Lenti-D Hematopoietic Stem Cell Gene Therapy Stabilizes Neurologic Function in Boys with Cerebral Adrenoleukodystrophy

Abstract

Cerebral adrenoleukodystrophy (CALD) is a rare metabolic disorder in which rapid and progressive inflammatory demyelination leads to irreversible loss of neurologic function and death. There is no approved treatment for CALD, although Lenti-D Drug Product (DP) is in development as an autologous hematopoietic stem cell (HSC) gene therapy. We have previously shown promising results from the ALD-102 clinical study of the safety and efficacy of Lenti-D DP in boys ≤17 years old with CALD; based on data from 29 patients, Lenti-D DP was generally safe and led to stabilization of disease progression. The primary efficacy endpoint in ALD-102 is the proportion of patients who are alive and free of major functional disabilities (MFD) at Month 24. The primary safety endpoint is the proportion of patients who experience acute (≥Grade 2) or chronic graft-versus-host disease (GVHD) by Month 24. ALD-102 has completed enrollment, with 32 boys having received Lenti-D DP as of April 2019. The median DP cell dose was 11.4 (min - max, 5.0 - 20.1) × 106 CD34 cells/kg; median DP vector copy number was 1.2 (min - max, 0.5 - 2.7) copies/diploid genome. Median day of neutrophil and platelet engraftment was 13.0 days (min-max, 11.0 - 41.0) and 32.0 days (min - max, 16.0 - 60.0), respectively. The median follow-up time for the cohort of 32 patients is 21.2 months (min - max, 0.0 – 60.2). Fifteen patients have completed 24 months of follow-up in ALD-102 and continue to be free of major functional disabilities (MFD) through their last follow-up in a long-term extension study. Fourteen patients remain in ALD-102; the longest follow-up among these patients is 20.4 months. Two patients were withdrawn and referred for allo-HSCT before their Month 24 visit; another experienced early and rapid disease progression while on-study resulting in MFDs and death. All other Lenti-D DP-treated patients showed stabilization of neurologic function score at their last follow-up (stable NFS was defined as NFS ≤4 without a change of >3 from baseline). There have been no reports of graft failure, GVHD, or transplant-related mortality; recorded adverse events are consistent with myeloablative conditioning. There is no evidence of replication competent lentivirus or insertional oncogenesis. Lenti-D DP appears to stabilize neurologic disease progression and continues to show favorable safety with the longest follow-up at 60.2 months. Additional follow-up is ongoing to assess durability of effects and long-term safety.