Capping AAV dose? Tweaking gene therapy trials? New animal models? FDA poses far-reaching questions for experts
Is it time to set a limit for how high a dose gene therapy developers and investigators are allowed to give patients in each trial?
That’s one of the questions the FDA is posing to its Cellular, Tissue, and Gene Therapies Advisory Committee as experts prepare for a two-day meeting next week. Depending on how the discussion goes — and what the agency makes of it — the results could completely redefine the rules for a major section of the booming gene therapy field: treatments that are delivered by adeno-associated virus vectors.
Coming in the shadow of preclinical red flags, safety alerts, clinical holds and patient deaths, the meeting is designed to go through any and all toxicity risks related to AAV. And the FDA wants to get input on how it should deal with each of those issues, with regulatory implications on everything from mouse studies to clinical trials to manufacturing standards.
So high are the stakes that BIO, the biotech trade group, is asking for more time to put together a full response to the meeting, which is scheduled for Sept. 2-3.
“The topics identified in the Federal Register Notice are key topics of interest to Sponsors,” reads a request posted online. “Given the importance of these topics, BIO respectfully requests a 60-day extension to the docket to allow commenting after conclusion of the meeting. Extending the deadline for comments to 60 days post-meeting will allow stakeholders to see the meeting materials, hear the discussion, and provide substantive comments to FDA for consideration.”
In a briefing document released ahead of the meeting, the FDA kicks off by noting just how big the space has grown: Between 2015 and 2020, CBER received 99 IND applications for AAV-based gene therapy candidates, and offered advice to an even larger group of drugmakers interested in starting a human study.
Yet as the number of trials ballooned, so did reports of serious side effects. It quoted a recent analysis pointing out that 35% of 149 AAV gene therapy trials had treatment-emergent serious adverse events, or TESAEs.
“These TESAEs include hepatotoxicities, thrombotic microangiopathies (TMA), and brain magnetic resonance imaging (MRI) findings of uncertain significance with some TESAEs resulting in the death of study subjects,” regulators wrote. “Other toxicities have largely been reported with AAV vector administration in animal studies. These include dorsal root ganglion (DRG) and peripheral nerve toxicities, which have primarily been characterized in nonhuman primates (NHP).”
Over five sections of the document, the FDA explored each of the safety concerns in greater detail and posed a set of draft questions to address them: Should animal studies be conducted differently, using different species, ages and models? Followed up for longer? How can patients be screened so that clinicians know their risk for developing, say, liver injury or neural damage? What kind of strategies can be deployed to mitigate those risks? Would giving other drugs help?
Then there’s the existential question:
Considering the risk of toxicities observed in clinical trials with high doses of AAV vectors,
a. please discuss whether an upper limit should be set for the total vector genome dose per subject.
b. given that many AAV products contain significant amounts of empty capsids, please discuss whether an upper limit should be set on the total capsid dose.
None of the concerns are new, to be sure. As early as 2018, gene therapy pioneer Jim Wilson had sounded the alarm on high-dose AAV after observing toxic reactions in monkeys — in one of the many studies quoted by the FDA. The field is still going through a reckoning in the aftermath of three patient deaths in a trial by Audentes, and safety is a constant talking point for a growing crew of next-generation startups promising to engineer their way out of the vector problems, as others propose somewhat more immediate solutions.
While acknowledging those advances in engineering, though, the FDA is clearly wondering if there is something intrinsically dangerous with AAV vectors.
Members of the advisory committee have likely run into these issues one way or another. Three of them — Roland Herzog at Indiana University, Kenneth Berns at the University of Florida and Charles Vite at the University of Pennsylvania — have declared conflicts of interest, either due to grants or stock holdings in affected companies. All were granted waivers to participate in the panel.
Social: AAV by Kateryna Kon/Shutterstock