Elivaldogene autotemcel

Elivaldogene autotemcel adds functional copies of the ABCD1 cDNA into patients' HSCs through transduction of autologous CD34+ cells with Lenti-D LVV. After elivaldogene autotemcel infusion, transduced CD34+ HSCs engraft in the bone marrow and differentiate into various cell types, including monocytes (CD14+) that migrate to the brain where they are believed to further differentiate into macrophages and cerebral microglia that can produce functional ALDP. The functional ALDP can then enable the local degradation of very long chain fatty acids (VLCFAs) in the brain, which in turn can stabilise the disease by preventing further inflammation and demyelination. However, it is not anticipated that elivaldogene autotemcel treatment will affect other manifestations of ALD including adrenal insufficiency. Impact of elivaldogene autotemcel treatment on adrenomyeloneuropathy has not been studied. Following successful engraftment with genetically modified cells, the expression of ALDP is expected to be life-long.

Pharmacodynamic effects

One month after elivaldogene autotemcel treatment, all evaluable patients in Study ALD-102 (N=25) produced ALDP in CD14+ peripheral blood cells with a median (min, max) CD14+ ALDP+ of 29.50% (8.20%, 49.65%) demonstrating early expression of the transgene. For patients with at least 6 months of follow-up, CD14+ ALDP+ cells generally declined slightly after elivaldogene autotemcel infusion and stabilized by approximately Month 6. Patients had a Month 6 median (min, max) CD14+ ALDP+ of 22.20 (2.00%, 71.40%) in Study ALD-102 (N=27).

The percentage of ALDP+ cells remained generally stable in CD14+ peripheral blood cells through Month 24 with a median (min, max) of 16.90% (5.80%, 44.60%) in Study ALD-102 (N=26). The percentage of CD14+ ALDP+ cells continued to be stable at last follow-up through Month 60, demonstrating long-term expression of transgenic ALDP in the progeny of haematopoietic stem cells.

Elivaldogene autotemcel is an autologous gene therapy medicinal product consisting of autologous cells that have been genetically modified ex vivo. The nature of elivaldogene autotemcel is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable.

Conventional mutagenicity, carcinogenicity and reproductive and developmental toxicity studies have not been conducted.

The pharmacology, toxicology and genotoxicity of the Lenti-D LVV used for transduction were evaluated in vitro and in vivo. In an in vitro immortalization assay, Lenti-D LVV-transduced mouse bone marrow cells showed strongly reduced mutagenic potential as compared to positive control vectors. Integration site analysis of pre-transplantation Lenti-D LVV-transduced human CD34+ HSCs demonstrated the expected self-inactivating LVV integration profile, with no enrichment for insertion in or near cancerrelated genes.

A pivotal GLP-compliant combined toxicity, genotoxicity and biodistribution study of Lenti-D LVV-transduced mobilized peripheral blood CD34+ HSCs was conducted in myeloablated immunodeficient mice. There was no evidence of toxicity, genotoxicity (insertional mutagenesis resulting in oncogenic mutations) or oncogenesis (tumorigenicity) related to Lenti-D LVV integration. Integration site analysis of post-transplantation bone marrow cells demonstrated no preferred integration in the proximity of or within cancer-related genes. An additional study with Lenti-D LVV-transduced human CD34+ HSCs administered to myeloablated, immunodeficient mice demonstrated engraftment of humanorigin microglial cells within brain tissues with no toxicity or tumorigenicity.