Elivaldogene autotemcel (Eli-cel) for treatment of Adrenoleukodystrophy (ALD): Regulatory Update


- Eli-cel is a one-time investigational gene therapy for the treatment of Adrenoleukodystrophy
- Marketing Authorization Application is submitted to EMA for commercial distribution in EU
- Target  the BLA submission to the U.S. FDA for eli-cel in mid-2021.
Long-term results from Phase 2/3 Starbeam study (ALD-102/LTF-304) suggest durability of response post eli-cel treatment
- 31 out of 32 patients in ALD-102 had stable Neurologic Function Scores following treatment with Eli-cel 
- No reports of graft failure, graft rejection, graft-versus-host disease (GVHD), replication-competent lentivirus, or insertional oncogenesis

Adrenoleukodystrophy (ALD)

ALD is a rare, X-linked metabolic disorder that is estimated to affect one in 21,000 male newborns worldwide. ALD is caused by mutations in the ABCD1 gene that affect the production of adrenoleukodystrophy protein (ALDP) and subsequently cause toxic accumulation of very-long-chain fatty acids (VLCFAs) primarily in the adrenal cortex and white matter of the brain and spinal cord.

Approximately 40% of boys with adrenoleukodystrophy will develop CALD, the most severe form of ALD. CALD is a progressive neurodegenerative disease that involves the breakdown of myelin, the protective sheath of the nerve cells in the brain that are responsible for thinking and muscle control. Symptoms of CALD usually occur in early childhood and progress rapidly, if untreated, leading to a severe loss of neurologic function, and eventual death, in most patients. CALD is associated with six MFDs, which severely compromise a patient’s ability to function independently: loss of communication, cortical blindness, need for tube feeding, total incontinence, wheelchair dependence, and complete loss of voluntary movement. Nearly half of boys with CALD who do not receive treatment will die within five years of symptom onset.

Lenti‐D (ALD 102; ALD‐102; ALD102) is used in gene therapy, which involves harvesting CD34+ haematopoietic stem cells from the patient's bone marrow and inserting a healthy version of the disease‐causing gene (ABCD1). The cells are then grown in culture and administered back to the patient after myeloablative treatment. Lenti‐D is the lentiviral vector used to deliver the gene, which is self inactivating and incorporates safety elements to prevent creation of replication‐competent viruses and unwanted gene activation. This gene addition should result in the production of functional adrenoleukodystrophy protein (ALDP), a protein critical for the breakdown of very‐long chain fatty acids (VLCFAs). Build up of VLCFAs in the central nervous system contributes to neurodegeneration in adrenoleukodystrophy (ALD).

Regulatory Statu

The U.S. Food and Drug Administration (FDA) granted eli-cel Orphan Drug status, Rare Pediatric Disease designation, and Breakthrough Therapy designation for the treatment of CALD. bluebird bio is currently on track to submit the Biologics License Application (BLA) in the U.S. in mid-2021.

The European Medicines Agency (EMA) accepted the company’s marketing authorization application (MAA) for its investigational elivaldogene autotemcel (eli-cel, Lenti-D™) gene therapy for the treatment of patients with cerebral adrenoleukodystrophy (CALD).

The EMA accepted eli-cel gene therapy for the treatment of CALD into its Priorities Medicines scheme (PRIME) in July 2018, and previously granted Orphan Medicinal Product designation to eli-cel. In July 2020, the Committee for Medicinal Products for Human Use (CHMP) of the EMA granted an accelerated assessment to eli-cel, potentially reducing the EMA’s active review time of the MAA from 210 days to 150 days.

Clinical Study Update 

Starbeam Study (ALD-102)/Long-Term Follow-Up Study (LTF-304)
The ALD-102 study has completed enrollment of total 32 subjects with ALD. 

The primary efficacy endpoint in the study is the proportion of patients who are alive and free of MFDs at Month 24. Of those patients who have or would have reached Month 24, 87% have met the primary endpoint and continue to be alive and MFD-free at more than two years of follow-up (N=20/23). Fourteen patients have at least four years of follow-up, including 10 patients who have reached at least their Year 5 follow-up visit. The nine patients from ALD-102 that have not reached Month 24 have shown no evidence of MFDs.

Data on several secondary and exploratory efficacy outcomes are reported, including changes in neurologic function score (NFS), a 25-point score used to evaluate the severity of gross neurologic dysfunction across 15 symptoms in six categories; resolution of gadolinium enhancement (GdE), an indicator of active inflammation in the brain; and change in Loes score, an MRI measurement of white matter changes in CALD. Of the 32 patients treated, 31 had stable NFS following treatment with eli-cel, defined as NFS <4, without a change of >3 from baseline, and 24 patients maintained an NFS of 0. An NFS of 0 indicates that there are no concerns with the neurologic functions that are assessed on the 25-point scale. Loes scores generally stabilized within 12-24 months and GdE was no longer seen in most patients following eli-cel treatment.

The primary safety endpoint is the proportion of patients who experience acute (≥Grade 2) or chronic GvHD by Month 24. GvHD is a condition that may occur after an allo-HSCT, where the donated cells view the recipient’s body as foreign and attack the body. No events of acute or chronic GvHD have been reported post-eli-cel treatment. There have been no reports of graft failure or graft rejection.

In addition, there have been no cases of replication-competent lentivirus or insertional oncogenesis to date. Integration site analysis (ISA) was conducted to determine the pattern of integration of post-eli-cel infusion and assess whether dominant or expanding clones were present. In one patient, now enrolled in LTF-304 for long-term follow-up, a case of benign clonal expansion was observed with three separate integrations in the DNA of the cell at ACER3, RFX3, and MECOM. As of the patient’s Month 62 visit in March 2020, the patient remained clinically stable. Bone marrow analyses showed no dysplasia (abnormal cell growth) or molecular abnormalities.

The treatment regimen, comprising mobilization/apheresis, conditioning, and eli-cel infusion, had a safety and tolerability profile primarily reflective of the known effects of mobilization/apheresis and conditioning. In ALD-102, as previously reported, three adverse events (AE) were considered possibly related to drug product and include one serious AE (SAE), BK viral cystitis (N=1, SAE, Grade 3), and two non-serious AEs, vomiting (N=2, Grade 1). All three AEs resolved using standard measures.

ALD-104 Phase 3 Study

bluebird bio is currently enrolling patients for ALD-104, a Phase 3 study designed to assess the efficacy and safety of eli-cel in patients with CALD after myeloablative conditioning using busulfan and fludarabine, a different chemotherapy conditioning regimen than what is used in ALD-102 (busulfan and cyclophosphamide). The primary efficacy endpoint is the proportion of patients who are alive and free of MFDs at Month 24, and the primary safety endpoint is the proportion of patients with neutrophil engraftment after eli-cel infusion. All reported data below are as of February 2020.

In ALD-104, the 13 patients currently on study have a median of 6.1 months of follow-up to date (min-max: 2.2 – 10.3 months). All 13 patients achieved neutrophil engraftment and 12/13 evaluable patients had platelet engraftment (platelet engraftment pending in one patient as of data cut date). Due to the limited duration of follow-up, only safety data are being presented.

No events of acute or chronic GvHD have been reported and there have been no reports of graft failure, graft rejection, cases of insertional oncogenesis, or replication competent lentivirus.

The treatment regimen, comprising mobilization/apheresis, conditioning, and eli-cel infusion had a safety and tolerability profile primarily reflective of the known effects of mobilization/apheresis and conditioning. In ALD-104, two AEs of pancytopenia were considered possibly related to eli-cel. These two ongoing AEs were deemed as suspected unexpected serious adverse reactions (SUSARs) by the principal investigator and were diagnosed approximately two months post-eli-cel infusion in two patients (one Grade 2 and one Grade 3). An additional AE was ongoing as of February 2020, a Grade 3 SAE of transverse myelitis that was diagnosed in the presence of viral infection (adenovirus and rhinovirus/enterovirus positivity) approximately six months after eli-cel infusion and deemed unrelated to eli-cel.