Innovative research in cell and gene therapy looms large on the horizon of medicine, and the implications for disease treatment and even eradication are thrilling. However, the current reality is that there are relatively few cell and gene therapies available in the United States, at least for right now. It is encouraging to see the recent clinical impact of products like ZOLGENSMA® (onasemnogene abeparvovec-xioi), TECARTUS™ (Brexucabtagene Autoleucel), LUXTERNA® (voretigene neparvovec-rzyl), and Libmeldy. The available reposit of cell and gene therapies is expected to grow significantly in the next 5 years, according to the Alliance for Regenerative Medicine (ARM), a coalition of over 370 global members encompassing manufacturers, researchers, academic institutions, health systems, payers, and patient advocacy groups1. According to their “State of the Industry Briefing” from January of 20212, there are now 1200 clinical trials occurring worldwide, 152 of which are in phase 3 trials. The dominant therapeutic area of interest is oncology, followed by central nervous system, monogenetic diseases, infectious diseases, and cardiovascular disorders.

According to Dr. Cynthia Tifft, Director of the Pediatric Undiagnosed Diseases Program at the National Institutes of Health, “The exponential growth phase” of gene therapy has arrived. This rapid proliferation of cutting-edge therapies has been the result of tremendous cooperative efforts by thousands of scientists around the world to advance this technology3. One such example lies in the collaboration of Jennifer Doudna, Berkeley professor and researcher, with European colleague Emmanuelle Charpentier. These brilliant scientists won the 2020 Nobel prize in science for their seminal work on clustered regularly interspaced palindromic repeats (CRISPR)Cas-9 gene-editing technology, greatly accelerating the process of editing genes and facilitating the recent explosion in relevant bench science and clinical trials4.

Dr. Isaac Kohane is Chairman of the Department of Biomedical Informatics at Harvard Medical School and heads the federally-funded Coordinating Center for the Undiagnosed Diseases Network.  He stated in a recent feature article in USA Today that “people are underestimating what it’s going to take to make (gene therapy) work in the short term and underappreciating how transformative it will be in the long term3”.

Gene therapies certainly appear promising but are not without inherent risk. These novel therapeutics can cause unanticipated adverse effects, as noted by the Mayo Clinic: targeting of incorrect cells, resulting in illness or cancer; unwanted immune system reactions; viral infection via recovery of potency; gene insertion at erroneous location with resultant tumor risk; and new mutation formation in primary and/or metastatic lesions.

Gene vector technology is varied and evolving, including the use of numerous viruses, lysosomes, and stem cells, which may pose potential ethical controversy. New delivery mechanisms are also currently being developed, such as SQZ Biotech’s efforts to incorporate gene edits into cells by temporarily facilitating cell membrane permeability, allowing entry of desired material into cells. Verve Therapeutics is exploring the use of CRISPR technology customized to specific targets and primarily focused on the liver, an organ quite amenable to gene assimilation.

Precision Advance, the Cell and Gene Therapy Collective, has been engaged with gene therapy since 2013 and closely monitoring its thrilling and rapid evolution. Precision Advance hosted the Gene Therapy and health economics and outcomes research (HEOR) webinar in October, 2020 and cohosted the webinar “Wish I Knew What I Know Now” with MassBio the same month. The organization also sponsored the Great Debate webinar with Endpoints, focused on internal vs external manufacturing for advanced therapies, and was featured in the 4th Annual Gene Therapy for Rare Disorders presentations5.

According to the Alliance for Regenerative Medicine (ARM), overall financing of cell and gene therapy more than doubled from 2019 to 2020, increasing from $9.8B to $19.9B, primarily through follow-on and venture capital financing. Annual financings of greater than $200M for individual cell and gene companies were not uncommon. This trend is continuing into the current year, as companies such as Sana Bio., lovance, bluebird bio, and Allogene have each raised more than $500M in 2021. There were several significant partnerships formed between large pharma and innovative developers, namely: Biogen and Sangamo, focusing on neurodegenerative disorders; Novartis and Sangamo, for neurodevelopmental disorders; Roche and Dyno, for central nervous system diseases; and Merck, Janssen, Bayer, and Novartis forming partnerships for cell-based immuno-oncology for hematologic and solid tumors, as well as COVID-19—induced Acute Respiratory Distress Syndrome (ARDS)2.

There have been significant efforts in the past few years to understand key payer issues and tactics for supporting and reimbursing for cell and gene therapies. At the forefront is MIT’s NEW Drug Development ParadIGmS (NEWWDIGS) initiative5. They have conducted 2 large Financing and reimbursement of Cures in the US (FoCUS) payer advisor surveys. The first was completed in fall 2017, as the initial CAR T-cell therapies, Kymriah (Novartis) and Yescarta (Kite Pharma) were being approved, and just prior to Luxterna (Spark Therapeutics) receiving FDA approval. The second survey ran from late 2018 through May 2019 and involved 153 payer respondents across a spectrum of plan types, sizes and lines of business. Additional payer surveys were conducted by the ARM jointly with the National Association of Managed Care Physicians (NAMCP), as well as by the National Pharmaceutical Council (NPC).

Critical findings from these surveys encompassed concerns about affordability of the upfront cost, performance uncertainty-durability, actuarial risk (over 6,000 rare diseases impacting potentially 25 million Americans), payment/ROI timing, off-label use, adverse selection, and value and performance contracting challenges such as data intermediation and scalability.  Payers expressed apprehension about the cumulative impact of cases and treatments potentially amenable to cell and gene therapy. The possibility of combination therapies, currently being trialed in the immuno-oncology arena, brings additional financial burden6,7.

Payer strategies implemented thus far include sequenced renegotiation of provider contracts (ie, one-offs), milestone-based contracts, pooling methods such as stop-loss insurance (CVS/Aetna), reinsurance, performance-based annuities, installment financing, multipayer pools, subscription models, and carve outs/riders (Cigna’s Embark program)7.

Impact on Manufacturers:

Manufacturers must appreciate the growth potential of cell, gene, and tissue therapies, and continue to engage with biomedical innovators through strategic partnerships, collaborations, and/or acquisitions. As an example, CSL Behring recently joined the NEWDIGS FoCUS initiative in March 2021.

Impact on Payers and Employers:

Payers must rapidly develop internal expertise regarding cell, gene, and tissue therapies. Payers should consider connecting to The Alliance for Regenerative Medicine to keep abreast of the precipitous evolution of this exciting new science and its commercialization. Companies can benefit from MIT’s NEWDIGS efforts and resources, particularly through use of their pipeline impact tools and research briefings on innovative financing methods, lessons learned, outcomes tracking, and options to manage spend and trend.


  • The Alliance for Regenerative Medicine website
  • ARM’s State of the Union briefing, Jan 2021 ppt
  • USA Today, April 27, 2021
  • The Code Breaker, Walter Isaacson
  • MIT NEWDIGS website homepage and links
  • FoCUS research briefings
  • Pharm Exec, Jane Barlow, payer perspectives on gene therapy reimbursement