An experimental gene therapy could benefit young boys with a rare genetic disease, despite considerable concerns that treatment may cause cancer, a panel of Food and Drug Administration advisers unanimously agreed Thursday.
The therapy, an infusion of genetically modified stem cells called eli-cel, is designed to treat cerebral adrenoleukodystrophy, or CALD, which causes severe disability and death, typically in the second decade of life. It's the product of years of research by Massachusetts drugmaker Bluebird bio, which asked the FDA for approval last year.
At Thursday’s meeting, advisers wrestled with eli-cel's safety risks, most notably a bone marrow cancer that developed in three patients many months after treatment and was directly linked to the therapy in two. Ultimately, though, they found the evidence of eli-cel's effectiveness convincing, and emphasized the lack of alternative options for many CALD patients.
On the main question of whether eli-cel’s benefits outweigh its risks, the advisers voted 15-0 in support of Bluebird’s treatment.
"It would be exceedingly difficult, if not impossible, to find a patient population more excruciatingly and acutely aware of the risks involved in the treatment options available to us,” said Kirsten Finn, the mother of a boy with ALD. “The moral injury of not having this life-saving option to patients, parents and providers alike can neither be overlooked nor understated.”
The FDA is not required to follow its advisers’ advice, although it usually does.
Still, the unanimous vote is a boost for Bluebird, which is struggling to stay afloat amid rapidly dwindling cash reserves. The biotech company is counting on approvals for eli-cel as well as another gene therapy, beti-cel, for the blood condition beta thalassemia.
The same group of experts, which included physicians, stem cell specialists and researchers, will meet again Friday to discuss beti-cel. The FDA is expected to make a decision on approvals of beti-cel and eli-cel by Aug. 19 and Sept. 16, respectively.
While supportive of eli-cel’s benefit, advisers agreed the treatment case is strongest in people who don’t have a matched donor for a stem cell transplant. For others with a match, stem cell transplants can be effective and are the standard option.
“I think that those without a matched donor are the patient population for eli-cel,” said Tabassum Ahsan, vice president of cell therapy operations at City of Hope hospital in California. “For those who do have the potential for a matched donor, we should leave that option open to the clinician to do it on a case-by-case basis.”
The FDA estimates only about 30% of CALD patients have matched sibling donors, which lowers the risk the transplant will fail. Patients can also match with unrelated donors, but finding one through national registries takes time and is less likely for people who are Black or Hispanic, research shows.
“The current unrelated donor pool is not sufficient for all patients, particularly non-Caucasian ones,” said Christine Duncan, a physician at Boston Children’s Hospital who helped run one of the eli-cel therapies and presented for Bluebird.
Bluebird is seeking clearance in children younger than 18 without an available and willing matched sibling donor.
The unanimous vote Thursday contrasted with documents prepared by FDA scientists, which indicated the agency was skeptical of eli-cel’s efficacy and alarmed by its cancer risk.
Wilson Bryan, a top FDA gene therapy official, told the panel Thursday that eli-cel’s application was “particularly challenging due to issues with the evidence for effectiveness as well as our concerns regarding safety.”
Much of the meeting was dedicated to the latter issue and the way in which eli-cel may have triggered the bone marrow cancer, known as myelodysplastic syndrome or MDS, in three patients.
MDS can evolve into leukemia and is not typically associated with CALD, nor often seen in children. Bluebird presented data showing the modified virus it uses to engineer stem cells into eli-cel likely spurred those cells to cancerous growth later on.
The FDA indicated it thinks more cases might emerge among recently treated patients, noting genetic changes in other patients that could signal future cancer risk. Bluebird has also reported cases of leukemia and MDS in two patients treated with a related gene therapy for sickle cell disease, although they were not definitively linked to treatment.
“Given where we're at right now, [MDS] remains of concern but I still think that the benefit to eli-cel is greater,” said Nirali Shah, a pediatric oncologist at the National Cancer Institute.
Advisers agreed the sickle cell cases did not directly impact their decision on eli-cel. But they supported strong monitoring for MDS — “as tight as FDA can insist on,” said John Coffin, a molecular biologist at Tufts University.
While Bluebird awaits the FDA’s decisions, its financial situation has grown dire. Earlier this year, the company warned investors of “substantial doubt” it could remain solvent for the next 12 months and in April said it would lay off 30% of its employees.
Clearances for eli-cel and beti-cel would give Bluebird a chance to earn money from commercial sales, as well as from selling the special regulatory vouchers it’s likely to receive from an approval.
But neither drug is expected to become a top-seller. The pool of patients who would be eligible for eli-cel is tiny, and Bluebird expects to treat about 10 per year, according to company executive Laura Demopolous.
Bluebird estimates a larger, but still modest, number of between 1,000 to 1,300 patients with severe beta thalassemia who could receive beti-cel.
If approved, eli-cel and beti-cel would become the third and fourth gene therapies cleared in the U.S. for inherited diseases, after Roche’s Luxturna and Novartis’ Zolgensma.
Editor’s note: This story has been updated with additional detail and comment throughout.