Gene Therapy's Safety Challenges Reshape Industry Economics and Development Strategies

In a rapidly evolving landscape, the gene therapy sector faces a critical juncture as safety concerns and economic realities collide, forcing companies to reevaluate their approaches to drug development and delivery. Recent setbacks have highlighted the need for innovative strategies to ensure both patient safety and commercial viability, with targeted delivery and human-relevant testing emerging as key focus areas.

Safety Failures Impact Bottom Line and Investor Confidence

The gene therapy industry has experienced a series of high-profile safety incidents, including patient deaths and clinical holds, which have had far-reaching consequences. These events have not only dampened investor confidence but have also triggered cascading effects across the sector, making capital harder to raise and putting entire programs at risk.

Sarepta Therapeutics, for instance, faced significant challenges when a patient died during a trial for their limb-girdle muscular dystrophy therapy, following two reported deaths of boys taking their approved Duchenne muscular dystrophy treatment, Elevidys. Such incidents have led investors to scrutinize not just individual assets but entire vector classes and delivery approaches.

The economic impact of safety failures in gene therapy is particularly severe. Unlike traditional small-molecule drugs, where adverse events might lead to dosing adjustments, a single safety incident in gene therapy can potentially destroy commercial viability. Regulatory delays can add years to development timelines and tens of millions in additional expenses, while payer resistance increases when safety profiles threaten to shift risk-benefit ratios.

Targeted Delivery and Dose Reduction: A Path to Safer, More Economical Therapies

Industry experts are increasingly advocating for a shift away from high-dose systemic delivery methods, which have been associated with off-target toxicity, liver damage, and harmful immune responses. Instead, they propose focusing on targeted delivery approaches, particularly for diseases affecting single organs.

Medera, a company co-founded by industry veterans with 55 years of combined experience in cardiac gene therapies, has demonstrated the potential of this approach. Their intracoronary delivery method has achieved therapeutic efficacy with approximately 100-fold less vector than IV approaches require, directly translating to improved safety profiles. Medera's approach is currently being deployed in three FDA-cleared trials with no gene therapy-related serious adverse events reported across all studies.

The benefits of targeted delivery extend beyond safety. Lower doses mean improved manufacturing scalability, with production capacity able to treat more patients at commercially viable cost levels. Clinical trial protocols can also be simplified, reducing the need for extended monitoring and potentially shortening hospital stays for patients.

Human-Relevant Models Gain Regulatory Support

Another critical aspect of improving gene therapy safety and efficacy is the use of human-relevant preclinical testing models. Traditional animal models often miss human-specific safety and efficacy signals, leading to expensive clinical failures. In response, the FDA is actively reshaping the preclinical landscape, moving away from mandatory animal testing and endorsing New Approach Methodologies (NAMs) such as human cell-based systems.

In April 2025, the FDA announced plans to phase out animal requirements for monoclonal antibodies and other drugs, with the goal of making animal studies the exception rather than the rule in preclinical safety testing. This shift is exemplified by platforms like Medera's patient-derived mini-Heart, which mimics human cardiac physiology and enables the identification of safety signals and optimization of dosing in a human context before trials begin.

As the industry adapts to these new approaches, companies that embrace organ-specific delivery, human-relevant models, and holistic safety design are positioning themselves to define the next generation of gene therapy. Those that continue pursuing mismatched delivery approaches may find themselves facing increasing scrutiny from investors and regulators alike.