Accelerated Approval For Bluebird’s Skysona Gives Teeth To US FDA Data Questions
Executive Summary
Two required confirmatory studies will bolster application that relied on historical controls for orphan neurodegenerative disease.
The US FDA-approved labeling of bluebird bio’s gene therapy Skysona (elivaldogene autotemcel) stayed consistent with the agency’s position at a June advisory committee meeting, but with one notable twist: the gene therapy received accelerated approval, an option that was not mentioned in the committee briefing documents or meeting transcript.
Neuroscience is not a field that has had much use for accelerated approval, with Biogen, Inc.’s Aduhelm standing as a cautionary outlier. Nor has the Center for Biologics Evaluation and Research’s Office of Tissues and Advanced Therapies seen much use of accelerated approval for other cell and gene therapy products.
While the accelerated approval of the one-time gene therapy provides the FDA with stronger assurance that long-term post-marketing studies will be conducted than a conventional post-marketing requirement would, the agency also extended the scope of the indication beyond the original proposal.
Skysona is indicated to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy (CALD), without reference to the availability of the only other treatment available, allogeneic hematopoietic stem cell transplant (HSCT).
Bluebird bio had proposed use for early CALD patients under 18 years old who lacked a matched donor for allo-HSCT, a population that received unanimous support for approval from the FDA’s Cellular, Tissue and Gene Therapies Advisory Committee on 9 June, with more than half of the panel saying eli-cel also should be an option for CALD patients who have a matched HSCT donor who is not a relative. (Also see "Bluebird’s Eli-Cel Gene Therapy Gets US Panel Nod For Some Cerebral Adrenoleukodystrophy Patients" - Pink Sheet, 9 Jun, 2022.)
Skysona’s approval rests on evidence from two small single-arm trials – 32 patients from the Phase II/III Starbeam (ALD-102) trial and 35 patients in the Phase III ALD-104 trial – compared with a retrospective natural history study, ALD-103, that enrolled 59 patients who had received allo-HSCT in 2013 or later. The data was collected from existing medical records for patients with CALD, labeling reports.
The primary endpoint for the studies was an assessment of major functional disability (MFDs)-free survival at two years after treatment. The six MFDs associated with CALD progression, which include loss of communication, cortical blindness, requirement for tube feeding, total incontinence, wheelchair dependence, or complete loss of voluntary movement. CALD-specific neurologic function scales have been used in research for at least two decades.
“Skysona patients had an estimated 72% likelihood of MFD-free survival at 24 months,” bluebird bio summarized, “compared to untreated patients who had only an estimated 43 percent likelihood of MFD-free survival.”
The real-world evidence component of the BLA appears to have been a sticking point in the approval decision. “Following the AdComm and discussions with the FDA, we came to the agreement that the most expedient way to get this to patients was through the accelerated approval pathway with that two-year endpoint on MFD-free survival and follow-up the patients in both our clinical trials and commercially,” bluebird bio CEO Andrew Obenshain told a 19 September 2022 conference call.
The follow-up is intended “to confirm the durability, not necessarily the product as it was working but more so the comparisons with historical controls,” he said.
The advisory committee meeting highlighted FDA’s concerns with the possibility that changing medical practice around genetic testing and HSCT could render the RWE from historical controls less than ideally comparable. (Also see "RWE On The Runway: Trio Of Upcoming Approval Decisions Will Test US FDA’s Thinking On RWE For Efficacy" - Pink Sheet, 5 Sep, 2022.)
Skysona’s approval comes with two postmarketing studies required by accelerated approval. The first is similar to the post-marketing requirements for other gene and CAR-T therapies: at least 10 years of follow-up assessing event-free survival – an endpoint requiring patients to be alive without MFD or need for HSCT – in patients treated in the ALD-102 and ALD-104 trials.
The second required study will buttress the contemporary evidence base. The sponsor must track event-free survival for at least five years in 24 boys with advanced early active CALD who will be newly treated with Skysona.