Megan Brooks

April 28, 2016

VANCOUVER — Autologous hematopoietic stem cell (HSC) gene therapy may offer a safe and effective alternative to allogeneic bone marrow transplant for patients with cerebral adrenoleukodystrophy, according to interim results of a phase 2/3 study.

After gene therapy with Lenti-D gene therapy (Bluebird Bio Inc), most patients have had evidence of neurologic and radiographic disease stabilization and all are free of major functional disabilities (MFDs) at up to 2 years' follow-up in some patients.

Principal investigator Florian Eichler, MD, director of the Leukodystrophy Service at Massachusetts General Hospital, Boston, presented the data April 20 during a clinical trials plenary session here at the American Academy of Neurology (AAN) 2016 Annual Meeting.

"These are clearly exciting and promising results," Brendan Lanpher, MD, medical geneticist at the Mayo Clinic, Rochester, Minnesota, who wasn't involved in the study, told Medscape Medical News.

Made famous by the movie Lorenzo's Oil, adrenoleukodystrophy (ALD) is a rare, fatal, X-linked, inherited, neurodegenerative disease primarily affecting boys and characterized by the buildup of very-long-chain fatty acids that causes acute and progressive inflammatory demyelination in the brain.

The worldwide incidence rate for ALD is roughly 1 in 21,000 male newborns, with 30% to 40% affected by CALD, the cerebral form of the disease.

ALD is caused by mutations in the ABCD1 (ATP-binding cassette, sub-family D, member 1) gene located on the X chromosome. The phase 2/3 Starbeam Study is assessing the safety and efficacy of autologous CD34+ HSCs transduced ex vivo with a lentiviral vector (Lenti-D) delivering a normal functional copy of ABCD1. After modification, the cells are transplanted back into the patient following myeloablative conditioning.

"This is very similar to allogeneic bone marrow transplantation. The key difference is that we are not using allogeneic bone marrow as a donor but the boys' autologous cells," Dr Eichler said. "The eligibly criteria were identical to those that would be used for allogenic bone marrow transplantation."

Sustained Response

The primary efficacy endpoint for the study is the proportion of patients free of MFDs at 24 months. MFDs are 6 components of the neurological function score (NFS) that can have a profound negative effect on patients' lives: loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence, and complete loss of voluntary movement.

Secondary endpoints include Loes score (a method for quantifying demyelination and atrophy in patients with CALD using brain MRI), NFS (a scoring system assessing clinical deficits across 15 functional domains), gadolinium enhancement on MRI, and safety.

As of March 31, 2016, 17 patients with CALD had received the investigational Lenti-D gene therapy. They were aged 17 years or younger with evidence of active CALD (gadolinium enhancement), with early disease (an average baseline Loes score of 2 and neurologically asymptomatic at enrollment [NFS score of 1 or less]) and no matched sibling donor for bone marrow transplant.

All patients had at least 6 months of follow-up, and 8 patients had between 12 and 24 months of follow-up. Initial data from the 17 patients suggest that "early treatment with Lenti-D gene therapy may halt neuro-inflammation and demyelination in most CALD patients, with promising safety," Dr Eichler reported here.

At the interim analysis, all patients remain free of MFDs. Sixteen of 17 (94%) patients had NFS stabilization (change of less than 3 points and an absolute NFS score of 4 or less). "This is marked contrast to what is seen in the untreated condition" based on historical controls, Dr Eichler noted. "The vast majority of patients who are untreated develop [MFDs] within a year of onset of cerebral ALD," he said.

Fourteen of 17 (82%) patients had a stable Loes score (change of 5 or fewer points or an absolute Loes score of 9 or less).

"Our neuroimaging mirrored the clinical stabilization," Dr Eichler said. Sixteen of 17 (94%) had resolution of gadolinium enhancement by 6 months. Re-emergence of diffuse contrast enhancement was seen in 5 patients at 12 months, but 2 of these patients followed for at least 18 months showed resolution of gadolinium enhancement at month 18. "In all patients, the enhancement remains much less extensive compared to screening," Dr Eichler said.

Attesting to the impact of the treatment, the vector copy number was detectable in all patients in the study and persisted in peripheral blood up to the last follow-up period, Dr Eichler noted. "More importantly, ALD gene expression, which is the gene product, was detected in 20% of peripheral blood mononuclear cells at the 12-month period," he said.

The safety profile of Lenti-D gene therapy appears consistent with myeloablative conditioning, Dr Eichler said. Febrile neutropenia occurred in 13 patients (76%), stomatitis in 5 (29%), nausea in 3 (18%), vomiting in 2 (12%), decreased appetite in 6 (35%), and epistaxis in 2 (12%).

One possibly drug-related serious adverse event (grade 3 BK virus–mediated cystitis) and one possibly drug-related adverse event (grade 1 tachycardia) occurred. All adverse events resolved with standard measures.

There was no graft failure or graft-vs-host disease, no molecular evidence of clonal dominance or insertional mutagenesis, and no replication competent lentivirus detected to date.

The interim findings of the Starbeam Study support a proof-of-concept study reported in Science in 2009, in which two patients with ALD had stabilization of neurodegeneration 14 to 16 months after gene therapy.

"Exciting" Results in Unrelenting Disease

"This is typically a tragic and unrelenting disease with rapid progression from very nonspecific and subtle neurologic signs (like attention-deficit/hyperactivity disorder) to complete disability and death within months to just a few years," Dr Lanpher said. "The only current effective treatment is a stem cell transplant, which comes with significant life-threatening complications because of the imperfect match between the patient and the stem cell donor and the subsequent need for immune suppression."

With this gene therapy concept, he explained, "the patient's own bone marrow (stem cells) would be removed, treated to add a normal ABCD1 gene (the gene responsible for cerebral ALD), and returned to the patient. The patient's 'new' immune system would be identical to his or her old one with the exception of now having a normal copy of the gene. This should mean that patients would need much less (if any) long-term immune suppression," Dr Lanpher noted.

Still, "one should always be cautious with early results. While these results are extremely promising and the patients reported clearly have done much better than one would expect with untreated disease, the long-term efficacy of the treatment will only be clear with time," he said.

"The only downside to this treatment," Dr Lanpher added, "is that it requires early identification of the disease. Currently, that is only possible in families who already have had an affected child, so aggressive and early screening can find the patients before symptoms are progressed. If this treatment is confirmed to be effective and becomes available, the need for universal newborn screening for this disease will become even more imperative."

The Starbeam Study is sponsored by Bluebird Bio Inc. Dr Eichler consults for Retrophin, Alexion Pharmaceuticals, and Third Rock Ventures.

American Academy of Neurology (AAN) 2016 Annual Meeting. PL02.002. Presented April 20, 2016.

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