Gene Therapy: Challenges and Regulatory Developments

posted in General Update

Our last gene therapy article highlighted several novel cures for rare, life-threatening illnesses using gene therapy technology. Many more treatments based on gene therapy are in the clinical trial phase. Despite the remarkable results thus far, significant challenges lie ahead. As with any new treatment modality, scientists must be cautious in their approach, carefully studying the potential side effects in the short and long term. Unlike conventional treatments, gene therapy research raises unique economic, distribution, and manufacturing concerns. Below, we will discuss the medical and social hurdles posed by gene therapy research and commercialization, and the nascent regulatory response underway to help move this new frontier of medicine forward in a safe and ethical manner.   

Health Risks

A prime example of the medical risks inherent in clinical research focused on a patient’s genetic makeup arose during the development of chimeric antigen receptor (CAR) T-cell therapy. In CAR T cell therapy, certain white blood cells called T cells, the body’s first line of defense against pathogens, are removed from the patient and genetically altered. Once infused back into the patient, the modified T cells can recognize and attack specific cancer cells. CAR T cell therapy was employed to develop Kymriah (tisagenlecleucel) from Novartis Pharmaceuticals Corporation to treat acute lymphoblastic leukemia (ALL), one of the most common childhood cancers. 

While Kymriah has been remarkably successful in treating this form of childhood leukemia, there are serious potential side effects, most notably the potential for cytokine release syndrome (CRS). CRS is a dangerous inflammatory response that ranges from mild flulike symptoms to multiorgan failure and even death. Physicians using Kymriah must be vigilant to monitor this response and address it immediately if signs of CRS arise. 

Researchers engaged in clinical trials using gene therapy also face other potential health risks. These include the possibility that gene therapy could cause allergic reactions, toxicity, immunogenicity, or even cancer or could damage organs or tissues during injection. While recent advances have made genetic therapies much safer, ongoing and long-term risks associated with newer gene therapy techniques are still under evaluation

Commercialization Hurdles

Once a gene therapy treatment is developed in the laboratory, life science companies face additional hurdles in the manufacturing and distribution process. In developing viral vectors to be introduced into a patient for treatment on a wider scale, companies must remain vigilant to ensure the purity and functionality of this unique product during commercialization

Commercialization of gene therapy treatments also poses non-medical challenges, most notably the cost of treatment. By way of example, Elevidys, an in-vivo gene therapy from Sarapeta Therapeutics approved by the FDA last year to treat pediatric patients with Duchenne muscular dystrophy, is expected to cost USD 3.2 million per patient. Roctavian, approved by the FDA to treat adult patients with severe Hemophilia A, has a price tag of approximately USD 2.9 million. Lenmeldy, a new gene therapy for the fatal genetic disorder metachromatic leukodystrophy, or MLD, is estimated to carry a wholesale price of $4.25 million

Of the 25 or so gene therapy drugs approved as of June 2023, the cost for each drug ranges from a few thousand to in excess of two million dollars. Demand for these new treatments is also likely to increase exponentially; it is estimated that more than one million individuals will be eligible for gene and cell therapy treatment within the next twelve years. The best way to pay for the treatment of eligible patients in the future continues to be a topic of intense discussion amongst employers, insurers, reinsurers, and society. 

Another societal issue raised by gene therapy centers around the types of treatments developed. Until recently, gene therapy drugs approved by the FDA primarily concerned rare diseases where death or serious debilitation was the outcome when patients were left untreated. More recently, scientists have been developing treatments addressing what many consider quality-of-life issues, where the risk-to-reward ratio may be lower. For example, Children’s Hospital of Philadelphia (CHOP) recently announced the initial results of an experimental gene therapy to treat an eleven-year-old born with hereditary hearing loss. The treatment allowed the child to hear sound for the first time, going from profound deafness in the treated ear to mild to moderate hearing loss. Despite the outcome, some in the deaf community have raised ethical concerns about what they consider treatment for a “genetic trait,” especially given the risks inherent in the delicate procedure of injecting the unmutated copy of the genetic recipe into a precise location in the inner ear. 

Regulatory Oversight

Of course, an assessment of the risk-to-reward ratio in approving a drug for commercialization remains, first and foremost, the province of the FDA. With the advent of gene therapy submissions in recent years, the FDA has established the Center for Biologics Evaluation and Research (CBER) to regulate cellular therapy products, human gene therapy products, and certain devices related to cell and gene therapy. CBER uses both the Public Health Services Act and the Federal Food Drug and Cosmetic Act as enabling statutes for oversight. In addition to regulatory oversight of clinical studies, CBER provides proactive scientific and regulatory advice to medical researchers and manufacturers engaged in novel product development. This includes the publication of guidance documents, including the recently issued “Human Gene Therapy Products Incorporating Human Genome Editing; Guidance for Industry,” 1/2024, and “Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products; Guidance for Industry,” 1/2024. 

In a further development, on January 8, 2024, the FDA announced the “Collaboration on Gene Therapies Global Pilot (CoGenT Global),” an initiative conducted in collaboration with the FDA’s global regulatory partners, including the World Health Organization and members of the International Council for Harmonisation (ICH), which includes the European Union (EU), Japan, Canada, and Switzerland. The initiative aims to explore the potential for concurrent, collaborative review of gene therapy applications on an international level. 

The Path Ahead

Fortunately, few personal injury claims have arisen from gene therapy to date. The few that have been reported generally center around the alleged failure of companies to comply with FDA regulations. One example is a personal injury lawsuit filed against Stemell, the manufacturer of a stem cell therapy treatment. Prior to the lawsuit, the FDA had sent Stemell a warning letter outlining the company’s failure to meet FDA requirements before administering an injection of stem cells into the plaintiff. As a result of the injection, the plaintiff allegedly suffered disfigurement to her temples, forehead, and scalp, eye pain and vision problems, eyelid ptosis, extreme fatigue, and elevated blood pressure. The case was reportedly settled before trial.

Despite the substantial risks inherent in gene therapy and the high cost of treatment when therapies are approved, clinical trials continue at a rapid pace. Careful research by scientists will likely result in the approval of multiple revolutionary, new gene therapy treatments in the next few years. For many, the treatments are lifesaving, such as the case of Lenmeldy. Physicians treated a young child with this new gene therapy to address a genetic defect the child’s parents were unaware of until she was tested, which surely would have led to her tragic death if not for gene therapy intervention. 

As aptly stated by the attending physician: “With this approval, we are now one significant step closer to ensuring future generations of children, families, and healthcare professionals no longer need to experience first-hand the terrible manifestations this disease has on untreated patients.” 

Authored by Maria-Cristina Smith, AVP, Products & Professional Liability Specialist

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