Cell and Gene Therapy Development – Three Key Challenges in 2023

About 50 years elapsed from when Rogers and Pfuderer provided the initial proof-of-concept for virus-mediated gene transfer to the first approved products using gene transfer in humans.¹ Additionally, it took almost 30 years from the demonstration of the concept of the chimeric antigen receptor by Gross et al. to the first product-approved chimeric antigen receptor T cell (CAR-T) products.¹

In 2023, we are experiencing a much faster roadmap from proof-of-concept to product approval. The U.S. Food and Drug Administration (FDA) has observed a surge of cell and gene therapy products entering development, based on the upswing in Investigational New Drug (IND) applications. The FDA predicts by 2025, there will be 10 to 20 approved cell and gene therapy products per year, evidenced by an assessment of the current pipeline and the clinical success rates of these products.²

This growth reflects the vast potential cell and gene therapy offers patients. Since attending the Bay Area Biotech Forum’s panel on “Development Challenges in Cell and Gene Therapies,” I reflected on the significant progress industry has made and expects to continue, as well as the challenges that remain for cell and gene therapy developers.

Bay Area Biotech brought together an esteemed panel of cell and gene development experts to talk through the impact of our current environment on this therapeutic modality. Attendees included prominent academic scientists, founders, investors, and other executives who are interested in ideating solutions to accelerate their business models.

Here are three key considerations, in light of our current environment, for cell and gene therapy developers to propel development forward amidst roadblocks.

Balancing Development Costs and Limited Fundraising

Balancing development costs against the current fundraising environment remains a major challenge for many life science companies, particularly those focused on the development of cell and gene therapies. Development costs, in general, are a major line item in a product’s research and development (R&D) budget, but developing a product in cell and gene therapy is even more expensive because of the high costs of running the trial, the manufacturing costs, and the stringent standards imposed by regulatory agencies to ensure safety and quality of these products to bring the product to market.³ It is estimated that developing a gene or cell therapy can cost 5x more than that of a traditional small molecule or therapeutic protein.⁴

Development costs and the current financing environment are at odds.

In our current environment, we’re seeing smaller, more frequent financing rounds. Investors are seemingly more comfortable with this inflection-point-focused, staged approach than the larger, more traditional rounds we’ve seen in previous years. 

The question remains, ‘how can cell and gene therapy developers operate with the resources they have, and ultimately, do more with less?’ While we don’t have all the answers, and there’s not a one-size-fits-all approach, we do know that companies must revise their development strategy to create additional inflection points based on their current resources to de-risk their development activities.

Too Many Companies and Too Little Experience

The number of cell and gene therapy-focused companies is rising rapidly, and the war for experienced talent continues to rage as more and more companies emerge. Finding experienced talent to advance cell and gene therapy pipelines is tough, especially in the areas of development strategy, regulatory, chemistry, manufacturing, and controls (CMC), and senior-level management roles.

Given the significant complexity of cell and gene therapy manufacturing and analytics, CMC aspects of these programs require frequent and thoughtful interaction(s) with health authorities to effectively de-risk product development. Regulatory CMC experts can be essential to the preparation of phase-appropriate development strategies aimed at ensuring regulatory compliance while also navigating accelerated timelines throughout the product lifecycle.

There are particular obstacles companies face when they don’t have the right regulatory CMC talent. This gap results in a lack of drug substance and drug product strategies fit for their stage of development, whether that be an early Investigational New Drug (IND) application or a marketing application.

The solution to fill the gaps is not easy, and certain geographic areas may have more available talent than others. Cell and gene therapy founders may consider collaborating with an organization, like Halloran, that acts as a leader of their company’s development team to establish strategy, advise, and take on interim roles, including regulatory CMC strategy.

Addressing Manufacturing Challenges  

CMO/CDMO Selection Considerations

Small, pre-clinical companies often seek out a smaller-scale Contract Development and Manufacturing Organization (CDMO) partner – a service provider that provides development and manufacturing services. Larger-scale CDMO processes are typically not compatible with pre-clinical development needs because of the extra layers of Quality Assurance (QA) and Quality Control (QC) processes. When the development phase and the CDMO quality processes are not aligned, this may add significant cost and timeline delays, often resulting in the success or failure of the developer.

Making the right CDMO selection is critical to ensure success. The ability to make the right choice in a partner hinges upon an ability to properly assess and evaluate the trade-offs each candidate manufacturer presents. The wrong selection can result in having to replace a CDMO, and if that is undertaken after launching the clinical trial (or approval), the transition often becomes more costly and time-consuming.

While the selection criteria are similar when selecting a CDMO or a Contract Manufacturing Organization (CMO), CDMO considerations are more complex because they offer both development and manufacturing services. A CDMO handles the outsourced manufacturing, along with innovation and development work that includes development, production, and analysis. A CDMO essentially removes the necessity for a sponsor to invest in staff dedicated to innovation and manufacturing.

A CMO is focused on the manufacturing and often works with sponsor companies who have research and development staff in-house. The choice of vendor depends on resources and capabilities at the sponsor.

Identifying Critical Quality Attributes

While cell and gene therapies currently focus primarily on rare diseases, emerging therapies are targeting larger patient populations and more chronic conditions. As this happens, manufacturing is in higher demand.⁵

The amount of cell and gene therapies progressing through the development pipeline drastically outnumbers the CDMOs that have the capabilities to manufacture these therapies. Once therapies are in manufacturing with a CDMO, many developers face production bottlenecks around process control, speed, sustainability, and costs, which slows down the manufacturing process.⁶

In large part, this is due to process and quality unknowns, and complex challenges that may disrupt the manufacturing process. Identifying critical quality attributes in advance of the manufacturing process is important to development success. While developers may understand a gene sequence that shows efficacy, they may not have addressed the quality, quantity, potency, and other requirements of the final gene therapy product. Addressing these questions help to prevent manufacturing disruption and enables the right support and partnership from the CDMO.⁵

Supply Chain Issues

It’s important to acknowledge changes will inevitably happen with the manufacturing process due to supply chain disruption. A supply chain is made up of all the participants in manufacturing and distribution channels. Supply chain issues are rampant, and while a process may appear feasible on paper, that process will be quite different if critical materials are delayed or constrained.⁵

Events or circumstances that may lead to a supply chain issue include natural disasters, political instability or conflicts, transportation disruptions, raw material shortages, and more. One of the key challenges facing the cell and gene therapy industry is the quality and reliability of raw materials. Variability in the quality and composition of raw materials may lead to inconsistent product quality, reduced efficiency in the manufacturing process, and increased risk of non-compliance with regulatory standards.⁷

Consider developing an inventory management system, conduct a gap assessment of raw materials, develop a risk-management plan for supply chain challenges before they arise, and consider the scalability of your raw materials suppliers (e.g., can they scale production to meet demand?)⁷

Conclusion

There are certainly roadblocks and barriers for cell and gene companies to navigate ranging from fundraising challenges, talent shortages, and manufacturing complexity, just to name a few. It is highly recommended to take opportunities for early engagement with the FDA where possible, and to ensure the right team is in place to successfully navigate programs through development to commercialization.

Successfully navigating the development journey requires the right team and the right mix of expertise.

Halloran supports cell and gene developers in the following ways:

• Regulatory strategy
• Regulatory CMC advising
• Regulatory submissions, execution, and ongoing maintenance
• CDMO / CMO vendor selection
• Integrated development plans
• Development program leadership
• Clinical development planning and execution

Contact Halloran today.

References:

1. Young C.M., Quinn C., Trusheim M.R. Durable cell and gene therapy potential patient and financial impact: US projections of product approvals, patients treated, and product revenues. Drug Discovery Today. 2022:27(1):17-30.
2. “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. January 2019. https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics
3. De Luca M., Cossu G. Cost and availability of novel cell and gene therapies. EMBO Reports. 2023:24.
4. “Paying for CRISPR Cures: The Economics of Genetic Therapies.” Innovative Genomics Institute. December 2019. https://innovativegenomics.org/news/paying-for-crispr-cures/
5. “Addressing Manufacturing Challenges in Gene Therapy Development.” Biopharma Dive. March 2023. https://www.biopharmadive.com/spons/addressing-manufacturing-challenges-in-gene-therapy-development/644918/
6. “As Few CMOs are Equipped to Manufacture Cell and Gene Therapies, Viral Vector Manufacturing and Speed Must Improve, Say Experts.” Pharmaceutical-Technology. July 2020. https://www.pharmaceutical-technology.com/comment/cell-and-gene-therapies-viral-vectors/
7. “Navigating The Complexities of Cell and Gene Therapy Supply Chain: A CEO’s Practical Guide.” Forbes. February 2023. https://www.forbes.com/sites/forbesbusinesscouncil/2023/02/28/navigating-the-complexities-of-cell-and-gene-therapy-supply-chain-a-ceos-practical-guide/?sh=558aa3bb5e16