bluebird bio has created a gene therapy for the treatment of cerebral adrenoleukodystrophy (CALD), which is now making its way through a clinical development program. According to Businesswire, bluebird has released data from two studies: the Phase 3 ALD-104 trial and the Phase 2/3 Starbeam study. All research divulged to the public was presented at the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation.

About Adrenoleukodystrophy

Adrenoleukodystrophy (ALD) is a rare, genetic disorder that is characterized by damage to the myelin sheath, which is the protective covering around the nerve cells in the brain. Very long chain fatty acids are able to build up in the nervous system and adrenal gland, causing the characteristic symptoms of the disease. There are multiple forms of this condition, such as Addison’s disease, adrenomyeloneuropathy, cerebral ALD (CALD), and female ALD. CALD sees symptoms like seizures, hearing and vision loss, muscle spasms, progressive dementia, issues swallowing, crossed eyes, attention deficit disorder, progressive intellectual decline, aggressive behavior, and the additional symptoms that are seen in Addison’s disease.

These symptoms are the result of a mutated ABCD 1 gene, which is carried on the X-chromosome. Because of this, males are affected more often than females, as they do not have the extra X chromosome to mask the defective gene if it is inherited. The mutation stops the body from breaking down very long chain fatty acids, leading to an accumulation and the destruction of the myelin sheath. Current treatments for this condition are symptomatic and supportive, although there are possible therapies in various stages of the research process.

Data Presented

bluebird bio released data from two of their trials: the Phase 3 ALD-104 trial and the Phase 2/3 Starbeam study. Both investigate bluebird’s investigational elivaldogene autotemcel (eli-cell) gene therapy as a treatment for those living with CALD. Overall, the data was positive, showing that patients live without major functional disabilities (MFDs) for a substantial amount of time.

Looking towards bluebird’s gene therapy, we see that it is a one-time treatment that is intended to add two working copies of the ABCD1 gene into one’s hematopoietic stem cells using the Lenti-D lentiviral vector. If successful, this treatment can preserve neurological function by stabilizing disease progression.

Phase 2/3 Starbeam Study

32 patients were given eli-cell in this trial, 27 of whom completed the study and participated in the follow-up (LTF-304). Researchers focused on the primary endpoint of the study, which was to be alive and free of MFDs two years after treatment. This goal was met; no patients have shown any signs of MFDs after nearly seven years of tracking. Other results include:

• Gadolinium enhancement was resolved
• Improvements in neurologic function score
  • 23 patients maintained a score of 0 (no observed impairment), and all but one had a stable neurologic function score
• Improvements in Loes score
  • 26 patients had stable scores
• No cases of Graft versus Host disease, graft failure, graft rejection, replication-competent lentivirus, or insertional oncogenesis
• Three adverse events were reported, one of which was serious
• Overall safety and tolerability profile was found to be favorable

Phase 3 ALD-104 Trial

This study evaluated eli-cell’s effect on patients who were treated with a different chemotherapy regimen beforehand (busulfan and cyclophosphamide). The goal was the same as the Starbeam study: patients remaining alive and MFD-free after two years. In terms of the safety endpoint, researchers looked for the number of patients with neutrophil engraftment after treatment.

There has not been as much time for follow-up in this trial – 19 patients were treated and followed for 8.6 months – when compared to the Starbeam study, leading bluebird to only release safety data. Efficacy data will be added after there has been a substantial amount of time for follow-up. Data includes:

• 17 participants reached neutrophil engraftment
• 15 participants reached platelet engraftment
• No cases of Graft versus Host disease, graft failure, graft rejection, replication-competent lentivirus, or insertional oncogenesis
• The safety and tolerability profile matched previous research
• There were two serious adverse events, both patients are now clinically stable

Looking Forward

bluebird is excited by future research into this gene therapy, as current data shows that it has the potential to improve the lives of cerebral adrenoleukodystrophy patients. Find the source article here.