OTL-103 Gene Therapy Safe, Efficacious as Alternative Treatment for Children With Wiskott-Aldrich Syndrome


At ASCGT 2022, Italian investigators report updated safety and efficacy data from a phase 1/2 trial, in which all evaluable subjects achieved platelet transfusion independence and reported improved median platelet counts.

Gene therapy could prove an effective treatment option for children and adolescents with Wiskott-Aldrich Syndrome (WAS) who are ≥ 5 years of age, as those patients carry a higher risk of complications when receiving allogeneic hematopoietic stem cell transplantation (HSCT), the only current curative treatment option for the rare, X-linked, primary immunodeficiency and platelet disorder.

Italian investigators reported updated safety and efficacy data with up to a decade of follow-up from the phase 1/2 trial (NCT01515462) of OTL-103, an investigational autologous hematopoietic stem and progenitor cell (HSPC) gene therapy for the potential treatment of WAS, during a presentation at the American Society of Gene & Cell Therapy 25th Annual Meeting, held in Washington, DC, and virtually May 16-19, 2022.1

All evaluable subjects who received OTL-103, in development by Orchard Therapeutics, achieved platelet transfusion independence and reported improved median platelet counts, lead investigator Francesca Ferrua, MD, told CGTL in a video interview.

“We observed an increase in platelet counts that allowed patients to stop bleeding prophylaxis, mainly to become independent of platelet transfusion,” Ferrua, of the San Raffaele Telethon Institute for Gene Therapy at San Raffaele Scientific Institute in Milan, Italy, said. “Patients, during the follow-up, started to lead a normal life, so they do not bleed even if they perform sports or if they travel. They live as normal kids or adolescents.”

OTL-103 is created via CD34+ HSPCs transduced ex vivo with a self-inactivating lentiviral vector encoding human WAS cDNA under the control of an endogenous human WAS promoter. A total of 17 male subjects were treated in either the phase 1/2 trial (n = 8) or Expanded Access Program (EAP) (n = 9) with a median follow-up of 8.4 years (range: 5.2–10.5) in the trial and 3.3 years in the EAP (range: 0.4–4.9).

Median age for subjects receiving the gene therapy in the trial was 2.2 years (range: 1.1–12.4) and 3.8 years in the EAP (range: 1.4–35.1).

Pre-administration of the therapy, all participants received rituximab and reduced-intensity conditioning with busulfan and fludarabine.

“Sustained engraftment of genetically modified HSPCs resulted in WAS-[protein] expression restoration in lymphocytes and platelets,” investigators reported. “A reduction in severe infection rate was observed and all evaluable subjects stopped immunoglobulin replacement therapy and prophylactic antimicrobials, suggesting immune reconstitution and T-cell function normalization.”

The team also observed a reduction in bleeding rate and severity with no severe events > 6 months post-administration. One year pre-therapy, the rate of moderate and severe bleeding events per person-years of observation (PYO) was 3.4 (95% CI, 2.2–4.9) in the trial and 1.9 (95% CI, 1.1–3.0) in the EAP. Post-therapy (> 6 months), the rate of moderate and severe bleeding events per PYO was 0.1 (95% CI, 0.0–0.2) in the trial and 0.1 (95% CI, 0.0–0.4) in the EAP. Median time to platelet transfusion independence was 85 days post-gene therapy (range: 15–261) in the trial and 20 days in the EAP (range: 9–68).

Eczema, a common recurrence for patients with WAS, resolved in all evaluable subjects. The clinical benefits reported were similar in participants > 5 years of age.

Investigators have received no reports of adverse events (AEs) related to OTL-103, serious AEs, or signs of insertional mutagenesis or replication-competent lentivirus. One EAP patient died 4.5 months after receiving the therapy; however, the cause was determined to be deterioration of a pre-existing neurological condition that was unrelated to OTL-103.

“This safety and efficacy analysis of subjects treated with OTL-103 demonstrates the potential of [gene therapy] as an effective treatment for patients with WAS, including in those ≥ 5 years,” the research team concluded.

Ferrua F, Cicalese M, Giannelli S, et al. Up to 10.5 years of follow-up in 17 subjects treated with hematopoietic stem and progenitor cell lentiviral gene therapy for Wiskott-Aldrich syndrome. Presented at: American Society of Gene & Cell Therapy 25th Annual Meeting; May 16-19, 2022; Washington, DC. Accessed May 9, 2022. https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=4046
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