Updated Safety and Efficacy Outcomes from an Ongoing Phase 2/3 Trial of Lenti-D Autologous Hematopoietic Stem Cell Gene Therapy for the Treatment of Cerebral Adrenoleukodystrophy

Abstract

Objective Adrenoleukodystrophy (ALD) is an X-linked disease caused by dysfunction of ALD protein which results in the accumulation of very-long chain fatty acids in adrenal and nervous system tissues. Cerebral ALD (CALD), affecting 35-40% of boys with ALD, is characterized by inflammatory demyelination leading to progressive loss of neurologic function and death. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has a stabilizing impact on indices of cerebral disease progression, if performed early, but can be associated with significant risks. Methods Lenti-D Drug Product (DP) is an investigational gene therapy for the treatment of CALD. Boys with CALD (≤17 years) enrolled in an open-label phase 2/3 study (Starbeam) of the safety and efficacy of Lenti-D DP underwent full myeloablation and lymphodepletion followed by infusion of autologous CD34+ cells transduced with Lenti-D lentiviral vector (elivaldogene tavalentivec). The primary efficacy endpoint is the proportion of patients who are alive and free of major functional disabilities (MFD) at Month 24. The success criterion for the primary efficacy endpoint, defined from an observational study of the natural history of CALD and supported by outcomes of allo-HSCT, will be met for the first 17 patients enrolled in the study with a point estimate of ≥76.5% (95% CI, 50.1%-93.2%) MFD-free survival at Month 24. Results As of April 2018, 29 patients received Lenti-D DP (median follow-up 34 months, min-max, 0.4-54.0). The median DP cell dose was 11 (min-max, 5.0-19.4) x106 CD34 cells/kg; median DP vector copy number was 1.2 (min-max, 0.5-2.5) copies/diploid genome. Median day of neutrophil and platelet engraftment was 13.0 (min-max, 11.0-39.0) and 30.5 (min-max, 16.0-55.0), respectively. Of the 17 patients with evaluable data at Month 24, 15 (88%, 95% CI, 63.6%-98.5%) remain alive and MFD-free with evidence of disease stabilization. The remaining 12 patients have not yet reached 24 months of follow-up; median follow-up time for this group was 4.2 months (min-max, 0.4-11.7). As of April 2018, there was no evidence of MFDs in these patients. Overall, no graft failure, GVHD, or transplant-related mortality have been reported, and there is no evidence of replication competent lentivirus or insertional oncogenesis through 54 months of follow-up. Most adverse events were consistent with myeloablative conditioning. Conclusion Lenti-D DP met the threshold for primary efficacy success in the first 17 patients to complete 24 months of follow-up. The data presented here suggest that Lenti-D DP stabilizes neurologic disease progression and may offer an alternative to allo-HSCT in patients with early cerebral disease. The study has met its enrollment target and additional follow-up is ongoing to assess durability of effects and long-term safety.