Cell and gene therapy developers have focused clinical programs around specific regulators in the absence of uniform global standards, with few sponsors successfully attempting approvals in both the US and the EU, a Pink Sheet analysis found.
The US FDA approved 10 cell and gene therapies between January 2023 and April 2024. Seven are not available in the European Union, the Pink Sheet’s US FDA Biologics Center Approvals and EU Approvals trackers show.
During the same time period, the EMA approved two gene therapies that had already cleared the FDA. The strong skew to US before European approvals is consistent with all the novel agent approvals in the 16-month analysis period. (See box for other pieces in this series.)
The FDA is working with other regulators on several harmonization and convergence projects to lay the groundwork for a global framework that is more aligned across regulators, especially for rare disease treatments, FDA Center for Biologics Evaluation and Research Director Peter Marks said. (Also see "Cell/Gene Therapies: Regulatory Strengthening Needed To Ensure Global Confidence" - Pink Sheet, 9 May, 2024.)
“The current lack of regulatory standardization between different countries is making it difficult for products that treat a few patients to make it to the few patients in each of the different countries,” he said.
Marks had briefly introduced one initiative that is just beginning, the Collaboration on Gene Therapies Global Pilot (CoGenT). (Also see "Don’t Call It Project Orbis: CoGenT Global Will Pilot Collaborative Review Of Gene Therapies" - Pink Sheet, 10 January, 2024.)
CoGenT will explore collaborative reviews of gene therapy applications and is modeled on the FDA Oncology Center of Excellence’s Project Orbis.
Unlike Project Orbis, however, the European Medicines Agency may take part in CoGenT, which is a project of the FDA and its global regulatory partners in the International Council for Harmonization. ICH includes the EU, Japan and other countries.
The EMA began observing Project Orbis conversations in 2024. (Also see "EMA To Become Observer Of FDA’s Project Orbis Early This Year" - Pink Sheet, 8 January, 2024.)
Rate-Limiting Steps In Regenerative Medicine
Emerging companies often are beset by financial and organizational stresses that limit the number of markets a sponsor can target, but the problem can be especially acute for regenerative medicine and other “living drugs,” like fecal microbiota transplantation.
Intensive and expensive production is required for regenerative products, many of which are personalized. Therapy is often a single dose with extended benefits, resulting in sometimes shocking price tags.
While scientifically exciting, the gene therapy field is proving commercially problematic. BioMarin, one prominent, orphan-experienced sponsor, recently said the future is uncertain for hemophilia A gene therapy Roctavian (valoctocogene roxaparvovec).
Roctavian received FDA approval 29 June 2023 after EU conditional approval 24 August 2022. (Also see "Gene Therapy Q1 Roundup: The Struggle Is Real" - Scrip, 9 May, 2024.)
Difficulty gaining European reimbursement for early gene therapy Zynteglo (betibeglogene autotemcel) spurred bluebird bio’s decision to exit the European market in 2021.
In the US, however, the FDA approved the sickle cell gene therapy Lyfgenia (lovotibeglogene autotemcel) as bluebird bio’s third commercial product from 8 December 2023. (Also see "Bluebird’s Lost Voucher: Lyfgenia Contains Same ‘Active Ingredient’ As Zynteglo, US FDA Says" - Pink Sheet, 14 December, 2023.)
US-based Krystal Biotech is building its initial infrastructure in Europe in advance of an anticipated EMA decision in the second half of 2024 on the MAA for Vyjuvek (beremagene geperpavec), a topical, redosable gene therapy for the rare skin disorder Epidermolysis Bullosa. The FDA granted the first approval worldwide for Vyjuvek on 19 May 2023.
In the fast-evolving gene therapy space, an approval gap can work to the company’s benefit, especially in orphan diseases with few patients available for trials. Orchard Therapeutics worked with the Italian San Raffaele Hospital and Telethon Foundation to develop rare disease gene therapy Libmeldy (atidarsagene autotemcel), which was approved in December 2020.
European clinical and expanded access data was then used in the US BLA approved 18 March as Lenmeldy.
Orchard is counting on the data to justify a US price of more than $4m, earning Lenmeldy the “most expensive drug in the world” title. (Also see "Keeping Track: Cardio-Renal Drugs At Heart Of US FDA’s March Approval Binge" - Pink Sheet, 1 April, 2024.)
Emerging companies often encounter funding trouble that curbs ambitions. Orchard Therapeutics found a lifeline in Kyowa Kirin, which acquired the gene therapy company in January.
Gamida Cell’s regenerative medicine Omisirge (omidubicel) and Seres Therapeutics’s Vowst (fecal microbiota spores, live) are not in development for Europe at present, likely reflecting resource constraints. Gamida Cell announced a restructuring and conversion to a private company in March and Seres announced a restructuring in November 2023 to prioritize the commercialization of Vowst in the US.
CellTrans, Inc. represents another, more regionally focused, cell therapy sponsor type: the start-up to build on academic research. The company launched out of the Islet Transplant Program at the University of Illinois and does not appear to have international aspirations for FDA-approved type 1 diabetes cell therapy Lantidra (donislecel).
A bigger partner can help small gene therapy companies access the American and European markets at similar times. CRISPR Therapeutics partnered with Vertex to develop the first CRISPR gene edited therapy, Casgevy (exagamglogene autotemcel). The collaboration brought Casgevy to US approval on 8 December 2023 and gained conditional approval in the EU two months later.
uniQure joined CSL Behring for Hemgenix (etranacogene dezaparvovec), which received conditional EU approval on 20 February 2023, three months after FDA approval.
Large Companies Seek Multi-Jurisdictional Approvals
Some of the biggest pharma companies want to develop gene therapies internationally. Pfizer’s Beqvez (fidanacogene elaparvovec) for hemophilia B cleared the FDA on 24 April, while EMA evaluation of the MAA started in June 2023.
Roche is responsible for bringing Elevidys (delandistrogene moxeparvovec-rokl) to market outside of the US, where Sarepta retained domestic marketing rights. The FDA granted a controversial accelerated approval on 22 June 2023, and on 20 June of this year converted the product to full approval in ambulatory Duchenne muscular dystrophy patients age 4 years and older.
The FDA also granted accelerated approval for a new population of non-ambulatory DMD patients that will be confirmed by the ongoing ENVISION trial. (Also see "Déjà Vu: CBER Director’s Intervention Saves Sarepta’s Elevidys Again" - Pink Sheet, 22 June, 2024.)
An MAA filing is predicted this year. (Also see "Is Sarepta’s Gene Therapy Elevidys Casting Doubt On A Popular DMD Endpoint?" - Pink Sheet, 18 January, 2024.)
This analysis drew on the Pink Sheet’s suite of regulatory tracking tools, including the US FDA Performance Tracker’s Novel CDER Approvals, Novel CBER Approvals and User Fee Goal Dates charts and the European Performance Tracker’s EU Approvals and EU CHMP Opinions & MAA Updates charts.
