BioMarin's ROCTAVIAN Wins Food and Drug Administration Approval As First Gene Therapy for Severe Hemophilia A

Abstract

The U.S. Food and Drug Administration (FDA) has approved BioMarin Pharmaceutical's ROCTAVIAN™ (valoctocogene roxaparvovec-rvox or “val rox”) as the first gene therapy to be authorized for severe hemophilia A. ROCTAVIAN is a one-time single-dose infusion indicated for the treatment of adults with severe hemophilia A (congenital factor VIII [FVIII] deficiency with FVIII activity <1 IU/dL) without antibodies to adeno-associated virus serotype 5 (AAV5) detected by an FDA-approved test.

FDA approval of ROCTAVIAN comes >3 years after the company first filed a regulatory application seeking approval for the gene therapy. The agency responded by requesting 2 years of follow-up data from the phase 3 GENEr8-1 clinical trial (NCT03370913), whose 6-month findings were used by the company to support its initial filing.

BioMarin resubmitted its application for ROCTAVIAN last year, then met an additional agency request for 3 years of follow-up data from the trial. The FDA determined that the 3-year data analysis constituted a major amendment due to the substantial amount of additional data furnished to the agency. The agency then set a new Prescription Drug User Fee Act target action date of June 30.

The European Commission approved ROCTAVIAN in August 2022 after review by the European Medicines Agency.

“We are proud to now offer adults with severe hemophilia A, a one-time, single-dose treatment option,” said Jean-Jacques Bienaimé, BioMarin's Chairman and CEO. “We are especially grateful to the bleeding disorders community for its support of this program, and to all the patients and healthcare providers who participated in our clinical trials.”¹

ROCTAVIAN will be manufactured by BioMarin at its facility in Novato, CA. The gene therapy carries a list price of $2.9 million per single treatment, BioMarin said.²

SANOFI, SCRIBE PARTNER ON SICKLE CELL DISEASE GENOMIC THERAPY

Sanofi and Scribe Therapeutics have launched an up to $1.2 billion-plus collaboration to develop an in vivo genome editing therapy for genomic diseases that include sickle cell disease (SCD).

“This in vivo collaboration further demonstrates the versatility of Scribe's design-based approaches to CRISPR, which enable greater activity, specificity, and deliverability, ultimately accelerating the development of life-changing therapeutics,” said Benjamin Oakes, PhD, Scribe's cofounder, president, and CEO.³

Sanofi and Scribe reason that combining Scribe's CRISPR X-Editing (XE) technologies with Sanofi's targeted nonviral delivery technologies could lead to a new and less costly in vivo therapy for SCD compared with ex vivo therapies

One ex vivo SCD therapy is under priority review by the U.S. FDA: Exagamglogene autotemcel (exa-cel), the autologous CRISPR/Cas9 gene-edited therapy developed by CRISPR Therapeutics and Vertex Pharmaceuticals. The FDA has set a target action date of December 8 on exa-cel in SCD (exa-cel is also under standard review in transfusion-dependent beta thalassemia, with a target action date in that indication of March 30).

Sanofi has obtained an exclusive license to use Scribe's XE genome editing technologies for the development of in vivo therapies for SCD and other genomic diseases. In return, the pharma giant agreed to pay Scribe $40 million upfront, and up to $1.2 billion plus in payments tied to achieving development and sales milestones.

Sanofi also agreed to pay Scribe tiered royalties ranging from high single digits to low double digits on net future sales of any products developed through the collaboration.

Scribe has a right to opt into sharing the cost of development, as well as sharing copromotion, profit, and loss with Sanofi on one future program.

The collaboration is the second one to emerge between Scribe and Sanofi. Last year, the companies launched an up to $1 billion partnership focused on developing CRISPR-based cell therapies to fight cancer.

ASTELLAS LICENSES RIGHTS TO 4D MOLECULAR THERAPEUTICS AAV VECTOR R100

Astellas Pharma has licensed rights to 4D Molecular Therapeutics (4DMT)'s intravitreal retinotropic R100 vector for an unspecified genetic target implicated in rare monogenic ophthalmic disease, with options to add up to two additional targets also implicated in rare monogenic ophthalmic diseases, under a collaboration that could generate >$1 billion for 4DMT.

R100 is an AAV vector designed to penetrate the internal limiting membrane barrier and efficiently transduce the entire retina, to generate robust transgene expression within retinal cells. All three of 4DMT clinical-stage ophthalmic product candidates use the R100 vector, including 4D-150 for wet age-related macular degeneration and diabetic macular edema.

4DMT has agreed to provide its proprietary R100 vector technology to Astellas to deliver Astellas' genetic payloads for the treatment of rare monogenic diseases, with Astellas agreeing to conduct all subsequent research, development, manufacturing, and commercialization activities.

In return, Astellas agreed to pay 4DMT $20 million upfront, and up to $942.5 million in option fees and payments tied to achieving milestones—including a $15 million near-term development milestone payment for the initial target. Astellas also agreed to pay 4DMT royalties ranging from the mid-single digits to double-digit subteens on net sales of all licensed products.

4DMT retains rights to large market nonhereditary ophthalmic diseases.

“We believe that this collaboration will bring synergies between the two companies' cutting-edge research, and will ultimately lead to the development of new therapeutics for patients with ophthalmic diseases at high risk of blindness,” said Adam Pearson, chief strategy officer at Astellas. Added David Kirn, MD, 4DMT's cofounder and CEO: “With over 70 patients dosed to-date with R100-based product candidates in wet age-related macular degeneration and rare ophthalmic diseases, this collaboration also demonstrates the modularity of the Therapeutic Vector Evolution platform, resulting in efficient design and development of new intravitreal products.”⁴

FDA APPROVES SAREPTA'S ELEVIDYS AS THE FIRST GENE THERAPY FOR DUCHENNE MUSCULAR DYSTROPHY

The U.S. FDA has granted Sarepta Therapeutics accelerated approval of ELEVIDYS (delandistrogene moxeparvovec-rokl), an AAV-based gene therapy for the treatment of ambulatory pediatric patients aged 4–5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene.

The FDA based its accelerated approval on increased expression of ELEVIDYS microdystrophin protein seen in the skeletal muscle of patients treated with the gene therapy.

Sarepta acknowledged that continued approval for ELEVIDYS may depend on showing verification and description of clinical benefit in confirmatory trial(s). To that end, Sarepta has committed to completing a phase 3 confirmatory trial. That study, EMBARK (NCT05096221), is fully enrolled and is expected to release topline results in late 2023, Sarepta said.

ELEVIDYS is a one-time treatment designed to address mutations in the dystrophin gene that result in the lack of dystrophin protein—the root genetic cause of DMD—by delivering a gene that codes for a shortened form of dystrophin to muscle cells known as ELEVIDYS microdystrophin.

“The approval of ELEVIDYS is a watershed moment for the treatment of Duchenne. ELEVIDYS is the first and only gene therapy approved for Duchenne, and this approval brings us closer to our goal of bringing forward a treatment that provides the potential to alter the trajectory of this degenerative disease,” said Doug Ingram, Sarepta's president and CEO.⁵

ELEVIDYS has been priced at $3.2 million per patient.⁶

In approving ELEVIDYS, the FDA heeded the advice of its Cellular, Tissue and Gene Therapies Advisory Committee, which by an 8 to 6 vote recommended that the FDA grant accelerated approval of Sarepta's gene therapy, formerly SRP-9001.

Opponents of accelerated approval urged the advisory committee to postpone action pending the expected release of efficacy data in September from a confirmatory clinical study of SRP-9001. Opponents also raised questions about whether expression of microdystrophin was, as Sarepta asserted, a surrogate endpoint that was reasonably likely to predict clinical benefit.

AVROBIO REDUCES ITS WORKFORCE, HALTS PROGRAMS, REVIEWS OPTIONS

AVROBIO has eliminated about half its workforce and halted further development of its programs, and is conducting what it said was a comprehensive review of strategic alternatives focused on maximizing shareholder value.

Those alternatives “may include, but are not limited to, an acquisition, merger, business combination, or other transaction,” AVROBIO said in a statement.⁷

The workforce reduction was estimated to amount to ∼40 jobs, based on the 78 full-time employees reported by the company as of December 31, 2022, according to its Form 10-K annual report for 2022.

“The Company estimates that the severance and termination-related costs will total approximately $2.8 million in the aggregate and expects to primarily record these charges in the third quarter of 2023,” AVROBIO stated in a regular filing.⁸

The layoffs and strategic review are the latest in a series of setbacks for the company, which have included erosion of its market value, termination of its Fabry disease gene therapy candidate after disappointing phase 2 clinical trial results, the decline of the financial markets since 2021, and the departure of its President and CEO Geoff McKay in May.⁹

AVROBIO's pipeline consists of three gene therapies: AVR-RD-02 (Gaucher disease, phase 1/2), AVR-RD_05 (Hunter syndrome, phase 1/2), and AVR-RD-03 (Pompe disease, preclinical).

AMERICAN GENE TECHNOLOGIES SPINS OUT ADDIMMUNE, PURSUING FUNCTIONAL HIV CURE

American Gene Technologies^® (AGT) has spun out a new company focused on bringing to market curative gene and cell treatments for HIV, starting with its phase 1-completed “one-and-done” autologous T cell therapy for the AIDS virus.

Addimmune™ will continue more than a decade's worth of R&D by AGT focused on developing gene and cell therapy technologies aimed at curing HIV. The new spinout company will continue the development of AGT103-T, which successfully completed the phase 1 RePAIR trial (Restore Potent Antiviral Immune Responses, NCT04561258) by showing positive safety results in seven patients. The phase 1 trial, along with another sponsor-initiated follow-on study named Durable Anti-Retroviral Withdrawal Initiative (NCT05529342), showed active immune responses to HIV up to 6 months after dosing.

Addimmune is committed to developing AGT103-T through the regulatory phase: “Hence, that's why we spun out Addimmune as a separate company in HIV, because we believe that the data justifies full focus and full funding,” said Jeff Galvin, CEO of Addimmune, and the founder and CEO of AGT.¹⁰

AGT103-T is a single-dose lentiviral-based autologous cell therapy delivering gene therapy-modified HIV-specific CD4 T cells to people with HIV. AGT103-T is designed to induce the exceptional control of viral replication and intact immune responses without antiretroviral drugs shown by two categories of people living with HIV—elite controllers and long-term nonprogressor individuals. AGT103-T is designed to induce the conditions seen in elite controllers and long-term nonprogressors by raising the number of Gag-specific CD4 T cells in patients and protecting those cells from HIV infection.

Last year, Galvin and researchers published positive topline phase 1 data showing that AGT103-T generated immune responses in all seven patients dosed with the therapy. Five received the low dose (<10⁹ genetically modified CD4+ T cells) and two received the high dose (≥10⁹ genetically modified CD4+ T cells). All seven patients demonstrated the persistence of AGT103-modified T cells by showing elevated Gag-specific CD4+ T cells up to 180 days after infusion.¹¹

By year's end, Addimmune researchers plan to publish additional data from a subsequent analytic treatment interruption study (NCT05540964) designed to assess the efficacy of AGT103-T in patients after they stopped taking an antiretroviral therapy. After finalization of the study and peer review, the company said it intends to have the study results published in a scientific journal.

Those data, Addimmune reasons, could help position AGT103-T as a functional cure for HIV—an option that is now not available among the 32 antiretroviral drugs, 1 pharmacokinetic enhancer, and 21 fixed-dose combinations all approved by the FDA to treat HIV/AIDS in the 4 decades since HIV was discovered.

References

BioMarin Pharmaceutical. U.S. Food and Drug Administration Approves BioMarin's ROCTAVIAN™ (valoctocogene roxaparvovec-rvox), the First and Only Gene Therapy for Adults with Severe Hemophilia A. June 29, 2023. Available from: https://investors.biomarin.com/2023-06-29-U-S-Food-and-Drug-Administration-Approves-BioMarins-ROCTAVIAN-TM-valoctocogene-roxaparvovec-rvox-,-the-First-and-Only-Gene-Therapy-for-Adults-with-Severe-Hemophilia-A [Last accessed: July 14, 2023 ].

Myshko

FDA Approves $2.9 Million Gene Therapy for Hemophilia A Formulary Watch. June 29, 2023. Available from: https://www.formularywatch.com/view/fda-approves-2-9-million-gene-therapy-for-hemophilia-a [Last accessed: June 14, 2023 ].

Scribe Therapeutics. Scribe Therapeutics Expands Collaboration with Sanofi to Advance In Vivo Genetic Medicines for Sickle Cell and Other Genomic Diseases. July 17, 2023. Available from: https://www.scribetx.com/press-release-scribe-therapeutics-expands-collaboration-with-sanofi-to-advance-in-vivo-genetic-medicines-for-sickle-cell-and-other-genomic-diseases/ [Last accessed: July 17, 2023 ].

Astellas Pharma and 4D Molecular Therapeutics. Astellas and 4D Molecular Therapeutics (4DMT) Enter into License Agreement to Use 4DMT's Proprietary Intravitreal R100 Vector for Rare Ophthalmic Targets. July 11, 2023. Available from: https://www.astellas.com/en/news/28136 [Last accessed: July 11, 2023 ].

Sarepta Therapeutics. Sarepta Therapeutics Announces FDA Approval of ELEVIDYS, the First Gene Therapy to Treat Duchenne Muscular Dystrophy. June 22, 2023. Available from: https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-fda-approval-elevidys-first-gene [Last accessed: June 14, 2023 ].

Blank

First Gene Therapy for Duchenne Priced at $3.2 Million. June 23, 2023. Formulary Watch. Available from: https://www.formularywatch.com/view/fda-approves-2-9-million-gene-therapy-for-hemophilia-a [Last accessed: June 14, 2023 ].

AVROBIO. AVROBIO to Explore Strategic Altrnatives. July 12, 2023. Available from: https://investors.avrobio.com/news-releases/news-release-details/avrobio-explore-strategic-alternatives [Last accessed: July 14, 2023 ].

U.S. Securities and Exchange Commission. Form 8-K filed July 12, 2023. Available from: https://investors.avrobio.com/static-files/9cc9a41d-3e74-4bca-955a-522c94847e65 [Last accessed: July 14, 2023 ].

Pagliarulo

Avrobio halts gene therapy research and considers a sale BioPharma Dive. July 12, 2023. Available from: https://www.biopharmadive.com/news/avrobio-strategic-alternatives-sale-gene-therapy-research/686643/ [Last accessed: July 14, 2023 ].

10.

Philippidis

AGT Spins Out Addimmune, Focusing on Functional HIV Cure. Genetic Engineering and Biotechnology News. July 7, 2023. Available from: https://www.genengnews.com/gen-edge/agt-spins-out-addimmune-focusing-on-functional-hiv-cure/ [Last accessed: July 11, 2023 ].

11.

Muvarak

, Li

, Lahusen

, et al. Safety and durability of AGT103-T autologous T cell therapy for HIV infection in a Phase 1 trial. Frontiers in Medicine. November 14, 2022. Available from: https://www.frontiersin.org/articles/10.3389/fmed.2022.1044713/full [Last accessed: July 11, 2023 ].