FDA Approves Etuvetidigene Autotemcel, First Gene Therapy for Wiskott-Aldrich Syndrome

The FDA approved etuvetidigene autotemcel (etu-cel, Waskyra; Fondazione Telethon ETS) for the treatment of Wiskott-Aldrich syndrome (WAS) in pediatric patients 6 months and older and adults who have a mutation in the WAS gene and for whom hematopoietic stem cell transplantation (HSCT) is appropriate and no suitable human leukocyte antigen (HLA)-matched related stem cell donor is available. This action makes etu-cel the first cell-based gene therapy approved for the treatment of WAS, according to an FDA news release.¹

“Today’s approval is a transformative milestone for patients with WAS, offering the first FDA-approved gene therapy that uses the patient's own genetically corrected hematopoietic stem cells to treat the disease,” Vinay Prasad, MD, MPH, chief medical and scientific officer and director of the FDA’s Center for Biologics Evaluation and Research, said in the news release. “The 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.”¹

What is Wiskott-Aldrich Syndrome?

WAS is a rare, life-threatening genetic disease caused by mutations in the WAS gene that affect 1 to 10 out of every 1 million boys, according to Boston Children’s Hospital. The disease makes it difficult for a child’s bone marrow to produce platelets, making the patient prone to bleeding. This frequent and hard to control bleeding can occur even from the mildest bumps or scrapes, and can occur under the skin, from the gums and mouth, in bowel movements, and even in the brain. Patients with WAS have T cells and B cells but they do not work properly, and their white blood cells do not reach the sites of infection. Without normal immune cells, a patient with WAS is at a constant risk of pneumonia, eczema, ear and sinus infections, chronic and bloody diarrhea, and viral infections (eg, herpes, Epstein-Barr virus, cytomegalovirus). Further, children with WAS are at a higher risk of developing autoimmune disease and inflammatory conditions.²

Until the approval of etu-cel, treatment options for patients with WAS have been limited to symptomatic management and allogeneic hematopoietic stem cell transplantation, of which the latter is most effective when performed earlier in life and is feasible only when matched donors are available.¹

What Contributed to Etu-Cel’s Approval?

The approval of etu-cel is based on data from 2 open-label, single-arm, multinational clinical studies, the phase 1/2 TIGET-WAS (NCT01515462)³ and phase 3 OTL-103-4 (NCT03837483)⁴ trials, both of which evaluated the safety and efficacy of etu-cel when treating participants with WAS.¹

Etu-cel was administered via intravenous (IV) infusions following rituximab and reduced-intensity conditioning. The primary efficacy end points were overall survival (OS), rate of severe infections from 6 to 18 months after autologous gene therapy, and rate of moderate or severe bleeding episodes in the first 12 months following treatment compared with 1 year prior to gene therapy. Additionally, secondary efficacy end points included engraftment of gene-corrected cells, WAS protein expression, T-cell function, platelet count, autoimmunity and eczema over time. Safety end points included adverse events (AEs), immune response to transgene, development of replication-competent lentivirus (RCL), and abnormal clonal proliferation (ACP).^1,3,4 Results were published in medRxiv.⁵

Combined Trial Results

Across both trials, a total of 27 participants (TIGET-WAS: n = 8; OTL-103-4 n = 10; and expanded access program: n = 9) with a mean age of 2.6 years at the time of treatment were enrolled and treated (range: 1.0–35.1 years). Median follow-up was about 5.7 years (range: 0.4–13.3 years).⁵

The investigators observed an OS of about 96%. The rate of severe infections per person-year of observation (PYO) decreased from about 2.00 (95% CI: 1.50–2.61) pre-gene therapy to 0.15 (95% CI: 0.04–0.39) in the 6- to 18-month period following gene therapy. Also of note, the rate of moderate and severe bleeding events per PYO decreased from 2.00 (95% CI: 1.50–2.61) to 0.80 (95% CI: 0.49–1.22) in the 12 months after gene therapy. Following treatment with gene therapy, multilineage engraftment of gene-corrected cells was sustained over time and WAS protein expression in both platelets and lymphocytes increased. Platelet count, T-cell functionality, eczema, and autoimmunity improved in all participants.⁵

The most common grade 3 adverse event (AE) was device-related infection. Generally, etu-cel was well-tolerated with no treatment-related AEs and no evidence of insertional oncogenesis. Only 1 patient in the EAP died early post-gene therapy; however, this was a result of the deterioration related to a preexisting neurological condition.⁵

“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,” Vijay Kumar, MD, acting director of the CBER Office of Therapeutic Products, said in the news release. “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.”¹

REFERENCES

1. US Food & Drug Administration. FDA Approves First Gene Therapy Treatment for Wiskott-Aldrich Syndrome. News release. December 9, 2025. Accessed December 10, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-wiskott-aldrich-syndrome

2. Boston Children’s Hospital. Wiskott-Aldrich Syndrome. Accessed December 10, 2025. https://www.childrenshospital.org/conditions-treatments/wiskott-aldrich-syndrome

3. Gene Therapy for Wiskott-Aldrich Syndrome (TIGET-WAS). ClinicalTrials.gov identifier: NCT01515462. Updated April 4, 2025. Accessed December 10, 2025. https://clinicaltrials.gov/study/NCT01515462

4. A Clinical Study to Evaluate the Use of a Cryopreserved Formulation of OTL-103 in Subjects With Wiskott-Aldrich Syndrome. ClinicalTrials.gov identifier: NCT03837483. Updated September 29, 2025. Accessed December 10, 2025. https://clinicaltrials.gov/study/NCT03837483

5. Ferrua F, Cenciarelli S, Giannelli S, et al. Etuvetidigene autotemcel for the treatment of Wiskott-Aldrich Syndrome. medRxiv. 2025.11.25.25340584. doi:10.64898/2025.11.25.25340584