Increasing the Efficacy and Impact of Cell and Gene Therapies

Decades of research into cell biology, gene editing, and biomanufacturing have culminated in the commercialization of more than a score of cell and gene therapy (CGT) products. In the United States, most of those are hematopoietic progenitor cells (HPCs) isolated from human umbilical cord blood. As of July 2022, the US Food and Drug Administration has approved five products based on chimeric antigen receptor (CAR) T cells, all since 2017, and two viral-vector gene therapies, beginning with the 2019 authorization of Novartis’s Zolgensma (onasemnogene abeparvovec) (1). The FDA now is evaluating several candidates, including a few gene therapies that could receive approval by the end of 2022.

Despite landmark approvals, the advanced-therapy industry remains nascent. The novelty and complexity of such products create difficulties not only for their manufacture and quality control, but also for developing regulatory guidelines, governmental policies, and healthcare reimbursement models. To learn more about how advanced therapies have evolved and about what difficulties remain, BPI corresponded with Susan Nichols, whose biotechnology experience spans over
20 years, including a decade of work in the advanced-therapies industry. She is president and chief executive officer of life-science consultancy Propel BioSciences as well as director of the executive board for the Alliance for Regenerative Medicine (ARM) and chair of the Rare Disease Innovations Institute.

Innovations in Regenerative Medicine
What has been the most important scientific or technical innovation in the past 20 years of bioprocessing? In 2012, Jennifer Doudna and Emmanuelle Charpentier developed the first gene-editing technology based on clustered regularly interspaced palindromic repeats (CRISPR). By enabling targeted cuts in DNA, the technology opened up opportunities for biological research, therapeutic drug development, and identification of critical biomarkers, thus accelerating drug discovery and development. Doudna and Charpentier’s  receipt of the 2020 Nobel Prize in Chemistry speaks to CRISPR’s global impact. Their research has led to the development of high-impact therapies to treat patients with genetic diseases that are currently without effective treatment options, such as sickle cell disease and beta thalassemia.

What has been the most notable development in bioprocess business strategy over the same period? As biopharmaceutical companies began to recognize the high potential of the regenerative medicine sector, large life-science companies started acquiring manufacturing facilities, analytical capabilities, and means for data-handling. Those actions were taken with the aim of addressing indications for which the standard of care was not improving quality of life, ceasing disease progression, or addressing underlying conditions.

Large companies have the cash, expertise, market channels, and ability to invest in long-term market growth. By combining what traditionally have been siloed technologies and services under one umbrella, such companies are creating truly end-to-end solutions. Further collaborations and acquisitions hold potential for “one-stop shopping” from research and development (R&D) through regulatory approval and current good manufacturing practice (CGMP)-compliant commercial manufacturing.

I like to envision a time when manufacturing options include multiple solutions based on the therapy type and patients served. Targeted diagnostics and “-omics” approaches that keep pace and inform therapies are the goals: Diagnose early, tailor therapies, and deliver them quickly to patients for the best disease outcomes.

Missed Opportunities
What expected regulatory, technical, and scientific advances didn’t occur, and how have those nonevents influenced the development of the industry? Coding, coverage, and reimbursement models to accommodate innovative regenerative medicine products and call for value-based payments have not kept pace with innovation. I hope that patients soon will have a greater voice and that their concerns will be at the heart of all value assessments. I believe that the future of healthcare is likely to incorporate patient-centered, multistakeholder dialogue to help create consensus about the determinants of product value.

Although cell and gene therapies could achieve durable and even curative outcomes — not only for rare diseases, but also for larger, more prevalent indications — the American healthcare system is not designed to accommodate rapid adoption of such life-altering therapies, so these products have difficulty reaching patients. Payors and innovators will learn to work together toward agreed-upon models for determining product value and payments. Determining reimbursement is critical to keeping investment fueling innovative therapies and to ensuring that as many patients as possible benefit from the biopharmaceutical industry’s technological advances.

The Future of Advanced Therapy
How might the industry look in the next five, 10, or even 20 years? Artificial intelligence (AI) has yet to be realized fully in the biopharmaceutical industry. AI uses and learns from different kinds of data from many sources, enabling drug companies to analyze and apply data more efficiently. AI is positioned to play a significant role in “smart manufacturing,” increasing efficiencies and driving down costs. My hope is that integrating “big data” and machine learning (ML) into the evolving -omics landscape will help companies to collect, process, and analyze large data sets quickly and efficiently, enabling the industry to identify commonalities in complex disease variables. Accelerating basic research and drug discovery could increase the number of options for addressing currently untreatable diseases.

Many difficulties with advanced therapies stem from their complexity and novel mechanisms of action. The industry will need to develop new technologies to gain a better understanding of safety concerns. Having such information will help the industry to minimize clinical holds as regulators become more comfortable with the constantly progressing advances in cell and gene therapy production.

I hope for the development of healthcare reimbursement models that recognize the long-term benefit of advanced therapies and that show strong inclusion of patient interests. I must stress the importance of access. For example, some Medicaid-program review processes take between 180 days and a year (or longer) before a patient receives a novel therapy for a rare disease. That is unacceptable when many such diseases are life threatening, and patients, many of whom are children, do not have the luxury of time to wait for Medicaid to make a product available after a year of delay. Patients would be best served when all drugs have established coverage upon FDA approval.

I would be over-the-top thrilled for cell and gene therapies to become first-line therapies as the industry continues to improve their manufacturability and decrease their production costs and timelines. I hope for platform cell and gene therapies that are designed to treat multiple diseases and for movement toward truly personalized medicines as well as “off-the-shelf” therapies with positive safety profiles, exceptional efficacy, and benefits of efficiencies of scale. And I am eager to witness what will come when researchers and developers have enhanced abilities to predict treatment responses in subsets of patients through immunogenic, genomic, epigenomic, and phenomic data. Such advances will change the paradigm from long-term treatment of chronic conditions to treatment of disease origin, thus enhancing quality of life.

References
1 Approved Cellular and Gene Therapy Products. US Food and Drug Administration: White Oak, MD, 1 July 2022; https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products.

Susan Nichols is chief executive officer of Propel BioSciences. She serves on the board of directors for the Alliance for Regenerative Medicine and chairs the board of directors for the Rare Disease Innovations Institute; [email protected].