Dark Horse Consulting Submits Guidance on Gene Therapy Safety

Dark Horse Consulting Group (DHC), based in Walnut Creek, CA, submitted proposed draft guidance to the U.S. Food and Drug Administration for gene therapy safety. Specifically, their proposed draft guidance was on “Testing of Adeno-Associated Viral (AAV) Vector-Based Human Gene Therapy Products for Empty Capsids During Product Manufacture.”

The FDA and drug developers have been grappling with increasing reports of safety issues in this space. Gene therapies are about as cutting-edge as biotechnology gets at the moment, and it’s relatively new. 

There has been a tendency to lump in gene therapies with cell therapies like CAR-T therapies. However, they are different from more straightforward gene therapies, such as Spark Therapeutics’ Luxturna (voretigene neparvovec-rzyl), used to treat patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy, which can cause blindness. While cell therapies typically use modified immune cells to treat cancers, traditional gene therapies use viral vectors to deliver genes to cells that then manufacture replacement proteins for the abnormal or missing genes.

However, in the last year or so, there has been an apparent surge in clinical holds placed on gene therapy-based clinical trials over safety concerns and, in some cases, patient deaths. Some of this may be that more and more trials are made up of cell and gene therapies. However, about 40% of the clinical holds in 2021 were for cell and gene therapy trials, although 50 to 60% of them were eventually lifted.

A September 2021 meeting of the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) noted that “In recent years … there have been multiple reports of treatment-emergent serious adverse events (TESAEs, serious adverse events that occur after treatment has started) in GT [gene therapy] studies with AAV vector-based products. These TESAEs include hepatotoxicities, thrombotic microangiopathies (TMA), and brain magnetic resonance imaging (MRIK) findings of uncertain significance with some TESAEs resulting in the death of study subjects.”

The FDA put out a call for proposed draft guidance. Dark Horse CEO Anthony Davies stated, “The FDA’s willingness to entertain draft guidance recommendations has been an underutilized opportunity to assist in furthering the guidance necessary for advancing this field. While discussing our collective response to last fall’s AdComm around high-dose AAV toxicity, we recognized that our expertise could be invaluable in moving this discussion forward.”

Dark Horse’s proposed draft guidance, submitted through the FDA's online submission platform, focuses on the criterion for empty AAV vector capsid impurity. They note, “If the FDA moves forward with guidance informed by this recommendation, the result will be a reasonable, achievable impurity limit that will maximize efficacy while minimizing adverse side effects.”

The draft guidance states, “It is considered likely the reported adverse events may be linked to patient total AAV capsid exposure. One potential contributor to the immunotoxicity observed is the presence of empty AAV capsids in the final gene therapy product. Empty AAV capsids are considered a product impurity as they do not carry genomic material intended to provide a therapeutic effect. This guidance provides sponsors of AAV vector-based human gene therapy products with the recommendation to establish a maximum release criterion for empty AAV capsids to better control immunogenicity that may be due to empty capsid product impurity and provide for improved product safety in the context of systemic administration.”

In previous guidance on Chemistry, Manufacturing, and Control (CMC) related to Human Gene Therapy Investigational New Drug Applications (INDs), the FDA outlined recommendations for manufacturing and control and impurities. DHC’s draft proposal expands on that guidance.