Phase 1/2 Study of SIG-001 for Hemophilia A on Hold Following Serious Adverse Event

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Study enrollment has been paused following the development of antibodies in the highest-dosed patient.

The FDA has put Sigilon Therapeutics’ phase 1/2 study (NCT04541628) evaluating SIG-001, an encapsulated cell therapy for hemophilia A, on hold after a serious adverse event (AE) was reported.1

SIG-001 treats patients with cells that produce factor VIII, of which they are deficient. The cells are encapsulated to protect them from the immune system and prevent scar tissue from forming around them. The patient that received the highest dose of the 3 patients treated so far developed antibodies that inhibit factor VIII, a well-known complication of factor VIII infusions.

“In collaboration with the regulatory agencies and our advisors, we are conducting a thorough investigation of this event to confirm whether there was a causal relationship between the development of inhibitors and SIG-001,” said Rogerio Vivaldi, MD, chief executive officer, Sigilon Therapeutics, in a statement.

Sigilon Therapeutics alerted the FDA to the AE and has temporarily halted enrollment in the study. They are investigating possible reasons why the patient may have developed antibodies, including family history and recent vaccinations that may have altered immune responses.

READ MORE: In-Human Gene Therapy BAY 2599023 Effective in Patients with Severe Hemophilia

Amid this pause in enrollment for Sigilon, the pipeline for hemophilia A has shown signs of activity in recent months. Another agent, BioMarin’s gene therapy treatment, valoctocogene roxaparvovec (BMN 270), received regenerative medicine advanced therapy (RMAT) designation from the FDA in March 2021.

The company had previously received a complete response letter from the FDA in August 2020 for the treatment. The agency requested long-term data from the single-arm phase 3 GENEr8-1 study to further establish the efficacy of the therapy on annualized bleeding rates (ABR) at 2 years post treatment. In early January, BioMarin released data from a mean 71.6-week follow-up indicating an ABR reduction from baseline of 84% with valoctocogene roxaparvovec.

The follow-up data also showed that patients experienced 4.8 annualized bleeds at baseline compared with 0.8 post-infusion with valoctocogene roxaparvovec, representing a statistically significant improvement (P <.0001). In a pre-specified observational rollover group (n = 112), 80% were bleed-free by week 5. In this group, mean annualized factor VIII was reduced by 99%, from an annualized rate of 135.9 to 2.0 infusions per year (P <.0001).

At 1-year post-infusion with valoctocogene roxaparvovec in the rollover group, the median factor VIII expression level was 24.2 UI/dL and the mean was 43.6 UI/dL. In a subset of HIV-negative patients dosed 2 or more years prior to the data cutoff, the median factor VIII expression level was 23.9 IU/dL at week 52 and 14.7 IU/dL by week 104. The mean was 42.2 IU/dL at week 52 and dropped to 24.4 IU/dL at week 104; however, there was 1 patient who was lost to follow up at 2 years who was calculated as 0 at the week 104 analysis. This group of patients maintained a mean ABR of 0.9.

"We are encouraged that the FDA granted RMAT Designation to valoctocogene roxaparvovec. This designation confirms our belief in this treatment's potential to address unmet medical needs for people with hemophilia A at this time," said Hank Fuchs, MD, president of Worldwide Research and Development, BioMarin, in a statement at that time.

"We look forward to continuing a productive dialogue with the FDA around the RMAT designation, which provides options for the agency to leverage data post approval, while also recognizing the agency's initial request to see 2 years of data from the phase 3 study to evaluate the safety and efficacy of this investigational treatment option that could potentially provide a transformational treatment choice for the hemophilia community,” he continued.

REFERENCES
1. FDA puts Sigilon's hemophilia cell therapy trial on hold thanks to safety concerns. News release. Sigilon Therapeutics. July 9, 2021. https://www.fiercebiotech.com/biotech/fda-puts-sigilon-s-hemophilia-cell-therapy-trial-hold-thanks-to-safety-concerns
2. RMAT designation granted by FDA during bleeding disorders awareness month. News release. BioMarin. March 8, 2021. Assessed July 13, 2021. https://investors.biomarin.com/2021-03-08-BioMarin-Announces-FDA-Regenerative-Medicine-Advanced-Therapy-RMAT-Designation-Granted-to-Valoctocogene-Roxaparvovec-Investigational-Gene-Therapy-for-Hemophilia-A
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