Advanced therapy medicinal products (ATMPs) are human therapeutics that are based on genes, tissues or cells. They offer groundbreaking new opportunities for the treatment of disease. In many ways, the term ATMP is used interchangeably with Cell & Gene Therapies (C>).
As of June 30, 2023, there were 14 approved gene therapy products and 18 approved cell therapy products on the market, with the most recent approval being BioMarin’s Roctavian for the treatment of hemophilia. However, there are approximately 500 ATMPs in clinical trials[1], and the technology is developing quickly.
A diversification of delivery platforms
Gene therapies are normally delivered via a so-called viral vector, vehicles which carry the gene payload into a patient’s cell. The most common viral vector used in approved and clinical projects is the recombinant adeno-associated viral (rAAV). rAAVs are known for their single dose gene payload delivery, high transduction rates, broad tissue specificity, low immunogenicity, and long-lasting therapeutic effects.[2] However, rAAVs are not without limitations, including immune tolerance, a limited size of the gene payload, and relatively high manufacturing costs as compared to other marketed therapeutics.[3]
These limitations mean that researchers have also investigated a number of other viral vectors for gene payload delivery, including lentivirus and herpes simplex virus (HSV). Skysona (Bluebird Bio) and Vyjuvek (Krystal Biotech) are examples of gene therapies which use lentivirus and HSV, respectively, as the viral vector. In the case of lentivirus, treatment is traditionally applied via ex vivo lentiviral gene transfer followed by autologous cell transplantation. However, recent studies have demonstrated that lentivirus may also carry promise for in-vivo applications.[4] At the same time, HSV overcomes the payload limitations of AAV by increasing the maximum from about 4.7 kb to 130 kb, although the practical limit of HSV may be closer to 12 kb based on current data.[5] Another advantage of HSV is that its genetics and molecular biology are very well-understood.
While today viral vectors are the preferred method of gene delivery, rapid advancements are being made in other areas. Synthetic nanoparticles have shown promise due to their tunable size, shape, surface, and biological behaviors, although challenges still exist, most prominently biodegradation.[6] Liposomes, commonly used to package cytotoxins in chemotherapy, have already been demonstrated to be useful in the delivery of nucleic acid-based therapies such as siRNA and mRNA.[7] But they have also been shown to carry promise for the delivery of gene payloads.[8] Finally, exosomes are cell-secreted nanoparticles, which hold promise for highly targeted deliveries of gene payloads.[9] However, the bankruptcy of Codiak Biosciences earlier this year (a leader in the exosome space) may slow progress in the short term for this modality.
Specialization of manufacturing organizations and technical competency
The fact that manufacturing methods for ATMPs are still relatively immature as compared to other therapeutics, such as antibodies, coupled with the aforementioned diversification of modalities in the space, has resulted in a high degree of specialization for manufacturing teams. Many developers of ATMPs rely on contract development and manufacturing organizations (CDMOs) to provide manufacturing capacity. Furthermore, global manufacturing capacity for ATMPs continues to be a bottleneck, as recently noted by FDA’s CBER Director Dr. Peter Marks, who pointed to CDMO batch size, consistency, and limited supply of overall manufacturing capacity as issues which the industry must address.
It is likely that increased levels of specialization at the CDMO level, and standardization at the industry level, will help to address some of these issues. However, experience in ATMP manufacturing is lacking at a global level, and talent acquisition remains an issue for many organizations. The demand for talent far outstrips supply today, and as a young and innovative industry, it is especially difficult to recruit experienced and qualified staff. Talent shortages exist right across the industry and at every level of seniority, from technicians and engineers to manufacturers and executives. And with hundreds of start-ups popping up in this space, the talent pool remains thin.
Globalization of ATMPs
For the past decade, ATMP development has occurred primarily in the US and Europe, but the globalization of these therapies is happening at a staggering pace. The 20th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production notes that in China, for example, there are 400 cell and gene therapy products currently in various phases of clinical trials, whereas 5 years ago, there were essentially none. This year’s report also notes that 63.7% of respondents report that their facility is involved in gene and/or cell therapies up from 58.6% in 2022 and 54.3% in 2021.
Elsewhere, South Korea, already a powerhouse in the global production of monoclonal antibodies, should not be underestimated when it comes to ATMP production. SK Group, Korea’s second largest conglomerate after Samsung, has invested heavily in ATMP manufacturing and currently has seven production facilities and five R&D centers in the U.S., Europe, and Korea. India has lagged conspicuously behind some of the other global production hubs for biologics when it comes to ATMPs, but the local experience with viral vaccine production could be leveraged to expand rapidly into the ATMP space. In late 2022, it was noted that a raft of new biotech startups in the country were focused on this therapy area.
As a rapidly developing field, choosing the correct ATMP partner is important
The market for ATMPs is expanding rapidly. Technology development, diversification, and globalization are all trends that will impact the industry in unforeseen (and positive) ways. Most companies in the ATMP space are partnering with raw material suppliers, CDMOs, and even quality consultants to ensure that their clinical candidates are produced reliably and consistently. Choosing the right partner can be tricky, but the importance of this selection should not be overlooked. In many cases, partnerships between organizations of similar size with common interests can be a key to success. A “right sized” partner can help strike the right balance between credible technical competency and focused attention which can be hard to achieve with partners that are too small or too large.
References
[1] https://doi.org/10.1016/j.drudis.2023.103549
[2] https://doi.org/10.1016/j.ymthe.2022.09.015
[3] https://doi.org/10.1016/j.addr.2021.01.017
[4] https://doi.org/10.1038/s41467-022-32576-7
[5] https://doi.org/10.1038/gt.2009.144
[6] https://doi.org/10.1038/mtm.2016.23
[7] https://doi.org/10.1016/j.onano.2023.100132
[8] https://doi.org/10.1155%2F2011%2F326497
[9] https://doi.org/10.3389/fcell.2021.751079
