Earlier this year, MedPage Today reported on an FDA advisory committee meeting in which it was unanimously recommended that two gene therapies be approved — betibeglogene autotemcel (beti-cel, Zynteglo) for patients with transfusion-dependent beta-thalassemia, a chronic inherited blood disorder; and elivaldogene autotemcel (eli-cel, Skysona) for select children with cerebral adrenoleukodystrophy (CALD). As part of our review of the year’s top stories, we follow up on what has happened since the panel’s vote.
In June, by a vote of 13-0, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee recommended approval of beti-cel for adult and pediatric patients with transfusion-dependent beta-thalassemia. The committee enthusiastically backed the therapy based on reports from two phase III trials in which 89% of patients achieved transfusion independence, with stable hemoglobin levels observed up to 7 years later.
The panelists supported the therapy despite some potential safety issues associated with beti-cel, such as delayed platelet engraftment, as well as the possible risk of future hematological malignancies.
The efficacy was “outstanding,” said committee member Jeannette Yen Lee, PhD, of the University of Arkansas for Medical Sciences in Little Rock, during the meeting. “The opportunity to be transfusion independent is really life-changing for the patients, and I felt the safety risks were definitely outweighed by the benefits.”
Two months later, the FDA approved beti-cel as the first gene therapy for the treatment of adult and pediatric patients with beta-thalassemia who require regular red blood cell (RBC) transfusions. However, the therapy comes with a high price tag, as the therapy’s developer Bluebird Bio set the wholesale acquisition cost in the U.S. at $2.8 million “in recognition of its robust and sustained clinical benefit demonstrated in clinical studies and its potential to alleviate a lifetime of healthcare costs associated with regular RBC transfusions and iron management.”
Research presented at the recent American Society of Hematology annual meeting provided further support of beti-cel’s efficacy.
During a press briefing, Franco Locatelli, MD, PhD, of the IRCCS Bambino Gesù Children’s Hospital in Rome, reported on 8-year follow-up results and patient-reported outcomes among 63 patients who received beti-cel across four studies (including the patients in the two phase III studies).
Of these 63 patients, 49 achieved transfusion independence, Locatelli said, and all 49 remained transfusion independent at 3 years.
In a separate analysis of health-related quality of life, 93.8% of patients were working or looking for work 3 years after receiving gene therapy, while 68.8% had been doing so before gene therapy. Among patients who were in school, 44.4% reported missing school due to their illness compared with 83.3% who had reported missing school before gene therapy. Eighty percent of patients reported improvement in physical activity at 3 years after gene therapy.
“Beti-cel is a potentially curative gene therapy for patients with transfusion-dependent beta-thalassemia across ages and genotypes through the achievement of transfusion independence and normal or near-normal hemoglobin levels,” Locatelli noted, adding that with this longer observation time, the data suggest “the therapeutic benefit is sustained over time.”
At the June meeting, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee also unanimously backed eli-cel for select children with CALD — a neurologically debilitating form of the disease that usually occurs in boys — arguing that the benefits outweigh the risks (including the possibility of malignancy).
By a 15-0 vote, committee members agreed that the therapy is best indicated in childhood CALD patients without an available and willing human leukocyte antigen (HLA)-matched sibling hematopoietic stem cell transplant donor.
The pivotal trial supporting eli-cel included boys with active early CALD and met its primary efficacy endpoint of improvement in major functional disability-free survival at 2 years. However, that success comes at the price of an increased risk of developing myelodysplastic syndrome.
However, that cancer risk “would be much more relevant in a population where there were other potential treatments,” said panelist Stephanie Keller, MD, of Emory University in Atlanta, who noted that as treatment options are limited for these patients, families may be more likely to tolerate the risks.
“This is such a devastating disorder,” Keller said, adding that while not a cure, the proposed gene therapy “at least gives these boys time until we can come up with something better.”
In September, Bluebird Bio announced that the FDA had granted accelerated approval to eli-cel to treat early, active childhood CALD in boys ages 4 to 17 years.
Like beti-cel, eli-cel is expensive, with a wholesale acquisition cost of $3 million.
“The agony of watching your child slip away is something no parent should have to bear,” said Elisa Seeger, co-founder of the ALD Alliance, in a statement released by Bluebird Bio in its approval announcement. “We have made significant strides in providing children diagnosed with CALD the best chance at life with early identification of ALD through expanded newborn screening. Yet with limited treatment options, early diagnosis is still cause for despair instead of hope for many families. Today, parents whose boys receive a CALD diagnosis can have renewed hope for the future.”