The biotechnology sector has seen important progress in the development of groundbreaking therapies in recent years, especially in the areas of immunotherapy and cell and gene therapy. In gene therapy alone, there are now clinical research programs targeting almost 50 different indications, up from only 10 a few years ago,1 and the rate of innovation is expected to continue to increase in the years ahead. A range of factors — including small patient populations, complex manufacturing processes, and lack of specialized expertise — are positioned to both drive up costs and require new options for stakeholder engagement and risk sharing along the development pathway. New approaches in development are needed to support the next generation of novel drugs on the horizon.
Recently, CRA completed an analysis of the unique challenges associated with development of cell and gene therapies. The results show clearly that traditional approaches may not be well suited to address many of the distinct factors that affect development of the emerging generation of cell and gene therapies. New and previously untried strategies may be essential to turn the promise of high-risk clinical development programs and technology platforms into commercially viable therapies that are broadly available to patients who can benefit from them.
Challenges In Accessing Specialized Expertise
While most small molecule drugs follow a fairly standardized process in discovery and clinical development, gene and cell therapies often have highly complex discovery paths and mechanisms of action. In many cases, researchers cannot determine the final mode of drug delivery until late in the development program, which presents significant risk. Efforts to confirm an optimal drug delivery platform can require very specialized clinical expertise and advanced manufacturing capabilities that are not typically found outside of major biotechnology hubs.
This is often the case when selecting the optimal viral vectors for delivery of certain gene therapies. Very few biotechnology companies have the expertise and capability to produce vectors on site, and demand for vector production from a limited range of third-party suppliers can result in multiyear wait lists and extremely high costs.
Complexity Of Clinical Trials
There are many special considerations for companies developing gene and cell therapies for the treatment of rare and ultra-rare diseases. Targeting very small patient populations can make it extremely difficult to find appropriate candidates for clinical trials and to meet timeline goals in patient recruitment. In addition, connecting patients with a limited range of treatment centers can be challenging.
Clinical results from trials involving small numbers of patients can also raise questions about the adequacy of safety and efficacy data, which can affect clinician confidence and adoption. In 2017, a gene therapy for lipoprotein lipase deficiency was pulled from the market in Europe after being used in only one patient. The patient’s physician highlighted the fact that the clinical trial leading to the therapy’s approval consisted of just 27 patients with no control group.2,3 Clinicians seemed hesitant to prescribe a drug based on results of a trial that was widely viewed to be under-enrolled.
To help address the lack of available patients with rare and ultra-rare diseases, the U.S. FDA recently issued guidance encouraging extrapolation of data across different populations, increased use of models and simulations, and use of a single control group as the basis for more than one investigational drug.4While these approaches can have a positive impact on development timelines and costs, they could also cause concern about the broader use of computer simulations or lower standards in statistical rigor of clinical trial results.
Emerging Strategies To Support New Drugs
Industry is working to identify and implement a range of adaptive development strategies that embrace the distinct advantages these drugs and platforms can offer.
In many cases, cell and gene therapies present promising opportunities in platform diversification that are not possible with small molecules or monoclonal antibodies engineered to target a single pathway. For example, when the development program for the investigational RNAi therapeutic revusiran for treatment of hereditary ATTR amyloidosis with cardiomyopathy was terminated, Alnylam Pharmaceuticals was able to shift its development focus to target other diseases such as hereditary TTR-mediated amyloidosis and acute hepatic porphyria.5 The opportunity to pivot and apply a platform to different therapeutic areas can help mitigate risk and expand a platform’s commercial potential.
Targeting Emerging Knowledge Hubs
To access the specialized expertise and manufacturing capabilities they need, some companies are setting up headquarters or separate operations in the established centers for advanced cell and gene therapy production, including London/Cambridge, Boston/Cambridge, and San Francisco. At least for the next few years, colocation within these clusters may be a prerequisite for success.
New Opportunities In Industry Collaboration
Promising cell and gene therapy development programs are likely to be of interest to well-established, cash-rich pharma/biotech companies looking to expand their pipelines. Earlier this year, Celgene acquired Juno Therapeutics and its pipeline of chimeric antigen receptor T cell and T cell receptor therapeutics.6 These types of deals and partnerships can help larger companies access innovative technology platforms and position them to advance complex new drugs at an accelerated pace.
Innovation In Stakeholder Engagement
To address the unique factors that can increase both risk and cost in cell and gene therapies, drug developers are also looking at new options for stakeholder engagement that may have seemed unthinkable even a few years ago. Broader collaboration among industry leaders — including academic centers, patient advocacy groups, investors, manufacturers, payers, and clinicians — has the potential to provide a broader base of support for drug development, as well as new sources of capital and expertise that will be essential to success. Partnerships between manufacturers and academic centers, in particular, show strong promise in advancing many higher-risk gene and cell therapies. For example, Orchard Therapeutics launched a transformative gene therapy development program built upon formal partnerships with UCLA, Boston Children’s Hospital, University College London, Great Ormond Street Hospital for Children NHS Foundation Trust, and the University of Manchester.7 The program will exploit ex-vivo autologous stem cell gene therapy for primary immune deficiencies, metabolic diseases, and hematological disorders.
As industry leaders continue to assess the impact of all factors associated with cell and gene therapy development programs, calls for new levels of innovation and new approaches to drug development and commercialization are likely to continue. In the years ahead, we likely will see a range of new partnerships and innovative approaches emerge in the design and execution of clinical development programs. Companies that fail to consider new models may face insurmountable challenges in the effort to remain competitive, while those that forge new paths forward may significantly improve their chance of advancing promising development programs to the finish line.
- Emily Mullin, “Gene Therapy 2.0,” MIT Technology Review, March/April 2017, available at https://www.technologyreview.com/s/603498/10-breakthrough-technologies-2017-gene-therapy-20/.
- Gina Kolata, “New Gene-Therapy Treatments Will Carry Whopping Price Tags,” New York Times, September 11, 2017, available at https://www.nytimes.com/2017/09/11/health/cost-gene-therapy-drugs.html.
- Antonio Regalado, “The World’s Most Expensive Medicine is a Bust,” MIT Technology Review, May 4, 2016, available at https://www.technologyreview.com/s/601165/the-worlds-most-expensive-medicine-is-a-bust/.
- FDA, “FDA In Brief: FDA recommends new, more efficient approach to drug development for rare pediatric diseases,” press release, December 6, 2017, available at https://www.fda.gov/NewsEvents/Newsroom/FDAInBrief/ucm587862.htm.
- Emma Court, “Alnylam stock more than tripled last year — and the company says 2018 will be big,” MarketWatch, January 22, 2018, available at https://www.marketwatch.com/story/alnylam-stock-more-than-tripled-last-year-and-the-company-says-2018-will-be-big-2018-01-17.
- Alex Philippidis, “Celgene to Acquire Juno for $9B, Expanding CAR-T, TCR Presence,” January 22, 2018, available at https://www.genengnews.com/gen-news-highlights/celgene-to-acquire-juno-for-9b-expanding-car-t-tcr-presence/81255403.
- Orchard Therapeutics, “Orchard Therapeutics launches and announces academic partnerships for development of transformative gene therapies,” press release, May 3, 2016, available at http://www.orchard-tx.com/2016/05/orchard-therapeutics-press-release/.
About The Authors:
Walter Colasante, Pascale Diesel, and Lev Gerlovin are VPs in CRA’s Life Sciences Practice. Colasante has worked extensively in both the pharmaceutical and consulting industries and across a range of therapeutic areas including oncology, the central nervous system, and rare diseases. Diesel has worked in global development, marketing, planning, and business development and has over a decade of strategic consulting experience focusing on portfolio optimization and valuation. Gerlovin has more than 11 years of experience in life sciences strategy consulting, focused on commercial and market access strategies. The authors wish to acknowledge the contributions of Stephanie Donahue and Michael Krepps to this article.
The views expressed herein are the authors and not those of Charles River Associates (CRA) or any of the organizations with which the authors are affiliated.