HIGH IMPACT – Small Pharma announced that the United States Patent and Trademark Office (USPTO) will be issuing a patent for its application pertaining to novel injectable formulations of N,N-dimethyltryptamine (DMT) based compounds including the company’s lead assets, SPL026 (DMT) and SPL028 (deuterated DMT). Additionally, the patent also covers novel injectable formulations of other known psychedelic compounds, including 5-methoxy-DMT and psilocybin. Read more

MODERATE IMPACT – The FDA placed a clinical hold on the FORTIS phase 1/2 trial of AT845 following a case of peripheral sensory neuropathy in one trial participant.

  • FORTIS is evaluating AT845, an investigational AAV8-based gene replacement therapy in adults with late-onset Pompe disease
  • To date, the serious adverse event (SAE) has been classified by the site investigator as Grade 1 (mild in severity) and deemed serious due to medical significance
  • The FDA informed Astellas that it did not have sufficient information to assess the risks to subjects and requires additional information about the SAE
  • A written explanation for the basis of the hold will be issued by the FDA and sent to Astellas within the next 30 days

inThought Analysis

Although Astellas’ AAV8 platform is currently the only clinical stage AAV-based gene therapy with the potential to deliver functional GAA in muscle (including skeletal and cardiac muscle), Astellas has had several recent setbacks that cast doubt on its ability to carry AT845 to the finish line. Earlier this year, Astellas terminated development for 3 gene therapy candidates for Duchenne muscular dystrophy. Last year, the FDA placed a clinical hold on Astellas’ trial for AT132 gene therapy for X-linked myotubular myopathy based on liver toxicity and patient deaths. Although AT845 uses the same vector platform as AT132, there has been no reports of significant liver toxicity with AT845. However, at WORLD Symposium 2022, 1 out of 3 treated patients had elevated transaminases. Also, liver toxicity in the AT132 trial was based on higher doses (≥1.3×1014 vg/kg) than what’s been tested in the FORTIS AT845 trial to-date (≤6.0×1013 vg/kg; a 1 x1014 vg/kg dose is planned). Thus, even if the clinical hold is lifted on FORTIS, safety concerns may remain.

MODERATE IMPACT – After a second day of presentations and discussions, the FDA has voted unanimously to endorse betibeglogene autotemcel (beti-cel) for the treatment of patients with beta-thalassemia who require regular red blood cell (RBC) transfusions.

  • Bluebird Bio presented a strong case for beti-cel in the treatment of beta-thal with emphasis on high transfusion-independent rate and 100% overall survival.
  • The FDA agreed that AE profiles were expected within the scope of the disease.
  • Concerns of longer engraftment time with beti-cel compared to allo-HSCT is not well understood.
  • The FDA did not believe SAEs and malignancies observed in Bluebird’s eli-cel and lovo-cel should impact the safety profiles for beti-cel, but recommends long-term monitoring.
  • Bluebird Bio continues to proactively recognize lentiviral vector insertions and acknowledge the need for follow-up.
  • The company will place all enrolled patients from beti-cel clinical trials on a long-term study with additional 13 years of follow-up.
  • Bluebird also plans to conduct a post-marketing registry, REG-501, to continue monitoring.
  • The FDA voted to endorse beti-cel for beta-thal treatment but also recommends specific testing including tracking transduction percentage, insertion integration sites, and using NGS to monitor driver mutations with established baseline.

inThought Analysis

The endorsement of beti-cel is within expectations. Bluebird Bio was able to convince the FDA AdCom Panel of beti-cel’s efficacy with strong supporting data. Safety concerns for beti-cel were not as prominent as eli-cel. Main issues of oncogenesis with insertion mutations were addressed during eli-cel’s AdCom yesterday. The PUDFA date for beti-cel is scheduled for August 19th, 2022 when the FDA will make its final decision.


Source: Bluebird Bio Press ReleaseFDA 72nd CTCTAC Meeting Day 2 Webcast

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

MODERATE IMPACT – Although no detailed data were provided, Alexion/AstraZeneca showed positive topline results for the phase 3 open-label CHAMPION-NMOSD trial for Ultomiris.

  • Ultomiris achieved a statistically significant and clinically meaningful reduction in the risk of relapse in adults with AQP4+ NMOSD compared to the external placebo arm from the pivotal Soliris PREVENT clinical trial.
  • Ultomiris met the primary endpoint of time to first on-trial relapse, as confirmed by an independent adjudication committee.
  • No relapse was observed in 58 patients over a median treatment duration of 73 weeks.
  • The safety and tolerability of Ultomiris in the CHAMPION-NMOSD trial were consistent with previous clinical studies and other approved indications.
  • Fifty-six patients are continuing to receive treatment in a long-term extension period, which is ongoing.

Full data will be presented at an upcoming medical meeting.

inThought Analysis

Another positive data read-out for Ultomiris, which will likely lead to a regulatory submission for Ultomiris in NMOSD. The trial design of the CHAMPION-NMOSD is interesting, since it has an historic placebo arm from the Soliris PREVENT trial. We don’t expect this to be a problem during regulatory submission, since this approach was likely discussed with the FDA before starting this pivotal trial. Approval can be expected in Q3 2023.


Source: AstraZeneca Press Release