Amicus Therapeutics Inc.

Haichen Yang

Development Risk Voice

As a new modality, gene therapy offers great promise to develop effective treatments or potential cures for many serious diseases that previously had no meaningful treatment. While bringing new promises and opportunities, the field of gene therapy also faces a unique set of challenges. During the past few years, regulatory agencies worldwide have taken a very cautious approach regarding gene therapy approval, demanding additional pre-clinical work, safety assessments, and durability data. As a result, the gene therapy field has encountered some regulatory headwinds, with programs put on clinical hold and regulatory filings significantly delayed or denied. In the US, there was no gene therapy approval for three years after the first two approvals in 2017 and 2019.

However, 2022 was a banner year in gene therapy regulatory successes. Four gene therapy products, Roctavian, Upstaza, Skysona, and Zynteglo received regulatory approvals in the US and/or EU during the past few months. The fresh momentum came after many important changes were made on the industry side in response to global regulatory guidance. There is reason to believe that this momentum will be here to stay.

From the pipeline perspective, the field of gene therapy has been enjoying a rich and diverse collection of pre-clinical assets, in thousands by the recent count. Compared with small molecules, it’s relatively easy to construct promising gene therapy assets at pre-clinical stages. However, according to the newly published American Society of Gene and Cell Therapy (ASGCT) Q2 2022 report, merely a small percentage of pre-clinical gene therapy assets have moved into clinical development stages. Among those clinical-stage gene therapy assets, most are genetically modified cell therapies for oncology, and only a few are gene therapies in other major therapeutic areas (e.g., neurological, sensory, alimentary/metabolic). The scarcity of clinical[1]stage gene therapy assets is not just a temporary phenomenon. Rather, the transition of pre-clinical gene therapy assets into clinical stages became much harder due to safety concerns, manufacturing difficulties, and elevated complexities in clinical development. It’s very important to recognize this transition bottleneck. Solutions have to be developed in order to accelerate gene therapy drug development.

Challenges in Clinical Development Exacerbate this Bottleneck

Among regulatory concerns toward gene therapy clinical studies, safety issues related to this new modality have for years been a major factor in slowing down clinical development. Currently, hepatoxicity is the most common and significant safety risk associated with Adeno-associated virus (AAV) based gene therapy. While gene therapies have been credited with saving thousands of lives, there have been a few severe hepatoxicity cases resulting in several patients’ deaths, such as with Zolgensma treatment for spinal muscular atrophy (SMA) and in Audentes/Astellas’ AT132 gene therapy clinical trials for X-linked Myotubular Myopathy (XLMTM). 

Those incidences rightfully called for a thorough investigation. Careful monitoring should be enforced to minimize the safety risks in ongoing and future gene therapy clinical programs.

The elevated complexity of gene therapy clinical development poses another major challenge. There are disease-related complexities, partly because most gene therapies are being developed for rare disease indications, where we have limited clinical knowledge and experience. The natural history of those rare diseases may need to be better understood. In addition, diagnostic tools and/or diagnostic criteria are less defined. To make matters worse, clinical presentation varies greatly with the small but heterogeneous patient population. Some complexities are directly related to gene therapy, such as choices of administrative routes and immunogenicity. Finally, there are complexities related to clinical trial design and implementation, such as not well-established clinical endpoints, unreliable biomarkers, lack of clear controls to be used to demonstrate efficacy and safety, etc.

" The scarcity of clinical stage gene therapy assets is not just a temporary phenomenon. Rather, the transition of pre-clinical gene therapy assets into clinical stages turned out to be much harder, due to safety concerns, manufacture difficulties, and elevated complexities in clinical development "

More Focused Approach

Unlike small molecule & biologic, gene therapies primarily tackle a particular set of disease indications known to be caused by defective genes. Therefore, there is no need to screen large number of drug candidates to select potentially effective treatment for any particular disease. Moreover, the technologies used to fit a piece of the correct gene onto a vector are similar across a large variety of disease indications. As a result, many gene therapy start-up companies quickly developed platforms that produce many pre-clinical assets targeting various disease indications in a number of diverse therapeutic areas.

However, once those pre-clinical gene therapy assets move into clinical stages, each asset requires a clinical team that is knowledgeable and experienced in the particular disease area. The platform approach that works so well at the pre-clinical stages is no longer usable at the clinical stages. By underestimating the challenges of clinical development, gene therapy startups can be caught off-guard by the complexity of clinical development in diverse disease fields, realizing that their small clinical team can’t cover multiple therapeutic areas and is destined for failure. Many are forced to consolidate their overly ambitious pipeline and instead focus on narrow therapeutic areas.