Quality Considerations for a Growing Gene Therapy Field

The approvals of Roche’s Luxturna® (2017) for inherited retinal disease and Novartis’ Zolgensma® (2019) for spinal muscular atrophy are indicative of a resurgence in the gene therapy field after a decline due to the death of a patient in 1999 (1, 2, 3).  The growth is reinforced by a 2019 US Food and Drug Administration (FDA) statement indicating that starting in 2020, the agency was expecting to see greater than 200 Investigational New Drug (IND) applications per year and projecting ten to twenty cell and gene therapies would be approved annually by 2025 (4).  Due to the “promise” of possibly being curative, gene therapies often receive expedited designations from regulators, including accelerated approval.  Shorter timelines for clinical trials means being ready earlier for later stage trial requirements and regulatory reviews.

Based on analyst projections, several gene therapies were expected to be approved in 2020.  Due to a variety of factors including the global pandemic, no gene therapies have been approved since 2019.  Gene therapy clinical trials have been put on hold and at least one Biologics License Application (BLA) received a response letter due to manufacturing issues.  Quality and regulatory aspects need to be considered and addressed, especially if changes have been made to materials, processes, and manufacturing locations between early and late stages.

One area to consider is your supply chain and the level of quality of your raw materials.  For viral vector manufacturing, plasmid DNA is a critical raw material.  Vendors offer multiple grade levels, including research-, high-quality- and GMP-grades.  Research-grade plasmid DNA is suitable for preclinical studies, but higher quality standards are necessary for material for in-human use. While “GMP-like” material may be acceptable for early phase studies, switching to GMP-grade plasmid DNA may require bridging studies to show comparability.  As processes are locked in, so too should be the raw materials.  Bringing in GMP-grade materials, including plasmid DNA, by Phase 1 studies will help remove additional steps that may slow down timelines.

Scaling up manufacturing processes between early and late-stage trials is not always straightforward.  Establishing critical quality attributes early, the analytical methods to measure those attributes and the manufacturing steps to ensure the final product will meet specifications are critical to safe and effective therapies.  For example, during the manufacturing of adeno-associated viral (AAV) vectors, different populations of capsids are produced:  full, containing the full gene of interest and empty, containing no DNA or DNA fragments.  Downstream processes are used to reduce the number of empty capsids and analytical methods are used to determine the effectiveness of those steps.  Aiming for a high percentage of full capsids improves potency, efficacy, and safety of AAV-based therapies.  Implementing manufacturing changes to reduce the number of empty capsids can mean fewer viral particles would be administered to patients, increasing safety.

Speed bumps in the road to success for new treatment modalities are not new.  During the development of monoclonal antibodies as therapies, there was a delay between the first approval in 1986 and the large amount of growth seen since the mid-1990s.  Manufacturing efficiencies and standardized processes have greatly impacted the success of the use of monoclonal antibodies in the treatment of diseases.  The gene therapy industry will likely see a smaller gap between the initial approvals and the steep increase in future approvals as manufacturing and analytical capabilities catch up to the expedited regulatory review timelines (5).

A partner like Catalent Cell & Gene Therapy, with proven experience in commercial manufacturing, including an EMA and FDA approved facility, can help innovator companies avoid Chemistry, Manufacturing and Control (CMC) issues.  We offer research-, high-quality- and GMP-grade plasmid DNA and help our partners develop scalable manufacturing processes for late phase and commercial needs.  We have analytical tools in place to assess critical quality attributes, such as using analytical ultracentrifugation for determining the full capsid percentage.  Ongoing evaluations of new technologies provide us with the opportunity to offer enhanced analytical methods to further support product quality measurements.  Catalent is committed to helping our partners get their advanced therapies to patients, faster.

References:

1:  https://www.fda.gov/news-events/press-announcements/fda-approves-novel-gene-therapy-treat-patients-rare-form-inherited-vision-loss

2:  https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease

3:  https://www.nytimes.com/1999/11/28/magazine/the-biotech-death-of-jesse-gelsinger.html

4: https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics)

5:  William Blair Industry Report: “Under the Microscope: does gene therapy represent the next revolution of biotech industrialization and commercialization?” June 2019

Luxturna is a registered trademark of Spark Therapeutics, Inc.

Zolgensma is a registered trademark of Novartis AG.