Cell and gene therapies (C>s) enjoyed “a landmark close” to 2023 and continued its momentum in Q1 2024 with “several notable approvals and strong growth in all stages of clinical development”, according to the latest quarterly Gene, Cell & RNA Therapy Landscape Report by Citeline in association with the American Society of Cell & Gene Therapy (ASCGT).1 In all, 32 gene therapies (including genetically modified cell therapies), 28 RNA therapies and 68 non-genetically modified cell therapies have been approved in at least one jurisdiction as of April 2024.
The 32 gene therapies approved since 2004 cover a very wide range of indications, most commonly in oncology, myeloma, leukemia, lymphoma, hemophilia, and limb ischemia, and often for more than one. Celgene’s Breyanzi (lisocabtagene maraleucel), for example, has variously been approved for diffuse large B-cell lymphoma, follicular lymphoma and chronic lymphocytic leukemia in the U.S., Japan, the EU, Switzerland, and the UK since it was launched in 2021.
There were 4,002 gene, cell, and RNA therapies in development at the end of Q1, of which 52% (2,093) were gene therapies. The number of gene therapies at all three phases of clinical pipeline development has increased since the end of 2023, with 11% growth in the number of Phase I candidates since to 301 and smaller increases in Phase II (282) and Phase III (35). Four were in pre-registration.
“There has been a continuation of trends we have been seeing in previous quarters,” says Shardha Yeeles, senior consultant at Citeline and co-author of the report. “There is very strong C> development in oncology and rare diseases, and lots of pre-clinical development, but interestingly and specifically for gene therapies, we have seen an increase in Phase I, II and III programmes since the previous quarter. It was the biggest increase in the number of Phase I programmes since before Q4 2022.”
Gene therapy is still mainly directed at oncology. Anti-cancer therapies, with 1,123, and rare diseases, with 1,035, accounted for the overwhelming majority of therapies being developed. All the rest combined added up to 1,082.
Moreover, 54% of the rare diseases are themselves in the oncology field, the top five being:
1. Myeloma (99)
2. Acute myelogenous leukemia (85)
3. Non-Hodgkin’s lymphoma (84)
4. B-cell lymphoma (70)
5. Ovarian cancer (67)
That said, oncology’s domination of clinical trial starts has fallen significantly in the past year, with non-oncology accounting for 43% of clinical trial starts in Q1 2024 against 32% in Q1 2023. Gene therapy is clearly addressing a wide and growing range of unmet needs.
There is a broadly similar pattern in in the non-GM cell therapy pipeline, where anticancer (292) and rare diseases (275, of which about 36% are for cancers) are comfortably the most important therapies by number of projects. More than 100 each in development for neurological, alimentary/metabolic, and musculoskeletal disorders. Of the 1,072 pipeline RNA therapies, 329 were for rare diseases (about 80% of them non-oncology), ahead of anti-infectives (264) and anticancer (224).
It is also noteworthy that financing in this field seems to be tilting away from start-ups and towards deal-making for advanced molecular therapies. Whether this proves to be a long-term trend remains to be seen, as this sector is constantly in flux, but there is certainly reason to think that the C> pipeline will continue to deliver a substantial number of new drugs to treat rare diseases, many of which are poorly, if at all, served by existing medicines.1
In 2022, Oliver Wyman projected drug approvals to boost the global C> market 55% by 2028 to nearly $14 billion by 2028, with over 100,000 patients in the U.S. alone will be eligible for C> by 2025.2 Another report by the Massachusetts Institute of Technology (MIT) in 2019 anticipated more than 60 U.S. approvals of C> products by 2030 and over 500,000 patients being treated.3
Nonetheless, many challenges loom ahead of C>s achieving their potential, starting with their often very high – and often unpredictable – cost. For instance, Zolgensma, a treatment for spinal muscular atrophy, costs $2 million per patient. An “affordable, scalable, and sustainable model” is needed, which will require collaboration between pharmaceutical companies, payers, providers, and regulators.4
At the development stage, obtaining the quality, safety, and efficacy data necessary to support a favorable risk-benefit profile is highly complex. Among the many reasons for this are the small patient and heterogenous patient pool for rare diseases, plus a lack of established clinical endpoints and/or critical quality attributes to prove a link to clinical outcomes. In addition, randomized trials may not be ethically acceptable when very serious conditions are being addressed.4,5
For reasons like these, promoters of C>s have advocated alternative trial designs and statistical techniques that maximize the use of data and post-approval confirmation of clinical benefits. Basket-type designs that group similar indications in early-phase studies of the same trial may offer some solutions.5
Novel trial designs that consolidate phases I-III could also help. The FDA has issued several guidance documents that address this and there have been publications modelling post-market study designs for advanced therapy medicinal product (ATMPs), including C>s.6-8
In many cases, the preclinical models of C>s for rare and genetic diseases have poor predictive values because of their limited duration, their dissimilarity to the actual condition of the patients, and the limited data available from biomarkers or surrogate measures from dose-response studies. To overcome this may require investment in AI and Big Data analytics that can better model the biology and effects of the therapies.9
Precisely because they are often targeted at unmet needs, C>s often benefit from accelerated approval pathways, like the EU’s Priority Medicines (PRIME) scheme and the U.S. FDA’s breakthrough therapy designation (BTD) and regenerative medicine advanced therapy (RMAT) designation. However, this can amplify the issues of the novel processes involved, causing additional pressure when the therapy moves from clinical to needing commercial-grade. The outcome can be higher costs and delayed launches.4
Capacity constraints in manufacturing, such as shortages of viral vectors and the lack of existing good manufacturing practice (GMP) facilities, have sometimes slowed development. It has also been difficult for some to obtain the raw materials for many reasons, including the need to source human- and animal-derived materials, and their biological complexity.4,5
In addition, producing C>s is complex, requiring many specialized skills and expensive materials. Very few CDMOs can produce viral vectors at scale, and they are often booked out long in advance. Capacity is now being installed, such as the Center for Breakthrough Medicines’ new $1.1 billion facility in the U.S., but this will take time to become fully available and is mostly concentrated at the clinical scale.10
Emerging manufacturing techniques as single-use bioprocessing, suspension cell culture, pluripotent stem cell lines and ‘doggybone’ DNA will potentially boost manufacturing capacity in the longer term. However, they will be of limited use for current late-stage or launched therapies, whose processes cannot be changed without causing further regulatory issues and delays.5,10
There are often backlogs at all stages of the process because of the difficulty of accessing materials in a timely manner, which in turn raises the risks of batches going out of specification or sterility problems arising. Manufacturers must work with suppliers and plan forward, often for 12-18 months, to reduce the risk of bottlenecks in supply.5
In large part because C> is so new and evolving so fast, regulation is not keeping up and there is a lack of established regulatory frameworks for developing these products in many jurisdictions. Some do not have specific regulations for C>. As a result, the vast majority of therapies have only been approved in one jurisdiction.
Convergence between jurisdictions, including mutual recognition agreements, and the harmonization of technical guidelines will be critical going forward but very difficult to achieve in practice, requiring multi-stakeholder collaboration. The ASCGT has been active in promoting this. In addition, more public-private partnerships specific to C> would be valuable to removing barriers to development.5,9,10
Continued development in technology will also spur the growth of the market. “In the future for genetic medicine, I think the focus is going to be very much on precision,” Yeeles says. “There have been some exciting technologies on show at previous ASCGT meetings, such as epigenetic editing and modification and how we can incorporate that in therapeutics.
“A lot of discussions at that latest meeting have been about the processes around gene therapies and how we can streamline manufacturing to get therapeutics to patients quicker. I think a lot of the future about gene therapy is also about having a lot of conversations about reducing the turnaround time from concept to getting the therapeutic to patients.”
For more information, see the latest Citeline/ASCGT report: Q2 2024 Gene, Cell + RNA Therapy Landscape Report | Citeline
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