Eli-cel Gene Therapy Continues to Show Encouraging Results for Boys with CALD, Clinical Data Show

Eli-cel Gene Therapy Continues to Show Encouraging Results for Boys with CALD, Clinical Data Show

Data from the Starbeam Phase 2/3 trial continues to support the safety and effectiveness of the gene therapy candidate elivaldogene autotemcel (eli-cel, formerly known as Lenti-D) for the treatment of cerebral adrenoleukodystrophy (CALD), Bluebird Bio announced.

About 87% of patients treated with eli-cel are alive and free of major functional disabilities two years after treatment. Moreover, patients’ neurological function has stabilized, suggesting the gene therapy may halt neurological decline.

The latest trial results were presented by Jörn-Sven Kühl, MD, from the Center for Women’s and Children’s Medicine, University Hospital Leipzig, Germany, during a presentation titled “Lenti-D hematopoietic stem cell gene therapy stabilizes neurologic function in boys with cerebral adrenoleukodystrophy” at the virtual 46th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT 2020).

“These results presented at EBMT 2020 are very encouraging and suggest treatment with eli-cel may prevent neurological decline in boys with CALD,” Kühl said in a press release.

CALD is the most severe form of adrenoleukodystrophy and it primarily affects young boys. Mutations in the gene ABCD1, which provides instructions for making the protein ALD, cause the disease. The mutations disrupt ALD activity, leading to the buildup of specific toxic molecules in the brain.

Bluebird’s eli-cel is a cell-based therapy candidate that uses patients’ own stem cells, collected from the bone marrow, which are then modified in the lab so that they no longer carry the mutated ABCD1 gene, but rather a working version of the gene.

The genetically modified stem cells then are infused back into the patient, in a single infusion, where they can mature into working cells capable of producing the ALD protein.

Eli-cel’s safety and efficacy is being investigated in: the Starbeam Phase 2/3 trial (ALD-102, NCT01896102), its long-term extension study that follows treated patients for up to 15 years (NCT02698579), and the ALD-104 Phase 3 trial (NCT03852498).

In total, the Starbeam study enrolled 32 boys 17 or younger who were followed for a median of 30 months (ranging from 9.1 to 70.7 months).

As of January, 20 patients have completed the trial and moved on to the long-term extension study. Nine patients, who have yet not reached 24 months post-treatment, continue to be followed, and two withdrew from the study (one died).

The trial’s main goal was to assess the proportion of patients alive and free from major functional disabilities (MFDs) by month 24. MFDs are severe complications that can result from CALD, including inability to communicate, wheelchair dependence, and need for a feeding tube.

Results showed that out of 23 assessed patients, 20 (87%) are alive and none showed evidence of MFDs after 24 months, including 10 patients followed for five years. Also, none of the nine patients still being followed in the trial have shown signs of MFDs.

Further efficacy analyses showed that 31 of the 32 treated patients maintained their neurologic function score (NFS) following treatment with eli-cel, including 24 patients with a score of zero as of the last available visit.

NFS is a 25-point score scale that evaluates the severity of gross neurologic dysfunction, in which a score below four means stability on symptoms, and a score of zero indicates no concerns with neurologic functions.

“Patients with CALD experience a rapid decrease in neurologic function after the initial onset of clinical symptoms … In the Phase 2/3 Starbeam study, 31 of 32 patients had a stable neurologic function score, suggesting that disease progression had stabilized and minimal neurological function was lost, following eli-cel infusion,” Kühl said.

Changes in the brain’s white matter generally stabilized within 12–24 months, and active brain lesions resolved in most patients after treatment.

To date, no cases have been reported of acute or chronic graft-versus-host disease (GvHD), — a serious adverse reaction that can occur when the body rejects transplanted cells — failure or rejection of the engraftment following eli-cel treatment.

“Eighty-seven percent of patients in our Phase 2/3 Starbeam study of eli-cel are alive and free of major functional disabilities (MFDs) at 24 months or more of follow-up. Importantly, there were no reports of graft failure, graft rejection, or GVHD. It is gratifying to see the consistent outcomes with eli-cel and the durability of the treatment effect demonstrated in the children participating in our long-term follow-up study,” said David Davidson, MD, chief medical officer, Bluebird Bio.

Additional safety analysis revealed no insertion of genetic alterations that may prompt abnormal cell growth as a result of the genetic manipulation of patient’s stem cells. Also, the modified harmless virus used to deliver the working version of the ABCD1 gene remained replication-incompetent (meaning, unable to replicate).

During the trial, three treatment-related adverse events (side effects) were reported, including a severe (grade 3) case of BK viral cystitis, a common clinical problem in bone marrow transplant recipients, and two cases of mild (grade 1) vomiting. All three cases were resolved following standard measures.

The ALD-104 study is still recruiting participants, boys, up to 17 years old. The study will evaluate the safety and effectiveness of eli-cel, given after a preconditioning chemotherapy regimen with busulfan and fludarabine. Commonly administered to patients before a stem cell transplant, the chemotherapy regimen aims to enhance the transplanted cells’ survival and proliferation after infusion.

As of February, 13 patients have been infused and followed for a median of 6.1 months (range 2.2 to 10.3 months). Safety analysis revealed that all patients increased their number of neutrophils — the most common type of immune white blood cells — and 12 patients had an increase of platelets, two standard parameters used to assess the safety of the transplant. Efficacy data is pending on longer follow-up.

To date, no cases have been reported of acute or chronic GvHD, transplant failure or rejection.

Possible treatment-related adverse events include two cases (one moderate and one severe) of pancytopenia, which is a condition characterized by low counts for all three types of blood cells: red blood cells, white blood cells, and platelets.

A third adverse event included a case of severe inflammation of the spinal cord (transverse myelitis) accompanied by a viral infection. This event was deemed unrelated to eli-cel treatment.

The European Medicines Agency (EMA) recently accepted an application requesting the approval of eli-cel to treat CALD. According to Bluebird Bio, a similar application will be submitted to the U.S. Food and Drug Administration by mid-2021.