HIGH IMPACT – After a full day of presentation and debates around the risk vs benefit of Bluebird Bio’s elivaldogene autotemcel (eli-cel) for the treatment of early active cerebral adrenoleukodystrophy (CALD), the FDA unanimously voted to endorse the gene therapy.

  • Initial concerns including malignancy with development of MDS, insertional oncogenesis, efficacy benchmarking, and long-term durability were released in the briefing documents a few days prior.
  • During the presentations, Bluebird Bio presented a strong case of unmet needs for CALD patients where there is not a matched sibling donor.
  • The company also argued the risk of MDS were more accepted among patients when compared to the negative impact on patients’ quality of life due to graft-versus-host disease from allo-HSCT treatment.
  • Bluebird Bio also proactively discussed risk mitigation strategies. While the company did not find any correlation between MDS and baseline assessments, Bluebird plans to perform monitoring for MDS with routine analysis every 6 months in a post-marking study REG-502.
  • Bluebird Bio also addressed the FDA’s concern for insertional oncogenesis head-on with a well-prepared safety presentation, highlighting that MDS was caused by lentiviral vector. The company emphasized that all lentiviral vector cause insertions mutagenesis, but not all lentiviral vector cause insertional oncogenesis.
  • The FDA discussion concluded that while the efficacy data has some problems with benchmark calculations and may be hard to interpret, the panel agrees that there is evidence for efficacy for eli-cel in a sub-population of CALD patients without matching donor and agrees to endorse eli-cel.
  • The FDA also agreed that a 2-year endpoint would be deemed reasonable to demonstrate efficacy and safety and post-marketing monitoring will be necessary.
  • The panel also discussed the overall safety of lentiviral vector and concluded in a 13 to 1 vote that the safety from lovo-cel for sickle cell disease is not relevant to the review of eli-cel.

inThought Analysis

The unanimous vote to endorse eli-cel for CALD, despite concerns over its efficacy and safety, may seem surprising especially given the recent FDA’s stringent attitude towards gene therapies. However, Bluebird Bio made a strong case for a sub-population of CALD patients with no matching sibling donors where patients do not have treatment options, or in the best-case scenario would likely face poor quality of life and prognosis due to graft-versus-host disease. This made the FDA’s concern for safety of eli-cel seem less impactful.
The favorable endorsement demonstrates that when a gene therapy is supported with irrefutable unmet needs, the FDA panel may be more lenient especially when the company takes actions to recognize shortcomings and address issues proactively.
The agency doesn’t always follow its advisory committee votes, but it typically does. eli-cel has a scheduled PDUFA date of September 16th, 2022 when the FDA will make its final decision.


Source: Bluebird Bio Press ReleaseFDA 72nd CTCTAC Meeting Day 1 Webcast