An Updated Snapshot of Gene Therapy Clinical Trials Worldwide

An updated aggregation of gene therapy clinical trials notes that as of March 2023, 3900such trials have been completed, are ongoing, or have been approved worldwide—specifically in 46 countries. The international team of authors, reporting in the Journal of Gene Medicine, focused on summarizing and analyzing the trials’ geographical distribution, the disease indications (or other reasons) for trials, the different vector types used, and the genes that have been transferred.¹

The team has provided a searchable database along with additional details of their analyses on the journal’s Gene Therapy Clinical Trials Worldwide website. The database consolidates information on gene therapy clinical activity gleaned from trial databases, official agency sources, published literature, and conference presentations and posters.

In the years since the first adeno-associated virus (AAV)-based gene therapy—voretigene neparvovec-rzyl (Luxterna; Spark Therapeutics)—was approved by the FDA in December 2017, the gene therapy landscape has changed dramatically, the authors wrote. Notably, more than 20 new gene therapy products have been approved, including onasemnogene abeparvovec-xioi (Zolgensma; Novartis), etranacogene dezaparvovec-drlb (Hemgenix; CSL Behring), and patisiran (Onpattro; Alnylam); patisiran is the first small interfering RNA therapy to reach the market.

The US leads the world in the most gene therapy clinical trials with 2054, followed by China with 651, the United Kingdom with 245, Germany with 115, France with 66, and Japan with 55. | Image Credit: ArtemisDiana-stock.adobe.com

The article captures key trends that have developed in the last half decade. The huge increase in gene therapy clinical trial activity includes the implementation of gene editing technologies that introduce permanent changes into the genome. Along with improvements in the efficiency of gene transfer and substantial commercial investment, this has expanded the clinical horizon and has the potential to transform the field, wrote the investigators.

Gene therapy is usually tolerated well by patients, and relatively few serious adverse events have occurred. Nonetheless, with therapeutic success more common, and potential therapeutic targets that were previously out of technological reach, “patient safety has never been more paramount,” they stressed. “Clinical outcomes are driving new avenues of research to improve the specificity and efficiency of the gene transfer technology while minimizing immunogenicity and undesired off-target effects.”

Among the most crucial safety considerations concern the use of recombinant AAV vectors, which can include toxicity related to high vector doses, immune responses, and vector integration with the potential risk of genotoxicity. Both the American Society of Gene and Cell Therapy and the European Society for Gene and Cell Therapy have discussed these in great detail.^2,3

In terms of diseases addressed so far by gene therapy clinical trials, most have focused on cancer (68.3%); inherited monogenic diseases are second (13.1%). Regarding geographical distribution, the US leads the world in the most trials undertaken: 2054 (52.7%). Next in line is China, with 651 trials (16.7%), followed by the United Kingdom (245; 6.3%), Germany (115; 2.9%), France (66; 1.7%), and Japan (55; 1.4%). Most notable to the authors, they said, is that the number of trials reported as multicountry increased from 130 in 2017 to 301 (7.7%) currently.

“This probably reflects both increased collaborative interaction between research centers as well as the need to access patient populations from more than 1 country, particularly in the case of rare and ultrarare diseases,” they hypothesized.

The diseases in that category are the top issue to be addressed and, eventually, fully resolved in the gene therapy space, they concluded. Rounding out the top 5, in their view, are:

• The ability to manufacture clinical-grade vectors at scale to supply current demand
• The high cost of gene therapy products
• Ensuring equitable access to treatments
• Maintaining a path to the clinic by ensuring freedom to operate

References

1. Ginn SL, Mandwie M, Alexander IE, Edelstein M, Abedi MR. Gene therapy clinical trials worldwide to 2023—an update.J Gene Med.2024;26(8):e3721.doi:10.1002/jgm.3721

2.Sabatino DE, Bushman FD, Chandler RJ, et al; American Society of Gene and Cell Therapy (ASGCT) Working Group on AAV Integration. Evaluating the state of the science for adeno-associated virus integration: an integrated perspective. Mol Ther. 2022;30(8):2646-2663. doi:10.1016/j.ymthe.2022.06.004

3. Gallagher T. Meeting summary: ESGCT 2022 AAV safety plenary session. Hum Gene Ther. 2022;33(23-24):1217-1220. doi:10.1089/hum.2022.29230.tga