Gene therapies are advancing rapidly after a difficult start marked by serious adverse events. The first successful gene therapies were introduced in the early 1990s for the treatment of severe combined immunodeficiency (SCID) resulting from the lack of adenosine deaminase (ADA). However, gene therapy research was temporarily halted in the late 1990s after cancer developed in five European children receiving treatment for a different form of SCID and U.S. teen Jesse Gelsinger died from a fatal immune response to the viral vector used to deliver the gene therapy.
In the early 2010s, however, gene therapy research underwent a resurgence as a result of improved and safer viral vectors, and a better grasp on gene expression and control of genome integration. Since then, two gene therapies have received FDA approval for rare diseases: Novartis’s Zolgensma for spinal muscular atrophy and Spark Therapeutics’s Luxturna for an inherited retinal disease. While both Zolgensma and Luxturna demonstrated sufficiently favorable efficacy/safety benefits to gain approval and several hundred other treatments are in clinical testing or rapidly advancing towards the clinic for a variety of indications, concerns over safety remain.
Both Zolgensma and Luxturna–as well as many of the other gene therapeutics in development–use an adeno-associated virus vector (AAV) for delivery. While these therapies are offering important advances for difficult-to-treat or untreatable conditions, several adverse events–although many relatively rare–have been reported for AAV-based gene treatments as well as those employing other vectors. About a third of the 500 patients who have received Zolgensma since its approval have experienced liver-related adverse events, including one case of liver failure. Additionally, nine of more than 1,400 children receiving that gene therapeutic since clinical trials began have experienced thrombotic microangiopathy (TMA), a rare disorder that can cause low platelet counts, organ damage and, in some cases, death.
Safety issues have been reported across a variety of industry- and academic-sponsored trials for a number of different indications. Cases of TMA have occurred in trials of both Pfizer’s and Solid Biosciences’ treatments for Duchenne muscular dystrophy (DMD), and incidents of kidney damage have been noted by the FDA in unspecified DMD gene therapy trials. AAV-based gene therapies have caused significant increases in liver enzyme counts and, in some cases, liver damage across many other clinical studies, including four deaths resulting from liver failure in Phase 1/2 trials of AT132 by Astellas Gene Therapies. Neuronal loss has also been observed in NIH-sponsored AAV-based gene therapy trials for familial amyotrophic lateral sclerosis (ALS) and giant axonal neuropathy. Furthermore, in early November 2021, Pfizer halted screening and dosing in its Phase 3 gene therapy trial for hemophilia A after “multiple” patients experienced Factor VIII levels above 150% of normal, which is associated with an increased risk of thrombosis. To date, no actual thrombotic events have occurred, and the company is amending its trial protocol to provide guidelines for the management of elevated Factor VIII levels.
As a result of these and other safety concerns, the FDA decided to revisit its regulatory framework to better oversee the development of gene and cell therapies. In May of this year, the agency called for the development of methods to better demonstrate consistency in the characteristics of these often complex products. Consistency is an important attribute in determining and potentially limiting overall product safety risk. Characterizing the exact composition of gene therapy doses is frequently difficult, as a treatment can sometimes contain extraneous genomic material along with the therapeutic DNA. It is also difficult to evaluate potential toxicity, as no product reference standards currently exist. Besides the quality of the product itself, scaling manufacturing is rarely straightforward and can result in differences between clinical-scale and commercial-scale products. Indeed, Pfizer, Sarepta Therapeutics, and Bluebird Bio each had to align with the FDA on how to compare their intended commercial product with that made for early clinical trials.
In September of this year, the FDA held an Advisory Meeting of experts on Cell and Gene Therapy Safety to discuss some of the complex questions around these therapies, based on what has been learned from the development of Zolgensma and Luxturna. While the committee concluded that the technology around gene therapeutics is still rapidly evolving, making it too early to create specific recommendations on how best to evaluate potential risks, it also raised a number of complex questions for further consideration. In particular, these centered around the merits and limitations of preclinical animal testing for predicting toxicity and which animal models might be most useful, given that many animal results are ultimately found to be not applicable to humans. Other questions concerned how patients might be formally screened before treatment for risk of liver injury; whether there should be a stated limit on vector dosing; whether treated patients need to be monitored long-term for potential issues that could arise; and what other strategies might be used to reduce risks associated with a specific therapeutic.
On October 27, the FDA, the National Institutes of Health (NIH), 10 industry partners (including Pfizer, Johnson & Johnson, Spark Therapeutics, ReGen Bio, and the contract and development manufacturing organization Thermo Fisher Scientific), and five non-profit organizations took a step forward to address some of these concerns with the formation of the Bespoke Gene Therapy Consortium (BGTC). The aims of this group are to optimize and streamline the gene therapy development process, and to ultimately define a standard, more efficient development model and analytic tests for demonstrating manufacturing consistency for products that include AAV as a common gene therapy vector. A clinical component of the BGTC-funded research will support four to six gene therapy trials, each focused on a different rare disease. These studies will evaluate different types of AAV vectors, each previously employed in clinical trials, with the goal of shortening the path from animal studies to human trials. The BGTC will also explore ways in which the regulatory requirements and processes for the approval of gene therapies might be streamlined, including the development of standardized approaches to preclinical and toxicology testing. To fund the consortium’s research activities, the NIH and its private partners will contribute $76 million over the next five years, with slightly over half the amount coming from various NIH institutes.