pursuant to the terms of the license agreements with some of our licensors, the licensors may have the right to control enforcement of our licensed patents or defense of any claims asserting the invalidity of these patents and, even if we are permitted to pursue such enforcement or defense, we cannot ensure the cooperation of our licensors.
Pursuant to the terms of the license agreements with some of 51 our licensors, the licensors may have the right to control enforcement of our licensed patents or defense of any claims asserting the invalidity of these patents and, even if we are permitted to pursue such enforcement or defense, we cannot ensure the cooperation of our licensors.
If our actions are found to be in violation of any laws and regulations, we may be subject to significant civil, criminal, and administrative damages, penalties, and fines, as well as exclusion from participation in government healthcare programs, curtailment or restructuring of our operations, and reputational harm, any of which could have a material adverse effect on our business, financial condition, or results of operations. 40 If a successful product liability or clinical trial claim or series of claims is brought against us for uninsured liabilities or in excess of insured liabilities, we could incur substantial liability.
If our actions are found to be in violation of any laws and regulations, we may be subject to significant civil, criminal, and administrative damages, penalties, and fines, as well as exclusion from participation in government healthcare programs, curtailment or restructuring of our operations, and reputational harm, any of which could have a material adverse effect on our business, financial condition, or results of operations. 43 If a successful product liability or clinical trial claim or series of claims is brought against us for uninsured liabilities or in excess of insured liabilities, we could incur substantial liability.
Requirements regarding clinical trial data may evolve, and any such changes to data requirements may cause the FDA or comparable foreign regulatory authorities to disagree with data from preclinical studies or clinical trials, and to require further studies. 41 To date, we believe our consultants, contract research organizations, and other third parties with which we are working have generally performed satisfactorily; however, if these third parties do not successfully carry out their contractual duties, meet expected deadlines, or comply with applicable regulations, we have been, and may be, required to replace them.
Requirements regarding clinical trial data may evolve, and any such changes to data requirements may cause the FDA or comparable foreign regulatory authorities to disagree with data from preclinical studies or clinical trials, and to require further studies. 44 To date, we believe our consultants, contract research organizations, and other third parties with which we are working have generally performed satisfactorily; however, if these third parties do not successfully carry out their contractual duties, meet expected deadlines, or comply with applicable regulations, we have been, and may be, required to replace them.
Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management. 51 Intellectual property rights do not necessarily address all potential threats to our competitive advantage.
Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management. Intellectual property rights do not necessarily address all potential threats to our competitive advantage.
Further, on September 21, 26 2023, the UK Secretary of State for Science, Innovation and Technology established a UK-U.S. data bridge (i.e., a UK equivalent of the Adequacy Decision) and adopted UK regulations to implement the UK-U.S. data bridge (“UK Adequacy Regulations”).
Further, on September 21, 2023, the UK Secretary of State for Science, Innovation and Technology established a UK-U.S. data bridge (i.e., a UK equivalent of the Adequacy Decision) and adopted UK regulations to implement the UK-U.S. data bridge (“UK Adequacy Regulations”).
Dividends paid by us may be subject to Irish dividend withholding tax. Although we do not currently anticipate paying cash dividends, if we were to do so in the future, a dividend withholding tax (currently at a rate of 25%) may arise.
Dividends paid by us may be subject to Irish dividend withholding tax. Although we do not currently anticipate paying cash dividends, if we were to do so in the future, an Irish dividend withholding tax (currently at a rate of 25%) may arise.
Method-of-use patents protect the use of a product for the specified method. This type of patent does not prevent a competitor from making and marketing a product that is identical to our product for an indication that is outside the scope of the patented method.
Method-of-use patents protect the use of a product 47 for the specified method. This type of patent does not prevent a competitor from making and marketing a product that is identical to our product for an indication that is outside the scope of the patented method.
In addition to the impact on changes in tax laws, our provision for income tax can be materially impacted, for example, by the geographical mix of our profits and losses, changes in our business, such as internal restructuring and acquisitions, changes and 54 accounting guidance and other regulatory, legislative or judicial developments changes in tax rates, tax audit determinations, changes in our uncertain tax positions, changes in our intent and capacity to permanently reinvest foreign earnings, changes to our transfer pricing practices, tax deductions attributed to equity compensation and changes in our need for a valuation allowance for deferred tax assets.
In addition to the impact of changes in tax laws, our provision for income tax can be materially impacted, for example, by the geographical mix of our profits and losses, changes in our business, such as internal restructuring and acquisitions, changes and accounting guidance and other regulatory, legislative or judicial developments changes in tax rates, tax audit determinations, changes in our uncertain tax positions, changes in our intent and capacity to permanently reinvest foreign earnings, changes to our transfer pricing practices, tax deductions attributed to equity compensation and changes in our need for a valuation allowance for deferred tax assets.
Our nonclinical studies or clinical trials may produce negative or inconclusive results, and we may decide, or regulators may require us, to conduct additional nonclinical studies or clinical trials, or to discontinue clinical trials altogether. 27 Furthermore, we have not marketed, distributed, or sold any products.
Our nonclinical studies or clinical trials may produce negative or inconclusive results, and we may decide, or regulators may require us, to conduct additional nonclinical studies or clinical trials, or to discontinue clinical trials altogether. Furthermore, we have not marketed, distributed, or sold any products.
These requirements include submissions of safety and other post-marketing information and reports, as well as continued compliance with current good manufacturing practice (“cGMP”) requirements and current good clinical practice (“cGCP”) requirements for any clinical trials that we conduct.
These requirements include submissions of safety and other post- 34 marketing information and reports, as well as continued compliance with current good manufacturing practice (“cGMP”) requirements and current good clinical practice (“cGCP”) requirements for any clinical trials that we conduct.
The rules governing the standards that must be met for management to assess our internal control over financial reporting are complex and require significant documentation, testing 53 and possible remediation to meet the detailed standards under the rules.
The rules governing the standards that must be met for management to assess our internal control over financial reporting are complex and require significant documentation, testing and possible remediation to meet the detailed standards under the rules.
Our collaboration with Roche is complex, particularly with respect to future U.S. commercialization of prasinezumab, with respect to financial provisions, allocations of responsibilities, cost estimates, and the respective rights of the parties in decision making.
Our collaboration with Roche is complex, particularly with respect to future U.S. commercialization of prasinezumab, with respect to financial provisions, allocations of responsibilities, cost estimates, and 36 the respective rights of the parties in decision making.
Because of the numerous risks and 22 uncertainties associated with the development and commercialization of our drug candidates, we are unable to estimate the amounts of increased capital outlays and operating expenses associated with completing the development and commercialization of our current drug candidates.
Because of the numerous risks and uncertainties associated with the development and commercialization of our drug candidates, we are unable to estimate the amounts of increased capital outlays and operating expenses associated with completing the development and commercialization of our current drug candidates.
We have been advised that the U.S. currently does not have a treaty with Ireland providing for the reciprocal recognition and enforcement of judgments in civil and commercial matters.
We have been advised that the U.S. currently does not have a ratified treaty providing for the reciprocal recognition and enforcement of judgments in civil and commercial matters with Ireland.
Adequate third-party reimbursement might not be available to enable us to maintain price levels sufficient to realize an appropriate return on investment in product development.
Adequate third-party reimbursement might not be available to enable us to maintain price levels 38 sufficient to realize an appropriate return on investment in product development.
For example, Washington recently passed the My Health My Data Act, which has a broader scope than HIPAA and includes a private right of action.
For example, Washington 27 recently passed the My Health My Data Act, which has a broader scope than HIPAA and includes a private right of action.
In the U.S., this must be done to the satisfaction of the FDA; in the EU, this must be done to the satisfaction of the European Medicines Agency (the “EMA”); and in other countries this must be done to the satisfaction of comparable regulatory authorities.
In the U.S., this must be done to the satisfaction of the FDA; in the EU, this must be 29 done to the satisfaction of the European Medicines Agency (the “EMA”); and in other countries this must be done to the satisfaction of comparable regulatory authorities.
Our future capital requirements will depend on many factors that are currently unknown to us, including, without limitation: • the timing of progress, results, and costs of our clinical trials, including the Phase 3 clinical trial for birtamimab, the Phase 2 clinical trial for prasinezumab being conducted by Roche, the Phase 2b clinical trial for prasinezumab being conducted by Roche, the Phase 2 clinical trial f or NNC6019 (formerly PRX004) bei ng conducted by Novo Nordisk, the Phase 1 clinical trial for BMS-986446 (formerly PRX005) being conducted by BMS, and the Phase 1 clinical trials for PRX012; • the timing, initiation, progress, results, and costs of these and our other research, development, and possible commercialization activities; • the results of our research, nonclinical studies, and clinical trials; • the costs of manufacturing our drug candidates for clinical development as well as for future commercialization needs; • if and when appropriate, the costs of preparing for commercialization of our drug candidates; • the costs of preparing, filing, and prosecuting patent applications, and maintaining, enforcing, and defending intellectual property-related claims; • our ability to establish strategic collaborations, licensing, or other arrangements; • the timing, receipt, and amount of any capital investments, cost-sharing contributions or reimbursements, milestone payments, or royalties that we might receive under current or potential future collaborations; • the costs to satisfy our obligations under current and potential future collaborations; and • the timing, receipt, and amount of revenues or royalties, if any, from any approved drug candidates.
Our future capital requirements will depend on many factors that are currently unknown to us, including, without limitation: • the timing of progress, results, and costs of our clinical trials, including the Phase 3 clinical trial for birtamimab, the Phase 2 clinical trial for prasinezumab being conducted by Roche, the Phase 2b clinical trial for prasinezumab being conducted by Roche, the Phase 2 clinical trial f or coramitug (formerly PRX004) bei ng conducted by Novo Nordisk, the Phase 2 clinical trial for BMS-986446 being conducted by BMS, the Phase 1 clinical trials for PRX012, and the Phase 1 clinical trial for PRX019; • the timing, initiation, progress, results, and costs of these and our other research, development, and possible commercialization activities; • the results of our research, nonclinical studies, and clinical trials; 24 • the costs of manufacturing our drug candidates for clinical development as well as for future commercialization needs; • if and when appropriate, the costs of preparing for commercialization of our drug candidates; • the costs of preparing, filing, and prosecuting patent applications, and maintaining, enforcing, and defending intellectual property-related claims; • our ability to establish strategic collaborations, licensing, or other arrangements; • the timing, receipt, and amount of any capital investments, cost-sharing contributions or reimbursements, milestone payments, or royalties that we might receive under current or potential future collaborations; • the costs to satisfy our obligations under current and potential future collaborations; and • the timing, receipt, and amount of revenues or royalties, if any, from any approved drug candidates.
We do not believe we were a PFIC for U.S. federal income tax purposes for our taxable year ended December 31, 2023. However, the application of the PFIC rules is subject to uncertainties in a number of respects, and we cannot assure that the U.S. Internal Revenue Service (the “IRS”) will not take a contrary position.
We do not believe we were a PFIC for U.S. federal income tax purposes for our taxable year ended December 31, 2024. However, the application of the PFIC rules is subject to uncertainties in a number of respects, and we cannot assure that the U.S. Internal Revenue Service (the “IRS”) will not take a contrary position.
W e expect to continue to incur substantial losses for the foreseeable future as we: • support the Phase 3 AFFIRM-AL clinical trial for birtamimab, the Phase 1 clinical trials for PRX012, and potential additional clinical trials for these and other programs, including PRX123; • develop and possibly commercialize our drug candidates, including birtamimab, PRX012, and PRX123; • undertake nonclinical development of other drug candidates and initiate clinical trials, if supported by nonclinical data; • pursue our early stage research and seek to identify additional drug candidates; and • potentially acquire rights from third parties to drug candidates or technologies through licenses, acquisitions, or other means.
We expect to continue to incur substantial losses for the foreseeable future as we: • support the Phase 3 AFFIRM-AL clinical trial for birtamimab, the Phase 1 clinical trials for PRX012, the Phase 1 clinical trial for PRX019, and potential additional clinical trials for these and other programs, including PRX123; • develop and possibly commercialize our drug candidates, including birtamimab, PRX012, and PRX123; • undertake nonclinical development of other drug candidates and initiate clinical trials, if supported by nonclinical data; • pursue our early stage research and seek to identify additional drug candidates; and • potentially acquire rights from third parties to drug candidates or technologies through licenses, acquisitions, or other means.
In July 2021, the Company sold the equity interests of a subsidiary that owns and has exclusive licenses to intellectual property rights and other assets pertaining to the investigational humanized monoclonal antibody known as NNC6019 (formerly PRX004), and we might not realize the anticipated benefits of such transaction.
In July 2021, the Company sold the equity interests of a subsidiary that owns and has exclusive licenses to intellectual property rights and other assets pertaining to the investigational humanized monoclonal antibody known as coramitug (formerly PRX004), and we might not realize the anticipated benefits of such transaction.
Responding to or defending against challenges from taxing authorities could be expensive and time consuming, and could divert management’s time and focus away from operating our business. We cannot predict whether and when taxing authorities will conduct an audit, challenge our tax structure or the cost involved in responding to any such audit or challenge.
Responding to or defending against challenges from taxing authorities may be expensive and time consuming, and may divert management’s time and focus away from operating our business. We cannot predict whether and when taxing authorities will conduct an audit, challenge our tax structure or the cost involved in responding to any such audit or challenge.
Pillar Two has been implemented into Irish law with effect for periods beginning on or after December 31, 2023.
Pillar Two has been implemented into Irish law with effect for periods 58 beginning on or after December 31, 2023.
We cannot assure that additional funds will be available when we need them on terms that are acceptable to us or at all. If we raise additional funds by issuing equity securities, including pursuant to our December 2021 Distribution Agreement (as may be amended from time to time, and as discussed below), substantial dilution to existing shareholders would result.
We cannot assure that additional funds will be available when we need them on terms that are acceptable to us or at all. If we raise additional funds by issuing equity securities, including pursuant to our Amended Distribution Agreement (as may be further amended from time to time, and as discussed below), substantial dilution to existing shareholders would result.
The loss of the services of Dr. Kinney or any other person on whom we are highly dependent might impede the achievement of our research, development, and commercial objectives. We do not carry “key person” insurance covering any members of our senior management. Attracting and retaining qualified scientific and other personnel are critical to our growth and future success.
Kinney or any other person on whom we are highly dependent might impede the achievement of our research, development, and commercial objectives. We do not carry “key person” insurance covering any members of our senior management. Attracting and retaining qualified scientific and other personnel are critical to our growth and future success.
We may license our trademarks and trade names to third 50 parties, such as distributors.
We may license our trademarks and trade names to third parties, such as distributors.
As with any publicly traded company, your percentage ownership in us may be diluted in the future because of equity issuances for acquisitions, capital raising transactions (including the sale of ordinary shares pursuant to our December 2021 Distribution Agreement, as may be amended from time to time, and as discussed below), or otherwise.
As with any publicly traded company, your percentage ownership in us may be diluted in the future because of equity issuances for acquisitions, capital raising transactions (including the sale of ordinary shares pursuant to our Amended Distribution Agreement, as may be further amended from time to time, and as discussed below), or otherwise.
There is no assurance that the results of the Phase 3 clinical trial for birtamimab, the Phase 2 clinical trial for prasinezumab, the Phase 2b clinical trial for prasinezumab, the Phase 2 clinical tr ial for NNC6019, the Ph ase 1 clinical trial for BMS-986446, and the Phase 1 clinical trials for PRX012 will support further development of these drug candidates.
There is no assurance that the results of the Phase 3 clinical trial for birtamimab, the Phase 2 clinical trial for prasinezumab, the Phase 2b clinical trial for prasinezumab, the Phase 2 clinical tr ial for coramitug , the Ph ase 2 clinical trial for BMS-986446, the Phase 1 clinical trials for PRX012, and the Phase 1 clinical trial for PRX019 will support further development of these drug candidates.
Our patents issued as of December 31, 2023, are anticipated to expire on dates ranging from 2024 to 2042, subject to any patent extensions that may be available for such patents. If patents are issued on our patent applications pending as of December 31, 2023, the resulting patents are projected to expire on dates ranging from 2025 to 2044.
Our patents issued as of December 31, 2024, are anticipated to expire on dates ranging from 2025 to 2042, subject to any patent extensions that may be available for such patents. If patents are issued on our patent applications pending as of December 31, 2024, the resulting patents are projected to expire on dates ranging from 2025 to 2045.
There can be no assurance that such remaining milestones will be met.
There can be no assurance that such remaining milestones 46 will be met.
There can be no assurance that our drug candidates, if they are approved for sale in the U.S. or in other countries, will be considered medically reasonable and necessary for a specific indication, that they will be considered cost-effective by third-party payers, that coverage or an adequate level of reimbursement will be available, or that third-party payers’ reimbursement policies will not adversely affect our ability to sell our drug candidates profitably if they are approved for sale.
There can be no assurance that our drug candidates, if they are approved for sale in the U.S. or in other countries, will be considered medically reasonable and necessary for a specific indication, that they will be considered cost-effective by third-party payers, that coverage or an adequate level of reimbursement will be available, or that third-party payers’ reimbursement policies will not adversely affect our ability to sell our drug candidates profitably if they are approved for sale. 40 The markets for our drug candidates are subject to intense competition.
Birtamimab and PRX012 have been granted Fast Track Designation by the FDA for the treatment of AL amyloidosis and Alzheimer’s disease, respectively. In addition, we may seek Fast Track designation for one or more of our future drug candidates.
Birtamimab, for the treatment of AL amyloidosis, and PRX012 and PRX123, each for the treatment of Alzheimer’s disease, have each been granted Fast Track Designation by the FDA. In addition, we may seek Fast Track designation for one or more of our future drug candidates.
In addition, if we do not obtain a license, develop or obtain non-infringing technology, fail to defend an infringement action successfully, or have infringed patents declared invalid, we may: • incur substantial monetary damages, including treble damages and attorneys’ fees for willful infringement; • obtain one or more licenses from third parties and potentially pay royalties; • redesign our infringing products, which may be impossible on a cost-effective basis or require substantial time and monetary expenditure; • encounter significant delays in bringing our drug candidates to market; and/or • be precluded from participating in the manufacture, use, or sale of our drug candidates or methods of treatment requiring licenses.
In addition, if we do not obtain a license, develop or obtain non-infringing technology, fail to defend an infringement action successfully, or have infringed patents declared invalid, we may: • incur substantial monetary damages, including treble damages and attorneys’ fees for willful infringement; • obtain one or more licenses from third parties and potentially pay royalties; • redesign our infringing products, which may be impossible on a cost-effective basis or require substantial time and monetary expenditure; • encounter significant delays in bringing our drug candidates to market; and/or • be precluded from participating in the manufacture, use, or sale of our drug candidates or methods of treatment requiring licenses. 53 In that event, we would be unable to further develop and commercialize our drug candidates, which could harm our business significantly.
Rentschler Biopharma SE (“Rentschler”) and Catalent Indiana, LLC (“Catalent Indiana”) are our third-party manufacturers of clinical supplies of birtamimab. We are dependent on Rentschler and Catalent Indiana to manufacture these clinical supplies. Catalent Pharma Solutions, LLC (“Catalent Pharma”) and Berkshire Sterile Manufacturing, LLC (“Berkshire”) are our third-party manufacturers of clinical supplies of our drug candidate PRX012.
Rentschler Biopharma SE (“Rentschler”) and Catalent Indiana, LLC (“Catalent Indiana”) are our third-party manufacturers of clinical supplies of birtamimab. We are dependent on Rentschler and Catalent Indiana to manufacture these clinical supplies. Catalent Pharma Solutions, LLC (“Catalent Pharma”) and Sharp Sterile Manufacturing, LLC (“Sharp Sterile”) are our third-party manufacturers of clinical supplies of our drug candidate PRX012.
We cannot predict whether we will encounter problems with the Phase 3 clinical trial for birtamimab, the Phase 2 clinical trial for prasinezumab, the Phase 2b clinical trial for prasinezumab, the Phase 2 clinical trial f or NNC6019, t he Phase 1 clinical trial for BMS-986446, the Phase 1 clinical trials for PRX012, or any other future clinical trials that will cause us or any regulatory authority to delay, suspend or terminate those clinical trials or delay the analysis of data derived from them.
We cannot predict whether we, or our partners (as applicable), will encounter problems with the Phase 3 clinical trial for birtamimab, the Phase 2 clinical trial for prasinezumab, the Phase 2b clinical trial for prasinezumab, the Phase 2 clinical trial f or coramitug , t he Phase 2 clinical trial for BMS-986446, the Phase 1 clinical trials for PRX012, the Phase 1 clinical trial for PRX019, or any other future clinical trials that will cause us or any regulatory authority to delay, suspend or terminate those clinical trials or delay the analysis of data derived from them.
We are dependent on BMS, and its third-party manufacturers if applicable, to manufacture clinical supplies of BMS-986446.
We are dependent on Novo Nordisk, and its third-party manufacturers if applicable, to manufacture clinical supplies of coramitug . We are dependent on BMS, and its third-party manufacturers if applicable, to manufacture clinical supplies of BMS-986446.
We rely on third-party suppliers for the raw materials required for the production of our drug candidates. Our dependence on these third-party suppliers and the challenges we may face in obtaining adequate supplies of raw materials involve several risks, including limited control over pricing, availability, quality, and delivery schedules.
Our dependence on these third-party suppliers and the challenges we may face in obtaining adequate supplies of raw materials involve several risks, including limited control over pricing, availability, quality, and delivery schedules.
We are dependent upon Novo Nordisk with respect to further developme nt of NNC6019, includin g the Phase 2 clinical trial and any future clinical trial of that drug candidate. We are dependent upon BMS with respect to further developme nt of BMS-986446 , includin g the Phase 1 clinical trial and any future clinical trial of that drug candidate.
We are dependent upon Novo Nordisk with respect to further developme nt of coramitug , includin g the Phase 2 clinical trial and any future clinical trial of that drug candidate.
We will require additional capital to fund our operations, and if we are unable to obtain such capital, we will be unable to successfully develop and commercialize drug candidates. As of December 31, 2023, we had cash and cash equivalents o f $618.8 million .
We will require additional capital to fund our operations, and if we are unable to obtain such capital, we will be unable to successfully develop and commercialize drug candidates. As of December 31, 2024, we had cash and cash equivalents o f $471.4 million .
As of December 31, 2023, the number of ordinary shares available for issuance pursuant to outstanding and future equity awards under our equity plans was 13,477,039. If we are unable to maintain effective internal controls, our business could be adversely affected. We are subject to the reporting and other obligations under the U.S.
As of December 31, 2024, the number of ordinary shares available for issuance pursuant to outstanding and future equity awards under our equity plans was 15,332,174 . If we are unable to maintain effective internal controls, our business could be adversely affected. We are subject to the reporting and other obligations under the U.S.
We may not generate the cash that is necessary to finance our operations in the foreseeable future. We incurred net income (losses) of $(147.0) million, $(116.9) million and $67.0 million for the years ended December 31, 2023, 2022 and 2021, respectively. As of December 31, 2023, we had an accumulated deficit of $(980.0) million.
We may not generate the cash that is necessary to finance our operations in the foreseeable future. We incurred net lo sses of $122.3 million, $147.0 million and $116.9 million for the years ended December 31, 2024 , 2023, and 2022 , respectively. As of December 31, 2024 , we had an accumulated deficit of $1.1 billion .
Our future success depends on our ability to retain key personnel and to attract, retain, and motivate qualified personnel. We are highly dependent on key personnel, including Dr. Gene G. Kinney, our President and Chief Executive Officer. There can be no assurance that we will be able to retain Dr. Kinney or any of our key personnel.
We are highly dependent on key personnel, including Dr. Gene G. Kinney, our President and Chief Executive Officer. There can be no assurance that we will be able to retain Dr. Kinney or any of our key personnel. The loss of the services of Dr.
In addition, funding provided by a collaborator might not be sufficient to advance drug candidates under the collaboration. 28 If a collaborator terminates a collaboration or a program under a collaboration, including by failing to exercise a license or other option under the collaboration, whether because we fail to meet a milestone or otherwise, any potential revenue from the collaboration would be significantly reduced or eliminated.
If a collaborator terminates a collaboration or a program under a collaboration, including by failing to exercise a license or other option under the collaboration, whether because we fail to meet a milestone or otherwise, any potential revenue from the collaboration would be significantly reduced or eliminated.
In the event we breach any of our obligations related to such prosecution, we may incur significant liability to our licensing partners. 48 We may wish to form collaborations in the future with respect to our drug candidates, but may not be able to do so or to realize the potential benefits of such transactions, which may cause us to alter or delay our development and commercialization plans.
We may wish to form collaborations in the future with respect to our drug candidates, but may not be able to do so or to realize the potential benefits of such transactions, which may cause us to alter or delay our development and commercialization plans.
Likewise, our collaborators, partners, contractors, and advisors may have in the past, or may currently, work with or for universities, or other biotechnology or pharmaceutical companies, including our competitors or potential competitors.
Many of our employees were previously employed at universities, Elan or Elan subsidiaries, or other biotechnology or pharmaceutical companies, including our competitors or potential competitors. Likewise, our collaborators, partners, contractors, and advisors may have in the past, or may currently, work with or for universities, or other biotechnology or pharmaceutical companies, including our competitors or potential competitors.

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Item 1C. Cybersecurity

Cybersecurity — threats and controls disclosure

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Biggest changeAs of the date of this report, we have not identified any risks from cybersecurity threats, including as a result of any previous cybersecurity incidents, that have materially affected us, our business strategy, results of operation or financial condition for the years of financial statements presented in this report. 57 Notwithstanding the approach we take to cybersecurity threats, we may not be successful in preventing or mitigating a cybersecurity incident that could have a material adverse effect on us.
Biggest changeAs of the date of this report, we have not identified any risks from cybersecurity threats, including as a result of any previous cybersecurity incidents, that have materially affected us, our business strategy, results of operation or financial condition for the years of financial statements presented in this report.
Our Head of IT, who reports to our Head of Human Resources, who reports to our Chief Legal Officer, is primarily responsible for assessing and managing risks related to cybersecurity threats. Our Head of IT has approximately 30 years of experience managing IT systems for organizations similarly situated to ours.
Our Head of IT, who reports to our Chief Legal Officer, is primarily responsible for assessing and managing risks related to cybersecurity threats. Our Head of IT has approximately 30 years of experience managing IT systems for organizations similarly situated to ours.
See Item 1A. “Risk Factors” for a discussion of risks related to cybersecurity threats.
Notwithstanding the approach we take to cybersecurity threats, we may not be successful in preventing or mitigating a cybersecurity incident that could have a material adverse effect on us. See Item 1A. “Risk Factors” for a discussion of risks related to cybersecurity threats.

Item 2. Properties

Properties — owned and leased real estate

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Biggest changeIn Brisbane, California, we occupy approximately 31,157 square feet of office and laboratory space under a sublease with Arcus Biosciences, Inc. which expires on September 30, 2028, unless terminated earlier. We believe that our facilities are sufficient to meet our current needs.
Biggest changeIn Brisbane, California, we occupy approximately 31,157 square feet of office and laboratory space under a sublease with Arcus Biosciences, Inc. which expires on September 30, 2028, unless terminated earlier. 61 We believe that our facilities are sufficient to meet our current needs.
ITEM 2. PROPERTIES Our corporate registered address and office is in Dublin, Ireland and our U.S. operations are in Brisbane, California. In Dublin, Ireland, we occupy approximately 920 square feet of office spaces under two leases which expire on July 31, 2024.
ITEM 2. PROPERTIES Our corporate registered address and office is in Dublin, Ireland and our U.S. operations are in Brisbane, California. In Dublin, Ireland, we occupy approximately 920 square feet of office spaces under two leases which expire on July 31, 2025.

Item 3. Legal Proceedings

Legal Proceedings — active lawsuits and investigations

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Biggest changeITEM 3. LEGAL PROCEEDINGS We are not currently a party to any material legal proceedings. We may at times be party to ordinary routine litigation incidental to our business. When appropriate in management’s estimation, we may record reserves in our financial statements for pending legal proceedings. ITEM 4. MINE SAFETY DISCLOSURES Not Applicable. 58 PART II
Biggest changeITEM 3. LEGAL PROCEEDINGS We are not currently a party to any material legal proceedings. We may at times be party to ordinary routine litigation incidental to our business. When appropriate in management’s estimation, we may record reserves in our financial statements for pending legal proceedings. ITEM 4. MINE SAFETY DISCLOSURES Not Applicable. 62 PART II

Item 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

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Biggest changePoints on the graph represent the performance as of end of each business day. 59 COMPARISON OF 5-YEAR CUMULATIVE TOTAL RETURN Among Prothena Corporation plc, the Nasdaq Composite Index, and the Nasdaq Biotechnology Index Cumulative Total Return as of 12/31/2018 12/31/2019 12/31/2020 12/31/2021 12/31/2022 12/31/2023 Prothena Corporation plc $100 $ 154 $ 117 $ 480 $ 585 $ 353 Nasdaq Composite Index $100 $ 135 $ 194 $ 236 $ 158 $ 226 Nasdaq Biotechnology Index $100 $ 124 $ 156 $ 155 $ 138 $ 144 (1) The information under the heading “Performance Graph” shall not be deemed “soliciting material” or to be “filed” with the SEC for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, or otherwise subject to the liabilities under that Section, and shall not be deemed incorporated by reference into any filing of Prothena Corporation plc under the Securities Act of 1933, as amended.
Biggest changePoints on the graph represent the performance as of end of each business day. 63 COMPARISON OF 5-YEAR CUMULATIVE TOTAL RETURN Among Prothena Corporation plc, the Nasdaq Composite Index, and the Nasdaq Biotechnology Index Cumulative Total Return as of 12/31/2019 12/31/2020 12/31/2021 12/31/2022 12/31/2023 12/31/2024 Prothena Corporation plc $ 100 $ 76 $ 312 $ 381 $ 230 $ 87 Nasdaq Composite Index $ 100 $ 144 $ 174 $ 117 $ 167 $ 215 Nasdaq Biotechnology Index $ 100 $ 126 $ 125 $ 111 $ 115 $ 114 (1) The information under the heading “Performance Graph” shall not be deemed “soliciting material” or to be “filed” with the SEC for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, or otherwise subject to the liabilities under that Section, and shall not be deemed incorporated by reference into any filing of Prothena Corporation plc under the Securities Act of 1933, as amended.
At present, the Transfers Act prohibits financial transfers involving the late Slobodan Milosevic and associated persons, certain persons indicted by the International Criminal Tribunal for the former Yugoslavia, the late Osama bin Laden, Al-Qaida, the Taliban of Afghanistan, certain persons, entities, and activities in Burma (Myanmar), Belarus, Democratic Republic of Congo, Democratic 60 People’s Republic of Korea (North Korea), Iran, Iraq, Côte d’Ivoire, Lebanon, Liberia, Zimbabwe, Sudan, Somalia, Republic of Guinea, Afghanistan, Egypt, Eritrea, Libya, Syria, Tunisia, Ukraine, Russia, certain known terrorists and terrorist groups, and countries that harbor certain terrorist groups, without the prior permission of the Central Bank of Ireland.
At present, the Transfers Act prohibits financial transfers involving the late Slobodan Milosevic and associated persons, certain persons indicted by the International Criminal Tribunal for the former Yugoslavia, the late Osama bin Laden, Al-Qaida, the Taliban of 64 Afghanistan, certain persons, entities, and activities in Burma (Myanmar), Belarus, Democratic Republic of Congo, Democratic People’s Republic of Korea (North Korea), Iran, Iraq, Côte d’Ivoire, Lebanon, Liberia, Zimbabwe, Sudan, Somalia, Republic of Guinea, Afghanistan, Egypt, Eritrea, Libya, Syria, Tunisia, Ukraine, Russia, certain known terrorists and terrorist groups, and countries that harbor certain terrorist groups, without the prior permission of the Central Bank of Ireland.
Our shareholders should consult their own tax advisers as to whether CAT is creditable or deductible in computing any domestic tax liabilities. Stamp Duty 61 Irish stamp duty may be payable in respect of transfers of our ordinary shares (currently at the rate of 1% of the price paid or the market value of the shares acquired, if greater).
Our shareholders should consult their own tax advisers as to whether CAT is creditable or deductible in computing any domestic tax liabilities. 65 Stamp Duty Irish stamp duty may be payable in respect of transfers of our ordinary shares (currently at the rate of 1% of the price paid or the market value of the shares acquired, if greater).
Performance Graph (1) The following graph shows a comparison from December 31, 2018, through December 31, 2023, of cumulative total return on assumed investment of $100.00 in cash in our ordinary shares, the Nasdaq Composite Index and the Nasdaq Biotechnology Index. Such returns are based on historical results and are not intended to suggest future performance.
Performance Graph (1) The following graph shows a comparison from December 31, 2019, through December 31, 2024, of cumulative total return on assumed investment of $100.00 in cash in our ordinary shares, the Nasdaq Composite Index and the Nasdaq Biotechnology Index. Such returns are based on historical results and are not intended to suggest future performance.
Holders There were approximately 5,221 shareholders of record of our ordinary shares as of February 15, 2024 . Because many of our shares are held by brokers and other institutions on behalf of shareholders, we are unable to estimate the total number of shareholders represented by these record holders.
Holders There were approximately 5,177 shareholders of record of our ordinary shares as of February 20, 2025. Because many of our shares are held by brokers and other institutions on behalf of shareholders, we are unable to estimate the total number of shareholders represented by these record holders.

Item 7. Management's Discussion & Analysis

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

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Biggest changeThe following table sets forth the R&D expenses for our major programs (specifically, any active program with successful first dosing in a Phase 1 clinical trial, which were birtamimab, prasinezumab, NNC6019 (PRX004) , BMS-986446 (PRX005), PRX012 and other R&D expenses for the years ended December 31, 2023 and 2022, and the cumulative amounts to date (in thousands): Year Ended December 31, Cumulative to Date (1) 2023 2022 Birtamimab (NEOD001) $ 68,831 $ 49,312 $ 472,317 PRX002/RG7935 (2) 34 261 106,815 NNC6019 (PRX004) (3) 91 1,038 79,891 BMS-986446 (PRX005) 10,063 14,444 57,363 PRX012 102,767 41,990 165,770 Other R&D (4) 38,785 28,517 $ 220,571 $ 135,562 (1) Cumulative R&D costs to date include the costs incurred from the date when the applicable program was separately tracked in preclinical development.
Biggest changeThe following table sets forth the R&D expenses for our major programs (specifically, any active program with successful first dosing in a Phase 1 clinical trial), which were birtamimab, prasinezumab, coramitug, BMS-986446 (PRX005), PRX012, PRX019 and other R&D expenses for the years ended December 31, 2024 , and 2023 (in thousands): Year Ended December 31, 2024 2023 Birtamimab (NEOD001) $ 85,649 $ 68,831 Prasinezumab (PRX002/RG7935) 49 34 Coramitug (NNC6019/PRX004) (1) 4 91 BMS-986446 (PRX005) 264 10,063 PRX012 116,359 102,767 PRX019 (2) 5,035 7,703 Other R&D (3) 15,159 31,082 Total research and development $ 222,519 $ 220,571 (1) On July 8, 2021, we sold shares of one of our wholly-owned subsidiaries to Novo Nordisk.
Contracts with Multiple Performance Obligations Significant judgment is required to apply the authoritative accounting guidance at the outset of a collaboration arrangement, and over time. Our License Agreement with Roche and our Collaboration Agreement with BMS contain multiple performance obligations.
Contracts with Multiple Performance Obligations Significant judgment is required to apply the authoritative accounting guidance at the outset of a collaboration arrangement, and over time. Our Collaboration Agreement with BMS and our License Agreement with Roche contain multiple performance obligations.
Factors considered in the determination of whether the license performance obligations are distinct included, among other things, the research and development capabilities of each of Roche and BMS and their respective sublicense rights, and for the remaining performance obligations the fact that they are not proprietary and can be and have been provided by other vendors.
Factors considered in the determination of whether the license performance obligations are distinct included, among other things, the research and development capabilities of each of BMS and Roche and their respective sublicense rights, and for the remaining performance obligations the fact that they are not proprietary and can be and have been provided by other vendors.
See Note 7, “Significant Agreements” to our Consolidated Financial Statements regarding the Collaboration Agreement with BMS for more 67 information. Pursuant to the share purchase agreement with Novo Nordisk, we are eligible to receive development and sales milestone payments. See Note 7, “Significant Agreements” to our Consolidated Financial Statements regarding the Novo Nordisk Share Purchase Agreement for more information.
See Note 7, “Significant Agreements” to our Consolidated Financial Statements regarding the Collaboration Agreement with BMS for more information. Pursuant to the share purchase agreement with Novo Nordisk, we are eligible to receive development and sales milestone payments. See Note 7, “Significant Agreements” to our Consolidated Financial Statements regarding the Novo Nordisk Share Purchase Agreement for more information.
Purchase obligations consist of non-cancelable purchase commitments to suppliers. Operating leases represent our future minimum rental 68 commitments under our non-cancelable operating leases. For additional information regarding the timing for our contractual obligations see Note 6, “Commitments and Contingencies” to our Consolidated Financial Statements.
Purchase obligations consist of non-cancelable purchase commitments to suppliers. Operating leases represent our future minimum rental commitments under our non-cancelable operating leases. For additional information regarding the timing for our contractual obligations see Note 6, “Commitments and Contingencies” to Consolidated Financial Statements.
Our R&D expenses primarily consist of personnel costs and related expenses, including share-based compensation and external costs associated with clinical activities and drug development related to our drug programs, including birtamimab, BMS-986446 ( PRX005), PRX012, PRX123 and preclinical activities related to our discovery programs.
Our R&D expenses primarily consist of personnel costs and related expenses, including share-based compensation and external costs associated with clinical activities and drug development related to our drug programs, including birtamimab, BMS-986446 ( PRX005), PRX012, PRX123, PRX019 and preclinical activities related to our discovery programs.
The level of judgment required to estimate research and development expenses varies based on 63 the nature of the services being performed and the underlying support obtained.
The level of judgment required to estimate research and development expenses varies based on the nature of the services being performed and the underlying support obtained.
(2) Purchase obligations as of the filing date includes additional $2.9 million purchase commitments to our contract manufacturers. In addition to the contractual obligations above, we also expect to have future material cash requirements related to our clinical trials, discovery and pre-clinical programs, human capital and intellectual property.
(2) Purchase obligations as of the filing date includes additional $2.1 million purchase commitments to our contract manufacturers. In addition to the contractual obligations above, we also expect to have future material cash requirements related to our clinical trials, discovery and pre-clinical programs, human capital and intellectual property.
Off-Balance Sheet Arrangements At December 31, 2023, we were not a party to any off-balance sheet arrangements that have, or are reasonably likely to have, a current or future effect on our financial condition, changes in financial condition, revenue or expenses, results of operations, liquidity, capital expenditures or capital resources.
Off-Balance Sheet Arrangements At December 31, 2024, we were not a party to any off-balance sheet arrangements that have, or are reasonably likely to have, a current or future effect on our financial condition, changes in financial condition, revenue or expenses, results of operations, liquidity, capital expenditures or capital resources.
See Note 7, “Significant Agreements” to our Consolidated Financial Statements regarding the Roche License Agreement for more information. Pursuant to the Collaboration Agreement with BMS (formerly Celgene), we are eligible to receive payments for commercial and regulatory milestones and royalties on net sales of Collaboration Products.
See Note 7, “Significant Agreements” to our Consolidated Financial Statements regarding the Roche License Agreement for more information. Pursuant to the Collaboration Agreement with BMS, we are eligible to receive payments for commercial and regulatory milestones and royalties on net sales of Collaboration Products.
At the inception of each arrangement that includes developmental, regulatory or commercial milestone payments, we evaluate whether achieving the milestones is considered probable and estimates the amount to be included in the transaction price using the most likely amount method, which includes judgment.
At the inception of each arrangement that includes developmental, regulatory or commercial milestone payments, we evaluate whether achieving the milestones is considered probable and estimate the amount to be included in the transaction price using the most likely amount method, which includes judgment.
We believe the following policies to be critical to the judgments and estimates used in the preparation of our financial statements. 62 Revenue Recognition Our collaboration revenue includes revenue recognized for milestone payments and reimbursements under our License Agreement with Roche as well as revenue recognized under our Collaboration Agreement with BMS.
We believe the following policies to be critical to the judgments and estimates used in the preparation of our financial statements. 66 Revenue Recognition Our collaboration revenue includes revenue recognized for milestone payments and reimbursements under our License Agreement with Roche as well as revenue recognized under our Collaboration Agreement with BMS.
Our cash and cash equivalents may also be potentially supplemented in the future by proceeds from our collaboration partners and milestone payments from Novo Nordisk. Pursuant to the Collaboration Agreement with Roche, we are eligible to receive payments for commercial and regulatory milestones and royalties on net sales of Collaboration Products.
Our cash and cash equivalents may also be potentially supplemented in the future by proceeds from our collaboration partners BMS (formerly Celgene), Roche and milestone payments from Novo Nordisk. Pursuant to the Collaboration Agreement with Roche, we are eligible to receive payments for commercial and regulatory milestones and royalties on net sales of Collaboration Products.
Other income (expense), net for the year ended December 31, 2023, was primarily foreign exchange losses from transactions with vendors denominated in Euros.
Other income (expense), net for the year ended December 31, 2024, was primarily foreign exchange losses from transactions with vendors denominated in euros.
We are also entitled to certain potential milestone payments pursuant to our share purchase agreement with Novo Nordisk pertaining to our ATTR amyloidosis business. We were formed on September 26, 2012, under the laws of Ireland and re-registered as an Irish public limited company on October 25, 2012.
We are also entitled to certain potential milestone payments pursuant to our share purchase agreement with Novo Nordisk pertaining to our ATTR amyloidosis business (inclusive of coramitug, formerly PRX004). We were formed on September 26, 2012, under the laws of Ireland and re-registered as an Irish public limited company on October 25, 2012.
As of December 31, 2023, $224.3 million of our outstanding cash and cash equivalents related to U.S. operations are considered permanently reinvested. We do not intend to repatriate these funds. However, if these funds were repatriated back to Ireland, we would incur a withholding tax from the dividend distribution.
As of December 31, 2024, $265.3 million of our outstanding cash and cash equivalents related to U.S. operations are considered permanently reinvested. We do not intend to repatriate these funds. However, if these funds were repatriated back to Ireland, we would incur a withholding tax from the dividend distribution.
Additionally, in order to develop and obtain regulatory approval for our potential products we will need to raise substantial additional funds.
Additionally, in order to develop and obtain regulatory approval for our potential products we will need to raise substantial additional capital.
The increase for the year ended December 31, 2023 , was primarily due to higher clinical trial expenses primarily related to the PRX012 and birtamimab programs, higher personnel expenses, and higher R&D consulting and other expenses; offset in part by lower manufacturing expense related primarily to the PRX019 and birtamimab programs.
The increase for the year ended December 31, 2024, was primarily due to higher clinical trial expenses primarily related to the PRX012 and birtamimab programs, higher personnel expenses; offset in part by lower manufacturing expense and lower other R &D expenses.
The measurement of these research and development cost and/or effort can impact the research and development expenses in the Consolidated Statements of Operations and of prepaid assets and accrued liabilities on the Consolidated Balance Sheets.
The measurement of these research and development costs and/or effort can impact the research and development expenses in the Consolidated Statements of Operations and of prepaid assets and accrued liabilities on the 67 Consolidated Balance Sheets.
Our G&A expenses primarily consist of personnel costs and related expenses, including share-based compensation and consulting expenses. Research and Development Expenses Our R&D expense increased by $85.0 million for the year ended December 31, 2023 , compared to the prior year.
Our G&A expenses primarily consist of personnel costs and related expenses, including share-based compensation and consulting expenses. Research and Development Expenses Our R&D expense increased by $1.9 million for the year ended December 31, 2024, compared to the prior year.
Our operating expenses were $282.4 million and $185.5 million for the years ended December 31, 2023, and 2022, respectively. Our research activities are aimed at developing new drug products. Our development activities involve the translation of our research into potential new drugs.
Our operating expenses were $289.7 million and $282.4 million for the years ended December 31, 2024, and 2023, respectively. Our research activities are aimed at developing new drug products. Our development activities involve the translation of our research into potential new drugs.
Years ended December 31, 2022 and 2021 Refer to “Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations — Liquidity and Capital Resources” in our 2022 Annual Report on Form 10-K for a discussion of the cash flows for the years ended December 31, 2022 and 2021.
Management’s Discussion and Analysis of Financial Condition and Results of Operations — Liquidity and Capital Resources” in our 2023 Annual Report on Form 10-K for a discussion of the cash flows for the years ended December 31, 2023 and 2022.
Assuming no significant change in our business, we expect the full year 2024 net cash used in operating and investing activities to be approximately $208 million to $225 million.
Assuming no significant change in our business, we expect the full year 2025 net cash used in operating and investing activities to be approximately $168 million to $175 million.
In addition, the Company entered into a lease agreement for additional office space in Dublin, Ireland, which commenced in August 2023 and has an initial term of one year.
In June 2021, we entered into a lease agreement for office space in Dublin, Ireland, which commenced in August 2021 and had an initial term of one year. In addition, we entered into a lease agreement for additional office space in Dublin, Ireland, which commenced in August 2023 and had an initial term of one year.
Contractual Obligations Our contractual obligations as of December 31, 2023, consisted of minimum cash payments under operating leases of $14.8 million, purchase obligations of $12.4 million (of which $6.3 million is included in current liabilities), and contractual obligations under license agreements of $0.4 million (of which $60,000 is included in current liabilities).
Contractual Obligations Our contractual obligations as of December 31, 2024, consisted of minimum cash payments under operating leases of $12.1 million, purchase obligations of $12.7 million (of which $1.8 million is included in current liabilities), and contractual obligations under license agreements of $0.3 million (of which nil is included in current liabilities).
The increase in benefit from income taxes for the year ended December 31, 2023 , compared to the prior year, was primarily due to an increase in defe rred tax assets related to Section 174 R&D Capitalization.
The decline in benefit from income taxes for the year ended December 31, 2024 , compared to the prior year, was primarily due to a lower increase in deferred tax assets related to Section 174 R&D Capitalization.
Cash Used in Investing Activities Net cash used in investing activities was $2.8 million for the year ended December 31, 2023, which primarily consisted of expenditures to purchase property and equipment.
Cash Used in Investing Activities Net cash used in investing activities w as $0.3 million for the year ended December 31, 2024, which primarily consisted of expenditures to purchase property and equipment.
(4) Other R&D is comprised primarily of preclinical development and discovery programs that have not progressed to first patient dosing in a Phase 1 clinical trial and close out costs for programs that we are no longer advancing. 65 We expect our R&D expenses to be relatively flat in 2024 over the prior year.
(3) Other R&D is comprised primarily of preclinical development and discovery programs that have not progressed to first patient dosing in a Phase 1 clinical trial and close out costs for programs that we are no longer advancing.
Provision for (benefit from) Income Taxes Year Ended December 31, Change 2023 2022 $ % (Dollars in thousands) Provision for (benefit from) income taxes $ (13,452) $ (8,656) $ (4,796) 55 % The benefit from income taxes increased by $4.8 million for the year ended December 31, 2023 , compared to the same period in the prior year.
Provision for (benefit from) Income Taxes Year Ended December 31, Change 2024 2023 $ % (Dollars in thousands) Benefit from income taxes $ (6,620) $ (13,452) $ 6,832 (51) % The benefit from income taxes decreased by $6.8 million for the year ended December 31, 2024, compared to the same period in the prior year.
Cash Flows The following table summarizes, for the periods indicated, selected items in our Consolidated Statements of Cash Flows (in thousands): Year Ended December 31, 2023 2022 2021 Net cash provided by (used in) operating activities $ (133,906) $ (108,821) $ 92,605 Net cash used in investing activities (2,773) (464) (575) Net cash provided by financing activities 45,103 241,457 190,332 Net increase (decrease) in cash, cash equivalents and restricted cash $ (91,576) $ 132,172 $ 282,362 Cash Used in Operating Activities Net cash used in operating activities was $133.9 million for the year ended December 31, 2023 , which was primarily due to ongoing research and development activities and general and administrative expenses to support those activities for a total of $282.4 million in operating expenses (adjusted to exclude non-cash charges of approximately $33.7 million ) partially offset by $55.0 million in cash from BMS related to the tau global option exercise fee and interest income on investments of $31.0 million .
Cash Flows The following table summarizes, for the periods indicated, selected items in our Consolidated Statements of Cash Flows (in thousands): Year Ended December 31, 2024 2023 2022 Net cash used in operating activities $ (150,050) $ (133,906) $ (108,821) Net cash used in investing activities (298) (2,773) (464) Net cash provided by financing activities 1,554 45,103 241,457 Net increase (decrease) in cash, cash equivalents and restricted cash $ (148,794) $ (91,576) $ 132,172 71 Cash Used in Operating Activities Net cash used in operating activities was $150.1 million for the year ended December 31, 2024 , which was primarily due to ongoing research and development activities and general and administrative expenses to support those activities for a total of $289.7 million in operating expenses (adjusted to exclude non-cash charges of approximately $40.2 million) partially offset by $80.0 million option exercise payment from BMS, interest income on investments o f $25.8 million, and c ash from collection of accounts receivable of $5.2 million .
Se e Note 7, “Significant Agreements” to the Consolidated Financial Statements regarding the Collaboration Agreement with BMS for more information. License and intellectual property revenue for the year ended December 31, 2023 was $50,000 compared to $40.1 million f or the year ended December 31, 2022.
License and intellectual property revenue for the year ended December 31, 2024 was $50,000 compared to $50,000 f or the year ended December 31, 2023 . See Note 7, “Significant Agreements” to the Consolidated Financial Statements regarding the Novo Nordisk Share Purchase Agreement for more information.
The following is a summary of our contractual obligations as of December 31, 2023 (in thousands): Total 2024 2025 2026 2027 2028 Thereafter Operating leases (1) $ 14,835 $ 2,833 $ 3,052 $ 3,158 $ 3,269 $ 2,523 $ — Purchase obligations (2) 12,433 12,397 36 — — — — Contractual obligations under license agreements 398 124 64 60 60 45 45 Total $ 27,666 $ 15,354 $ 3,152 $ 3,218 $ 3,329 $ 2,568 $ 45 (1) See Note 6, “ Commitments and Contingencies ” to our Consolidated Financial Statements.
Of this obligation, approximately $12.0 million remains outstanding as of December 31, 2024. 72 The following is a summary of our contractual obligations as of December 31, 2024 (in thousands): Total 2025 2026 2027 2028 Thereafter Operating leases (1) $ 12,129 $ 3,179 $ 3,158 $ 3,269 $ 2,523 $ — Purchase obligations (2) 12,729 12,633 96 — — — Contractual obligations under license agreements 274 64 60 60 45 45 Total $ 25,132 $ 15,876 $ 3,314 $ 3,329 $ 2,568 $ 45 (1) See Note 6, “ Commitments and Contingencies ” to our Consolidated Financial Statements.
Assuming no significant change in our business, we expect our 2024 revenue to decline over the prior year as our 2023 revenue was primarily comprised of nonrecurring revenue. 64 Operating Expenses Year Ended December 31, Change 2023 2022 $ % (Dollars in thousands) Research and development $ 220,571 $ 135,562 $ 85,009 63 % General and administrative 61,835 49,900 11,935 24 % Total operating expenses $ 282,406 $ 185,462 $ 96,944 52 % Total operating expenses consist of R&D expenses, general and administrative (“G&A”) expenses.
Assuming no significant change in our business, we expect our 2025 revenue to decline over the prior year as our 2024 revenue was primarily comprised of nonrecurring revenue. 68 Operating Expenses Year Ended December 31, Change 2024 2023 $ % (Dollars in thousands) Research and development $ 222,519 $ 220,571 $ 1,948 1 % General and administrative 67,199 61,835 5,364 9 % Total operating expenses $ 289,718 $ 282,406 $ 7,312 3 % Total operating expenses consist of R&D expenses, general and administrative (“G&A”) expenses.
Results of Operations Comparison of Years Ended December 31, 2023 and 2022 Revenue Year Ended December 31, Change 2023 2022 $ % (Dollars in thousands) Collaboration revenue $ 91,320 $ 13,855 $ 77,465 559 % Revenue from license and intellectual property 50 40,050 (40,000) (100) % Total revenue $ 91,370 $ 53,905 $ 37,465 70 % Total revenue was $91.4 million and $53.9 million for the years ended December 31, 2023, and 2022, respectively.
Results of Operations Comparison of Years Ended December 31, 2024 and 2023 Revenue Year Ended December 31, Change 2024 2023 $ % (Dollars in thousands) Collaboration revenue $ 135,107 $ 91,320 $ 43,787 48 % Revenue from license and intellectual property 50 50 — — % Total revenue $ 135,157 $ 91,370 $ 43,787 48 % Total revenue was $135.2 million and $91.4 million for the years ended December 31, 2024, and 2023, respectively.
Collaboration revenue from BMS was $91.3 million f or the year ended December 31, 2023, compared to $13.9 million for the year ended December 31, 2022.
Collaboration revenue from BMS increased $43.8 million f or the year ended December 31, 2024 , compared to the year ended December 31, 2023.
This decrease in working capital during the year ended December 31, 2023 , was primarily attributable to cash use of $282.4 million for operating expenses (adjusted to exclude non-cash charges) offset in part by $55.0 million in cash from BMS related to the tau global option exercise fee, net proceeds of approximately $20.7 million from the underwriters partial exercise of their 30-day option to purchase additional ordinary shares as part of the December 2022 public offering, interest income on investments of $31.0 million , net proceeds received from stock option exercises of approximately $21.5 million and proceeds of approximately $2.9 million from issuances of ordinary shares pursuant to the December 2021 Distribution Agreement.
This decrease in working capital during the year ended December 31, 2024 , was 70 primarily attributable to cash use of $289.7 million for operating expenses (adjusted to exclude non-cash charges) offset in part by $80.0 million option exercise payment from BMS, interest income on investments of $25.8 million , and net proceeds received from stock option exercises of approximately $1.9 million .
We expect that the level of judgment in estimating research and development expenses may increase over time as we are entering later stage, more extensive, clinical trials. The information contained in Note 2 to the Consolidated Financial Statements under the heading “Recent Accounting Pronouncements” is hereby incorporated by reference into this Part II, Item 7.
We expect that the level of judgment in estimating research and development expenses may increase over time as we are entering later stage, more extensive, clinical trials.
Other Income (Expense) Year Ended December 31, Change 2023 2022 $ % (Dollars in thousands) Interest income $ 31,014 $ 6,349 $ 24,665 388 % Other income (expense), net (458) (397) (61) 15 % Total other income (expense), net $ 30,556 $ 5,952 $ 24,604 413 % Interest income increased by $24.7 million for the year ended December 31, 2023 , compared to the prior year, primarily due to higher interest income from our cash and money market accounts resulting from higher interest rates.
General and Administrative Expenses Our G&A expe nses increased by $5.4 million , for the year ended December 31, 2024 , compared to the prior year primarily due to higher personnel expense. 69 Other Income (Expense) Year Ended December 31, Change 2024 2023 $ % (Dollars in thousands) Interest income $ 25,816 $ 31,014 $ (5,198) (17) % Other income (expense), net (185) (458) 273 (60) % Total other income (expense), net $ 25,631 $ 30,556 $ (4,925) (16) % Interest income decreased by $5.2 million for the year ended December 31, 2024, compared to the prior year, primarily due to lower interest income from our cash and money market accounts resulting from lower interest rates and lower cash and money market balances.
Our partnered programs include prasinezumab, in collaboration with Roche for the potential treatment of Parkinson’s disease and other related synucleinopathies, and programs that target tau (BMS-986446, formerly PRX005), TDP-43, and an undisclosed target (PRX019) in collaboration with Bristol Myers Squibb (BMS) for the potential treatment of Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and other neurodegenerative diseases, respectively.
In addition, we have partnered BMS-986446 (formerly PRX005) for the potential treatment for Alzheimer’s disease that targets tau and PRX019 for the potential treatment of neurodegenerative diseases with an undisclosed target in two separate license agreements with Bristol Myers Squibb (BMS).
Although we believe, based on our current business plans, that our existing cash and cash equivalents will be sufficient to meet our obligations for at least the next twelve months, we anticipate that we will require additional capital in the future in order to continue the research and development of our drug candidates.
As of December 31, 2024, we had $471.4 million in cash a nd cash equivalents. Based on our current business plans, we believe that our existing cash and cash equivalents at December 31, 2024 are sufficient to meet our obligations for at least the next twelve months.
We are obligated to make lease payments totaling approximately $14.9 million over the lease term, which expires on September 30, 2028 , unless terminated earlier. Of this obligation, approximately $14.7 million remains outstanding as of December 31, 2023.
In October 2022, we entered into a noncancelable operating sublease to lease approximately 31,157 square feet of office and laboratory space in Brisbane, California. We are obligated to make lease payments totaling approximately $14.9 million over the lease term, which expires on September 30, 2028 , unless terminated earlier.
We expect to raise any such additional funds through public or private equity or debt financings, colla borative agreements with corporate partners, or other arrangements, including pursuant to the December 2021 Distribution Agreement (See Note 8, “Shareholders’ Equity” to the Consolidated Financial Statements for more information).
We expect to continue to finance future capital needs that exceed our existing cash and cash equivalents, payments pursuant to our agreements with Roche, BMS, and Novo Nordisk, and, to the extent necessary, other collaboration agreements with corporate partners, or other arrangements, and through proceeds from public or private equity or debt financings, and loans, including pursuant to the Amended Distribution Agreement (See Note 8, “Shareholders’ Equity” to the Consolidated Financial Statements for more information).
(3) On July 8, 2021, we sold shares of one of our wholly-owned subsidiaries to Novo Nordisk. In connection with the transaction, Novo Nordisk acquired our ATTR amyloidosis business, including the clinical stage antibody NNC6019 (PRX004). Expenses incurred in 2023 and 2022 relate to certain close out activities and transition services provided to Novo Nordisk.
In connection with the transaction, Novo Nordisk acquired our ATTR amyloidosis business, including the clinical stage antibody coramitug (PRX004). Expenses incurred relate to certain close out activities and transition services provided to Novo Nordisk. (2) R&D costs include the costs incurred from the date when PRX019 was separately tracked in preclinical development.
Cash Provided by Financing Activities Net cash provided by financing activities was $45.1 million for the year ended December 31, 2023, primarily from net proceeds of approximately $20.7 million from the underwriters partial exercise of their 30-day option to purchase additional ordinary shares as part of the December 2022 public offering, proceeds from issuances of ordinary shares upon exercises of stock options of $21.5 million and net proceeds of $2.9 million f rom issuances of ordinary shares pursuant to the December 2021 Distribution Agreement.
Cash Provided by Financing Activities Net cash provided by financing activitie s was $1.6 million for the year ended December 31, 2024, primarily from proceeds from issuances of ordinary shares upon exercises of stock o ptions of $1.9 million. Years ended December 31, 2023 and 2022 Refer to “Item 7.
Both of these leases have an automatic renewal clause, pursuant to which the agreement will be extended automatically for successive periods equal to the current term, unless the agreement is cancelled by us. In October 2022, we entered into a noncancelable operating sublease to lease approximately 31,157 square feet of office and laboratory space in Brisbane, California.
In April 2024, we renewed both leases, each for another one year term with termination dates in July 2025. Both leases have an automatic renewal clause, pursuant to which each agreement will be extended automatically for successive periods equal to their current terms, unless each agreement is cancelled by us.
Management’s Discussion and Analysis of Financial Condition and Results of Operations—Results of Operations” in our 2022 Annual Report on Form 10-K for a discussion of the results of operations for the year ended December 31, 2022 compared to the year ended December 31, 2021. 66 Liquidity and Capital Resources Overview December 31, 2023 2022 (Dollars in thousands) Working capital $ 582,391 $ 668,951 Cash and cash equivalents $ 618,830 $ 710,406 Total assets $ 696,382 $ 758,035 Total liabilities $ 135,017 $ 135,993 Total shareholders’ equity $ 561,365 $ 622,042 Working capital was $582.4 million as of December 31, 2023 , a decrease of $86.6 million from working capital of $669.0 million as of December 31, 2022 .
Liquidity and Capital Resources Overview December 31, 2024 2023 (Dollars in thousands) Working capital $ 436,911 $ 582,391 Cash and cash equivalents $ 471,388 $ 618,830 Total assets $ 547,108 $ 696,382 Total liabilities $ 60,182 $ 135,017 Total shareholders’ equity $ 486,926 $ 561,365 Working capital was $436.9 million as of December 31, 2024 , a decrease of $145.5 million from working capital of $582.4 million as of December 31, 2023 .
Comparison of the years ended December 31, 2022 and 2021 Refer to “Item 7.
Comparison of the years ended December 31, 2023 and 2022 Refer to “Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations—Results of Operations” in our 2023 Annual Report on Form 10-K for a discussion of the results of operations for the year ended December 31, 2023 compared to the year ended December 31, 2022.
See Note 7, “Significant Agreements” to the Consolidated Financial Statements regarding the Novo Nordisk Share Purchase Agreement for more information.
Collaboration revenue from BMS for 2023 included recognition of $91.3 million from the Tau Global License Agreement and related development services. Se e Note 7, “Significant Agreements” to the Consolidated Financial Statements regarding the Collaboration Agreement with BMS for more information.
Removed
The increase of $77.5 million was primarily due to $72.9 million recognized for the Tau Global License Agreement ($17.9 million of deferred revenue recognized for the Global Right and $55.0 million for the option exercise fee) and $4.7 million under a Supply Agreement .
Added
Our partnered programs include prasinezumab for the potential treatment of Parkinson’s disease and other related synucleinopathies that targets alpha-synuclein in collaboration with Roche.
Removed
The decrease of $40.0 million was due to the $40.0 million milestone payment from Novo Nordisk related to the continued advancement of NNC6019 (formerly PRX004) in a Phase 2 clinical study for the treatment of ATTR cardiomyopathy in 2022 with no corresponding amount in 2023 .
Added
The information contained in Note 2 to the Consolidated Financial Statements under the headings “Recently Issued Accounting Pronouncements Not Yet Adopted” and “Recently Adopted Accounting Pronouncement - Segment Reporting” are hereby incorporated by reference into this Part II, Item 7.
Removed
Expenditures in the early discovery stage are not tracked by program and accordingly have been excluded from the applicable cumulative amount. (2) Through May 28, 2021, Prasinezumab costs include payments to Roche for our share of the development expenses incurred by Roche related to prasinezumab programs .
Added
Collaboration revenue from BMS for 2024 included recognition of $110.1 million from the PRX019 Global License Agreement and related development services and $25.0 million was related to BMS’s material rights for the US Rights and Global Rights for the TDP-43 Collaboration Target that expired unexercised as a result of the expiration of the research term of the Collaboration Agreement.
Removed
General and Administrative Expenses Our G&A expenses increased by $11.9 million, for the year ended December 31, 2023 , compared to the prior year primarily due to higher personnel expense and higher consulting expense. We expect our G&A expenses to increase in 2024 compared to the prior ye ar, primarily related to anticipated higher personnel costs including share-based compensation.
Added
To operate beyond such period, or if we elect to increase our spending on research and development programs significantly above current long-term plans or enter into potential licenses and/or other acquisitions of complementary technologies, products or companies, we may need additional capital.
Removed
As of December 31, 2023, we had $618.8 million in cash and cash equivalents.
Added
We do not consider the renewals in the lease term as we do not believe it to be reasonably certain that we will renew these leases, as our real estate needs are subject to change based on our business needs.
Removed
We had a noncancelable operating sublease covering 128,751 square feet of office and laboratory space in South San Francisco, California, which expired on December 31, 2023. We also had a sub-sublease covering approximately 46,641 square feet of such space, which terminated in connection with the sublease.
Removed
In June 2021, we entered into a lease agreement for office space in Dublin, Ireland, which commenced in August 2021 and had an initial term of one year. In April 2023, the Company renewed the lease for another one year term with a termination date of July 2024.

Item 7A. Quantitative and Qualitative Disclosures About Market Risk

Market Risk — interest-rate, FX, commodity exposure

6 edited+2 added−2 removed1 unchanged
Biggest changeOur investment policy also specifies credit quality standards for our investments and limits the amount of credit exposure to any single issue, issuer or type of investment. 69 Credit Risk Financial instruments that potentially subject us to concentration of credit risk consist of cash and cash equivalents and accounts receivable.
Biggest changeCredit Risk Financial instruments that potentially subject us to concentration of credit risk consist of cash and cash equivalents and accounts receivable. We place our cash and cash equivalents with high credit quality financial institutions and pursuant to our investment policy, we limit the amount of credit exposure with any one financial institution.
If we increase our business activities that require the use of foreign currencies, we may be exposed to losses if the Euro and other such currencies continue to strengthen against the U.S. dollar. Interest Rate Risk Our exposure to interest rate risk is limited to our cash equivalents, which consist of accounts maintained in money market funds.
If we increase our business activities that require the use of foreign currencies, we may be exposed to losses if the euro and other such currencies strengthen against the U.S. dollar. Interest Rate Risk Our exposure to interest rate risk is limited to our cash equivalents, which consist of accounts maintained in money market funds.
In the future, we anticipate that our exposure to interest rate risk will primarily be related to our investment portfolio. We may invest any surplus funds in accordance with a policy approved by our board of directors which will specify the categories, allocations, and ratings of securities we may consider for investment.
In the future, we anticipate that our exposure to interest rate risk will primarily be related to our investment portfolio, which is currently invested in money market accounts. We may invest any surplus funds in accordance with a policy approved by our board of directors which will specify the categories, allocations, and ratings of securities we may consider for investment.
We are exposed to credit risk in the event of a default by the financial institutions holding our cash and cash equivalents. We have not experienced any losses on our deposits of cash and cash equivalents. Our credit risk exposure is up to the extent recorded on the Company's Consolidated Balance Sheets. 70
Deposits held with banks have exceeded, and will continue to exceed, federally insured limits on such deposits. We are exposed to credit risk in the event of a default by the financial institutions holding our cash and cash equivalents. We have not experienced any losses on our deposits of cash and cash equivalents.
The primary objectives of our investment policy are to preserve principal and maintain proper liquidity to meet our operating requirements.
The primary objectives of our investment policy are to preserve principal and maintain proper liquidity to meet our operating requirements. Our investment policy also specifies credit quality standards for our investments and limits the amount of credit exposure to any single issue, issuer or type of investment.
ITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK Foreign Currency Risk Our business is primarily conducted in U.S. dollars except for our agreements with contract manufacturers for drug supplies which are primarily denominated in Euros.
Foreign Currency Risk Our business is primarily conducted in U.S. dollars except for our agreements with contract manufacturers for drug supplies wh ich are primarily denominated in euros. We recor ded losses on foreign currency exchange rate differences of approximately $185,000, $458,000 and $397,000 during the years ended December 31, 2024, 2023 and 2022, respectively.
Removed
We recorded a loss on foreign currency exchange rate differences of approximately $458,000 , $397,000, and $96,000 during the years ended December 31, 2023, 2022 and 2021, respectively .
Added
ITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK We are exposed to market risks in the ordinary course of our business including the effect of changes in foreign currency exchange rates and interest rates. Market risk represents the risk of loss that may impact our financial position due to adverse changes in financial market prices and rates.
Removed
We place our cash and cash equivalents with high credit quality financial institutions and pursuant to our investment policy, we limit the amount of credit exposure with any one financial institution. Deposits held with banks have exceeded, and will continue to exceed, federally insured limits on such deposits.
Added
Our credit risk exposure is up to the extent recorded on the Company's Consolidated Balance Sheets. 73

Other PRTA 10-K year-over-year comparisons