Clinical Highlights: Echoes from the Future of Gene Therapy

What amazes most people about the ASGCT Annual Meeting is the progress each year towards a deeper understanding of the promise of gene therapy across patients and therapeutic areas and indications.

Just a few years ago, even some of the most clinically advanced programs were in the position of triangulating on therapeutic expectations for durable efficacy by using experience in preclinical models and a limited number of patients. Now, we are at the stage where many investigators are presenting multiple years of clinical data across dozens of patients. This is wonderful to see because at the heart of the goal for almost every gene therapy program is not just efficacy but durable efficacy for patients.

Preclinical Beginnings

Of course, the gene therapy community has benefited greatly from preclinical models. These models have been useful to guide initial clinical dose selection. But we all acknowledge that they are often imperfect models for all the complexities involved, including species differences in tissue tropism, transduction efficiency, immunogenicity, immune surveillance, clearance of transduced cells, gene pharmacology, disease progression, and more. As a result, calculations of clinical minimal effective dose for first-in-human testing are challenging to scale between animal models and humans. And until the challenges of re-dosing are addressed, we as a community are still tasked with using these limited data to impute a clinical dosing approach that provides not just safety for the patients in the trial, but also a benefit/risk profile with an expectation that their one-time therapy might limit their alternate options moving forward.

Furthermore, animal models are perhaps even more limited in understanding what to expect regarding inter-patient differences. Certainly, many of us have seen animal to animal variability in preclinical studies for which it has been difficult to account (e.g. was it due to pre-existing capsid immunity, genetic differences between animals, administration issues? etc). These data created further challenges to understand the risks to patients undertaking these therapies as it is unknown if animal non-responders should predict the same in the clinic, or if animal high-responders might suggest risks for supra-pharmacology in the clinic.

Clinical Present (and ASGCT Presentations!)

With all these unknowns, the community has come together annually, and, this year, virtually, for ASGCT’s Annual Meeting. It is here we unite to share and attempt to understand the successes, limitations, and failures in the field. I believe we all appreciate that we are still at the stage where individual clinical trial learnings can reveal novel lessons for the next R&D program and help to guide decisions on constructs, capsids, manufacturing approach, and more.

Having been in the role of gene therapy program lead, I know there are lots of venues where clinical results are shared. And sometimes, even if you can do this from your couch, as we did this year, it feels like a lot. However, I was thrilled to see the clinical updates at each of the AAV Clinical Study and Clinical Spotlight sessions. And I know that with the 800 applications on file at the FDA and 200 additional applications expected in 2020, the volume of this work will only grow further and deepen our experience as we as a community seek to do the best for patients. And while some of the learnings presented may be arguably disease-specific, many of the lessons of the field’s clinical endeavors will be shared across indications. And these clinical findings have previously and can continue to guide the goals of the new technological innovation in capsid engineering, payload/vector engineering, delivery approaches, immune modulation, and preclinical modeling; all of these topics are close to the heart of many ASGCT researchers.

The Future

As we look ahead to next year, one thing is certain. The depth of our clinical understanding of gene therapy will only grow. And if you are like me, you probably aspire to a 2021 ASGCT Annual Meeting with log-fold increase in the clinical highlight presentations as we move the field forward in addressing unmet patient need.

Emily Walsh Martin, Ph.D., is a principal at Tremont Therapeutics and a member of the ASGCT Communications Committee.

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