Regulatory Trends in the Nonclinical Development of Viral Vector-Based Gene Therapies: A Benchmark Analysis of Approved Products

Main Article Content

Cécile F Rousseau, PhD Arnaud Beurdeley, MSc Déborah Revaud, PhD Emmanuelle M. Voisin, PhD Carlo Chiavaroli, PhD

Abstract

As it is often the case with innovative technologies, regulatory agencies are highly demanding in product safety demonstration from those pioneering breakthrough therapy products. Since the first historically approved gene therapy medicinal product (Gencidine in 2003) by the Chinese National Medicinal Products Administration, gene therapy medicinal products have slowly been emerging in other regions, as illustrated by the first European-approved gene therapy medicinal product (Glybera in 2012) and the first US-approved product (Imlygic in 2015). From then, with the rise of new molecular technologies (e.g., non-viral and viral vector systems), an exponential growth of gene therapies development could be gauged with, for example, the approval of more than thirty gene therapies between 2016-2022.


Using a method based on Preferred Reporting Items for Systematic reviews and Meta-Analyses principle, throughout different literature databases, this review is restricted to the evaluation of viral vector-based gene therapy medicinal products (VV-GTMPs). It also considered relevant guidelines and public assessment reports issued by the EMA and / or the FDA on the products these agencies approved. Then, a benchmark was performed to help stakeholders to identify regulatory trends and to design appropriate nonclinical programs establishing the benefit / risk ratio for patients to be enrolled in clinical trials. The analysis was focused on the nonclinical activities (pharmacology, biodistribution / persistence / shedding, and toxicology) performed by Applicants / Sponsors.


As of 30 March 2023, 18 VV-GTMPs have been authorized by the EMA and 14 by the FDA to treat either orphan diseases or limited number of oncology patients. The majority of these therapies are based on adeno-associated or retroviral viruses (often lentiviruses able to transfect hematopoietic CD34+ cells or T-cells). Based on an analysis of the ongoing clinical trials, there is now a trend for developing gene therapies for larger patient populations.


In conclusion, given the VV-GTMPs diversity and targeted indications, a “one-size fits all” nonclinical development plan cannot be considered by default. Instead, individual, risk-based, tailored nonclinical development programs appear more appropriate to assess such products, taking into consideration the lessons learned from the past. In such fast-evolving environment, regulatory agencies need to adapt their evaluation process very rapidly.

Article Details

How to Cite
ROUSSEAU, Cécile F et al. Regulatory Trends in the Nonclinical Development of Viral Vector-Based Gene Therapies: A Benchmark Analysis of Approved Products. Medical Research Archives, [S.l.], v. 11, n. 5, may 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/3885>. Date accessed: 03 oct. 2024. doi: https://doi.org/10.18103/mra.v11i5.3885.
Section
Research Articles

References

1. EMA. Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials. EMA/CAT/852602/2018. 2019;
2. FDA U. Draft Guidance Human Gene Therapy Products Incorporating Human Genome Editing. 2022;
3. PMDA. Ensuring the Quality and Safety of Gene THerapy Products. 2019;
4. TGA. Accessed 23Mar2023, 2023. https://www.tga.gov.au/advanced-therapies#rat
5. Yin C, Gao J, Li G, et al. Gene and cell therapies in China: booming landscape under dual-track regulation. J Hematol Oncol. Oct 5 2022;15(1):139. doi:10.1186/s13045-022-01354-9
6. Rittie L, Athanasopoulos T, Calero-Garcia M, et al. The Landscape of Early Clinical Gene Therapies outside of Oncology. Mol Ther. Oct 2 2019;27(10):1706-1717. doi:10.1016/j.ymthe.2019.09.002
7. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. Jul 21 2009;339:b2535. doi:10.1136/bmj.b2535
8. Iglesias-Lopez C, Agustí A, Obach M, Vallano A. Regulatory and clinical development to support the approval of advanced therapies medicinal products in Japan. Expert Opinion on Biological Therapy. 2022/07/03 2022;22(7):831-842. doi:10.1080/14712598.2022.2093637
9. Shahryari A, Burtscher I, Nazari Z, Lickert H. Engineering Gene Therapy: Advances and Barriers. Advanced Therapeutics. 2021;4(9):2100040. doi:https://doi.org/10.1002/adtp.202100040
10. Lundstrom K. Viral Vectors in Gene Therapy: Where Do We Stand in 2023? Viruses. Mar 7 2023;15(3)doi:10.3390/v15030698
11. EMA. Skysona, withdrawal of marketing authorization in EU. EMA/706673/2021. 2021;EMEA/H/C/003690
12. EMA. Zynteglo, withdrawal of the marketing authorization in EU. EMA/192892/2022. 2022;EMEA/H/C/003691
13. EMA. Glybera, Expiry of the marketing authorization in EU. EMA/713863/2017. 2017;EMEA/H/C/002145
14. EMA. Zalmoxis, Withdrawal of the marketing authorization in EU. EMA/587151/2019. 2019;EMEA/H/C/002801
15. Zhang WW, Li L, Li D, et al. The First Approved Gene Therapy Product for Cancer Ad-p53 (Gendicine): 12 Years in the Clinic. Hum Gene Ther. Feb 2018;29(2):160-179. doi:10.1089/hum.2017.218
16. EMA. Strimvelis, European Public Assessment Report (EPAR). EMA/CHMP/272303/2016 Rev 1. 2016;
17. FDA U. Yescarta, NDA Assessment Report. STN #125643000. 2017;
18. EMA. Yescarta, European Public Assessment Report (EPAR). EMA/481168/2018. 2018;
19. EMA. Kymriah, European Public Assessment Report (EPAR). EMA/485563/2018. 2018;
20. FDA U. Luxturna, NDA Assessment Report. STN #125610000. 2017;
21. EMA. Luxturna, European Public Assessment Report (EPAR). EMA/CHMP/700911/2018. 2018;
22. FDA U. Zolgensma, NDA Assessment Report. STN #125694000. 2019;
23. EMA. Zolgensma, European Public Assessment Report (EPAR). EMA/200482/2020. 2020;
24. Daya S, Berns KI. Gene therapy using adeno-associated virus vectors. Clin Microbiol Rev. Oct 2008;21(4):583-93. doi:10.1128/CMR.00008-08
25. EMA. EPAR of approved gene therapy products. https://www.ema.europa.eu/en/search/search/field_ema_web_categories%253Aname_field/Human/ema_group_types/ema_medicine?search_api_views_fulltext=approved%20gene%20therapy%20products
26. FDA. Approved Cellular and Gene Therapy Products. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products
27. EMA. Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products. EMA/CAT/80183/2014. 2018;
28. EMA. ICH Topic S 7 A Safety Pharmacology Studies for Human Pharmaceuticals. CPMP/ICH/539/00. 2001;
29. EMA. Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells. EMA/CAT/GTWP/671639/2008 Rev 1 - corr. 2020;
30. EMA. ICH S5 (R3) guideline on reproductive toxicology: Detection of Toxicity to Reproduction for Human Pharmaceuticals. EMA/CHMP/ICH/544278/1998. 2020;
31. Verdera HC, Kuranda K, Mingozzi F. AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer. Mol Ther. Mar 4 2020;28(3):723-746. doi:10.1016/j.ymthe.2019.12.010
32. Sarepta. Sarepta Therapeutics’ Investigational Gene Therapy SRP-9001 for Duchenne Muscular Dystrophy Demonstrates Significant Functional Improvements Across Multiple Studies. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-investigational-gene-therapy-srp-9001
33. Mendell JR, Al-Zaidy S, Shell R, et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. Nov 2 2017;377(18):1713-1722. doi:10.1056/NEJMoa1706198
34. EMA. Glybera, European Public Assessment Report (EPAR). EMA/882900/2011. 2012;
35. EMA. Upstaza, European Public Assessment Report (EPAR). EMA/CHMP/571076/2022. 2022;
36. FDA U. Adstiladrin, NDA Assessment Report. STN #125700000. 2020;
37. EMA. Hemgenix, European Public Assessment Report (EPAR). EMA/46569/2023. 2022;
38. EMA. Roctavian, European Public Assessment Report (EPAR). EMA/685615/2022. 2022;
39. EMA. Imlygic, European Public Assessment Report (EPAR). EMA/734400/2015/ corr 1. 2015;
40. FDA U. Imlygic, NDA Assessment Report. STN #125518000. 2015;
41. EMA. Zalmoxis, European Public Assessment Report (EPAR). EMA/CHMP/589978/2016. 2016;
42. EMA. Zynteglo, European Public Assessment Report (EPAR). EMA/56140/2020/Corr. 2019;
43. FDA U. Zynteglo, NDA Assessment Report. STN #125717000. 2022;
44. EMA. Libmeldy, European Public Assessment Report (EPAR). EMA/584450/2020. 2020;
45. EMA. Skysona, European Public Assessment Report (EPAR). EMA/332184/2021. 2021;
46. FDA U. Skysona, NDA Assessment Report. STN #125755000. 2022;
47. EMA. Tecartus, European Public Assessment Report (EPAR). EMA/588798/2020. 2020;
48. FDA U. Tecartus, NDA Assessment Report. STN #125703000. 2020;
49. EMA. Abecma, European Public Assessment Report (EPAR). EMA/409800/20212021. 2021;
50. FDA U. Abecma, NDA Assessment Report. STN # 125736000. 2020;
51. EMA. Breyanzi, European Public Assessment Report (EPAR). EMA/134759/2022. 2022;
52. FDA U. Breyanzi, NDA Assessment Report. STN #125714000. 2020;
53. EMA. Carvykti, European Public Assessment Report (EPAR). EMA/594558/2022. 2022;
54. FDA U. Carvykti, NDA Assessment Report. STN #125746000. 2021;
55. Regalado A. The World’s Most Expensive Medicine Is a Bust. Accessed 30Mar2023, 2023. https://www.technologyreview.com/2016/05/04/245988/the-worlds-most-expensive-medicine-is-a-bust/
56. Sagonowsky E. With its launch fizzling out, UniQure gives up on $1M+ gene therapy Glybera. Accessed 30Mar2023, 2023. https://web.archive.org/web/20170901212655/http://www.fiercepharma.com/pharma/uniqure-gives-up-1m-gene-therapy-glybera
57. Yildirim S, Kocabas, F. Gene Therapy Products Reached to Market by 2021. Gene Editing. 2021;02:1-21. doi:10.29228/genediting.54101
58. Bulaklak K, Gersbach CA. The once and future gene therapy. Nat Commun. Nov 16 2020;11(1):5820. doi:10.1038/s41467-020-19505-2
59. Gottlieb S. Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies. Accessed 23Mar2023, 2023. https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics
60. Vikita T. Gene Therapy Market by Vector Type (Viral Vector, Non Viral Vector), by Therapy (In Vivo Therapy, Ex Vivo Therapy), by Gene Type (Antigen, Cytokine, Tumor Suppressor, Suicide, Deficiency, Growth factors, Receptors, Others), by Application (Oncological Disorders, Rare Diseases, Neurological Disorders, Other Diseases): Global Opportunity Analysis and Industry Forecast, 2020-2030. Accessed 24Fev2023, 2023. https://www.alliedmarketresearch.com/gene-therapy-market