Clinical deep dive 

WAS is a rare, X-linked, genetic disorder characterized by thrombocytopenia, eczema, immunodeficiency, and increased risk of autoimmunity and lymphoma/leukemia. Mutations in the WAS gene lead to a deficiency in the WASP, which is essential for proper functioning of certain blood cells. The spectrum of the disease depends upon the gene mutations and can range from a severe phenotype (classic WAS) to milder phenotypes (X-linked thrombocytopenia and X-linked neutropenia). Immune cells (T cells and B cells) that lack WASP have compromised immunological synapse formation, cell migration and cytotoxicity. As such, WAS leads to a decreased ability of immune cells to respond to the environment and fight infection and affects the formation of functional platelets. 

WAS is predominantly seen in boys. The incidence is approximately 4 in 1 million live male births in the U.S. The Wiskott-Aldrich Foundation reports that there are approximately 500 patients in the U.S. with WAS.  

HSCT, preferably within the first two years of life, is the standard of care (SOC) for WAS. It is a potential curative treatment if an adequate donor is available. Without HSCT, life expectancy of patients with a classic severe WAS phenotype is approximately 15 years. Other current treatment options are supportive and include administration of immunoglobulins, platelet transfusions or eltrombopag (Alvaiz, Promacta) to increase platelet counts, antibiotic and antiviral therapies to prevent infection, topical products to manage eczema and medications (e.g., rituximab) to manage autoimmunity.  

Drug and clinical trial overview 

Etuvetidigene autotemcel was studied in boys with severe WAS who do not have a suitable matched donor for allogeneic HSCT. Complete data from eight boys from the open-label, single-arm Phase 1/2 TIGET-WAS (NCT01515462) clinical trial and nine boys who received etuvetidigene autotemcel as part of an expanded access program (EAP) were analyzed. Etuvetidigene autotemcel was administered via a single IV infusion at a target dose of 5–10 × 10⁶ CD34+ cells per kg, with an acceptable range of 2–20 × 10⁶ cells per kg. All subjects received rituximab and reduced-intensity conditioning with busulfan and fludarabine prior to etuvetidigene autotemcel treatment. Patients who participated in the clinical trial were hospitalized for a median of 52 days (range, 36–82 days). Data revealed WASP expression was restored 3 months after administration of etuvetidigene autotemcel, as evidenced by increases in the fraction of WASP-positive lymphocytes and platelets, and response was maintained throughout the study follow-up. As platelet counts improved, frequency and severity of bleeding events declined. All subjects achieved platelet transfusion-independence and absence of severe bleeding by 9 months after the etuvetidigene autotemcel dose, and all evaluable patients discontinued immunoglobulin supplementation at a median of 0.9 years (range, 0.2–5 years) after the dose. A reduction in the rate of severe infections was also observed after administration of etuvetidigene autotemcel. At a median follow-up of 8.4 years (trial range, 5.2–10.5 years; EAP range, 0.4–4.9 years), overall survival was 94% – one patient in the EAP group died 4.5 months after the etuvetidigene autotemcel dose due to an unrelated underlying condition. No treatment-emergent adverse events (TEAEs) related to etuvetidigene autotemcel have been reported; however, mild to moderate TEAEs due to conditioning therapy were reported in most patients. 

An ongoing, open-label, single-arm Phase 3 trial (NCT03837483) is evaluating a cryopreserved formulation of etuvetidigene autotemcel in patients with WAS who do not have a matching donor for HSCT. Study completion is anticipated in 2027 (primary completion, September 2025).