FDA Decision Accelerates Rare Disease Gene Therapy Regulatory Pathways

FDA has approved the biologics license application for etuvetidigene autotemcel (brand name Waskyra), making it the first agency-approved cell-based gene therapy for treating Wiskott-Aldrich syndrome (WAS) and the first approved cell and gene therapy (CGT) product from a non-profit applicant, in this case, Fondazione Telethon, an Italian biomedical organization (1,2). This decision marks a notable shift in FDA’s regulatory, manufacturing, and development expectations for rare disease gene therapies, according to a Dec. 9, 2025 press release (1).

The product is indicated for pediatric patients aged six months and older and for adults with WAS who carry a mutation in the disease-linked gene and who lack access to a suitable human leukocyte antigen-matched related stem cell donor despite being candidates for hematopoietic stem cell transplantation (1).

“Today’s approval is a transformative milestone for patients with Wiskott-Aldrich syndrome, offering the first FDA-approved gene therapy that uses the patient's own genetically corrected hematopoietic stem cells to treat the disease,” said Vinay Prasad, MD, chief medical and scientific officer, FDA, and director of FDA’s Center for Biologics Evaluation and Research (CBER), in the release (1). “[FDA] continues to exercise flexibility in the regulatory approach for rare diseases by considering all available data sources, including, as appropriate, data from expanded access programs, to facilitate the advancement of life-changing treatments while ensuring scientific requirements are satisfied.”

WAS is a rare, inherited, life-threatening condition marked by bleeding, eczema, recurrent infections, autoimmune complications, and elevated risks of lymphoreticular malignancies. Historically, disease management has relied on symptomatic care and allogeneic hematopoietic stem cell transplantation, a curative-intent approach that is limited by donor availability and timing (1,3).

How does autologous gene-modified cell manufacturing change development for hematologic gene therapies?

Etuvetidigene autotemcel is manufactured by collecting a patient’s own hematopoietic stem cells and genetically modifying them to contain functional copies of the defective gene. According to FDA, patients receive reduced-intensity conditioning before intravenous infusion of the modified cells. Once engrafted, these cells restore expression of the missing or defective protein, directly addressing the disease mechanism rather than downstream symptoms.

For drug developers and manufacturers, the approval reinforces an emerging standard for autologous, patient-specific manufacturing that integrates cell collection, viral or non-viral gene transfer, and tight control of release specifications (4). The regulatory precedent of accepting manufacturing and quality data from a comparably approved product may influence future chemistry, manufacturing, and controls strategies for CGT developers facing small patient populations and limited batch sizes (5).

What do clinical outcomes signal for trial design in rare genetic disease drug development?

FDA’s decision was supported by two open-label, single-arm, multinational studies and an expanded access program enrolling 27 patients with severe disease. These data showed sustained clinical benefit across multiple disease drivers of morbidity.

The rate of severe infections decreased by 93% during the six-to-18-month period following treatment compared with the year before therapy. Moderate and severe bleeding events declined by 60% within the first year after treatment, and most patients reported no moderate to severe bleeding after four years of follow-up (1).

“Today’s approval addresses the urgent need in the WAS community, where patients have described living ‘a life of terrifying worry and fear’ without any approved therapies available,” said Vijay Kumar, MD, acting director of CBER’s Office of Therapeutic Products, in the release (1). “This action marks significant progress in the development of much-needed treatment options for patients affected by this debilitating and life-threatening disease, enabling them to engage in everyday activities such as going to school or participating in sports.”

The agency also noted that reported adverse events included rash, respiratory tract infection, febrile neutropenia, catheter-related infection, vomiting, diarrhea, liver injury, and petechiae (1).

Why does regulatory flexibility and non-profit sponsorship matter for future CGT pipelines?

FDA stated that it applied regulatory flexibility across rare disease frameworks, clinical trial design, mechanism-of-action assessment, and chemistry, manufacturing, and controls review (1). The acceptance of manufacturing and quality data from a similar approved product represents a potential model for future biologics license applications in ultra-rare indications.

The therapy had previously received orphan drug, rare pediatric disease, and regenerative medicine advanced therapy designations, which underscore the agency’s continued policy direction toward favoring accelerated development pathways in high-unmet-need genetic disorders (1). Most notably, the granting of this approval to a non-profit organization highlights the expanding role of academic and non-commercial entities in advanced therapy development (2).

References

1. FDA. FDA Approves First Gene Therapy Treatment for Wiskott-Aldrich Syndrome. Press Release. Dec. 9, 2025.
2. Fondazione Telethon. Fondazione Telethon Announces FDA approval of Waskyra (etuvetidigene autotemcel), a Gene Therapy for the Treatment of Wiskott-Aldrich Syndrome. Press Release. Dec. 10, 2025.
3. Soresina, A.; Rondelli, R.; Notarangelo, L. D.; et al. Long-term Outcome in Wiskott-Aldrich Syndrome and X-linked Thrombocytopenia Patients: An Observational -Prospective Multi-Center Study of the Italian Primary Immune Deficiency Network (IPINET). EClinicalMedicine 2025, 84, 103271. DOI: 10.1016/j.eclinm.2025.103271
4. Ferrua, F.; Cicalese, M. P.; Galimberti, S.; et al. Lentiviral Hemopoietic Stem/Progenitor Cell Gene Therapy for Treatment of Wiskott-Aldrich Syndrome: Interim Results of a Non-Randomized, Open-Label, Phase 1/2 Clinical Study. Lancet Haematol. 2019, 6 (5), e239–e253. DOI: 10.1016/S2352-3026(19)30021-3
5. Keam, S. J. Elivaldogene Autotemcel: First Approval. Mol. Diagn. Ther. 2021, 25 (6), 803–809. DOI: 10.1007/s40291-021-00555-1