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.^1–3 This growth is reinforced by a 2019 U.S. 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 that 10–20 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.

2020: A Speed Bump for Approvals

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 were approved in 2020. COVID-19, in addition to delaying enrollment in some trials, impacted the FDA with the influx of vaccines and treatments for COVID that required review. In addition to less review time for gene therapies, the FDA’s Director Peter Marks, speaking at the Alliance for Regenerative Medicine’s Meeting on the Mesa in October 2020, indicated that manufacturing is “a rate-limiting” step for their approval.⁵ 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.

Challenges Not Surprising for New Modalities

Speed bumps in the road to success for new treatment modalities are not new. Looking back at the development history of monoclonal antibodies, 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.⁶ 

Supply Chain Quality Considerations

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 I studies will help remove additional steps that may slow down timelines. 

And what about your manufacturing process? If your discovery and preclinical work included material made in adherent cells, do you see a clear path to scaling up or scaling out the process for large scale studies and commercialization? Early decisions on staying with adherent processes for clinical material or converting to a suspension culture–based process can help establish a reliable supply chain. It is important to build relationships with vendors that have the necessary quality and supply management systems in place to assure that critical items, such as cell stacks, bioreactors, bags, media, and other consumables, are ready when you need them. Planning for raw materials, consumables, and optimized processes is key to keeping up with the accelerated timelines facing gene therapies.

Addressing Quality Attributes and Regulatory Expectations

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 can 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. 

Establishing a manufacturing and testing plan early, prior to phase III studies, can help address potential missteps and avoid associated delays. When building the plan, referencing FDA guidance documents will help you understand the information that is expected in the chemistry, manufacturing, and controls (CMC) section of your submission and what is necessary for changes made after the initial submission.⁷ In addition to manufacturing aspects, early planning for supplying the finished therapies to the clinical trial sites is critical and should include packaging, labeling, kitting, and delivery. There are regulatory expectations for handling of the product at the clinical sites that need to be considered. From raw materials and supply chain to manufacturing and clinical trial site logistics, the path to the patient can be overwhelming. Early planning is key to successfully managing the path.

Partners Supporting Growth

A partner like Catalent Cell and Gene Therapy with proven experience in commercial manufacturing, including an FDA-licensed facility, can help innovator companies avoid 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 Clinical Supply Services supports planning and forecasting, packaging solutions, distribution, and logistics for clinical trials. Our regulatory experience, including successful inspections, can help our partners avoid delays due to CMC issues and clinical supply. Catalent is committed to helping our partners get their advanced therapies to patients, faster.

References

1. FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss. U.S. Food and Drug Administration. 18 Dec. 2017.
2. FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality. U.S. Food and Drug Administration. 24 May. 2019.
3. Stolberg, Sheryl Gay. “The Biotech Death of Jesse Gelsinger.” New York Times. 28 Nov. 1999.
4. Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies. U.S. Food and Drug Administration. 15 Jan. 2019.
5. Amorosi, Drew. “COVID-19, manufacturing challenges limit cell and gene therapy progress, FDA official says.” Healio News. 29 Oct. 2020.
6. Under the Microscope: does gene therapy represent the next revolution of biotech industrialization and commercialization? William Blair Industry Report. Jun. 2019.
7. Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs). U.S. Food and Drug Administration. Jan. 2020

Luxturna is a registered trademark of Spark Therapeutics, Inc. 
Zolgensma is a registered trademark of Novartis AG.