Phase 1/2 Trial Set to Test ASC618, Gene Therapy for Hemophilia A

The U.S. Food and Drug Administration (FDA) has approved ASC Therapeutics’ request to open a clinical trial in the U.S. into the safety and early efficacy of ASC618, its second-generation gene therapy for hemophilia A.

A Phase 1/2 trial (NCT04676048), set to start this month, will test the one-time therapy in up to 12 adults with moderate to severe hemophilia A. Contact information can be found here; enrollment sites have not yet been disclosed.

“FDA’s IND [investigational new drug] clearance of ASC618 is a significant endorsement of the discovery, pre-clinical, analytical, clinical, regulatory, quality, manufacturing, and overall capabilities of our organization,” Ruhong Jiang, PhD, ASC Therapeutics’ CEO, said in a press release.

“This milestone culminates our transformation into a clinical-stage gene and cell therapy biopharmaceutical company,” Jiang added.

The FDA previously designated ASC618 an orphan drug as a possible treatment for hemophilia A. This designation is intended to provide regulatory support and financial benefits to accelerate the therapy’s clinical development and review, and to ensure a seven-year period of marketing exclusivity in the U.S. upon regulatory approval.

Given as a single injection directly into the bloodstream, ASC618 uses a modified and harmless adeno-associated virus variant 8 (AAV8) to deliver a proprietary, bioengineered version of the F8 gene, which is mutated in this disease, specifically to patients’ liver cells.

Preclinical studies showed that the optimized F8 version in ASC618 increased the levels of blood clotting factor VIII (FVIII), which is missing in hemophilia A patients. It also did so at doses significantly lower than those used for gene therapies delivering the natural F8 version and currently being tested in clinical trials, the company reported.

ASC618 was reported to result in a 10-fold greater production and release (secretion) of FVIII, compared with the other gene therapy approaches.

As such, ASC618 might not only restore FVIII production, lowering both the risk of bleeds and the need for preventive FVIII replacement therapy, but also promote more durable effects by minimizing cellular stress in liver cells, which can lower FVIII production. Of note, the liver is the main producer of clotting factors in the body.

ASC618 was developed by drawing on work into a second-generation gene therapy for hemophilia A done by researchers at Emory University and optimized through a partnership between ASC Therapeutics and Expression Therapeutics.

The company conducted IND-enabling studies in several animal models, and also partnered with Vigene Biosciences to support the manufacturing process of its current and future gene therapy clinical platforms.

“ASC618 design provides a novel perspective to the field of hemophilia gene therapy,” said Steven Pipe, MD, PhD, the principal investigator of the upcoming trial. Pipe is a professor of pediatrics and pathology and the pediatric medical director of the hemophilia and coagulation disorders program at the University of Michigan.

“For the first time we will be able to investigate in a clinical setting the relevance of a novel bioengineered construct that has been proven in pre-clinical studies to significantly improve the biosynthesis, protein folding and secretion of factor VIII,” he added.

The clinical trial will evaluate the safety, tolerability, and preliminary effectiveness of ASC618 in adults with moderate to severe hemophilia A. Its main goal is to assess the number of adverse events and serious adverse events, while secondary goals include evaluating changes in FVIII activity, use of FVIII products, and bleeding rates, all at one-year post-dosing.

Top-line results are expected in 2023, and the trial is anticipated to end in July 2026.

ASC Therapeutics, a division of Applied StemCell, is also working on potential gene editing therapies for both hemophilia A (ASC518) and hemophilia B (ASC519).