FDA Puts Hold on SIG-001 Phase 1/2 Trial for Hemophilia A
The U.S. Food and Drug Administration (FDA) has placed a clinical hold on Sigilon Therapeutics’ Phase 1/2 study evaluating the investigational therapy SIG-001 in adults with severe or moderately severe hemophilia A.
The move comes after a serious adverse event (SAE) occurred involving one of the three participants dosed thus far with SIG-001.
Sigilon submitted data to the FDA and other regulatory agencies regarding that SAE, which prompted the company to temporarily pause enrollment for the first-in-human trial (NCT04541628) of SIG-001.
The patient who received the highest dose developed inhibitors to factor VIII (FVIII) — the blood clotting protein delivered by SIG-001 that is missing in people with hemophilia A. Of note, inhibitors are antibodies generated by the body’s immune system targeting FVIII and reducing its effectiveness.
According to the company, this patient is responding to medical treatment and his health continues to improve. All other participants will remain in the study while Sigilon seeks to determines whether SIG-001 caused this particular SAE.
Meanwhile, the FDA also has requested additional information about this participant in an effort to identify potential factors that might have contributed to inhibitor development, such as a family history or a recent vaccination that might have stimulated his immune system.
The SAE investigation will be reviewed by the Safety Review Committee for SIG-001 — a panel of independent experts that monitors the safety and welfare of clinical trial participants.
“Patient safety is our top priority, and we are encouraged that the patient is recovering,” Rogerio Vivaldi, MD, president and CEO of Sigilon, said in a press release.
“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,” Vivaldi said. “We are committed to working with the FDA to resolve the clinical hold.”
SIG-001 is composed of human cells engineered to produce human FVIII. Thousands of cells are encapsulated in Sigilon’s proprietary Afibromer artificial biomaterials matrix, forming a dual-layer sphere, allowing for the influx of nutrients and the protein’s release.
These spheres are especially designed to minimize immune rejection and scar tissue formation (fibrosis) while remaining in the body to promote sustained FVIII release.
In a preclinical study, SIG-001 allowed for the continuous production of FVIII for more than six months in a hemophilia A mouse model. The investigational therapy also helped controlling bleeds in the animals, effectively reducing bleeding time and blood loss.
The Phase 1/2 trial is a dose-escalation study evaluating the safety, tolerability, and preliminary effectiveness of SIG-001 in up to 18 adults with severe or moderately severe hemophilia A without FVIII inhibitors.
The trial’s primary goal is safety, which will be determined by measuring the number and proportion of participants who experience treatment-related adverse events or SAEs.
Secondary goals include assessing the number and proportion of participants developing FVIII inhibitors, as well as the levels of FVIII in the bloodstream. The annualized bleeding rates also will be evaluated. The investigators also are noting the total number of FVIII replacement therapies administered overall.
Sigilon will continue to provide new information when available, the company said.