Amicus Therapeutics Inc

Haichen Yang

A s 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 difficult challenges. During the past few years, regulatory agencies around the world have been taking very cautious approaches regarding gene therapy approval, demanding additional preclinical work, safety assessments and durability data. As a result, the gene therapy field encountered some regulatory headwinds, with programs put on clinical hold and regulatory filings significantly delayed or denied. There was no more gene therapy in the US approvals for three years after the first two approvals in 2017 and 2019.

However, 2022 turned out to be 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 made Haichen Yang on the industry side in response to global regulatory guidance. There is reason to hope 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 preclinical assets, in the thousands by recent count. Compared with small molecules, it’s relatively easy to construct promising gene therapy assets at preclinical stages. However, according to the newly published ASGCT Q2 2022 report, merely a small percentage of preclinical gene therapy assets have moved into clinical development stages. Among those clinical-stage gene therapy assets, most are genetically modified cell therapies for oncology indications, and only a minority are gene therapies in other major therapeutic areas (e.g., neurological, sensory, alimentary/metabolic). The scarcity of clinical-stage gene therapy assets is not just a temporary phenomenon. Rather, the transition of preclinical gene therapy assets into clinical stages turned out to be 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 to break it in order to accelerate gene therapy drug development.

“Unlike small molecule & biological, gene therapies primarily tackle a particular set of disease indications known to be caused by defective genes”

What challenges in clinical development exacerbate this bottleneck?

 Among regulatory concerns toward gene therapy clinical studies, safety issues related to this new modality have been major factors slowing down clinical development for years. Currently, hepatoxicity is the most common and significant safety risk associated with AAV-based gene therapy. While gene therapies have been credited with saving thousands of lives, there have been a few severe hepatoxicity cases that resulted 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 incidents 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 scarcity of clinical-stage gene therapy assets is not just a temporary phenomenon. Rather, the transition of preclinical gene therapy assets into clinical stages turned out to be much harder due to safety concerns, manufacturing difficulties, and elevated complexities in clinical development.”

Furthermore, the elevated complexity of gene therapy clinical development poses another major challenge. There are diseaserelated complexities, partly because most gene therapies so far are being developed for rare disease indications, and we have limited clinical knowledge and experience. The natural history of those rare diseases may not be well understood. In addition, diagnostic tools and/or diagnostic criteria are less well-defined. To make matters worse, clinical presentation varies greatly with the tiny but heterogeneous patient population. Some unique 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.

More focused approach

Unlike small molecule & biological, gene therapies primarily tackle a particular set of disease indications known to be caused by defective genes. Therefore, there is no need to screen a large number of drug candidates to select potentially effective treatments 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 startup companies quickly developed platforms that produce many preclinical assets targeting various disease indications in a number of diverse therapeutic areas.

However, once those preclinical 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 preclinical stages is no longer usable at 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.