Lenti-D Hematopoietic Stem Cell Gene Therapy to Arrest Progression of Cerebral Adrenoleukodystrophy: Interim Results of an International Phase 2/3 Trial

In X-linked adrenoleukodystrophy (ALD), mutations in ABCD1 lead to loss of function of the peroxisomal membrane half-transporter ALD protein and toxic accumulation of very long chain fatty acids. Cerebral ALD (CALD) is characterized by demyelination and neurodegeneration with generally fatal outcome. Disease progression, leading to loss of neurologic function and death, can only be halted with allogeneic hematopoietic stem cell transplantation (allo-HSCT). We enrolled boys ≤ 17 years of age in STARBEAM, a single-arm, open-label, phase 2/3 study of the safety and efficacy of Lenti-DTM gene therapy for CALD. Patients were required to have low scores on radiologic and clinical measures (MRI Loes score between .5 and 9; Neurologic Function Score [NFS] ≤ 1), with active cerebral disease measured by gadolinium enhancement on MRI. Patients received myeloablative conditioning with busulfan and cyclophosphamide followed by intravenous infusion of Lenti-D drug product (DP), consisting of G-CSF (and plerixafor in 5 patients) mobilized autologous peripheral blood CD34+ cells transduced with the Lenti-D lentiviral vector (elivaldogene tavalentivec). Assessments included development of major functional disabilities (MFDs), changes in NFS and MRI lesion severity score, and mortality. As of August 2017, 17 patients had completed the primary 24-month analysis period (median 33 months follow-up, range 26 to 46 months) and an additional 4 patients had been treated (<4 months of follow-up). Most adverse events (AEs) were consistent with myeloablative conditioning. Three AEs were considered possibly or probably related to DP: BK-mediated viral cystitis (serious, grade 3), tachycardia (non-serious, grade 1) and vomiting (non-serious, grade 1). Following Lenti-D DP infusion, all subjects with evaluable data demonstrated neutrophil engraftment (N = 21; without G-CSF (N = 4), median Day +31, range +20 to +39; with G-CSF (N = 17), median Day +12, range +11 to +20) and platelet engraftment (N = 18; median day +28.5, range +16 to +55). There was no evidence of preferential integration near known oncogenes or of clonal outgrowth. Measurable ALD protein expression in peripheral blood was observed by month 2. No transplant-related mortality or graft failure were reported. At 24 months, 15 of the first 17 patients (88%) treated with Lenti-D DP remain alive and MFD-free with minimal clinical symptoms (NFS ≤ 1). Loes progression stabilized between 12-18 months in most patients. One patient had rapid neurological deterioration. Another patient with radiographic disease progression was withdrawn by the treating physician for allo-HSCT and later died of transplant-related complications. These results suggest that Lenti-D gene therapy may offer an alternative to allo-HSCT. Additional follow-up is needed to assess durability of efficacy and long-term safety.