An investigational gene therapy, elivaldogene autotemcel (eli-cel, Bluebird Bio), appears to hold at bay the devastating neurodegenerative disease cerebral adrenoleukodystrophy (ALD).  

Two years after receiving a single gene therapy treatment, there was no deterioration in 27 of 30 boys (90%) in a phase 2/3 study.

Longer-term follow-up also shows that the X-linked disease, which almost exclusively affects males, was held in check throughout 82.7 months (6 years, 10 months) of follow-up. There was no evidence of any of the six major functional disabilities (MFDs) that are the hallmarks of advanced cerebral ALD: loss of communication, cortical blindness, need for tube feeding, total incontinence, wheelchair dependence, and complete loss of voluntary movement.

The findings were presented by Jörn-Sven Kühl, MD, from University Hospital Leipzig, Germany, in a presidential symposium at the annual meeting of the European Society for Blood and Bone Marrow Transplantation (EBMT).

X-Linked Disorder

ADL is a rare X-linked metabolic disorder with an incidence of about 1 in 21,000 male newborns worldwide; females, once thought to be exclusively carriers, may develop symptoms later in life, but rarely develop the most severe cerebral form.

The disease is caused by mutations in the gene ABCD1, which encodes for production of adrenoleukodystrophy protein (ALDP). The impaired function of ALDP results in accumulation of very-long-chain fatty acids, primarily in the adrenal cortex and white matter in the central nervous system.

Cerebral ALD is marked by rapidly progressive inflammatory cerebral demyelination that, if left untreated, leads to the aforementioned major functional disabilities and death.

“Allogeneic stem cell transplantation is the currently the only treatment that — if performed at the early stages of cerebral ALD — improves survival. However, it has significant risks, such as treatment-related mortality, graft failure, and graft versus host disease,” said Kühl.

In contrast, autologous hematopoietic stem cell gene therapy appears to offer efficacy comparable to that of allogeneic transplantation, but without the associated immunologic risks, he added.

Co-investigator Christine Duncan, MD, from Boston Children’s Hospital, Boston, Massachusetts, said in an interview with Medscape Medical News that gene therapy to date has been a promising approach to preventing the devastating complications associated with cerebral ALD.

“We’ve seen the disease plateau and not progress in the way that you would expect it to do if you had a therapy that wasn’t working,” she said.

“For patients with this particular disease, it’s certainly rare, but it’s devastating and it’s devastating quickly, and so one of the advantages, I think, of an autologous therapy platform compared to allogeneic is the timing of the transplant. We talk about ‘time means brain’ when people have strokes, but in this disease that really is the case. Gene therapy allows us to move quickly,” she told Medscape.

Replacing ABCD1

The single-arm open-label ALD-102 (phase 2/3 “Starbeam”) trial and ALD-104 (phase 3) trials include patients who were 17 years or younger at the time of enrolment. All had evidence of active early cerebral disease as seen on gadolinium-enhanced MRI and scored according to the ALD disease severity measure called the Loes score (baseline scores of 0.5-9.0, with a score greater than 13 considered severe disease).

Patients undergo stem-cell mobilization with granulocyte-colony stimulating factor, with or without plerixafor, and then undergo hematopoietic stem cell (HSC) harvesting with apheresis.

In a central lab, CD34-positive cells are selected and transduced with a lentiviral vector (Lenti-D) encoding ABCD1 complementary DNA, and the cells are then infused into the patient. The transduced HSCs and progenitors, ideally, will engraft and differentiate into cerebral microglia expressing functioning levels of ALDP.

Kühl reported data on 32 patients enrolled in ALD-102, including the aforementioned 27 who met the primary endpoint of alive and free of MFDs at 24 months following a single infusion. These patients were also enrolled in LTF-304, a long-term follow-up study.

Two additional patients remained on study at the time of data cutoff, and three had discontinued, two at the discretion of investigators due to neuroimaging changes (these patients were referred for allogeneic HSCT). The remaining patient experienced early and rapid disease progression on study leading to multiple MFDs and death.

At the most recent follow-up there were no reported cases of grade 2 or greater acute or chronic graft versus host disease.

Following eli-cel infusion, 31 of the 32 patients enrolled in the ALD-102 and LTF-304 studies had stable neurologic function score (NFS). NFS evaluates severity of gross neurologic dysfunction in cerebral ALD by scoring 15 symptoms across the categories of hearing, communication, vision, feeding, locomotion, and incontinence.

Although Loes scores increase for 1-2 years after infusion, in 26 of the 32 patients the scores remained stable thereafter, and in some case declined.

At their last visit, 28 of the 32 patients (88%) had no evidence of active inflammation on gadolinium-enhanced MRI.

Three adverse events were considered to be possibly related to eli-cel: one case of grade 3 BK viral cystitis, and two cases of grade 1 vomiting.

Adverse events possibly related to eli-cel in ALD-104 were pancytopenia in two patients, diagnosed about 2 months after infusion. At the last visit, about 13 months after infusion, both patients had persistent low platelet levels.  In addition, one patient in this study had a grade 3 transverse myelitis of unknown origin.

Why Not Allo-HSCT?

In a discussion of presidential symposium abstracts, moderator Nicolaus Kröger, MD, from University Medical Center Hamburg-Eppendorf in Germany asked Kühl whether, given a survival rate of around 90% with allogeneic HSCT, there were any specific advantages to gene therapy with eli-cel.

“This is correct; with a matched donor there are survival rates of around 90%,” Kühl said.

He noted, however, that treatment-related mortality with allogeneic HSCT is still about 15%.

“From my personal view, I think that gene therapy is clearly something for these patients who lack well-matched donors,” he said. “It may not be for everybody, but at least these patients, who lack a matched marrow donor, should be potential candidates.”

Also, because with gene therapy the patient’s own stem cells are used, it requires a milder conditioning regimen than the aggressive chemotherapy needed when donor stem cells are used, even from a well-matched donor.

Kühl also noted that the patients in the gene therapy study all had early disease, because newborns in the US are now routinely screened for ALD. There is no transplant study that has enrolled comparable early patients.

“For this terrible disease, that should definitely be a goal: to discover patients early so that they can have therapy early on, and from my perspective it’s then not much a question of whether it’s transplantation or gene therapy. Early-on therapy is important, and for those who lack matched donors, gene therapy should be an option,” he said.

The study was funded by Bluebird bio Inc. Kühl disclosed consulting fees/honoraria from Bluebird, and travel grants from Jazz Pharmaceuticals and Neovii. Kröger has disclosed no relevant financial relationships.

European Society for Blood and Marrow Transplantation Annual Meeting: Abstract GS2-8. Presented March 15, 2021.

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