Sarepta Therapeutics Profile
Sarepta Therapeutics, Inc. operates as a commercial-stage biopharmaceutical company.
The company is focused on helping patients through the discovery and development of unique RNA-targeted therapeutics, gene therapy and other genetic therapeutic modalities for the treatment of rare diseases. Applying the company's proprietary, highly-differentiated and innovative technologies, and through collaborations with the company's strategic partners, the company has developed multiple approved products for the treatment of Duchenne muscular dystrophy ('Duchenne') and are developing potential therapeutic candidates for a broad range of diseases and disorders, including Duchenne, Limb-girdle muscular dystrophies ('LGMDs') and other neuromuscular and central nervous system ('CNS') related disorders.
As of December 31, 2023, the company had developed and commercialized the following four approved products for the treatment of Duchenne: EXONDYS 51 (eteplirsen) Injection ('EXONDYS 51'), VYONDYS 53 (golodirsen) Injection ('VYONDYS 53'), AMONDYS 45 (casimersen) Injection ('AMONDYS 45'), and ELEVIDYS.
Technology and Platforms
Exon skipping is intended to promote the production of an internally truncated but functional dystrophin protein. The original phosphorodiamidate morpholino oligomer ('PMO') structure and variations of this structure that are so-called PMO-based (collectively 'PMO-based') are central to the company's proprietary chemistry platform. PMO technologies can be used to selectively up-regulate or down-regulate the production of a target protein through pre-mRNA splice alteration. PMO-based compounds have the potential to be designed to create more, less, or none of certain proteins, or produce analogues of endogenous proteins. This technology can be used to correct disease-causing genetic errors by inducing the targeted expression of novel proteins.
The PMO chemistry platform is highly adaptable, and the company has developed next-generation PMO-based chemistries for advancing RNA-targeted therapeutics. These next-generation chemistries are specifically designed to enhance tissue targeting, intracellular delivery, target selectivity and drug potency. One of these novel technologies is based on cell-penetrating peptide-conjugated PMO ('PPMO'). The PPMO features covalent attachment of a cell-penetrating peptide to a PMO with the goal of enhanced delivery into the cell. The company's most advanced PPMO product candidate is SRP-5051, which is designed to treat Duchenne in patients with genetic mutations amenable to exon 51 skipping. In pre-clinical research and clinical trials for SRP-5051, the company's proprietary class of PPMO compounds demonstrated an increase in dystrophin production and a more durable response compared to PMO. In addition, PPMO treatment in non-human primates resulted in high levels of exon-skipping in skeletal, cardiac and smooth muscle tissues. Pre-clinical trials and clinical trials for SRP-5051 also indicated that PPMOs may require less frequent dosing than PMOs, and that PPMOs could potentially be tailored to reach other organs beyond muscle.
As part of the company's multifaceted approach to Duchenne, the company is also developing gene therapy technologies to treat Duchenne. The company's gene therapy aims to express a smaller but still functional version of dystrophin. The company uses a unique adeno-associated virus ('AAV') vector called AAVrh.74 to transport the transgene - the genetic material that will make the protein of interest - to the target cells.
The company is also developing gene therapy programs for various forms of LGMDs. The company's most advanced LGMD product candidate, SRP-9003, is designed to transfer a gene that codes for and restores beta-sarcoglycan protein with the goal of restoring the dystrophin associated protein complex. SRP-9003 utilizes the AAVrh.74 vector, the same vector used in ELEVIDYS.
The company's pipeline includes more than 40 programs at various stages of discovery, pre-clinical and clinical development, reflecting the company's aspiration to apply its multifaceted approach and expertise in precision genetic medicine to make a profound difference in the lives of patients suffering from rare diseases.
Business Strategy
The company's business strategies include continuing to build its gene therapy engine, including developing gene therapy product candidates, operationalizing the company's manufacturing strategy and furthering the company's commercial capabilities in preparation for potential regulatory approvals; advancing the company's RNA technologies (e.g., PMO and PPMO), launching potential approved products and supporting commercialization of approved products; investing in next-generation precision medicine through internal research, strategic partnerships, collaborations and other potential opportunities; and continuing to nurture the company's culture, which is based on strong patient focus, bias to action, a self-starter mentality, smart and appropriate risk-taking and high ethics.
Commercial Products
EXONDYS 51
The company launched its first commercial product, EXONDYS 51, in 2016. EXONDYS 51 is indicated for the treatment of Duchenne in patients who have a confirmed mutation of the dystrophin gene that is amenable to exon 51 skipping. EXONDYS 51 uses the company's PMO chemistry and exon-skipping technology to skip exon 51 of the dystrophin gene. PMO-based compounds are synthetic compounds that bind to complementary sequences of RNA by standard Watson-Crick nucleobase pairing. The two key structural differences between PMO-based compounds and naturally occurring RNA are that the PMO nucleobases are bound to synthetic morpholino rings instead of ribose rings, and the morpholino rings are linked by phosphorodiamidate groups instead of phosphodiester groups. Replacement of the negatively charged phosphodiester in RNA with the uncharged phosphorodiamidate group in PMO eliminates linkage ionization at physiological pH. Due to these modifications, PMO-based compounds are resistant to degradation by plasma and intracellular enzymes. Unlike the RNA-targeted technologies, such as siRNAs and DNA gapmers, PMO-based compounds operate by steric blockade rather than by cellular enzymatic degradation to achieve their biological effects. Thus, PMOs use a fundamentally different mechanism from other RNA-targeted technologies.
EXONDYS 51 targets the most frequent series of mutations that cause Duchenne. Approximately 13% of Duchenne patients are amenable to exon 51 skipping.
VYONDYS 53
The company launched VYONDYS 53 in 2019. VYONDYS 53 is indicated for the treatment of Duchenne in patients who have a confirmed mutation of the dystrophin gene that is amenable to exon 53 skipping. VYONDYS 53 uses the company's PMO chemistry and exon-skipping technology to skip exon 53 of the dystrophin gene. VYONDYS 53 has the potential to treat up to 8% of Duchenne patients who are amenable to exon 53 skipping.
AMONDYS 45
The company launched AMONDYS 45 in 2021. AMONDYS 45 is indicated for the treatment of Duchenne in patients who have a confirmed mutation of the dystrophin gene that is amenable to exon 45 skipping. AMONDYS 45 uses the company's PMO chemistry and exon-skipping technology to skip exon 45 of the dystrophin gene. AMONDYS 45 has the potential to treat up to 8% of Duchenne patients who are amenable to exon 45 skipping.
The company is conducting various clinical trials for EXONDYS 51, VYONDYS 53 AND AMONDYS 45, including studies that are required to comply with the company's post-marketing FDA requirements and commitments to verify and describe the clinical benefit of the three products.
ELEVIDYS
The company launched ELEVIDYS in the second quarter of 2023. ELEVIDYS is an adeno-associated virus based gene therapy for the treatment of ambulatory pediatric patients aged 4 through 5 years with Duchenne with a confirmed mutation in the Duchenne gene. ELEVIDYS is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the Duchenne gene.
The company is conducting various clinical trials for ELEVIDYS and announced the company's submission of an efficacy supplement to the biologics license application ('BLA') for ELEVIDYS to expand its label indication to remove age and ambulatory restrictions from the approved indication on December 22, 2023. The FDA granted priority review with a review goal date of June 21, 2024. The company also submitted the company's postmarketing requirement related to the Phase 3 SRP-9001-301 confirmatory study for ELEVIDYS requesting conversion from accelerated approval to traditional approval during December 2023.
Pipeline - Key Programs
SRP-5051 (Duchenne PPMO program) uses the company's next-generation PPMO and the company's exon-skipping technology to skip exon 51 of the dystrophin gene.
In 2019, the company commenced a multiple ascending dose study for the treatment of Duchenne with SRP-5051 in patients who are amenable to exon 51 skipping ('Study 5051-201'). In December 2020 and May 2021, the company announced results from Part A of Study 5051-201. The company initiated Part B of Study 5051-201 in the fourth quarter of 2021. In August 2022, the FDA lifted the clinical hold placed on Study 5051-201 following a serious adverse event of hypomagnesemia. In January 2024, the company announced results from Part B of Study 5051-2021. The company plans to meet with FDA to discuss next steps in the second half of 2024.
SRP-9003 (LGMD, gene therapy program). The company is developing gene therapy programs for various types of LGMDs. The company's LGMD programs use the AAVrh.74 vector, the same vector used in the company's SRP-9001 gene therapy program, to transfect a restorative gene. The most advanced of the company's LGMD product candidates, SRP-9003, aims to treat LGMD2E, also known as beta-sarcoglycanopathy, a severe and debilitating form of LGMD characterized by progressive muscle fiber loss, inflammation and muscle fiber replacement with fat and fibrotic tissue. SRP-9003 is designed to transfect a gene that codes for and restores beta-sarcoglycan protein with the goal of restoring the dystrophin associated protein complex. SRP-9003 has generated positive pre-clinical safety and efficacy data utilizing the AAVrh.74 vector.
A Phase 1/2a trial of SRP-9003 commenced in the fourth quarter of 2018. In February 2019, the company announced two-month biopsy data from the first three-patient cohort dosed in the SRP-9003 trial, and in October 2019, the company announced nine-month functional data from these three patients. In June 2020, the company announced safety and expression results from three clinical trial participants in the high-dose cohort measured at 60 days, and one-year functional data from three clinical trial participants in the low-dose cohort. In September 2020, the company announced six-month functional data from three clinical trial participants in the in the high-dose cohort, and 18-month functional data from three clinical trial participants in the low-dose cohort. The company also announced one-year functional data in the high-dose cohort and two-year functional data in the low-dose cohort in March 2021. In March 2022, the company announced 36-month functional data from three clinical trial participants in the low-dose cohort and 24-month functional data from two clinical trial participants in the high-dose cohort. In January 2024, the company announced that the company had begun screening in Study SRP-9003-301, a Phase 3, multi-national, open-label study of SRP-9003.
Manufacturing, Supply and Distribution
The company's gene therapy manufacturing capabilities have been greatly enhanced through partnerships with Thermo Fisher Scientific Inc. ('Thermo'), Catalent, Inc. ('Catalent') and Aldevron LLC ('Aldevron').
Material Agreements
F. Hoffman-La Roche Ltd
License, Collaboration, and Option Agreement
On December 21, 2019, the company entered into a license, collaboration, and option agreement (the 'Collaboration Agreement') with F. Hoffman-La Roche Ltd ('Roche') pursuant to which the company granted Roche an exclusive license under certain of the company's intellectual property rights to develop, manufacture, and commercialize ELEVIDYS (SRP-9001) in all countries outside of the U.S. The company retained all rights to SRP-9001 in the U.S. The transaction closed on February 4, 2020. The company has entered into Amendments 1 through 14 to the Collaboration Agreement on: October 23, 2020, October 28, 2020, February 4, 2021, June 23, 2021, August 31, 2021, November 30, 2021, January 5, 2022, January 28, 2022, March 23, 2022, May 31, 2022, June 23, 2022, July 28, 2022, August 31, 2022 and October 31, 2022, respectively.
Also, under the terms of the Collaboration Agreement, Roche granted the company a license to use certain of its intellectual property rights to perform development activities worldwide under a joint global development plan, commercialize ELEVIDYS in the U.S., and perform certain manufacturing and medical affairs activities worldwide. Such license is non-exclusive under Roche's background intellectual property rights, exclusive in the U.S. under intellectual property rights developed by Roche under the Collaboration Agreement, and non-exclusive outside the U.S. under intellectual property rights developed by Roche under the Collaboration Agreement.
The company intends to manufacture and supply ELEVIDYS in the relevant markets in which the company has approval, or in the future receive approval.
Roche Options and Negotiation Rights
Pursuant to the Collaboration Agreement, the company granted Roche an exclusive option to obtain an exclusive license to develop, manufacture and commercialize the following products outside of the U.S.: (i) certain exon-skipping products that target the dystrophin gene to induce exon skipping, including eteplirsen, golodirsen, casimersen and SRP-5051; (ii) certain gene therapy products other than ELEVIDYS that encode and directly express dystrophin or a derivative thereof; and (iii) certain gene-editing products that modify, repair, or activate an endogenous dysfunctional dystrophin gene. The products subject to Roche's options are collectively referred to as the 'Option Products.' Upon option exercise, the Option Product that is the subject of the option exercise will be included under the Collaboration Agreement as a product licensed to Roche subject to similar obligations, including with respect to development, manufacturing, commercialization, and cost-sharing as those that apply to ELEVIDYS.
Pursuant to the Collaboration Agreement, Roche has a right of first negotiation if the company seek to grant a third-party license to commercialize ELEVIDYS in the U.S. Roche had a similar right of first negotiation with respect to the company's LGMDs products, but such right has expired.
BioMarin Pharmaceutical Inc. ('BioMarin')
License Agreement
On July 17, 2017, the company executed a license agreement (as amended on April 14, 2019 and November 17, 2021, the 'License Agreement') with BioMarin Leiden Holding BV, BioMarin Nederlands BV and BioMarin Technologies BV (collectively, the 'BioMarin Parties'), pursuant to which BioMarin Parties granted the company a royalty-bearing, worldwide license under patent rights ('Licensed Patents') and know-how ('Licensed Know-How') controlled by the BioMarin Parties with respect to BioMarin's Parties' Duchenne program, which are potentially necessary or useful for the treatment of Duchenne, to practice and exploit the Licensed Patents and Licensed Know-How in all fields of use and for all purposes, including to develop and commercialize antisense oligonucleotide products that target one or more exons of the dystrophin gene to induce exon skipping, including eteplirsen, golodirsen and casimersen (collectively, the 'Products').
The license granted to the company by the BioMarin Parties is co-exclusive with the BioMarin Parties, with respect to the Licensed Patents, and is non-exclusive with respect to Licensed Know-How. Pursuant to the amendment to the License Agreement dated November 17, 2021 (the '2021 Amendment'), the BioMarin Parties exercised their rights to convert the exclusive license under the Licensed Patents to the co-exclusive license.
University of Western Australia
In April 2013, the company entered into an agreement with UWA under which an existing exclusive license agreement between the two parties was amended and restated and, in June 2016, the company entered into the first amendment to the license agreement (the 'UWA License Agreement'). The UWA License Agreement grants the company specific rights to compounds for the treatment of Duchenne by inducing exon skipping. EXONDYS 51, VYONDYS 53 and AMONDYS 45 fall under the scope of the license agreement.
The latest date on which an issued patent covered by the UWA License Agreement expires is November 2030 (excluding any patent term extension, supplemental protection certificate or pediatric extensions that may be available); however, patents granted from pending patent applications could result in a later expiration date.
Catalent Maryland, Inc.
Catalent Supply Agreement
On November 28, 2022, the company entered into an amended and restated product manufacturing and supply agreement with Catalent Maryland, Inc. ('Catalent', and such agreement, as amended on November 28, 2022,the 'Catalent Supply Agreement'). Under the Catalent Supply Agreement, Catalent has agreed, to manufacture and supply ELEVIDYS delandistrogene moxeparvovec-rokl, the company's micro-dystrophin gene therapy drug targeting Duchenne muscular dystrophy. Catalent is responsible for the operation of dedicated clean room suites for the manufacture of the company's ELEVIDYS product subject to Sarepta placing minimum annual orders. Catalent may not develop or manufacture products that compete with the company's ELEVIDYS product.
Nationwide Children's Hospital
On October 8, 2018, the company entered into an exclusive license agreement (as amended on May 19, 2019 and July 11, 2023, the 'License Agreement') with Nationwide Children's Hospital ('Nationwide') pursuant to which the company acquired an exclusive license under certain intellectual property rights to develop, manufacture and commercialize ELEVIDYS in all countries. The company entered into Amendment 1 and Amendment 2 to the License Agreement on May 29, 2019 and July 11, 2023, respectively.
Patents and Proprietary Rights
Key Patents & Regulatory Exclusivities
Delandistrogene moxeparvovec-rokl
In connection with its FDA approval on June 22, 2023, the FDA granted ELEVIDYS (delandistrogene moxeparvovec-rokl) data exclusivity until June 22, 2035, and Orphan Drug Exclusivity until June 22, 2030.
Golodirsen
In connection with its FDA approval on December 12, 2019, the FDA granted VYONDYS 53 (golodirsen) new chemical entity ('NCE') exclusivity until December 12, 2024, and Orphan Drug Exclusivity until December 12, 2026.
Casimersen
In connection with its FDA approval on February 25, 2021, the FDA granted AMONDYS 45 (casimersen) NCE exclusivity until February 25, 2026, and Orphan Drug Exclusivity until February 25, 2028.
Trademarks
The company typically files trademark applications and pursues their registration in the U.S., Europe and other markets in which the company anticipates using such trademarks. The company is the owner of multiple federal trademark registrations in the U.S., including, but not limited to, Sarepta, Sarepta Therapeutics, the double-helix logo, ELEVIDYS, EXONDYS, EXONDYS 51, the EXONDYS 51 Logo, VYONDYS, VYONDYS 53, the VYONDYS 53 Logo, AMONDYS, AMONDYS 45, and the AMONDYS 45 Logo. In addition, the company has multiple pending trademark applications and registrations in the U.S. and in major foreign markets.
Government Regulation
To obtain the U.S. Food and Drug Administration (FDA) approval of a product candidate, the company must, among other things, submit clinical data providing substantial evidence of safety and efficacy of the product for its intended use, as well as detailed information on product composition, its manufacture and controls and proposed labeling. In addition to regulations enforced by the FDA and foreign authorities relating to the clinical development and marketing of products, the company is or may become subject to regulation under the Occupational Safety and Health Act, the Toxic Substances Control Act, the Resource Conservation and Recovery Act and other present and potential future foreign, federal, state and local laws and regulations.
Competition
The company faces competition in the field of Duchenne by third parties who are developing or who had once developed: (i) exon skipping product candidates, such as Wave (notably for exons 51 and 53), Nippon Shinyaku (notably for exon 44 and exon 53, for which it has received FDA approval for its product Viltepso (viltolarsen)), Daiichi (notably for exon 45), Dyne Therapeutics pursuing antibody-oligonucleotide conjugates for exons 44, 45, 51, and 53, Avidity Biosciences pursuing antibody-oligonucleotide conjugates for exons 44, 45 and 51, PepGen (notably for exon 51), SQY Therapeutics and BioMarin (BMN-351 for exon 51); (ii) gene therapies, such as Pfizer and Solid (in partnership with Ultragenyx), and Regenxbio; (iii) gene editing, including CRISPR/Cas 9 approaches, such as Exonics Therapeutics (acquired by Vertex Pharmaceuticals), CRISPR Therapeutics, Editas Medicine, and Precision Biosciences (in partnership with Eli Lilly); (iv) other disease modifying approaches, such as PTC Therapeutics, which has a small molecule candidate, ataluren, that targets nonsense mutations; and (v) other approaches that may be palliative in nature or potentially complementary with the company's products and product candidates and that are or were once being developed by Santhera, Catabasis, Fibrogen, ReveraGen, Capricor Therapeutics (in partnership with Nippon Shinyaku), BioPhytis, Mallinckrodt, Antisense Therapeutics, Italfarmco, Dystrogen and Edgewise Therapeutics.
History
Sarepta Therapeutics, Inc. was founded in 1980. The company was incorporated in the state of Oregon in 1980 and reincorporated in the state of Delaware in 2013.
