UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 10-K
| (Mark One) | |||||||||||
| ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 | |||||||||||
For the fiscal year ended | |||||||||||
| OR | |||||||||||
| TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 | |||||||||||
| For the transition period from __________ to __________ | |||||||||||
Commission File Number: | |||||||||||
(Exact name of registrant as specified in its charter)
| (State or other jurisdiction of incorporation or organization) | (I.R.S. Employer Identification No.) | |||||||
| (Address of principal executive offices, including zip code) | |||||||||||
(914 ) 847-7000
(Registrant's telephone number, including area code)
Securities registered pursuant to Section 12(b) of the Act:
| Title of each class | Trading Symbol | Name of each exchange on which registered | ||||||
Securities registered pursuant to section 12(g) of the Act: None
| Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. | ☒ | No | ☐ | |||||||||||
| Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. | Yes | ☐ | ☒ | |||||||||||
| Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. | ☒ | No | ☐ | |||||||||||
| Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). | ☒ | No | ☐ | |||||||||||
| Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company. See the definitions of "large accelerated filer," "accelerated filer," "smaller reporting company," and "emerging growth company" in Rule 12b-2 of the Exchange Act. | ||||||||||||||
| ☒ | Accelerated filer | ☐ | Non-accelerated filer | ☐ | Smaller reporting company | Emerging growth company | |||||||||||||||||||||||||||||||||||||||||
| If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. | ☐ | |||||||||||||
| Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. | ||||||||||||||
| Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act). | Yes | No | ☒ | |||||||||||
The aggregate market value of the voting and non-voting common stock held by non-affiliates of the registrant was $ | ||||||||||||||
The number of shares outstanding of each of the registrant's classes of common stock as of January 26, 2023: | ||||||||||||||
| Class of Common Stock | Number of Shares | |||||||
| Class A Stock, $.001 par value | ||||||||
| Common Stock, $.001 par value | ||||||||
| DOCUMENTS INCORPORATED BY REFERENCE | ||
| Specified portions of the Registrant's definitive proxy statement to be filed in connection with solicitation of proxies for its 2023 Annual Meeting of Shareholders are incorporated by reference into Part III of this Form 10-K. Exhibit index is located on pages 96 to 101 of this filing. | ||
REGENERON PHARMACEUTICALS, INC.
ANNUAL REPORT ON FORM 10-K
TABLE OF CONTENTS
| Page Numbers | ||||||||||||||
"Altibodies™," "ARCALYST®," "Evkeeza®," "EYLEA®," "Inmazeb®," "Libtayo®," "Praluent®" (in the United States), "REGEN-COV®," "Regeneron®," "Regeneron Genetics Center®," "RGC™," "Veloci-Bi®," "VelociGene®," "VelociHum®," "VelociMab®," "VelocImmune®," "VelociMouse®," "VelociSuite®," "VelociT®," and "ZALTRAP®" are trademarks of Regeneron Pharmaceuticals, Inc. Trademarks and trade names of other companies appearing in this report are, to the knowledge of Regeneron Pharmaceuticals, Inc., the property of their respective owners. This report refers to products of Regeneron Pharmaceuticals, Inc., its collaborators, and other parties. Consult the product label in each territory for specific information about such products. | ||
PART I
Item 1. Business
This Annual Report on Form 10-K contains forward-looking statements that involve risks and uncertainties relating to future events and the future performance of Regeneron Pharmaceuticals, Inc. (where applicable, together with its subsidiaries, "Regeneron," "Company," "we," "us," and "our"), and actual events or results may differ materially from these forward-looking statements. Words such as "anticipate," "expect," "intend," "plan," "believe," "seek," "estimate," variations of such words, and similar expressions are intended to identify such forward-looking statements, although not all forward-looking statements contain these identifying words. These statements concern, and these risks and uncertainties include, among others, the impact of SARS-CoV-2 (the virus that has caused the COVID-19 pandemic) on Regeneron's business and its employees, collaborators, and suppliers and other third parties on which Regeneron relies, Regeneron's and its collaborators’ ability to continue to conduct research and clinical programs, Regeneron's ability to manage its supply chain, net product sales of products marketed or otherwise commercialized by Regeneron and/or its collaborators or licensees (collectively, "Regeneron’s Products"), and the global economy; the nature, timing, and possible success and therapeutic applications of Regeneron's Products and product candidates being developed by Regeneron and/or its collaborators or licensees (collectively, "Regeneron's Product Candidates") and research and clinical programs now underway or planned, including without limitation EYLEA® (aflibercept) Injection, Dupixent® (dupilumab) Injection, Libtayo® (cemiplimab) Injection, Praluent® (alirocumab) Injection, Kevzara® (sarilumab) Injection, Evkeeza® (evinacumab), aflibercept 8 mg, pozelimab, odronextamab, itepekimab, fianlimab, garetosmab, linvoseltamab, REGN5713-5714-5715, Regeneron's other oncology programs (including its costimulatory bispecific portfolio), Regeneron's and its collaborators' earlier-stage programs, and the use of human genetics in Regeneron's research programs; the likelihood and timing of achieving any of our anticipated development milestones referenced in this report; safety issues resulting from the administration of Regeneron's Products and Regeneron's Product Candidates in patients, including serious complications or side effects in connection with the use of Regeneron's Products and Regeneron's Product Candidates in clinical trials; the likelihood, timing, and scope of possible regulatory approval and commercial launch of our late-stage product candidates and new indications for Regeneron's Products, including without limitation those listed above; the extent to which the results from the research and development programs conducted by us and/or our collaborators may be replicated in other studies and/or lead to advancement of product candidates to clinical trials, therapeutic applications, or regulatory approval; ongoing regulatory obligations and oversight impacting Regeneron's Products, research and clinical programs, and business, including those relating to patient privacy; determinations by regulatory and administrative governmental authorities which may delay or restrict our ability to continue to develop or commercialize Regeneron's Products and Regeneron's Product Candidates; competing drugs and product candidates that may be superior to, or more cost effective than, Regeneron's Products and Regeneron's Product Candidates; uncertainty of the utilization, market acceptance, and commercial success of Regeneron's Products and Regeneron's Product Candidates and the impact of studies (whether conducted by Regeneron or others and whether mandated or voluntary) or recommendations and guidelines from governmental authorities and other third parties on the commercial success of Regeneron's Products and Regeneron's Product Candidates; our ability to manufacture and manage supply chains for multiple products and product candidates; the ability of our collaborators, suppliers, or other third parties (as applicable) to perform manufacturing, filling, finishing, packaging, labeling, distribution, and other steps related to Regeneron's Products and Regeneron's Product Candidates; the availability and extent of reimbursement of Regeneron's Products from third-party payors, including private payor healthcare and insurance programs, health maintenance organizations, pharmacy benefit management companies, and government programs such as Medicare and Medicaid; coverage and reimbursement determinations by such payors and new policies and procedures adopted by such payors; unanticipated expenses; the costs of developing, producing, and selling products; our ability to meet any of our financial projections or guidance, including without limitation capital expenditures, and changes to the assumptions underlying those projections or guidance; the potential for any license or collaboration agreement, including our agreements with Sanofi and Bayer (or their respective affiliated companies, as applicable), to be cancelled or terminated; and risks associated with intellectual property of other parties and pending or future litigation relating thereto (including without limitation the patent litigation and other related proceedings described further in Note 16 to our Consolidated Financial Statements included in this report), other litigation and other proceedings and government investigations relating to the Company and/or its operations (including without limitation those described in Note 16 to our Consolidated Financial Statements included in this report), the ultimate outcome of any such proceedings and investigations, and the impact any of the foregoing may have on our business, prospects, operating results, and financial condition. These statements are made based on management's current beliefs and judgment, and the reader is cautioned not to rely on any such statements. In evaluating such statements, shareholders and potential investors should specifically consider the various factors identified under Part I, Item 1A. "Risk Factors," which could cause actual events and results to differ materially from those indicated by such forward-looking statements. We do not undertake any obligation to update (publicly or otherwise) any forward-looking statement, whether as a result of new information, future events, or otherwise.
2
General
Regeneron Pharmaceuticals, Inc. is a fully integrated biotechnology company that invents, develops, manufactures, and commercializes medicines for people with serious diseases. Our products and product candidates in development are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, pain, hematologic conditions, infectious diseases, and rare diseases.
Our core business strategy is to maintain a strong foundation in basic scientific research and discovery-enabling technologies, and to build on that foundation with our clinical development, manufacturing, and commercial capabilities. Our objective is to continue to be an integrated, multi-product biotechnology company that provides patients and medical professionals with important medicines for preventing and treating human diseases.
Selected financial information is summarized as follows:
| Year Ended December 31, | ||||||||||||||||||||
| (In millions, except per share data) | 2022 | 2021 | 2020 | |||||||||||||||||
| Revenues | $ | 12,172.9 | $ | 16,071.7 | $ | 8,497.1 | ||||||||||||||
| Net income | $ | 4,338.4 | $ | 8,075.3 | $ | 3,513.2 | ||||||||||||||
| Net income per share - diluted | $ | 38.22 | $ | 71.97 | $ | 30.52 | ||||||||||||||
For purposes of this report, references to our products encompass products marketed or otherwise commercialized by us and/or our collaborators or licensees and references to our product candidates encompass product candidates in development by us and/or our collaborators or licensees (in the case of collaborated or licensed products or product candidates under the terms of the applicable collaboration or license agreements), unless otherwise stated or required by the context.
Products
Products that have received marketing approval are summarized in the table below.
| Product | Disease | Territory | ||||||||||||||||||||||||||||||
| U.S. | EU | Japan | ROW(e) | |||||||||||||||||||||||||||||
EYLEA (aflibercept) Injection(a) | Neovascular age-related macular degeneration ("wet AMD") | a | a | a | a | |||||||||||||||||||||||||||
| Diabetic macular edema ("DME") | a | a | a | a | ||||||||||||||||||||||||||||
Macular edema following retinal vein occlusion ("RVO"), which includes macular edema following central retinal vein occlusion ("CRVO") and macular edema following branch retinal vein occlusion ("BRVO") | a | a | a | a | ||||||||||||||||||||||||||||
| Myopic choroidal neovascularization ("mCNV") | a | a | a | |||||||||||||||||||||||||||||
| Diabetic retinopathy ("DR") | a | |||||||||||||||||||||||||||||||
| Neovascular glaucoma ("NVG") | a | |||||||||||||||||||||||||||||||
Retinopathy of prematurity ("ROP") | a | a | ||||||||||||||||||||||||||||||
Dupixent (dupilumab) Injection(b) | Atopic dermatitis (in adults and adolescents) | a | a | a | a | |||||||||||||||||||||||||||
| Atopic dermatitis (in pediatrics 6–11 years of age) | a | a | a | |||||||||||||||||||||||||||||
| Atopic dermatitis (in pediatrics 6 months–5 years of age) | a | a | ||||||||||||||||||||||||||||||
| Asthma (in adults and adolescents) | a | a | a | a | ||||||||||||||||||||||||||||
| Asthma (in pediatrics 6–11 years of age) | a | a | a | |||||||||||||||||||||||||||||
| Chronic rhinosinusitis with nasal polyposis ("CRSwNP") | a | a | a | a | ||||||||||||||||||||||||||||
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Product (continued) | Disease | Territory | ||||||||||||||||||||||||||||||
| U.S. | EU | Japan | ROW(e) | |||||||||||||||||||||||||||||
Dupixent (dupilumab) Injection(b) (continued) | Eosinophilic esophagitis ("EoE") (in adults and adolescents) | a | a | a | ||||||||||||||||||||||||||||
| Prurigo nodularis | a | a | a | |||||||||||||||||||||||||||||
Libtayo (cemiplimab) Injection(c) | Metastatic or locally advanced first-line non-small cell lung cancer ("NSCLC") | a | a | a | ||||||||||||||||||||||||||||
Metastatic or locally advanced first-line NSCLC (in combination with chemotherapy) | a | |||||||||||||||||||||||||||||||
Metastatic or locally advanced basal cell carcinoma ("BCC") | a | a | a | |||||||||||||||||||||||||||||
| Metastatic or locally advanced cutaneous squamous cell carcinoma ("CSCC") | a | a | a | |||||||||||||||||||||||||||||
Metastatic or recurrent second-line cervical cancer | a | a | a | |||||||||||||||||||||||||||||
Praluent (alirocumab) Injection(d) | LDL-lowering in heterozygous familial hypercholesterolemia ("HeFH") or clinical atherosclerotic cardiovascular disease ("ASCVD") | a | a | a | ||||||||||||||||||||||||||||
| Cardiovascular risk reduction in patients with established cardiovascular disease | a | a | a | |||||||||||||||||||||||||||||
| Homozygous familial hypercholesterolemia ("HoFH") | a | |||||||||||||||||||||||||||||||
REGEN-COV®(f) | COVID-19 | a | a | a | ||||||||||||||||||||||||||||
Kevzara (sarilumab) Solution for Subcutaneous Injection(b) | Rheumatoid arthritis ("RA") | a | a | a | a | |||||||||||||||||||||||||||
Evkeeza (evinacumab) Injection(g) | HoFH (in adults and adolescents) | a | a | a | ||||||||||||||||||||||||||||
Inmazeb® (atoltivimab, maftivimab, and odesivimab-ebgn) Injection | Infection caused by Zaire ebolavirus | a | ||||||||||||||||||||||||||||||
ARCALYST® (rilonacept) Injection for Subcutaneous Use(h) | Cryopyrin-associated periodic syndromes ("CAPS"), including familial cold auto-inflammatory syndrome ("FCAS") and Muckle-Wells syndrome ("MWS") (in adults and adolescents) | a | ||||||||||||||||||||||||||||||
| Deficiency of interleukin-1 receptor antagonist ("DIRA") (in adults and pediatrics) | a | |||||||||||||||||||||||||||||||
Recurrent pericarditis (in adults and adolescents) | a | |||||||||||||||||||||||||||||||
ZALTRAP® (ziv-aflibercept) Injection for Intravenous Infusion(i) | Metastatic colorectal cancer ("mCRC") | a | a | a | a | |||||||||||||||||||||||||||
Note: Refer to table below (net product sales of Regeneron-discovered products) for information regarding whether net product sales for a particular product are recorded by us or others. In addition, unless otherwise noted, products in the table above are generally approved for use in adults in the above-referenced diseases. | ||||||||||||||||||||||||||||||||
(a) In collaboration with Bayer outside the United States | ||||||||||||||||||||||||||||||||
(b) In collaboration with Sanofi | ||||||||||||||||||||||||||||||||
(c) In collaboration with Sanofi prior to July 2022. Effective July 2022, the Company is solely responsible for the development, commercialization, and manufacturing of Libtayo. Refer to "Collaboration, License, and Other Agreements" section below for further details. | ||||||||||||||||||||||||||||||||
(d) The Company is solely responsible for the development and commercialization of Praluent in the United States, and Sanofi is solely responsible for the development and commercialization of Praluent outside of the United States. | ||||||||||||||||||||||||||||||||
4
(e) Rest of world ("ROW"). A checkmark in this column indicates that the product has received marketing approval in at least one country outside of the United States, European Union ("EU"), or Japan. | ||||||||||||||||||||||||||||||||
(f) Known as REGEN-COV in the United States and Ronapreve™ in other countries. | ||||||||||||||||||||||||||||||||
(g) The Company is solely responsible for the development and commercialization of Evkeeza in the United States. In January 2022, the Company entered into a license and collaboration agreement for Ultragenyx to develop and commercialize Evkeeza outside of the United States. | ||||||||||||||||||||||||||||||||
(h) Kiniksa is solely responsible for the development and commercialization of ARCALYST. | ||||||||||||||||||||||||||||||||
(i) Sanofi is solely responsible for the development and commercialization of ZALTRAP. | ||||||||||||||||||||||||||||||||
Net product sales of Regeneron-discovered products consist of the following:
| Year Ended December 31, | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 2022 | 2021 | 2020 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| (In millions) | U.S. | ROW | Total | U.S. | ROW | Total | U.S. | ROW | Total | |||||||||||||||||||||||||||||||||||||||||||||||
EYLEA(a) | $ | 6,264.6 | $ | 3,382.8 | $ | 9,647.4 | $ | 5,792.3 | $ | 3,450.9 | * | $ | 9,243.2 | $ | 4,947.2 | $ | 2,820.7 | * | $ | 7,767.9 | ||||||||||||||||||||||||||||||||||||
Dupixent(b) | $ | 6,668.0 | $ | 2,013.2 | $ | 8,681.2 | $ | 4,713.0 | $ | 1,485.3 | $ | 6,198.3 | $ | 3,226.2 | $ | 818.6 | $ | 4,044.8 | ||||||||||||||||||||||||||||||||||||||
Libtayo(c) | $ | 374.5 | $ | 203.5 | $ | 578.0 | $ | 306.3 | $ | 151.9 | $ | 458.2 | $ | 270.7 | $ | 77.5 | $ | 348.2 | ||||||||||||||||||||||||||||||||||||||
Praluent(d) | $ | 130.0 | $ | 337.4 | $ | 467.4 | $ | 170.0 | $ | 251.1 | $ | 421.1 | $ | 186.0 | $ | 172.8 | $ | 358.8 | ||||||||||||||||||||||||||||||||||||||
REGEN-COV(e) | $ | — | $ | 1,769.6 | $ | 1,769.6 | $ | 5,828.0 | $ | 1,745.9 | $ | 7,573.9 | $ | 185.7 | $ | — | $ | 185.7 | ||||||||||||||||||||||||||||||||||||||
Kevzara(b) | $ | 199.7 | $ | 158.3 | $ | 358.0 | $ | 161.9 | $ | 176.1 | $ | 338.0 | $ | 141.6 | $ | 128.3 | $ | 269.9 | ||||||||||||||||||||||||||||||||||||||
Other products(f) | $ | 56.1 | $ | 69.1 | $ | 125.2 | $ | 25.9 | $ | 86.4 | $ | 112.3 | $ | 18.9 | $ | 97.9 | $ | 116.8 | ||||||||||||||||||||||||||||||||||||||
* Effective January 1, 2022, the Company and Bayer commenced sharing equally in profits and losses based on sales from Bayer to its distributor in Japan. Previously, the Company received from Bayer a tiered percentage of sales based on sales by Bayer's distributor in Japan. Consequently, the prior year net product sales amount has been revised for comparability purposes. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(a) Regeneron records net product sales of EYLEA in the United States. Bayer records net product sales of EYLEA outside the United States. The Company records its share of profits/losses in connection with sales of EYLEA outside the United States. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(b) Sanofi records global net product sales of Dupixent and Kevzara. The Company records its share of profits/losses in connection with global sales of Dupixent and Kevzara. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(c) Prior to July 1, 2022, Regeneron recorded net product sales of Libtayo in the United States and Sanofi recorded net product sales of Libtayo outside the United States. The parties equally shared profits/losses in connection with global sales of Libtayo. Effective July 1, 2022, the Company began recording net product sales of Libtayo outside the United States and pays Sanofi a royalty on global sales. Refer to "Collaboration, License, and Other Agreements" section below for further details. Included in this line item is approximately $34 million of net product sales recorded by Sanofi in the second half of 2022 in connection with sales in certain markets (Sanofi will record net product sales in such markets during a transition period until inventory on hand as of July 1, 2022 is sold through to the end customers). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(d) Effective April 1, 2020, Regeneron records net product sales of Praluent in the United States. Also effective April 1, 2020, Sanofi records net product sales of Praluent outside the United States and pays the Company a royalty on such sales. Previously, Sanofi recorded global net product sales of Praluent and the Company recorded its share of profits/losses in connection with such sales. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(e) Regeneron records net product sales of REGEN-COV in the United States and Roche records net product sales of Ronapreve outside the United States. The parties share gross profits from global sales of REGEN-COV and Ronapreve based on a pre-specified formula. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(f) Included in this line item are products which are sold by the Company and others. Refer to Part II, Item 7. "Management's Discussion and Analysis of Financial Condition and Results of Operations - Results of Operations - Revenues" for a complete listing of net product sales recorded by the Company. Not included in this line item are net product sales of ARCALYST subsequent to the first quarter of 2021, which are recorded by Kiniksa. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Programs in Clinical Development
Product candidates in clinical development, which are being developed by us and/or our collaborators, are summarized in the table below.
There are numerous uncertainties associated with drug development, including uncertainties related to safety and efficacy data from each phase of drug development (including any post-approval studies), uncertainties related to the enrollment and performance of clinical trials, changes in regulatory requirements, changes to drug pricing and reimbursement regulations and requirements, and changes in the competitive landscape affecting a product candidate. The planning, execution, and results of our clinical programs are significant factors that can affect our operating and financial results.
Refer to Part I, Item 1A. "Risk Factors" for a description of risks and uncertainties that may affect our clinical programs. Any of such risks and uncertainties may, among other matters, negatively impact the development timelines set forth in the table below.
5
| Clinical Program | Phase 1 | Phase 2 | Phase 3 | Regulatory Review(h) | 2022 and 2023 Events to Date | Select Upcoming Milestones | ||||||||||||||||||||||||||||||||
| Ophthalmology | ||||||||||||||||||||||||||||||||||||||
EYLEA (aflibercept)(a) | –ROP(c) | –ROP (U.S.) | –Granted pediatric exclusivity by U.S. Food and Drug Administration ("FDA") in connection with ROP study, extending period of EYLEA U.S. market exclusivity by six months through May 17, 2024 –Approved by European Commission ("EC") for ROP –Approved by Ministry of Health, Labour and Welfare ("MHLW") for ROP in Japan –Withdrew supplemental Biologics License Application ("sBLA") for every-16-weeks dosing regimen in patients with DR | –FDA decision on sBLA for ROP (target action date of February 11, 2023) | ||||||||||||||||||||||||||||||||||
Aflibercept 8 mg(a) | –Wet AMD –DME | –Wet AMD and DME (U.S.) | –Reported that Phase 3 trials in wet AMD and DME met their primary endpoints | –FDA decision on BLA for wet AMD and DME (third quarter 2023) –Submit regulatory application in the EU for wet AMD and DME (first quarter 2023) –Report two-year data from Phase 3 studies in wet AMD and DME (third quarter 2023) | ||||||||||||||||||||||||||||||||||
6
Clinical Program (continued) | Phase 1 | Phase 2 | Phase 3 | Regulatory Review(h) | 2022 and 2023 Events to Date | Select Upcoming Milestones | ||||||||||||||||||||||||||||||||
| Immunology & Inflammation | ||||||||||||||||||||||||||||||||||||||
Dupixent (dupilumab)(b) Antibody to IL-4R alpha subunit | –EoE in pediatrics(c) –Chronic obstructive pulmonary disease ("COPD") –Bullous pemphigoid (Phase 2/3)(c) –Chronic spontaneous urticaria ("CSU") –Chronic inducible urticaria - cold –Chronic rhinosinusitis without nasal polyposis –Allergic fungal rhinosinusitis –Chronic pruritus of unknown origin | –Atopic dermatitis in pediatrics (6 months–5 years of age) (EU) and in pediatrics and adolescents (6 months–14 years of age (Japan) –Prurigo nodularis (Japan) –CSU in adults and adolescents (U.S.) | –Approved by FDA for atopic dermatitis in pediatrics (6 months–5 years of age) –European Medicines Agency's ("EMA") Committee for Medicinal Products for Human Use ("CHMP") adopted positive opinion for atopic dermatitis in pediatrics (6 months–5 years of age) –Approved by EC for severe asthma in pediatrics (6–11 years of age) –Approved by FDA and EC for EoE in adults and adolescents –Reported that Phase 3 trial in EoE in pediatrics (1–11 years of age) met its primary endpoint –Approved by FDA and EC for prurigo nodularis –Stopped one of the Phase 3 trials in CSU (in patients refractory to omalizumab) due to futility, based on pre-specified interim analysis –Initiated additional Phase 3 trial in CSU (in biologic-naïve patients) –Discontinued further clinical development in peanut allergy | –EC decision on regulatory submission for atopic dermatitis in pediatrics (6 months–5 years of age) (first half 2023) –MHLW decision on regulatory submission for atopic dermatitis in pediatrics and adolescents (6 months–14 years of age) in Japan (second half 2023) –Submit sBLA for EoE in pediatrics (mid-2023) –Report results from first Phase 3 study in COPD (first half 2023) –FDA decision on sBLA for CSU in adults and adolescents (second half 2023) –Report results from Phase 3 study in chronic inducible urticaria - cold (first half 2023) | ||||||||||||||||||||||||||||||||||
7
Clinical Program (continued) | Phase 1 | Phase 2 | Phase 3 | Regulatory Review(h) | 2022 and 2023 Events to Date | Select Upcoming Milestones | ||||||||||||||||||||||||||||||||
Kevzara (sarilumab)(b) Antibody to IL-6R | –Polyarticular-course juvenile idiopathic arthritis ("pcJIA") –Systemic juvenile idiopathic arthritis ("sJIA") | –Polymyalgia rheumatica ("PMR") (U.S.) | –FDA decision on sBLA for PMR (target action date of February 28, 2023) | |||||||||||||||||||||||||||||||||||
Itepekimab(b) (REGN3500) Antibody to IL-33 | –COPD | –Report results from Phase 3 study in COPD (2024) | ||||||||||||||||||||||||||||||||||||
REGN5713-5714-5715 Multi-antibody therapy to Bet v 1 | –Birch allergy | |||||||||||||||||||||||||||||||||||||
| Solid Organ Oncology | ||||||||||||||||||||||||||||||||||||||
Libtayo (cemiplimab)(n)(g) Antibody to PD-1 | –Neoadjuvant CSCC –Second-line cervical cancer, ISA101b combination | –Adjuvant CSCC | –First-line NSCLC, chemotherapy combination (EU) | –Approved by FDA in combination with chemotherapy for NSCLC –Approved by EC and MHLW for cervical cancer –Voluntarily withdrew sBLA for cervical cancer due to inability to align with FDA on certain post-marketing studies –Positive data from Phase 2 trial in neoadjuvant CSCC presented at European Society for Medical Oncology ("ESMO") Congress 2022 and published in New England Journal of Medicine | –EC decision on regulatory submission for NSCLC, chemotherapy combination (first half 2023) | |||||||||||||||||||||||||||||||||
Fianlimab(f) (REGN3767) Antibody to LAG-3 | –Solid tumors and advanced hematologic malignancies | –First-line metastatic melanoma –First-line adjuvant melanoma | –Presented positive data from Phase 1 trial (in combination with Libtayo) in advanced melanoma at ESMO Congress 2022 | –Initiate Phase 3 study (in combination with Libtayo) in perioperative melanoma (mid-2023) | ||||||||||||||||||||||||||||||||||
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Clinical Program (continued) | Phase 1 | Phase 2 | Phase 3 | Regulatory Review(h) | 2022 and 2023 Events to Date | Select Upcoming Milestones | ||||||||||||||||||||||||||||||||
Fianlimab(f) (continued) | –Positive initial data from Phase 1 trial (in combination with Libtayo) in NSCLC presented at ESMO Immuno-Oncology Congress 2022 | –Initiate Phase 2/3 studies (in combination with Libtayo) in first-line advanced NSCLC (first half 2023) –Initiate Phase 2 study (in combination with Libtayo) in perioperative NSCLC (second half 2023) | ||||||||||||||||||||||||||||||||||||
Vidutolimod Immune activator targeting TLR9 | –Solid tumors | –Initiate Phase 2 study in melanoma | ||||||||||||||||||||||||||||||||||||
Ubamatamab(f) (REGN4018) Bispecific antibody targeting MUC16 and CD3 | –Platinum-resistant ovarian cancer | –Presented positive initial data from monotherapy dose escalation portion of Phase 1/2 study in platinum-resistant ovarian cancer at ESMO Congress 2022 | –Report results from Phase 1/2 study (in combination with Libtayo) in platinum-resistant ovarian cancer (2023) | |||||||||||||||||||||||||||||||||||
REGN5668(o) Bispecific antibody targeting MUC16 and CD28 | –Platinum-resistant ovarian cancer | |||||||||||||||||||||||||||||||||||||
REGN5678 Bispecific antibody targeting PSMA and CD28 | –Prostate cancer | –Reported preliminary data from dose escalation portion of Phase 1/2 study (in combination with Libtayo) in prostate cancer | –Report additional results from Phase 1/2 study (in combination with Libtayo) in prostate cancer (2023) | |||||||||||||||||||||||||||||||||||
REGN4336 Bispecific antibody targeting PSMA and CD3 | –Prostate cancer | |||||||||||||||||||||||||||||||||||||
REGN5093 Bispecific antibody targeting two distinct MET epitopes | –MET-altered advanced NSCLC | –Presented positive initial data from dose escalation portion of Phase 1/2 study in MET-altered advanced NSCLC at ESMO Congress 2022 | ||||||||||||||||||||||||||||||||||||
REGN5093-M114 Bispecific antibody-drug conjugate targeting two distinct MET epitopes | –MET overexpressing advanced cancer | |||||||||||||||||||||||||||||||||||||
REGN6569 Antibody to GITR | –Solid tumors | |||||||||||||||||||||||||||||||||||||
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Clinical Program (continued) | Phase 1 | Phase 2 | Phase 3 | Regulatory Review(h) | 2022 and 2023 Events to Date | Select Upcoming Milestones | ||||||||||||||||||||||||||||||||
REGN7075 Bispecific antibody targeting EGFR and CD28 | –Solid tumors | |||||||||||||||||||||||||||||||||||||
| Hematology | ||||||||||||||||||||||||||||||||||||||
Odronextamab(i) (REGN1979) Bispecific antibody targeting CD20 and CD3 | –Certain B-cell malignancies(c)(m) | –B-cell non-Hodgkin lymphoma ("B-NHL")(m) (pivotal study) | –Presented positive data from two cohorts of pivotal Phase 2 study in patients with diffuse large B-cell lymphoma ("DLBCL") and follicular lymphoma ("FL") at American Society of Hematology ("ASH") Annual Meeting | –Initiate Phase 3 studies in FL and DLBCL, including earlier lines of therapy (first half 2023) –Submit BLA for relapsed/refractory FL and DLBCL (second half 2023) | ||||||||||||||||||||||||||||||||||
Linvoseltamab(f) (REGN5458) Bispecific antibody targeting BCMA and CD3 | –Multiple myeloma(c) | –Multiple myeloma (pivotal study)(c) | –Completed enrollment in pivotal Phase 2 study in multiple myeloma –Presented positive data from pivotal Phase 2 study in multiple myeloma at ASH Annual Meeting | –Initiate Phase 3 study in multiple myeloma, including earlier lines of therapy (first half 2023) –Submit BLA for relapsed/refractory multiple myeloma (second half 2023) | ||||||||||||||||||||||||||||||||||
REGN5459(f) Bispecific antibody targeting BCMA and CD3 | –Transplant desensitization in patients with chronic kidney disease | |||||||||||||||||||||||||||||||||||||
Pozelimab(f) (REGN3918) Antibody to C5; studied as monotherapy and in combination with cemdisiran | –CD55-deficient protein-losing enteropathy ("CHAPLE"), monotherapy(c)(e) (potentially pivotal study) | –Myasthenia gravis, cemdisiran combination(k) –Paroxysmal nocturnal hemoglobinuria ("PNH"), cemdisiran combination(c)(k) | –CHAPLE, monotherapy (U.S.) | –FDA decision on BLA for CHAPLE, monotherapy (second half 2023) | ||||||||||||||||||||||||||||||||||
REGN7257 Antibody to IL2Rg | –Aplastic anemia | |||||||||||||||||||||||||||||||||||||
NTLA-2001(j) TTR gene knockout using CRISPR/Cas9 | –Transthyretin ("ATTR") amyloidosis(c) | –Reported positive interim data from Phase 1 trial in ATTR | ||||||||||||||||||||||||||||||||||||
REGN9933 Antibody to Factor XI | –Thrombosis | |||||||||||||||||||||||||||||||||||||
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Clinical Program (continued) | Phase 1 | Phase 2 | Phase 3 | Regulatory Review(h) | 2022 and 2023 Events to Date | Select Upcoming Milestones | ||||||||||||||||||||||||||||||||
REGN7508 Antibody to Factor XI | –Thrombosis | |||||||||||||||||||||||||||||||||||||
REGN7999 Antibody to TMPRSS6 | –Transfusion dependent iron overload | |||||||||||||||||||||||||||||||||||||
| General Medicine | ||||||||||||||||||||||||||||||||||||||
"Next Generation" Covid Antibodies Antibodies to SARS-CoV-2 variants | –Initiate clinical development of "next generation" antibody | |||||||||||||||||||||||||||||||||||||
Praluent (alirocumab) Antibody to PCSK9 | –HeFH in pediatrics | –Submit sBLA for HeFH in pediatrics (mid-2023) | ||||||||||||||||||||||||||||||||||||
Evkeeza (evinacumab)(f)(l) Antibody to ANGPTL3 | –HoFH in pediatrics (5–11 years of age) (U.S.) | –Reported that Phase 3 trial for HoFH in pediatrics (5–11 years of age) met its primary endpoint | –FDA decision on sBLA for HoFH in pediatrics (5–11 years of age) (target action date of March 30, 2023) | |||||||||||||||||||||||||||||||||||
Garetosmab(f) (REGN2477) Antibody to Activin A | –Fibrodysplasia ossificans progressiva ("FOP")(c)(d)(e) | |||||||||||||||||||||||||||||||||||||
Mibavademab(f) (REGN4461) Agonist antibody to leptin receptor ("LEPR") | –Generalized lipodystrophy(e) –Partial lipodystrophy | |||||||||||||||||||||||||||||||||||||
REGN5381/REGN9035 Agonist antibody to NPR1/reversal agent to REGN5381 | –Reversal agent in healthy volunteers | –Heart failure | –Report initial data in healthy volunteers (2023) | |||||||||||||||||||||||||||||||||||
ALN-HSD(p) RNAi therapeutic targeting HSD17B13 | –Nonalcoholic steatohepatitis ("NASH") | –Reported preliminary data from Phase 1 study in NASH | –Initiate Phase 2 study in NASH (first quarter 2023) | |||||||||||||||||||||||||||||||||||
ALN-PNP(k) RNAi therapeutic targeting PNPLA3 | –NASH | |||||||||||||||||||||||||||||||||||||
ALN-APP(k) RNAi therapeutic targeting APP | –Early-onset Alzheimer’s disease | –Report results from Phase 1 study in early-onset Alzheimer’s disease (mid-2023) | ||||||||||||||||||||||||||||||||||||
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| Note 1: For purposes of the table above, a program is classified in Phase 1, 2, or 3 clinical development after recruitment for the corresponding study or studies has commenced. | ||||||||||||||
Note 2: We have discontinued further clinical development of fasinumab (REGN475), an antibody to NGF, which was previously being studied in osteoarthritis pain of the knee or hip in collaboration with Teva and Mitsubishi Tanabe Pharma Corporation ("MTPC"); REGN6490, an antibody to IL-36R, which was previously being studied in palmo-plantar pustulosis; and the Phase 3 study of REGN1908-1909, a multi-antibody therapy to Fel d 1, in cat allergy, due to futility. | ||||||||||||||
(a) In collaboration with Bayer outside the United States | ||||||||||||||
(b) In collaboration with Sanofi | ||||||||||||||
(c) FDA granted orphan drug designation | ||||||||||||||
(d) FDA granted Breakthrough Therapy designation | ||||||||||||||
(e) FDA granted Fast Track designation | ||||||||||||||
(f) Sanofi did not opt-in to or elected not to continue to co-develop the product candidate. Under the terms of our agreement, Sanofi is entitled to receive royalties on sales of the product, if any. | ||||||||||||||
(g) Studied as monotherapy and in combination with other antibodies and treatments | ||||||||||||||
(h) Information in this column relates to U.S., EU, and Japan regulatory submissions only | ||||||||||||||
(i) In collaboration with Zai Lab in mainland China, Hong Kong, Taiwan, and Macau | ||||||||||||||
(j) In collaboration with Intellia | ||||||||||||||
(k) In collaboration with Alnylam | ||||||||||||||
(l) In collaboration with Ultragenyx outside the United States | ||||||||||||||
(m) FDA granted Fast Track designation for follicular lymphoma and diffuse large B-cell lymphoma | ||||||||||||||
(n) In collaboration with Sanofi prior to July 2022. Effective July 2022, the Company is solely responsible for the research, development, and commercialization of Libtayo. Refer to "Collaboration, License, and Other Agreements" section below for further details. | ||||||||||||||
(o) Studied in combination with ubamatamab | ||||||||||||||
(p) Alnylam elected to opt-out of the product candidate. Under the terms of our agreement, Alnylam is entitled to receive royalties on sales of the product, if any. | ||||||||||||||
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Additional Information - Clinical Development Programs
Aflibercept 8 mg
In September 2022, the Company announced that the primary endpoints were met in two pivotal trials investigating aflibercept 8 mg with 12- and 16-week dosing regimens in patients with DME and wet AMD. The PHOTON trial in DME and the PULSAR trial in wet AMD both demonstrated that aflibercept 8 mg 12- and 16-week dosing regimens achieved non-inferiority in vision gains compared to the EYLEA 8-week dosing regimen. Furthermore, of the patients randomized to 12- and 16-week dosing intervals, 91% and 89% of DME patients, respectively, and 79% and 77% of wet AMD patients, respectively, maintained those intervals through 48 weeks. The safety of aflibercept 8 mg was similar to EYLEA in both trials, and consistent with the known safety profile of EYLEA from previous clinical trials. The Company is utilizing a priority review voucher in connection with the December 2022 submission of the BLA for DME and wet AMD.
REGEN-COV (casirivimab and imdevimab)
REGEN-COV, a multi-antibody therapy to SARS-CoV-2 virus, previously received an EUA for use in certain post-exposure prophylaxis settings and as a treatment for people with mild to moderate COVID-19 who are at high risk of serious consequences from COVID-19. Based on laboratory data, in January 2022, the FDA revised the EUA for REGEN-COV to exclude its use in geographic regions where, based on available information including variant susceptibility and regional variant frequency, infection or exposure is likely due to a variant such as an Omicron-lineage variant that is not susceptible to the treatment. With this EUA revision, REGEN-COV is not currently authorized for use in any U.S. states, territories, or jurisdictions, since Omicron-lineage variants are currently dominant across the United States. In December 2022, the FDA issued a complete response letter ("CRL") on the BLA for REGEN-COV to treat COVID-19 in non-hospitalized patients and as prophylaxis in certain individuals.
Descriptions of Marketed Products Studied in Additional Indications and Product Candidates in Late-Stage Clinical Development
EYLEA (aflibercept)
EYLEA is a soluble fusion protein that acts as a vascular endothelial growth factor ("VEGF") inhibitor, formulated as a 2 mg intravitreal injection for the eye. It is designed to block the growth of new blood vessels and decrease the ability of fluid to pass through blood vessels (vascular permeability) in the eye by blocking VEGF-A and PLGF, two growth factors involved in angiogenesis.
Aflibercept 8 mg
Aflibercept 8 mg is an investigational soluble fusion protein that acts as a VEGF inhibitor. Through a novel formulation, it is designed to deliver a concentrated dose of aflibercept to block VEGF-A and PLGF and inhibit the growth of new blood vessels and decrease vascular permeability. Aflibercept 8 mg is being studied in wet AMD and DME using extended dosing intervals of every 12 weeks and every 16 weeks.
Dupixent (dupilumab)
Dupixent is a fully human monoclonal antibody that inhibits signaling of the IL-4 and IL-13 pathways, and is not an immunosuppressant. IL-4 and IL-13 are key and central drivers of the type 2 inflammation that plays a major role in atopic dermatitis, asthma, CRSwNP, EoE, prurigo nodularis, and potentially other chronic allergic and inflammatory diseases.
Kevzara (sarilumab)
Kevzara is a fully human monoclonal antibody that binds specifically to the IL-6 receptor and inhibits IL-6-mediated signaling. IL-6 is a signaling protein produced in increased quantities in patients with RA and has been associated with disease activity, joint destruction, and other systemic problems.
Itepekimab
Itepekimab is an investigational, fully human monoclonal antibody that inhibits IL-33, a protein that is believed to play a key role in lung inflammation in COPD.
REGN5713-5714-5715
REGN5713-5714-5715 is an investigational combination of three fully human monoclonal antibodies designed to treat allergic inflammatory conditions caused by the allergen Betv1, which is the main allergen responsible for birch pollen allergies. Birch pollen allergy is one of the most common causes of seasonal allergies that occur in the spring, and is also believed to trigger "oral allergy syndrome" food reactions to related allergens found in nuts and fruits such as apples, pears, and cherries.
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Libtayo (cemiplimab)
Libtayo is a fully human monoclonal antibody targeting the immune checkpoint receptor PD-1 on T-cells. The PD-1/PD-L1 immune checkpoint pathway is a well-known mechanism by which cancers evade immune destruction. Regeneron is studying Libtayo as monotherapy and in combination with either conventional or novel therapeutic approaches in various solid tumors and blood cancers. It is also being studied in combination with proprietary anti-cancer assets of other companies.
Fianlimab
Fianlimab is an investigational, fully human monoclonal antibody targeting the immune checkpoint receptor LAG-3 on T-cells. In melanoma, LAG-3 expression in the tumor microenvironment may be associated with therapeutic resistance to PD-1 inhibitors. Fianlimab is being investigated in combination with Libtayo to determine whether concurrent blockade of LAG-3 and PD-1 can help overcome this resistance and release the brakes on T-cell activation.
Odronextamab
Odronextamab is an investigational bispecific monoclonal antibody designed to bind to a component of the T-cell receptor ("TCR") complex (CD3), while also binding and bridging T-cells to a protein expressed on B-cells (CD20). We are studying whether odronextamab may help to activate T-cells via their CD3 receptors and trigger targeted, T-cell mediated killing of cancerous cells in several types of B-cell non-Hodgkin lymphoma.
Linvoseltamab
Linvoseltamab is an investigational bispecific monoclonal antibody designed to bind to CD3 while also binding and bridging T-cells to the BCMA protein on multiple myeloma cells. We are studying whether linvoseltamab may help to activate T-cells via their CD3 receptors and trigger targeted, T-cell mediated killing of multiple myeloma.
Pozelimab
Pozelimab is an investigational, fully human monoclonal antibody designed to block complement factor C5 in order to treat diseases mediated by abnormal complement pathway activity, including PNH, CHAPLE, and myasthenia gravis. Pozelimab is being studied as monotherapy and also in combination with Alnylam’s investigational small interfering RNA ("siRNA") therapy, cemdisiran.
Praluent (alirocumab)
Praluent is a fully human monoclonal antibody that inhibits the binding of PCSK9 to the LDL receptor. Through inhibiting PCSK9, Praluent increases the number of available LDL receptors on the surface of liver cells to clear LDL, which lowers LDL cholesterol levels in the blood.
Evkeeza (evinacumab)
Evkeeza is a fully human monoclonal antibody that specifically binds to and blocks ANGPTL3. ANGPTL3 plays a key role in regulating plasma lipid levels, including triglycerides, LDL cholesterol, and HDL cholesterol, through inhibition of lipase enzymes (lipoprotein lipase and endothelial lipase).
Garetosmab
Garetosmab is an investigational, fully-human monoclonal antibody that binds to and neutralizes Activin A, which drives the abnormal bone formation that is the main pathology of the ultra-rare genetic disorder FOP. This abnormal bone formation in soft tissue outside of the normal skeleton, a process known as heterotopic ossification, leads to loss of mobility and premature death in FOP patients. Garetosmab is being investigated to determine whether it can help reduce and/or prevent the formation of heterotopic bone lesions by neutralizing the Activin A protein.
Other Programs
Our preclinical research programs include the areas of oncology/immuno-oncology, angiogenesis, ophthalmology, metabolic and related diseases, muscle diseases and disorders, inflammation and immune diseases, bone and cartilage, pain and neurobiology, auditory conditions, enzyme replacement therapy, cardiovascular diseases, infectious diseases, and diseases related to aging. These preclinical research programs include both rare diseases and those involving broader populations.
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Research and Development Technologies
Many proteins that play an important role in biology and disease are secreted by cells or located on the cell surface. Moreover, cells communicate through secreted factors and surface molecules. Our scientists have developed two different technologies to make protein therapeutics that potently and specifically block, activate, or inhibit the action of specific cell surface or secreted molecules. The first technology fuses receptor components to the constant region of an antibody molecule to make a class of drugs we call "Traps". EYLEA, ZALTRAP, and ARCALYST are drugs generated using our Trap technology. VelociSuite® is our second technology platform, which is used for discovering, developing, and producing fully human antibodies that can address both secreted and cell-surface targets.
VelociSuite
VelociSuite consists of VelocImmune®, VelociGene®, VelociMouse®, VelociMab®, Veloci-Bi®, VelociT®, VelociHum®, and other related technologies. The VelocImmune mouse platform is utilized to produce fully human antibodies. VelocImmune was generated by leveraging our VelociGene technology (see below), in a process in which six megabases of mouse immunoglobulin gene loci were replaced, or "humanized," with corresponding human immunoglobulin gene loci. VelocImmune mice can be used efficiently to generate fully human antibodies to targets of therapeutic interest. VelocImmune and our entire VelociSuite offer the potential to increase the speed and efficiency through which human antibody therapeutics may be discovered and validated, thereby improving the overall efficiency of our early-stage drug development activities. We are utilizing the VelocImmune technology to produce our next generation of therapeutic antibody drug candidates for preclinical and clinical development.
Our VelociGene platform allows custom and precise manipulation of very large sequences of DNA to produce highly customized alterations of a specified target gene, or genes, and accelerates the production of knock-out and transgenic expression models. In producing knock-out models, a color or fluorescent marker may be substituted in place of the actual gene sequence, allowing for high-resolution visualization of precisely where the gene is active in the body during normal body functioning as well as in disease processes. For the optimization of preclinical development and pharmacology programs, VelociGene offers the opportunity to humanize targets by replacing the mouse gene with the human homolog or variants thereof. Thus, VelociGene allows scientists to rapidly identify the physical and biological effects of deleting or over-expressing the target gene, as well as to characterize and test potential therapeutic molecules.
Our VelociMouse technology platform allows for the direct and immediate generation of genetically altered mice from embryonic stem cells ("ES cells"), thereby avoiding the lengthy process involved in generating and breeding knockout mice from chimeras. Mice generated through this method are normal and healthy and exhibit a 100% germ-line transmission. Furthermore, mice developed using our VelociMouse technology are suitable for direct phenotyping or other studies.
We have also developed our VelociMab platform for the rapid screening of antibodies and rapid generation of expression cell lines for our Traps and our VelocImmune human antibodies.
We have utilized our VelociSuite technologies to develop a class of potential drug candidates, known as bispecific antibodies. Veloci-Bi allows for the generation of full-length bispecific antibodies similar to native antibodies that are amenable to production by standard antibody manufacturing techniques, and are likely to have favorable antibody-like pharmacokinetic properties. In the area of immunotherapies in oncology, we are exploring the use of bispecific antibodies that target tumor antigens and the CD3 receptor on T-cells to harness the oncolytic properties of T-cells. We are exploring additional indications and applications for our bispecific technologies, including a new class of CD28 and 4-1BB costimulatory bispecifics. We are also exploring a variety of alternative antibody formats (Altibodies™) that can bring binding partners together in restrained geometries.
The VelociT mouse extends our research and drug discovery capabilities into cell-mediated immunity and therapeutic TCRs for oncology and other indications. VelociT was developed by using our VelociGene technology to humanize genes encoding TCRα and TCRβ variable sequences, CD4 and CD8 co-receptors, β2m, and class-I and -II major histocompatibility complexes. As a result, VelociT mice generate fully human TCRs, providing for customized modeling of T-cell function in different diseases and a powerful platform for the discovery of unique TCR-based therapies. We are also able to produce antibodies that recognize intracellular peptides bound in the groove of human leukocyte antigen ("HLA"), enabling the targeting of intracellular proteins in cancer cells.
VelociHum is our immunodeficient mouse platform that can be used to accurately test human therapeutics against human immune cells and to study human tumor models. Through genetic humanizations, VelociHum mice have been optimized to allow for better development of human immune cells in vivo, as well as to allow for engraftment of primary patient-derived tumors that do not take in other commercially available mice.
15
Regeneron Genetics Center®
Regeneron Genetics Center LLC (RGC™), a wholly owned subsidiary of Regeneron Pharmaceuticals, Inc., leverages de-identified clinical, genomic, and other types of molecular data from properly consented human volunteers from around the world to identify medically relevant associations in a blinded fashion designed to preserve a patients' privacy while uncovering the unique characteristics of their health and wellness. The objective of RGC is to expand the use of human genetics for discovering and validating genetic factors that cause or influence a range of diseases where there are major unmet medical needs, with the prospect of improving the drug discovery and development process and to advance innovation in clinical care design. RGC is undertaking multiple collaborative approaches to study design and implementation, including large population-based efforts that engage study participants to more discrete disease specific and founder populations with data on strategic phenotypes of interest. RGC utilizes laboratory automation and innovative approaches to cloud computing to achieve high-quality throughput, attaining approximately 2 million samples sequenced to date.
Central to the work of RGC is the portfolio of collaborations with over 100 academic and clinical collaborators around the world, including the University of Colorado, Geisinger Health System, Mayo Clinic, University of Pennsylvania, UCLA Medical Center, UK Biobank, University of Oxford, University of Cambridge, and the University of Helsinki. These collaborations provide access to biological samples and associated phenotype data from properly consented patient volunteers for purposes of genomic research. RGC undertakes genetic sequencing of these samples to create a unique resource of de-identified genetic data and associated phenotype data for research. Furthermore, the RGC has deployed bulk RNA sequencing, whole genome sequencing, and an O-LINK proteomic assay to complement whole exome sequencing and genotyping. In addition, the RGC leverages organoid models, siRNA, and CRISPR knockout models to validate genetic associations that lead to new therapeutic targets. The RGC continues to publish results from its research efforts in journals and publications in partnership with its collaborators to advance the field of genomics.
These efforts at the RGC have led to the identification of more than 20 novel genetic targets. Through our Regeneron Genetics Medicines initiative, we are currently advancing these targets using either our VelociSuite technologies or other technologies, such as siRNA gene silencing, genome editing, and targeted viral-based gene delivery and expression. See the "Collaboration, License, and Other Agreements" section below for descriptions of our collaborations with Alnylam and Intellia.
Agreements Related to COVID-19
U.S. Government
In 2020, the Company expanded its Other Transaction Agreement with the Biomedical Advanced Research Development Authority ("BARDA"), pursuant to which the U.S. Department of Health and Human Services ("HHS") was obligated to fund certain of our costs incurred for research and development activities related to COVID-19 treatments. In 2020, the Company also entered into an agreement with entities acting at the direction of BARDA and the U.S. Department of Defense to manufacture and deliver filled and finished drug product of REGEN-COV to the U.S. government. The agreement, as subsequently amended, provided for payments to the Company of up to $465.9 million in the aggregate for bulk manufacturing of the drug substance, as well as fill/finish, storage, and other activities.
In January 2021, the Company entered into an agreement with the U.S. Department of Defense and HHS to manufacture and deliver additional filled and finished drug product of REGEN-COV to the U.S. government. Pursuant to the agreement, the U.S. government was obligated to purchase 1.25 million doses of drug product, resulting in payments to the Company of $2.625 billion.
In September 2021, the Company entered into an amendment to its January 2021 agreement to supply the U.S. government with an additional 1.4 million doses of REGEN-COV. Pursuant to the agreement, the U.S. government was obligated to purchase all filled and finished doses of such additional drug product delivered by January 31, 2022, resulting in payments to the Company of $2.940 billion in the aggregate. Additionally, Roche supplied a portion of the doses to Regeneron to fulfill our agreement with the U.S. government (see "Roche" section below for further details regarding our collaboration agreement with Roche).
As of December 31, 2021, the Company had completed its final deliveries of drug product under the agreements described above.
Roche
In 2020, we entered into a collaboration agreement with Roche to develop, manufacture, and distribute the casirivimab and imdevimab antibody cocktail (known as REGEN-COV in the United States and Ronapreve in other countries). We have the right to distribute the product in the United States and Roche has the right to distribute the product outside of the United States. The parties share gross profits from worldwide sales based on a pre-specified formula, depending on the amount of manufactured product supplied by each party to the market.
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Collaboration, License, and Other Agreements
Sanofi
Antibody
We are collaborating with Sanofi on the global development and commercialization of Dupixent, Kevzara, and itepekimab (the "Antibody Collaboration"). Under the terms of the Antibody License and Collaboration Agreement (the "LCA"), Sanofi is generally responsible for funding 80% to 100% of agreed-upon development costs. We are obligated to reimburse Sanofi for 30% to 50% of worldwide development expenses that were funded by Sanofi based on our share of collaboration profits from commercialization of collaboration products. Under the terms of the LCA, we were required to apply 10% of our share of the profits from the Antibody Collaboration in any calendar quarter to reimburse Sanofi for these development costs. On July 1, 2022, an amendment to the LCA became effective, pursuant to which the percentage of Regeneron’s share of profits used to reimburse Sanofi for such development costs increased from 10% to 20%.
Under our collaboration agreement, Sanofi records product sales for commercialized products, and Regeneron has the right to co-commercialize such products on a country-by-country basis. We co-commercialize Dupixent in the United States and in certain countries outside the United States. We supply certain commercial bulk product to Sanofi. We and Sanofi equally share profits and losses from sales within the United States. We and Sanofi share profits outside the United States on a sliding scale based on sales starting at 65% (Sanofi)/35% (us) and ending at 55% (Sanofi)/45% (us), and share losses outside the United States at 55% (Sanofi)/45% (us). In each of 2020 and 2021, we earned a $50.0 million sales-based milestone from Sanofi, upon aggregate annual sales of antibodies outside the United States (including Praluent) exceeding $1.0 billion and $1.5 billion, respectively, on a rolling twelve-month basis. In 2022, we earned two additional $50.0 million sales-based milestones, upon aggregate annual sales of antibodies outside the United States (including Praluent) exceeding $2.0 billion and $2.5 billion, respectively, on a rolling twelve-month basis. We are entitled to receive the final sales milestone payment of $50.0 million when such sales outside the United States exceed $3.0 billion on a rolling twelve-month basis.
In April 2020, the Company and Sanofi entered into an amendment to the LCA in connection with, among other things, the removal of Praluent from the LCA such that (i) effective April 1, 2020, the LCA no longer governs the development, manufacture, or commercialization of Praluent and (ii) the quarterly period ended March 31, 2020 was the last quarter for which Sanofi and the Company shared profits and losses for Praluent under the LCA. The parties also entered into a Praluent Cross License & Commercialization Agreement (the "Praluent Agreement") pursuant to which, effective April 1, 2020, the Company, at its sole cost, became solely responsible for the development and commercialization of Praluent in the United States, and Sanofi, at its sole cost, is solely responsible for the development and commercialization of Praluent outside of the United States. Under the Praluent Agreement, Sanofi pays the Company a 5% royalty on Sanofi’s net product sales of Praluent outside the United States until March 31, 2032. The Company does not owe Sanofi royalties on the Company’s net product sales of Praluent in the United States. Although each party will be responsible for manufacturing Praluent for its respective territory, the parties have entered into definitive supply agreements under which, for a certain transitional period, the Company will continue to supply drug substance to Sanofi and Sanofi will continue to supply finished product to Regeneron. With respect to any intellectual property or product liability litigation relating to Praluent, the parties have agreed that, effective April 1, 2020, Regeneron and Sanofi each will be solely responsible for any such litigation (including damages and other costs and expenses thereof) in the United States and outside the United States, respectively, arising out of Praluent sales or other activities on or after April 1, 2020 (subject to Sanofi's right to set off a portion of any third-party royalty payments resulting from certain patent litigation proceedings against up to 50% of any Praluent royalty payment owed to Regeneron). The parties will each bear 50% of any damages arising out of Praluent sales or other activities prior to April 1, 2020.
Immuno-Oncology
We previously collaborated with Sanofi for antibody-based cancer treatments in the field of immuno-oncology (the "IO Collaboration"). Under the terms of the Immuno-oncology License and Collaboration Agreement, the parties were co-developing and co-commercializing Libtayo. The parties shared equally, on an ongoing basis, development and commercialization expenses for Libtayo. We had principal control over the development of Libtayo and led commercialization activities in the United States, while Sanofi led commercialization activities outside of the United States. The parties shared equally in profits and losses in connection with the commercialization of Libtayo.
Effective July 1, 2022, the Company obtained the exclusive right to develop, commercialize, and manufacture Libtayo worldwide under an Amended and Restated Immuno-oncology License and Collaboration Agreement with Sanofi (the "A&R IO LCA"). In connection with the A&R IO LCA, in 2022, the Company made a $900.0 million up-front payment to Sanofi, as well as a $100.0 million regulatory milestone payment. In addition, Sanofi earned a $65.0 million sales-based milestone upon the achievement of a specified amount of worldwide net product sales of Libtayo in 2022, and is eligible to receive an additional $35.0 million sales-based milestone upon the achievement of a specified amount of worldwide net product sales of Libtayo in 2023. We also pay
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Sanofi an 11% royalty on net product sales of Libtayo through March 31, 2034. The parties have also entered into a transition services agreement, a transitional distribution agreement, and a manufacturing services agreement, pursuant to which, during certain transitional periods, Sanofi will perform for Regeneron certain transition, distribution, and manufacturing services, respectively.
Under the Amended and Restated Immuno-oncology Discovery and Development Agreement, we were obligated to reimburse Sanofi for half of the development costs it funded that were attributable to clinical development of product candidates from our share of profits from commercialized IO Collaboration products. Under the A&R IO LCA, the amount of development costs incurred under the IO Collaboration for which we are obligated to reimburse Sanofi was $35.0 million as of the effective date of the A&R IO LCA, and we pay Sanofi a 0.5% royalty on net product sales of Libtayo until all such development costs have been reimbursed by us.
Bayer
We and Bayer are parties to a license and collaboration agreement for the global development and commercialization of EYLEA and aflibercept 8 mg outside the United States. Agreed-upon development expenses incurred by the Company and Bayer are generally shared equally. Bayer markets EYLEA outside the United States, and the companies share equally in profits and losses from such sales. In Japan, we were entitled to receive a tiered percentage of between 33.5% and 40.0% of EYLEA net sales through 2021, and, effective January 1, 2022, the companies share equally in profits and losses from sales.
We are obligated to reimburse Bayer for 50% of the development costs that it has incurred under the agreement from our share of the collaboration profits. The reimbursement payment in any quarter will equal 5% of the then outstanding repayment obligation, but never more than our share of the collaboration profits in the quarter unless we elect to reimburse Bayer at a faster rate.
Within the United States, we retain exclusive commercialization rights and are entitled to all profits from such sales.
Teva
We and Teva are parties to a collaboration agreement to develop and commercialize fasinumab globally, excluding certain Asian countries that are subject to our collaboration agreement with MTPC. In connection with the agreement, Teva made a $250.0 million non-refundable up-front payment in 2016. We led global development activities, including the manufacturing of fasinumab, and the parties shared development costs equally. As of December 31, 2022, we had received an aggregate $120.0 million of development milestones from Teva.
During the third quarter of 2022, we discontinued further clinical development of fasinumab.
Alnylam
In 2018, we and Alnylam Pharmaceuticals, Inc. entered into a collaboration to discover RNA interference ("RNAi") therapeutics for NASH and potentially other related diseases, as well as to research, co-develop and commercialize any therapeutic product candidates that emerge from these discovery efforts (including ALN-HSD, which is currently in clinical development). Under the terms of the collaboration agreement, the parties share development costs equally. During the fourth quarter of 2022, Alnylam elected to opt-out of further development activities related to ALN-HSD; as a result, we retain the exclusive right to develop and commercialize such product and Alnylam will receive a royalty on sales (if any).
In 2019, we and Alnylam entered into a global, strategic collaboration to discover, develop, and commercialize RNAi therapeutics for a broad range of diseases by addressing therapeutic disease targets expressed in the eye and central nervous system ("CNS"), in addition to a select number of targets expressed in the liver. In connection with the collaboration, the Company made an up-front payment of $400.0 million to Alnylam, and also purchased shares of Alnylam common stock for $400.0 million. For each program, we provide Alnylam with a specified amount of funding at program initiation and at lead candidate designation, and Alnylam is eligible to receive up to an aggregate of $200.0 million in clinical proof-of-principle milestones for eye and CNS programs.
Under the collaboration, the parties plan to perform discovery research until designation of lead candidates. Following designation of a lead candidate, the parties may further advance such lead candidate under either a co-development/co-commercialization collaboration agreement ("Co-Co Collaboration Agreement") (under which the parties are advancing ALN-APP and ALN-PNP, which are currently in clinical development) or a License Agreement structure. The initial target nomination and discovery period is five years (which may under certain situations automatically be extended for up to seven years in the aggregate) (the "Research Term"). In addition, we have an option to extend the Research Term for an additional five-year period for a research extension fee ranging from $200.0 million to $400.0 million; the actual amount of the fee will be determined based on the acceptance of one or more Investigational New Drug Applications ("INDs") (or their equivalent in certain other countries) for programs in the eye and CNS.
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At the stage of designation of a lead candidate for CNS programs and liver programs, the parties have alternating rights to be a lead party for collaboration products. At the stage of designation of a lead candidate for eye programs, we have the sole right to take the product forward as a licensee. The lead party is required to take the program forward under the License Agreement structure unless the other party exercises its rights to opt-in to a Co-Co Collaboration Agreement as a participating party, in which case the lead party is required to take the program forward under the Co-Co Collaboration Agreement structure. Alnylam does not have rights to opt-in to a Co-Co Collaboration Agreement for eye programs.
Under a License Agreement, the lead party is designated as the licensee and has the right to develop and commercialize the collaboration product under such program. The licensee will be responsible for its own costs and expenses incurred in connection with the development and commercialization of the collaboration products under the License Agreement. The licensee will pay to the licensor certain development and/or commercialization milestone payments, as well as certain tiered royalty payments to the licensor based on the aggregate annual net sales of the collaboration product.
For CNS programs and liver programs, under a Co-Co Collaboration Agreement, the party designated as the lead party will lead development and commercialization of the program and the parties will split profits and share costs equally, subject to certain co-funding opt-outs at specified clinical trial phases or under other conditions. If a party exercises its co-funding opt-out right, the lead party will be required to make certain tiered royalty payments to the other party based on the aggregate annual net sales of the collaboration product and the timing of the exercise of the co-funding opt-out right.
Under the collaboration, when we are the licensee under a License Agreement or the lead party under a Co-Co Collaboration Agreement, Alnylam will be responsible for the manufacture and supply of the product to us for Phase 1 and Phase 2 clinical trials.
In addition, during 2019, the parties entered into a Co-Co Collaboration Agreement for cemdisiran, an siRNA therapeutic targeting the C5 component of the human complement pathway being developed by Alnylam, with Alnylam as the lead party, and a License Agreement for a combination consisting of cemdisiran and pozelimab, with us as the licensee. Under the C5 siRNA Co-Co Collaboration Agreement, the parties shared costs equally, and under the License Agreement, we as the licensee are responsible for our own costs and expenses. The C5 siRNA License Agreement contains a flat low double-digit royalty payable to Alnylam on potential future net sales of the combination only subject to customary reductions, as well as up to $325.0 million in sales milestones.
During the fourth quarter of 2022, we elected to opt-out of further development activities pursuant to the Co-Co Collaboration Agreement for cemdisiran as a monotherapy; as a result, Alnylam retains the right to develop and commercialize such product and we will receive a royalty on sales (if any).
Intellia
In 2016, we entered into a license and collaboration agreement with Intellia Therapeutics, Inc. to advance CRISPR/Cas9 gene-editing technology for in vivo therapeutic development. NTLA-2001, which is in clinical development, is subject to a co-development and co-commercialization arrangement pursuant to which Intellia will lead development and commercialization activities and the parties share an agreed-upon percentage of development expenses and profits (if commercialized).
In 2020, we expanded our existing collaboration with Intellia to provide us with rights to develop products for additional in vivo CRISPR/Cas9-based therapeutic targets and for the companies to jointly develop potential products for the treatment of hemophilia A and B, with Regeneron leading development and commercialization activities. In addition, we also received non-exclusive rights to independently develop and commercialize ex vivo gene edited products. In connection with the 2020 agreement, we made a $70.0 million up-front payment to Intellia.
BARDA
We and BARDA are parties to agreements pursuant to which HHS provided certain funding to develop, test, and manufacture a treatment for Ebola virus infection. In 2020, HHS exercised its option under an existing agreement to provide additional funding for the manufacture and supply of Inmazeb. We expect to deliver a pre-specified number of Inmazeb treatment doses over the course of approximately six years.
See "Agreements Related to COVID-19 - U.S. Government" section above for information related to our COVID-19 agreements.
Kiniksa
Pursuant to a 2017 license agreement, we granted Kiniksa Pharmaceuticals, Ltd. the right to develop and commercialize certain new indications for ARCALYST. During the first quarter of 2021, Kiniksa received marketing approval in the United States for a new indication of ARCALYST, recurrent pericarditis. The quarterly period ended March 31, 2021 was the last quarter for which the Company recorded net product sales of ARCALYST.
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Following this approval, Kiniksa is solely responsible for the U.S. development and commercialization of ARCALYST in all approved indications, and Regeneron will continue to supply clinical and commercial product to Kiniksa. Kiniksa will pay Regeneron 50% of its profits from sales of ARCALYST and the parties will not share in any losses incurred by Kiniksa in connection with commercialization of ARCALYST.
Ultragenyx
In January 2022, we entered into a license and collaboration agreement for Ultragenyx Pharmaceutical Inc. to develop and commercialize Evkeeza in countries outside of the United States. In connection with the agreement, Ultragenyx made a $30.0 million non-refundable up-front payment to the Company. Ultragenyx will share in certain costs for global trials led by the Company and also have the right to continue to clinically develop Evkeeza in countries outside of the U.S. We will supply commercial product to Ultragenyx at a tiered purchase price, which is calculated as a percentage of net sales of the product (subject to adjustment in certain circumstances), and are eligible to receive additional regulatory and sales milestone payments.
Checkmate
In May 2022, the Company completed its acquisition of Checkmate Pharmaceuticals, Inc. for a total equity value of approximately $250 million. In connection with the acquisition, the Company obtained the rights to vidutolimod, which is in clinical development for oncology.
Manufacturing
We currently manufacture bulk drug materials and products at our manufacturing facilities in Rensselaer, New York and Limerick, Ireland. These facilities consist of owned and leased research, manufacturing, office, laboratory, and warehouse space. In addition, the construction of a fill/finish facility in Rensselaer, New York is in process.
We currently have approximately 100,000 liters of cell culture capacity at our Rensselaer facility and approximately 120,000 liters of cell culture capacity at our Limerick facility. Each of these facilities is approved by the FDA and certain other regulatory agencies to manufacture our bulk drug materials and products.
Certain bulk drug materials and products are also manufactured by our collaborators, and certain raw materials or products necessary for the manufacture and formulation of our products and product candidates are provided by single-source unaffiliated third-party suppliers. In addition, we rely on our collaborators or third parties to perform packaging, filling, finishing, labeling, distribution, laboratory testing, and other services related to the manufacture of our products and product candidates, and to supply various raw materials and other products. See Part I, Item 1A. "Risk Factors - Risks Related to Manufacturing and Supply" for further information.
Among the conditions for regulatory marketing approval of a medicine is the requirement that the prospective manufacturer's quality control and manufacturing procedures conform to the good manufacturing practice ("GMP") regulations of the health authority. In complying with standards set forth in these regulations, manufacturers must continue to expend time, money, and effort in the areas of production and quality control to ensure full technical compliance. Manufacturing establishments, both foreign and domestic, are also subject to inspections by or under the authority of the FDA and by other national, federal, state, and local agencies.
Commercial
Our medicines are marketed through our commercial group, which includes experienced professionals in the fields of marketing, sales, professional education, patient education, reimbursement and market access, trade and distribution, commercial operations, commercial analytics, and market research.
In the United States, we sell our marketed products primarily to wholesalers and specialty distributors that serve pharmacies, hospitals, government agencies, physicians, and other healthcare providers. We had sales to two customers (Besse Medical, a subsidiary of AmerisourceBergen Corporation, and McKesson Corporation) that each accounted for more than 10% of total gross product revenue for the year ended December 31, 2022. On a combined basis, our product sales to these customers accounted for 83% of our total gross product revenue for the year ended December 31, 2022. We promote approved medicines to healthcare professionals via our team of field employees, as well as medical journals, medical exhibitions, distribution of literature and samples, and online channels. In addition, we advertise certain products directly to consumers and maintain websites with information about our medicines. The commercial group also evaluates opportunities for our targets and product candidates and prepares for market launches of new medicines.
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We have established certain commercial capabilities outside the United States in connection with co-commercializing some products in accordance with our collaboration agreements. In addition, we are in process of building additional commercial capabilities outside the United States as a result of us obtaining the rights, in 2022, to commercialize Libtayo outside the United States. Refer to "Collaboration, License, and Other Agreements" section above for additional information related to these agreements.
Competition
We face substantial competition from pharmaceutical, biotechnology, and chemical companies. Our ability to compete depends, to a great extent, on how fast we can develop safe and effective product candidates, complete clinical testing and approval processes, and supply commercial quantities of the product to the market. Competition among products approved for sale is based on efficacy, safety, reliability, availability, price, patent and other intellectual property position, and other factors.
Marketed Products
The table below provides an overview of the current competitive landscape for the key products marketed by us and/or our collaborators in such products' currently approved indications. The table below is provided for illustrative purposes only and is not exhaustive. For additional information regarding the substantial competition these marketed products face, including potential future competition from product candidates in clinical development, see also Part I, Item 1A. "Risk Factors - Risks Related to Commercialization of Our Marketed Products, Product Candidates, and New Indications for Our Marketed Products - The commercial success of our products and product candidates is subject to significant competition."
| Marketed Product | Competitor Product | Competitor | Indication | Territory(a) | ||||||||||||||||||||||
| EYLEA | Lucentis® (ranibizumab injection) | Novartis AG and Genentech/Roche | Wet AMD, DME, macular edema following RVO (including CRVO and BRVO), diabetic retinopathy, mCNV, and ROP | Worldwide | ||||||||||||||||||||||
Byooviz™ (ranibizumab-nuna) (biosimilar referencing Lucentis) | Samsung Bioepis Co., Ltd. and Biogen Inc. | Wet AMD, DME, macular edema following RVO (including CRVO and BRVO), diabetic retinopathy, and mCNV | United States, EU | |||||||||||||||||||||||
Ximluci® (ranibizumab) (biosimilar referencing Lucentis) | Xbrane Biopharma AB, Bausch + Lomb, and STADA Arzneimittel AG | Wet AMD, DME, macular edema following RVO (including CRVO and BRVO), diabetic retinopathy, and CNV | EU | |||||||||||||||||||||||
Cimerli™ (ranibizumab-eqrn) (biosimilar referencing Lucentis) | Formycon AG, Bioeq AG, Coherus BioSciences, Inc., and Teva Ltd. | Wet AMD, DME, macular edema following RVO (including CRVO and BRVO), diabetic retinopathy, and CNV | United States, EU | |||||||||||||||||||||||
Susvimo® (ranibizumab ocular implant) | Genentech/Roche | Wet AMD | United States | |||||||||||||||||||||||
Vabysmo™ (faricimab-svoa) | Genentech/Roche | Wet AMD, DME | Worldwide | |||||||||||||||||||||||
Avastin® (bevacizumab) (off-label and repackaged) | Genentech/Roche | Wet AMD, DME, and macular edema following RVO | Worldwide | |||||||||||||||||||||||
Beovu® (brolucizumab) Injection | Novartis AG | Wet AMD, DME | Worldwide | |||||||||||||||||||||||
Ozurdex® (dexamethasone intravitreal implant) | Allergan/AbbVie Inc. | DME, RVO | United States, EU | |||||||||||||||||||||||
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Marketed Product (continued) | Competitor Product | Competitor | Indication | Territory(a) | ||||||||||||||||||||||
EYLEA (continued) | Iluvien® (fluocinolone acetonide intravitreal implant) | Alimera Sciences, Inc. | DME | United States, EU | ||||||||||||||||||||||
| Conbercept | Chengdu Kanghong Pharmaceutical Group Co., Ltd. | Wet AMD, DME, mCNV | China | |||||||||||||||||||||||
| Dupixent | Eucrisa®/Staquis® (crisaborole) | Pfizer Inc. | Mild-to-moderate atopic dermatitis | United States, EU | ||||||||||||||||||||||
Opzelura® (ruxolitinib) | Incyte Corporation | Mild-to-moderate atopic dermatitis | United States | |||||||||||||||||||||||
Olumiant® (baricitinib) | Eli Lilly and Company/Incyte Corporation | Moderate-to-severe atopic dermatitis | EU, Japan | |||||||||||||||||||||||
Cibinqo® (abrocitinib) | Pfizer | Moderate-to-severe atopic dermatitis | Worldwide | |||||||||||||||||||||||
Rinvoq® (upadacitinib) | AbbVie | Moderate-to-severe atopic dermatitis | Worldwide | |||||||||||||||||||||||
Adbry™/Adtralza® (tralokinumab) | LEO Pharma Inc. | Moderate-to-severe atopic dermatitis | Worldwide | |||||||||||||||||||||||
Corectim® (delgocitinib) | Japan Tobacco Inc./Torii Pharmaceutical Co., Ltd. | Atopic dermatitis | Japan | |||||||||||||||||||||||
Mitchga® (nemolizumab) | Maruho Co., Ltd./Chugai Pharmaceutical Co., Ltd. | Pruritus associated with atopic dermatitis | Japan | |||||||||||||||||||||||
Xolair® (omalizumab) | Roche/Novartis | Asthma, nasal polyps | Worldwide (asthma); United States, EU (nasal polyps) | |||||||||||||||||||||||
Nucala® (mepolizumab) | GlaxoSmithKline ("GSK") | Asthma, nasal polyps | Worldwide (asthma); United States, EU (nasal polyps) | |||||||||||||||||||||||
Cinqair® (reslizumab) | Teva | Asthma | United States, EU | |||||||||||||||||||||||
Fasenra® (benralizumab) | AstraZeneca | Asthma | Worldwide | |||||||||||||||||||||||
Tezspire™ (tezepelumab-ekko) | AstraZeneca/Amgen | Asthma | Worldwide | |||||||||||||||||||||||
| Libtayo | Keytruda® (pembrolizumab) | Merck & Co., Inc. | Various cancers | Worldwide | ||||||||||||||||||||||
Opdivo® (nivolumab) | Bristol-Myers Squibb | Various cancers | Worldwide | |||||||||||||||||||||||
Tecentriq® (atezolizumab) | Roche | Various cancers | Worldwide | |||||||||||||||||||||||
Imfinzi® (durvalumab) | AstraZeneca | Various cancers | Worldwide | |||||||||||||||||||||||
Bavencio® (avelumab) | Pfizer/Merck KGaA | Various cancers | Worldwide | |||||||||||||||||||||||
Jemperli® (dostarlimab) | GSK | Various cancers | United States, EU | |||||||||||||||||||||||
| Praluent | Repatha® (evolocumab) | Amgen | Reduce the risk of myocardial infarction, stroke, and coronary revascularization in adults with established cardiovascular disease; primary hyperlipidemia; and HoFH | Worldwide | ||||||||||||||||||||||
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Marketed Product (continued) | Competitor Product | Competitor | Indication | Territory(a) | ||||||||||||||||||||||
Praluent (continued) | Leqvio® (inclisiran) | Novartis | Primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia | United States, EU | ||||||||||||||||||||||
| Kevzara | Actemra® (tocilizumab) | Genentech/Roche/Chugai Pharmaceutical Co., Ltd. | Rheumatoid arthritis | Worldwide | ||||||||||||||||||||||
Orencia® (abatacept) | Bristol-Myers Squibb | Rheumatoid arthritis | Worldwide | |||||||||||||||||||||||
Xeljanz® (tofacitinib) | Pfizer | Rheumatoid arthritis | Worldwide | |||||||||||||||||||||||
Olumiant® (baricitinib) | Eli Lilly/Incyte | Rheumatoid arthritis | Worldwide | |||||||||||||||||||||||
Rinvoq® (upadacitinib) | AbbVie | Rheumatoid arthritis | Worldwide | |||||||||||||||||||||||
Jyseleca® (filgotinib) | Gilead Sciences, Inc./Galapagos NV | Rheumatoid arthritis | EU, Japan | |||||||||||||||||||||||
(a) This table focuses primarily on the United States, EU, and Japan. "Worldwide" indicates that the relevant product is approved in the United States, EU, Japan, and at least one other country. | ||||||||||||||||||||||||||
Product Candidates
Our late-stage and earlier-stage clinical candidates (including those being developed in collaboration with our collaborators) face competition from many pharmaceutical and biotechnology companies. For example, we are aware of other pharmaceutical and biotechnology companies actively engaged in the research and development of antibody-based products against targets that are also the targets of our early- and late-stage product candidates. These companies are using various technologies in competition with our VelocImmune technology and our other antibody generation technologies, including their own antibody generation technologies and other approaches such as RNAi, chimeric antigen receptor T cell (CAR-T cell), and gene therapy technologies. We are also aware of several companies developing or marketing small molecules that may compete with our antibody product candidates in various indications, if such product candidates obtain regulatory approval in those indications.
For additional information regarding our product candidates (including those being developed in collaboration with our collaborators) and the substantial competition they face, see also Part I, Item 1A. "Risk Factors - Risks Related to Commercialization of Our Marketed Products, Product Candidates, and New Indications for Our Marketed Products - The commercial success of our products and product candidates is subject to significant competition."
Other Areas
Many pharmaceutical and biotechnology companies are attempting to discover new therapeutics for indications in which we invest substantial time and resources. In these and related areas, intellectual property rights have been sought and certain rights have been granted to competitors and potential competitors of ours, and we may be at a substantial competitive disadvantage in such areas as a result of, among other things, our inferior intellectual property position or lack of experience, trained personnel, and expertise. A number of corporate and academic competitors are involved in the discovery and development of novel therapeutics that are the focus of other research or development programs we are now conducting. Some of these competitors are currently conducting advanced preclinical and clinical research programs in these areas. These and other competitors also may have established substantial intellectual property and other competitive advantages.
If any of these or other competitors announces a successful clinical study involving a product that may be competitive with one of our product candidates or the grant of marketing approval by a regulatory agency for a competitive product, such developments may have an adverse effect on our business, operating results, financial condition, cash flows, or future prospects.
We also compete with academic institutions, governmental agencies, and other public or private research organizations, which conduct research, seek patent and other intellectual property protection, and establish collaborative arrangements for the development and marketing of products that would provide royalties or other consideration for use of their technology. These institutions are becoming more active in seeking patent and other intellectual property protection and licensing arrangements to collect royalties or other consideration for use of the technology they have developed. Products developed in this manner may compete directly with products we develop. We also compete with others in acquiring technology from these institutions, agencies, and organizations.
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Patents, Trademarks, and Trade Secrets
We rely on a combination of intellectual property laws, including patent, trademark, copyright, trade secret, and domain name protection laws, as well as confidentiality and license agreements, to protect our intellectual property and proprietary rights.
Our success depends, in part, on our ability to obtain patents, maintain trade secret protection, and operate without infringing on the proprietary rights of third parties (see Part I, Item 1A. "Risk Factors - Risks Related to Intellectual Property and Market Exclusivity - We may be restricted in our development, manufacturing, and/or commercialization activities by patents or other proprietary rights of others, and could be subject to awards of damages if we are found to have infringed such patents or rights"; and Note 16 to our Consolidated Financial Statements). Our policy is to file patent applications to protect technology, inventions, and improvements that we consider important to our business and operations. We hold an ownership interest in a number of issued patents in the United States and foreign countries with respect to our products and technologies. In addition, we hold an ownership interest in thousands of patent applications in the United States and foreign countries.
Our patent portfolio includes granted patents and pending patent applications covering our VelociSuite technologies, including our VelocImmune mouse platform which produces fully human antibodies. Our issued patents covering these technologies generally expire between 2022 and 2032. However, we continue to file patent applications directed to improvements to these technology platforms.
Our patent portfolio also includes issued patents and pending applications relating to commercialized products and our product candidates in clinical development. These patents cover, among other things, proteins, DNA and RNA molecules, manufacturing patents, method of use patents, and pharmaceutical compositions and formulations.
The following table describes our U.S. patents, European patents ("EP"), and Japanese patents ("JP") that are of particular relevance to key products marketed or otherwise commercialized by us and/or our collaborators, including the territory, patent number, general subject matter class, and expected expiration dates. The noted expiration dates include any patent term adjustments. Certain of these patents may also be entitled to term extensions. We continue to pursue additional patents and patent term extensions in the United States and other jurisdictions covering various aspects of our products that may, if issued, extend exclusivity beyond the expiration of the patents listed in the table below. One or more patents with the same or earlier expiry date may fall under the same "general subject matter class" for certain products and may not be separately listed.
| Product | Molecule | Territory | Patent No. | General Subject Matter Class | Expiration | |||||||||||||||||||||||||||
EYLEA(a) | aflibercept | US | 7,070,959 | Composition of Matter | June 16, 2023(b) | |||||||||||||||||||||||||||
| US | 8,092,803 | Formulation | June 21, 2027 | |||||||||||||||||||||||||||||
| US | 10,464,992 | Formulation | June 14, 2027 | |||||||||||||||||||||||||||||
| US | 10,857,231 | Formulation | March 22, 2026 | |||||||||||||||||||||||||||||
| US | 11,066,458 | Formulation | June 14, 2027 | |||||||||||||||||||||||||||||
| US | 11,084,865 | Formulation | June 14, 2027 | |||||||||||||||||||||||||||||
| US | 9,254,338 | Methods of Treatment | May 22, 2032 | |||||||||||||||||||||||||||||
| US | 10,857,205 | Methods of Treatment | January 11, 2032 | |||||||||||||||||||||||||||||
| US | 10,828,345 | Methods of Treatment | January 11, 2032 | |||||||||||||||||||||||||||||
| US | 10,888,601 | Methods of Treatment | January 11, 2032 | |||||||||||||||||||||||||||||
| US | 11,253,572 | Methods of Treatment | January 11, 2032 | |||||||||||||||||||||||||||||
| US | 10,406,226 | Method of Manufacturing | March 22, 2026 | |||||||||||||||||||||||||||||
| EP | 1183353 | Composition of Matter (Supplementary Protection Certificate) | (May 23, 2025)(c) | |||||||||||||||||||||||||||||
| EP | 2364691 | Formulation | June 14, 2027 | |||||||||||||||||||||||||||||
| EP | 2944306 | Formulation | June 14, 2027 | |||||||||||||||||||||||||||||
| JP | 4,723,140 | Composition of Matter | December 29, 2022 – December 25, 2023(d) | |||||||||||||||||||||||||||||
| JP | 5,273,746 | Methods of Treatment | June 24, 2022 | |||||||||||||||||||||||||||||
| JP | 5,216,002 | Formulation | February 27, 2028 – October 1, 2029(d) | |||||||||||||||||||||||||||||
24
Product (continued) | Molecule | Territory | Patent No. | General Subject Matter Class | Expiration | |||||||||||||||||||||||||||
| Dupixent | dupilumab | US | 7,608,693 | Composition of Matter | March 28, 2031(e) | |||||||||||||||||||||||||||
| US | 8,945,559 | Formulation | October 17, 2032 | |||||||||||||||||||||||||||||
| US | 9,238,692 | Formulation | October 5, 2031 | |||||||||||||||||||||||||||||
| US | 10,435,473 | Formulation | October 5, 2031 | |||||||||||||||||||||||||||||
| US | 11,059,896 | Formulation | October 5, 2031 | |||||||||||||||||||||||||||||
| US | 8,075,887 | Methods of Treatment | April 17, 2028 | |||||||||||||||||||||||||||||
| US | 8,337,839 | Methods of Treatment | October 2, 2027 | |||||||||||||||||||||||||||||
| US | 9,290,574 | Methods of Treatment | July 10, 2034 | |||||||||||||||||||||||||||||
| US | 9,574,004 | Methods of Treatment | December 22, 2033 | |||||||||||||||||||||||||||||
| US | 11,421,036 | Methods of Treatment | July 10, 2034 | |||||||||||||||||||||||||||||
| US | 10,137,193 | Methods of Treatment | March 18, 2036 | |||||||||||||||||||||||||||||
| US | 10,485,844 | Methods of Treatment | September 21, 2037 | |||||||||||||||||||||||||||||
| US | 10,059,771 | Methods of Treatment | June 20, 2034 | |||||||||||||||||||||||||||||
| US | 11,214,621 | Methods of Treatment | March 11, 2036 | |||||||||||||||||||||||||||||
| US | 11,167,004 | Methods of Treatment | September 21, 2037 | |||||||||||||||||||||||||||||
| US | 11,034,768 | Methods of Treatment | March 23, 2039 | |||||||||||||||||||||||||||||
| US | 11,292,847 | Methods of Treatment | May 10, 2039 | |||||||||||||||||||||||||||||
| EP | 2356151 | Composition of Matter | October 27, 2029(c) | |||||||||||||||||||||||||||||
| EP | 2356151 | (Supplementary Protection Certificate) | (September 28, 2032)(c) | |||||||||||||||||||||||||||||
| EP | 3010539 | Methods of Treatment | June 20, 2034 | |||||||||||||||||||||||||||||
| EP | 2888281 | Methods of Treatment | August 20, 2033 | |||||||||||||||||||||||||||||
| EP | 3064511 | Methods of Treatment | October 27, 2029 | |||||||||||||||||||||||||||||
| EP | 3107575 | Methods of Treatment | February 20, 2035 | |||||||||||||||||||||||||||||
| EP | 3470432 | Methods of Treatment | August 20, 2033 | |||||||||||||||||||||||||||||
| EP | 3019191 | Methods of Treatment | July 10, 2034 | |||||||||||||||||||||||||||||
| EP | 2624865 | Formulation | October 5, 2031 | |||||||||||||||||||||||||||||
| EP | 3354280 | Formulation | October 5, 2031 | |||||||||||||||||||||||||||||
| JP | 5,291,802 | Composition of Matter | October 27, 2029 – October 27, 2034(d) | |||||||||||||||||||||||||||||
| JP | 5,918,246 | Formulation | October 5, 2031 – September 14, 2035(d) | |||||||||||||||||||||||||||||
| JP | 6,306,588 | Methods of Treatment | August 20, 2033 – August 29, 2034(d) | |||||||||||||||||||||||||||||
| JP | 6,353,838 | Methods of Treatment | September 4, 2033 | |||||||||||||||||||||||||||||
| JP | 6,673,840 | Methods of Treatment | February 20, 2035 | |||||||||||||||||||||||||||||
| JP | 6,463,351 | Methods of Treatment | June 20, 2034 – September 2, 2035(d) | |||||||||||||||||||||||||||||
| JP | 6,861,630 | Methods of Treatment | November 13, 2035 | |||||||||||||||||||||||||||||
| JP | 7,164,530 | Methods of Treatment | September 21, 2037 | |||||||||||||||||||||||||||||
| Libtayo | cemiplimab | US | 9,987,500 | Composition of Matter | September 18, 2035 | |||||||||||||||||||||||||||
| US | 10,737,113 | Composition of Matter | April 10, 2035 | |||||||||||||||||||||||||||||
| US | 10,457,725 | Methods of Treatment | May 12, 2037 | |||||||||||||||||||||||||||||
| US | 11,292,842 | Methods of Treatment | July 18, 2038 | |||||||||||||||||||||||||||||
| US | 11,505,600 | Methods of Treatment | July 2, 2038 | |||||||||||||||||||||||||||||
| EP | 3097119 | Composition of Matter | January 23, 2035 | |||||||||||||||||||||||||||||
| EP | 3455258 | Methods of Treatment | May 12, 2037 | |||||||||||||||||||||||||||||
| EP | 3932951 | Methods of Treatment | May 12, 2037 | |||||||||||||||||||||||||||||
| JP | 6,425,730 | Composition of Matter | January 23, 2035 | |||||||||||||||||||||||||||||
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Product (continued) | Molecule | Territory | Patent No. | General Subject Matter Class | Expiration | |||||||||||||||||||||||||||
Libtayo (continued) | JP | 6,999,577 | Methods of Treatment | May 12, 2037 | ||||||||||||||||||||||||||||
| JP | 7,054,680 | Methods of Treatment | May 12, 2037 | |||||||||||||||||||||||||||||
Praluent(a)(f) | alirocumab | US | 8,062,640 | Composition of Matter | December 15, 2029 | |||||||||||||||||||||||||||
| US | 10,023,654 | Composition of Matter | December 15, 2029 | |||||||||||||||||||||||||||||
| US | 10,472,425 | Formulation | July 27, 2032 | |||||||||||||||||||||||||||||
| US | 8,357,371 | Methods of Treatment | December 21, 2029 | |||||||||||||||||||||||||||||
| US | 9,550,837 | Methods of Treatment | December 15, 2029 | |||||||||||||||||||||||||||||
| US | 9,724,411 | Methods of Treatment | January 15, 2031 | |||||||||||||||||||||||||||||
| US | 11,246,925 | Methods of Treatment | April 11, 2032 | |||||||||||||||||||||||||||||
| US | 11,306,155 | Methods of Treatment | July 16, 2035 | |||||||||||||||||||||||||||||
| US | 10,428,157 | Methods of Treatment | December 26, 2037 | |||||||||||||||||||||||||||||
| US | 10,544,232 | Methods of Treatment | March 13, 2035 | |||||||||||||||||||||||||||||
| US | 10,995,150 | Methods of Treatment | June 6, 2034 | |||||||||||||||||||||||||||||
| US | 11,116,839 | Methods of Treatment | June 14, 2033 | |||||||||||||||||||||||||||||
| EP | 2358756 | Composition of Matter | December 15, 2029(c) | |||||||||||||||||||||||||||||
| EP | 2358756 | (Supplementary Protection Certificate) | (September 25, 2030)(c) | |||||||||||||||||||||||||||||
| EP | 3156422 | Composition of Matter | December 15, 2029 | |||||||||||||||||||||||||||||
| EP | 2756004 | Methods of Treatment | September 12, 2032 | |||||||||||||||||||||||||||||
| EP | 3055333 | Methods of Treatment | October 10, 2034 | |||||||||||||||||||||||||||||
| EP | 3689913 | Methods of Treatment | October 10, 2034 | |||||||||||||||||||||||||||||
| EP | 3169353 | Methods of Treatment | July 16, 2035 | |||||||||||||||||||||||||||||
| EP | 3169362 | Methods of Treatment | July 16, 2035 | |||||||||||||||||||||||||||||
| EP | 3004171 | Methods of Treatment | June 6, 2034 | |||||||||||||||||||||||||||||
| EP | 3068803 | Methods of Treatment | November 12, 2034 | |||||||||||||||||||||||||||||
| EP | 3395836 | Methods of Manufacturing | January 27, 2032 | |||||||||||||||||||||||||||||
| Kevzara | sarilumab | US | 7,582,298 | Composition of Matter | May 22, 2031(g) | |||||||||||||||||||||||||||
| US | 10,072,086 | Formulation | September 19, 2031 | |||||||||||||||||||||||||||||
| US | 11,098,127 | Formulation | January 7, 2031 | |||||||||||||||||||||||||||||
| US | 8,080,248 | Methods of Treatment | June 1, 2027 | |||||||||||||||||||||||||||||
| US | 8,568,721 | Methods of Treatment | June 1, 2027 | |||||||||||||||||||||||||||||
| US | 9,943,594 | Methods of Treatment | December 28, 2033 | |||||||||||||||||||||||||||||
| US | 10,927,435 | Methods of Treatment | October 10, 2032 | |||||||||||||||||||||||||||||
| EP | 2041177 | Composition of Matter | June 1, 2027(c) | |||||||||||||||||||||||||||||
| EP | 2041177 | (Supplementary Protection Certificate) | (June 1, 2032)(c) | |||||||||||||||||||||||||||||
| EP | 2766039 | Methods of Treatment | October 10, 2032 | |||||||||||||||||||||||||||||
| EP | 3071230 | Methods of Treatment | November 21, 2034 | |||||||||||||||||||||||||||||
| EP | 3409269 | Formulation | January 7, 2031 | |||||||||||||||||||||||||||||
| EP | 3756652 | Formulation | January 7, 2031 | |||||||||||||||||||||||||||||
| JP | 5,307,708 | Composition of Matter | June 1, 2027 – August 22, 2031(d) | |||||||||||||||||||||||||||||
| JP | 5,805,660 | Formulation | January 7, 2031 – October 24, 2031(d) | |||||||||||||||||||||||||||||
| JP | 6,122,018 | Methods of Treatment | October 10, 2032 – March 29, 2033(d) | |||||||||||||||||||||||||||||
| JP | 7,025,477 | Methods of Treatment | October 10, 2032 | |||||||||||||||||||||||||||||
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Product (continued) | Molecule | Territory | Patent No. | General Subject Matter Class | Expiration | |||||||||||||||||||||||||||
Kevzara (continued) | JP | 6,657,089 | Methods of Treatment | November 21, 2034 | ||||||||||||||||||||||||||||
| JP | 7,166,925 | Methods of Treatment | March 7, 2037 | |||||||||||||||||||||||||||||
(a) See Note 16 to our Consolidated Financial Statements for information regarding inter partes review and post-grant review petitions filed in the U.S. Patent and Trademark Office relating to EYLEA and patent infringement proceedings relating to Praluent. | ||||||||||||||||||||||||||||||||
(b) A patent term extension has been granted by the U.S. Patent and Trademark Office, extending the original patent term (May 23, 2020), insofar as it covers EYLEA, to June 16, 2023. | ||||||||||||||||||||||||||||||||
(c) Supplementary protection certificates ("SPCs") are pending and/or have been granted in various European countries, extending the original patent terms in those countries, where granted, to the applicable dates indicated in parentheses. | ||||||||||||||||||||||||||||||||
(d) The patent term extension ("PTE") system in Japan allows for a patent to be extended more than once provided the later approval is directed to a different indication from that of the previous approval. This may result in multiple PTE approvals for a given patent, each with its own expiration date. In this table, date ranges are shown for the expiration of Japanese patents for which multiple PTEs have been granted, with the later date indicating the latest expiring PTE for the corresponding patent. | ||||||||||||||||||||||||||||||||
(e) A patent term extension has been granted by the U.S. Patent and Trademark Office, extending the original patent term (October 2, 2027), insofar as it covers Dupixent, to March 28, 2031. | ||||||||||||||||||||||||||||||||
(f) This table excludes Japanese patents related to Praluent because Praluent is not being commercialized in Japan at this time. | ||||||||||||||||||||||||||||||||
(g) A patent term extension has been granted by the U.S. Patent and Trademark Office, extending the original patent term (June 1, 2027), insofar as it covers Kevzara, to May 22, 2031. | ||||||||||||||||||||||||||||||||
In addition to our patent portfolio, in the United States and certain other countries, our competitive position may be enhanced due to the availability of market exclusivity under relevant law (for additional information regarding market exclusivity, see Part I, Item 1A. "Risk Factors - Risks Related to Intellectual Property and Market Exclusivity - Loss or limitation of patent rights, and regulatory pathways for biosimilar competition, could reduce the duration of market exclusivity for our products"). For example, in the United States, the regulatory exclusivity period for EYLEA (i.e., the period during which no biosimilar product can be approved by the FDA) extends through May 17, 2024 following the pediatric exclusivity granted by the FDA. The effect of expiration of a patent relating to a particular product also depends upon other factors, such as the nature of the market and the position of the product in it, the growth of the market, the complexities and economics of the process for manufacture of the active ingredient of the product, and the requirements of new drug provisions of the Federal Food, Drug and Cosmetic Act or similar laws and regulations in other countries.
We also are the nonexclusive licensee of a number of additional patents and patent applications. These include a license agreement with Bristol-Myers Squibb, E. R. Squibb & Sons, L.L.C., and Ono Pharmaceutical Co., Ltd. to obtain a license under certain patents owned and/or exclusively licensed by one or more of these parties that includes the right to develop and sell Libtayo. Under the agreement, we pay royalties of 8.0% on worldwide sales of Libtayo through December 31, 2023, and royalties of 2.5% from January 1, 2024 through December 31, 2026.
Patent law relating to the patentability and scope of claims in the biotechnology field is evolving and our patent rights are subject to this additional uncertainty. The degree of patent protection that will be afforded to our products in the United States and other important commercial markets is uncertain and is dependent upon the scope of protection decided upon by the patent offices, courts, and governments in these countries. There is no certainty that our existing patents or others, if obtained, will provide us protection from competition or provide commercial benefit.
Others may independently develop similar products or processes to those developed by us, duplicate any of our products or processes or, if patents are issued to us, design around any products and processes covered by our patents. We expect to continue, when appropriate, to file product and process applications with respect to our inventions. However, we may not file any such applications or, if filed, the patents may not be issued. Patents issued to or licensed by us may be infringed by the products or processes of others.
We seek to file and maintain trademarks around the world based on commercial activities in most jurisdictions where we have, or desire to have, a business presence for a particular product or service. Trademark protection varies in accordance with local law, and continues in some countries as long as the trademark is used and in other countries as long as the trademark is registered. Trademark registrations generally are for fixed but renewable terms.
Defense and enforcement of our intellectual property rights is expensive and time consuming, even if the outcome is favorable to us. It is possible that patents issued or licensed to us will be successfully challenged, that a court may find that we are infringing validly issued patents of third parties, or that we may have to alter or discontinue the development of our products or pay licensing fees to take into account patent rights of third parties (see Part I, Item 1A. "Risk Factors - Risks Related to Intellectual Property
27
and Market Exclusivity - We may be restricted in our development, manufacturing, and/or commercialization activities by patents or other proprietary rights of others, and could be subject to awards of damages if we are found to have infringed such patents or rights"; and Note 16 to our Consolidated Financial Statements).
Government Regulation
Regulation by government authorities in the United States and foreign countries is a significant factor in the research, development, manufacture, and marketing of our products and our product candidates. A summary of the primary areas of government regulation that are relevant to our business is provided below. For a description of material regulatory risks we face, also refer to Part I, Item 1A. "Risk Factors."
Preclinical Requirements
The activities required before a product candidate may be marketed in the United States or elsewhere begin with preclinical tests. Preclinical tests include laboratory evaluations of, among other things, product chemistry and formulation and toxicological and pharmacological studies in animal species to assess the toxicity and dosing of the product candidate. In the United States, certain preclinical trials must comply with the FDA's Good Laboratory Practice requirements ("GLPs") and the U.S. Department of Agriculture's Animal Welfare Act. The results of these studies must be submitted to the FDA or the relevant regulatory authority outside the United States as part of an IND or clinical trial application (as applicable), which must be reviewed by the FDA or the relevant government authority before proposed clinical testing can begin in the applicable country or jurisdiction. In the United States, unless the FDA raises concerns, the IND becomes effective 30 days following its receipt by the FDA, and the clinical trial proposed in the IND may begin. The FDA or other regulatory authorities may ask for additional data in order to begin a clinical trial. Rules that are equivalent in scope but which vary in application apply in foreign countries.
Product Approval
All of our product candidates require regulatory approval by relevant government authorities before they can be commercialized. In particular, human therapeutic products are subject to rigorous preclinical and clinical trials and other pre-market approval requirements by the FDA, EMA, and other foreign regulatory authorities. The structure and substance of the FDA and foreign pharmaceutical regulatory practices may evolve over time. The ultimate outcome and impact of such developments cannot be predicted.
Clinical trials involve the administration of a drug to healthy human volunteers or to patients under the supervision of a qualified investigator. The conduct of clinical trials is subject to extensive regulation, including compliance with the FDA's bioresearch monitoring regulations and Good Clinical Practice requirements ("GCPs"), which establish standards for conducting, recording data from, and reporting the results of, clinical trials, and are intended to assure that the data and reported results are credible and accurate, and that the rights, safety, and well-being of study participants are protected. Clinical trials must be conducted under protocols that detail the study objectives, parameters for monitoring safety, and the efficacy criteria, if any, to be evaluated. In addition, each clinical trial must be reviewed and approved by, and conducted under the auspices of, an Institutional Review Board ("IRB") for each clinical site within the United States or, where applicable, an Ethics Committee and/or the competent authority for clinical sites outside the United States. Companies sponsoring the clinical trials, investigators, and IRBs/Ethics Committees also must comply with, as applicable, regulations and guidelines for obtaining informed consent from the study patients, following the protocol and investigational plan, adequately monitoring the clinical trial, and timely reporting of adverse events. Foreign studies conducted under an IND must meet the same requirements that apply to studies being conducted in the United States. Data from a foreign study not conducted under an IND may be submitted in support of a BLA if the study was conducted in accordance with GCPs and the FDA is able to validate the data. The sponsor of a clinical trial or the sponsor's designated responsible party may be required to register certain information about the trial and disclose certain results on government or independent registry websites, such as clinicaltrials.gov.
Typically, clinical testing involves a three-phase process, which may overlap or be subdivided in some cases. Phase 1 trials are usually conducted with a small number of healthy volunteers to determine the early safety profile, metabolism, and pharmacological actions of the product candidate, the side effects associated with increasing doses, and, if possible, to gain early evidence of effectiveness. Although Phase 1 trials are typically conducted in healthy human subjects, in some instances, the trial subjects are patients with the targeted disease or condition. Phase 2 clinical trials are conducted with a relatively small sample of the intended patient population to provide enough data to evaluate the preliminary safety, tolerability, and efficacy of different potential doses of the product candidate. Phase 3 clinical trials are larger trials conducted with patients with the target disease or disorder intended to gather additional information about dosage, safety, and effectiveness necessary to evaluate the drug's overall risk-benefit profile. Phase 3 data often form the core basis on which the FDA and comparable foreign regulatory authorities evaluate a product candidate's safety and effectiveness when considering the product application for regulatory approval. If concerns arise about the safety of the product candidate, the FDA or other regulatory authorities can stop clinical trials by placing them on a "clinical hold" pending receipt of additional data, which can result in a delay or termination of a clinical development
28
program. The sponsoring company, the FDA or other regulatory authorities, or the IRB or Ethics Committee and competent authority may suspend or terminate a clinical trial at any time on various grounds, including a finding that the patients are being exposed to an unacceptable health risk.
The results of the preclinical and clinical testing of a biologic product candidate are then submitted to the FDA in the form of a BLA for evaluation to determine whether the product candidate may be approved for commercial sale under the Public Health Service Act. Under the Prescription Drug User Fee Act, we typically must pay fees to the FDA for review of any BLA. When a BLA is submitted, the FDA makes an initial determination as to whether the application is sufficiently complete to be accepted for review. If the application is not, the FDA may refuse to accept the BLA for filing and request additional information. A refusal to file, which requires resubmission of the BLA with the requested additional information, delays review of the application. If the application is accepted for review, the FDA reviews the application to determine, among other things, whether a product is safe and effective for its intended use and whether the manufacturing controls are adequate to assure and preserve the product's identity, strength, quality, and purity.
FDA performance goals generally provide for action on a BLA within 10 months of the 60-day filing date (or within 12 months of the BLA submission). That deadline can be extended by FDA under certain circumstances, including by the FDA's requests for additional information. The targeted action date can be 6 months after the 60-day filing date (or 8 months after BLA submission) for product candidates that are granted priority review designation because they are intended to treat serious or life-threatening conditions and demonstrate the potential to address unmet medical needs. The FDA has other programs to expedite development and review of product candidates that address serious or life-threatening conditions.
For some BLAs, the FDA may convene an advisory committee to seek insights and recommendations on issues relevant to approval of the application. Although the FDA is not bound by the recommendation of an advisory committee, the agency considers such recommendations carefully when making decisions. Before approving a new drug or biologic product, the FDA also requires that the facilities at which the product will be manufactured or advanced through the supply chain be in compliance with current Good Manufacturing Practices, or cGMP, requirements and regulations governing, among other things, the manufacture, shipment, and storage of the product. The FDA also can audit the sponsor of the BLA to determine if the clinical studies were conducted in compliance with current GCPs. After review of a BLA, the FDA may grant marketing approval, request additional information, or issue a CRL outlining the deficiencies in the submission. The CRL may require additional testing or information, including additional preclinical or clinical data, for the FDA to reconsider the application. Even if such additional information and data are submitted, the FDA may decide that the BLA still does not meet the standards for approval. Data from clinical trials are not always conclusive and the FDA may interpret data differently than the sponsor. If FDA grants approval, an approval letter authorizes commercial marketing of the product candidate with specific prescribing information for specific indications.
Any approval required by the FDA for any of our product candidates may not be obtained on a timely basis, or at all. The designation of a clinical trial as being of a particular phase is not necessarily indicative that such a trial will be sufficient to satisfy the parameters of a particular phase, and a clinical trial may contain elements of more than one phase notwithstanding the designation of the trial as being of a particular phase. The results of preclinical studies or early-stage clinical trials may not predict long-term safety or efficacy of our compounds when they are tested or used more broadly in humans. Additionally, as a condition of approval, the FDA may impose restrictions that could affect the commercial prospects of a product and increase our costs, such as a Risk Evaluation and Mitigation Strategy ("REMS") to mitigate certain specific safety risks, and/or post-approval commitments or requirements to conduct additional clinical trials or non-clinical studies or to conduct surveillance programs to monitor the product's effects.
Approval of a product candidate by comparable regulatory authorities in foreign countries is generally required prior to commencement of marketing of the product in those countries. The approval procedure varies among countries and may involve different or additional testing, and the time required to obtain such approval may differ from that required for FDA approval. Approval by a regulatory authority in one jurisdiction does not guarantee approval by comparable regulatory authorities in other jurisdictions. In the European Economic Area ("EEA") (which is comprised of 27 Member States of the EU plus Norway, Iceland, and Liechtenstein), medicinal products can only be commercialized after a related Marketing Authorization has been granted. Marketing authorization for biologics must be obtained through a centralized procedure, which allows a company to submit a single application to the EMA. If a related positive opinion is provided by the EMA, the EC will grant a centralized marketing authorization that is valid in the EEA.
In many jurisdictions, pediatric data or an approved Pediatric Investigation Plan ("PIP"), or a waiver of such studies, is required to have been approved by regulatory authorities prior to submission of a marketing application. In some EU countries, we may also be required to have an approved PIP before we can begin enrolling pediatric patients in a clinical trial. In the United States, under the Pediatric Research Equity Act ("PREA"), certain applications for approval must include an assessment, generally based on clinical study data, of the safety and effectiveness of the subject product in relevant pediatric populations, unless a waiver or
29
deferral is granted. However, a pediatric study plan is not required for orphan products and the timing of the submission is subject to negotiation with FDA, but such plan cannot be submitted later than submission of a BLA.
Various federal, state, and foreign statutes and regulations also govern or influence the research, manufacture, safety, labeling, storage, record keeping, marketing, transport, and other aspects of developing and commercializing pharmaceutical product candidates. The lengthy process of seeking these approvals and the compliance with applicable statutes and regulations require the expenditure of substantial resources. Any failure by us or our collaborators or licensees to obtain, or any delay in obtaining, regulatory approvals could adversely affect the manufacturing or marketing of our products and our ability to receive product or royalty revenue.
For additional information regarding U.S. and foreign regulatory approval processes and requirements, see Part I, Item 1A. "Risk Factors - Risks Related to Maintaining Approval of Our Marketed Products and the Development and Obtaining Approval of Our Product Candidates and New Indications for Our Marketed Products - Obtaining and maintaining regulatory approval for drug products is costly, time-consuming, and highly uncertain."
Emergency Use Authorization
The Secretary of HHS may authorize unapproved medical products to be marketed in the context of an actual or potential emergency that has been designated by the U.S. government. The COVID-19 pandemic has been designated as such a national emergency, with such designation currently expected to expire on May 11, 2023. After an emergency has been announced, the Secretary of HHS may authorize the issuance of, and the FDA Commissioner may issue, EUAs for the use of specific products based on criteria established by the Food, Drug, and Cosmetic Act, including that the product at issue may be effective in diagnosing, treating, or preventing serious or life-threatening diseases when there are no adequate, approved, and available alternatives. Although the criteria of an EUA differ from the criteria for approval of a BLA, EUAs nevertheless require the development and submission of data to satisfy the relevant FDA standards, as well as a number of ongoing compliance obligations. The FDA expects EUA holders to work toward submission of full applications, such as a BLA, as soon as possible. An EUA is also subject to additional conditions and restrictions and is product-specific. An EUA terminates when the emergency determination underlying the EUA terminates. An EUA is not a long-term alternative to obtaining FDA approval, licensure, or clearance for a product. The FDA may revoke, revise, or restrict an EUA for a variety of reasons, including where it is determined that the underlying health emergency no longer exists or warrants such authorization or the medical product is no longer effective in diagnosing, treating, or preventing the underlying health emergency.
Post-Approval Regulation
The FDA and comparable regulatory authorities in other jurisdictions may also require us to conduct additional clinical trials or to make certain changes related to a product after granting approval of the product. The FDA has the explicit authority to require postmarketing studies (also referred to as post-approval or Phase 4 studies) and labeling changes based on new safety information, and may impose and enforce a REMS at the time of approval or after the product is on the market. Post-approval modifications to the drug, such as changes in indications, labeling, or manufacturing processes or facilities, may require a sponsor to develop additional data or conduct additional preclinical studies or clinical trials, to be submitted in a new or supplemental BLA, which would require FDA approval.
Following approval, the FDA and comparable regulatory authorities outside the United States regulate the marketing and promotion of our products, which must comply with the Food, Drug, and Cosmetic Act and applicable FDA regulations and standards thereunder and equivalent foreign laws. The review of promotional activities by the FDA and comparable regulatory authorities outside the United States includes, but is not limited to, healthcare provider-directed and direct-to-consumer advertising, communications regarding unapproved uses, industry-sponsored scientific and educational activities, promotional activities involving the Internet, and sales representatives' communications. After approval, product promotion can include only those claims relating to safety and effectiveness that are consistent with the labeling approved by the FDA and comparable foreign regulatory authorities. FDA and comparable foreign regulatory authorities' regulations impose restrictions on manufacturers' communications regarding unapproved uses, but under certain conditions may engage in non-promotional, balanced, scientific communication regarding such use. Failure to comply with applicable FDA and comparable foreign regulatory authorities' requirements and restrictions in this area may subject a company to adverse publicity and enforcement action by the FDA, the Department of Justice, or the Office of the Inspector General of the Department of Health and Human Services, as well as state authorities and comparable regulatory authorities outside the United States. This could subject a company to a range of penalties that could have a significant commercial impact, including civil and criminal fines and agreements that materially restrict the manner in which a company promotes or distributes a drug. See Part I, Item 1A. "Risk Factors - Other Regulatory and Litigation Risks - Our business activities have been, and may in the future be, challenged under U.S. federal or state and foreign healthcare laws, which may subject us to civil or criminal proceedings, investigations, or penalties."
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Adverse-event reporting and submission of periodic reports are required following marketing approval. The FDA requires BLA holders to employ a system for obtaining and reviewing safety information, adverse events, and product complaints associated with each drug and to submit safety reports to the FDA, with expedited reporting timelines in certain situations. Based on new safety information after approval, the FDA can, among other things, mandate product labeling changes, require new post-marketing studies, impose or modify a risk evaluation and mitigation strategy for the product, or suspend or withdraw approval of the product. We may be subject to audits by the FDA and other regulatory authorities to ensure that we are complying with the applicable requirements. Rules that are equivalent in scope but which vary in application apply in foreign countries in which we conduct clinical trials.
The holder of an EU marketing authorization for a medicinal product must also comply with the EU's pharmacovigilance legislation. This includes requirements to conduct pharmacovigilance, or the assessment and monitoring of the safety of medicinal products. Marketing authorization holders are required to maintain a Pharmacovigilance System Master File ("PSMF"), which supports and documents the compliance of the marketing authorization holder with the requirements of EU pharmacovigilance legislation. Marketing authorization holders are also required to have a Qualified Person for Pharmacovigilance ("QPPV"), who, among other things, maintains the PSMF. A QPPV must reside in the EEA and must also prepare pharmacovigilance reports, respond to potential requests from competent authorities concerning pharmacovigilance on a 24 hour basis, and provide competent authorities with any other information that may be relevant to the safety of the medicinal product in accordance with Good Pharmacovigilance Practices.
The EC can also require marketing authorization holders to conduct post-authorization safety and/or efficacy studies. A post-authorization safety study ("PASS") is a study that is carried out after a medicinal product has been authorized to obtain further information on a medicinal product's safety, or to measure the effectiveness of risk-management measures. Such studies may be clinical trials or non-interventional studies. A post-authorization efficacy study ("PAES") is a study that is carried out for complementing available efficacy data in the light of well-reasoned scientific uncertainties on aspects of the evidence of benefits that is to be or only can be addressed post-authorization. The EC may, in particular, impose a PASS and/or PAES on marketing authorization holders when a marketing authorization is granted upon conditions. The EC may grant conditional marketing authorizations in the interest of public health, when there is less comprehensive clinical data available than would be required, if the EC considers that the benefit of immediate availability may outweigh the risk that the absence of the required clinical data poses.
In addition, we and our third-party suppliers are required to maintain compliance with cGMP, and are subject to inspections by the FDA or comparable regulatory authorities in other jurisdictions to confirm such compliance. Changes of suppliers or modifications of methods of manufacturing may require amending our application(s) to the FDA or such comparable foreign regulatory authorities and acceptance of the change by the FDA or such comparable foreign regulatory authorities prior to release of product(s). FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting and documentation requirements upon us and our third-party suppliers. Prescription drug manufacturers in the U.S. must comply with applicable provisions of the Drug Supply Chain Security Act and provide and receive product tracing information, maintain appropriate licenses, ensure they only work with other properly licensed entities, and have procedures in place to identify and properly handle suspect and illegitimate products. We may also be subject to state regulations related to the manufacturing and distribution of our products.
Failure to comply with these laws, regulations, and conditions of product approval may lead the FDA and comparable regulatory authorities in other jurisdictions to take regulatory action or seek sanctions, including fines, issuance of warning letters, civil penalties, injunctions, suspension of manufacturing operations, operating restrictions, withdrawal of FDA approval of a product, seizure or recall of products, and criminal prosecution.
Pricing and Reimbursement
Sales in the United States of our marketed products are dependent, in large part, on the availability and extent of reimbursement from third-party payors, including private payor healthcare and insurance programs, health maintenance organizations, pharmacy benefit management companies, and government programs such as Medicare and Medicaid. Sales of our marketed products in other countries are dependent, in large part, on coverage and reimbursement mechanisms and programs administered by health authorities in those countries. See Part I, Item 1A. "Risk Factors - Risks Related to Commercialization of Our Marketed Products, Product Candidates, and New Indications for Our Marketed Products - Sales of our marketed products are dependent on the availability and extent of reimbursement from third-party payors, and changes to such reimbursement may materially harm our business, prospects, operating results, and financial condition."
We participate in, and have certain price reporting obligations to, the Medicaid Drug Rebate program, state Medicaid supplemental rebate program(s), and other governmental pricing programs. We also have obligations to report the average sales price for certain drugs to the Medicare program. Under the Medicaid Drug Rebate program, we are required to pay a rebate to each state Medicaid program for our covered outpatient drugs that are dispensed to Medicaid beneficiaries and paid for by a state
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Medicaid program as a condition of having federal funds being made available for our drugs under Medicaid and Part B of the Medicare program.
Medicaid is a joint federal and state program that is administered by the states for low-income and disabled beneficiaries. Medicaid rebates are based on pricing data reported by us on a monthly and quarterly basis to the Centers for Medicare & Medicaid Services ("CMS"), the federal agency that administers the Medicaid and Medicare programs. These data include the average manufacturer price and, in the case of innovator products, the best price for each drug which, in general, represents the lowest price available from the manufacturer to any entity in the U.S. in any pricing structure, calculated to include all sales and associated rebates, discounts, and other price concessions. The amount of the rebate is adjusted upward if average manufacturer price increases more than inflation (measured by reference to the Consumer Price Index - Urban). Currently, the rebate is capped at 100 percent of the average manufacturer price, but effective January 1, 2024, this cap on the rebate will be removed, and our rebate liability could increase accordingly.
If we become aware that our reporting for a prior quarter was incorrect, or has changed as a result of recalculation of the pricing data, we are obligated to resubmit the corrected data for up to three years after those data originally were due, which revisions could affect our rebate liability for prior quarters. The federal Patient Protection and Affordable Care Act (the "PPACA") made significant changes to the Medicaid Drug Rebate program, and CMS issued a final regulation, which became effective on April 1, 2016, to implement the changes to the Medicaid Drug Rebate program under the PPACA. CMS recently modified Medicaid Drug Rebate program regulations to, among other things, permit reporting multiple best price figures with regard to value‑based purchasing arrangements and provide definitions for "line extension," "new formulation," and related terms with the practical effect of expanding the scope of drugs considered to be line extensions (beginning in 2022).
Medicare is a federal program that is administered by the federal government that covers individuals age 65 and over or that are disabled as well as those with certain health conditions. Medicare Part B generally covers drugs that must be administered by physicians or other health care practitioners; are provided in connection with certain durable medical equipment; or are certain oral anti-cancer drugs and certain oral immunosuppressive drugs. Medicare Part B pays for such drugs under a payment methodology based on the average sales price of the drugs. Manufacturers, including us, are required to report average sales price information to CMS on a quarterly basis. The manufacturer-submitted information may be used by CMS to calculate Medicare payment rates. Starting in 2023, manufacturers must pay refunds to Medicare for single-source drugs or biological products, or biosimilar biological products, reimbursed under Medicare Part B and packaged in single-dose containers or single-use packages for units of discarded drug reimbursed by Medicare Part B in excess of 10 percent of total allowed charges under Medicare Part B for that drug. Manufacturers that fail to pay refunds could be subject to civil monetary penalties. Further, starting in 2023, the Inflation Reduction Act ("IRA") establishes a Medicare Part B inflation rebate scheme under which, generally speaking, manufacturers will owe rebates if the average sales price of a Part B drug increases faster than the pace of inflation. Failure to timely pay a Part B inflation rebate is subject to a civil monetary penalty.
The IRA also creates a drug price negotiation program under which, after being on the market for a certain period of time, the prices for certain high Medicare spending drugs and biological products provided to Medicare patients without generic or biosimilar competition will be capped by reference to, among other things, a specified non-federal average manufacturer price, starting in 2026. Failure to comply with requirements under the drug price negotiation program is subject to an excise tax and a civil monetary penalty. This or any other legislative change could impact the market conditions for our products. See Part I, Item 1A. "Risk Factors - Risks Related to Commercialization of Our Marketed Products, Product Candidates, and New Indications for Our Marketed Products - Sales of our marketed products are dependent on the availability and extent of reimbursement from third-party payors, and changes to such reimbursement may materially harm our business, prospects, operating results, and financial condition."
Civil monetary penalties can be applied if we are found to have knowingly submitted any false pricing or other information to the government, if we are found to have made a misrepresentation in the reporting of our average sales price, or if we fail to submit the required data on a timely basis. Such conduct also could be grounds for CMS to terminate our Medicaid drug rebate agreement, in which case federal payments may not be available under Medicaid or Medicare Part B for our covered outpatient drugs.
Federal law requires that any company that participates in the Medicaid Drug Rebate program also participate in the Public Health Service's 340B drug pricing program (the "340B program") in order for federal funds to be available for the manufacturer's drugs under Medicaid and Medicare Part B. The 340B program, which is administered by the Health Resources and Services Administration ("HRSA"), requires participating manufacturers to agree to charge statutorily defined covered entities no more than the 340B "ceiling price" for the manufacturer's covered outpatient drugs. Covered entities include hospitals that serve a disproportionate share of financially needy patients, community health clinics, and other entities that receive certain types of grants under the Public Health Service Act. The PPACA expanded the list of covered entities to include certain free-standing cancer hospitals, critical access hospitals, rural referral centers, and sole community hospitals, but exempts "orphan drugs" from
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the ceiling price requirements for these covered entities. The 340B ceiling price is calculated using a statutory formula, which is based on the average manufacturer price and Medicaid rebate amount for the covered outpatient drug as calculated under the Medicaid Drug Rebate program. In general, products subject to Medicaid price reporting and rebate liability are also subject to the 340B ceiling price calculation and discount requirement.
HRSA issued a final regulation regarding the calculation of the 340B ceiling price and the imposition of civil monetary penalties on manufacturers that knowingly and intentionally overcharge covered entities, which became effective on January 1, 2019. It is currently unclear how HRSA will apply its enforcement authority under this regulation. Any charge by HRSA that we have violated the requirements of the regulation could result in civil monetary penalties. Moreover, under a final regulation effective January 13, 2021, HRSA established a new administrative dispute resolution ("ADR") process for claims by covered entities that a manufacturer has engaged in overcharging, and by manufacturers that a covered entity violated the prohibitions against diversion or duplicate discounts. Such claims are to be resolved through an ADR panel of government officials rendering a decision that could be appealed only in federal court. An ADR proceeding could subject us to onerous procedural requirements and could result in additional liability. On November 30, 2022, HRSA issued a notice of proposed rulemaking that proposes several changes to the ADR process. HRSA also implemented a price reporting system under which we are required to report our 340B ceiling prices to HRSA on a quarterly basis, which then publishes those prices to 340B covered entities. In addition, legislation could be passed that would further expand the 340B program to additional covered entities or would require participating manufacturers to agree to provide 340B discounted pricing on drugs used in an inpatient setting.
In order to be eligible to have our products paid for with federal funds under the Medicaid and Medicare Part B programs and purchased by certain federal agencies and grantees, we participate in the U.S. Department of Veterans Affairs ("VA") Federal Supply Schedule ("FSS") pricing program. FSS participation is required for our products to be purchased by the VA, Department of Defense ("DoD"), Coast Guard, and Public Health Service ("PHS"). Prices for innovator drugs purchased by the VA, DoD, Coast Guard, and PHS are subject to a cap (known as the "Federal Ceiling Price") equal to 76% of the annual non-federal average manufacturer price ("non-FAMP") minus, if applicable, an additional discount. The additional discount applies if non-FAMP increases more than inflation (measured by reference to the Consumer Price Index - Urban). We also participate in the Tricare Retail Pharmacy Program, under which we pay quarterly rebates to DoD for prescriptions of our innovator drugs dispensed to Tricare beneficiaries through Tricare Retail network pharmacies. The governing statute provides for civil monetary penalties for failure to provide information timely or for knowing submission of false information to the government.
Medicare Part D provides coverage to enrolled Medicare patients for self-administered drugs (i.e., drugs that are not administered by a physician). Medicare Part D is administered by private prescription drug plans approved by the U.S. government and, subject to detailed program rules and government oversight, each drug plan establishes its own Medicare Part D formulary for prescription drug coverage and pricing, which the drug plan may modify from time to time. The prescription drug plans negotiate pricing with manufacturers and pharmacies, and may condition formulary placement on the availability of manufacturer discounts. In addition, manufacturers, including us, are required to provide to CMS a 70% discount on brand name prescription drugs utilized by Medicare Part D beneficiaries when those beneficiaries are in the coverage gap phase of the Part D benefit design. The IRA includes a sunset provision with respect to the coverage gap discount program starting in 2025 and replaces it with a new manufacturer discount program. In addition, as of October 2022, the IRA established a Medicare Part D inflation rebate scheme under which, generally speaking, manufacturers will owe additional rebates if the average manufacturer price of a Part D drug increases faster than the pace of inflation. Failure to timely pay a Part D inflation rebate is subject to a civil monetary penalty.
Private payor healthcare and insurance providers, health maintenance organizations, and pharmacy benefit managers in the United States are adopting more aggressive utilization management techniques and are increasingly requiring significant discounts and rebates from manufacturers as a condition to including products on formulary with favorable coverage and copayment/coinsurance. These payors may not cover or adequately reimburse for use of our products or may do so at levels that disadvantage them relative to competitive products.
Outside the United States, within the EU, our products are paid for by a variety of payors, with governments being the primary source of payment. Government health authorities in the EU determine or influence reimbursement of products, and set prices or otherwise regulate pricing. Negotiating prices with governmental authorities can delay commercialization of our products. Governments may use a variety of cost-containment measures to control the cost of products, including price cuts, mandatory rebates, value-based pricing, and reference pricing (i.e., referencing prices in other countries or prices of competitive products and using those reference prices to set a price). Budgetary pressures in many EU countries are continuing to cause governments to consider or implement various cost-containment measures, such as price freezes, increased price cuts and rebates, and expanded generic substitution and patient cost-sharing.
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Other Regulatory Requirements
We are subject to health care "fraud and abuse" laws, such as the federal civil False Claims Act, the anti-kickback provisions of the federal Social Security Act, and other state and federal laws and regulations. Federal and state anti-kickback laws prohibit, among other things, payments or other remuneration to induce or reward someone to purchase, prescribe, endorse, or recommend a product that is reimbursed under federal or state healthcare programs. Federal false claims laws prohibit any person from knowingly presenting, or causing to be presented, a false claim for payment of government funds, or knowingly making, or causing to be made, a false statement to get a false claim paid. See Part I, Item 1A. "Risk Factors - Other Regulatory and Litigation Risks - Our business activities have been, and may in the future be, challenged under U.S. federal or state and foreign healthcare laws, which may subject us to civil or criminal proceedings, investigations, or penalties."
We are subject to the Foreign Corrupt Practices Act, or FCPA, and similar anti-bribery or anti-corruption laws, regulations or rules of other countries in which we operate, including the U.K. Bribery Act. See Part I, Item 1A. "Risk Factors - Other Regulatory and Litigation Risks - Risks from the improper conduct of employees, agents, contractors, or collaborators could adversely affect our reputation and our business, prospects, operating results, and financial condition."
In the United States, there are numerous federal and state laws and regulations governing data privacy of personal data and the collection, use, disclosure, and protection of health data, genetic data, consumer data, and children's data. Such laws and regulations include the Health Insurance Portability and Accountability Act of 1996 and its implementing regulations (collectively, "HIPAA"), as well as state data breach notification laws, state health information and/or genetic privacy laws, and federal and state consumer protection laws (such as Section 5 of the Federal Trade Commission Act (the "FTC Act") and the California Consumer Privacy Act (the "CCPA")). Many of these laws differ from each other in significant ways and have different effects. Many of the state laws enable a state attorney general to bring actions and provide private rights of action to consumers as enforcement mechanisms. There is also heightened sensitivity around certa