The European landscape for gene therapies in orphan diseases: 6-year experience with the EMA Committee for Orphan Medicinal Products

Abstract

In 2000, the European Union (EU) introduced the orphan pharmaceutical legislation to incentivize the development of medicinal products for rare diseases. The Committee for Orphan Medicinal Products (COMP), the European Medicines Agency committee responsible for evaluation of applications for orphan designation (OD), received an increasing flow of applications in the field of gene therapies over the last years. Here, the COMP has conducted a descriptive analysis of applications regarding gene therapies in non-oncological rare diseases, with respect to (a) targeted conditions and their rarity, (b) characteristics of the gene therapy products proposed for OD, with a focus on the type of vector used, and (c) regulatory aspects pertaining to the type of sponsor and development, by examining the use of available frameworks offered in the EU such as protocol assistance and PRIME. It was noted that gene therapies are being developed by sponsors from different backgrounds. Most conditions being targeted are monogenic, the most common being lysosomal disorders, and with a very low prevalence. Generally, adeno-associated viral vectors were being used to deliver the transgene. Finally, sponsors are not frequently using the incentives that may support the development and the reasons for this are unclear.

Keywords: COMP; EMA; PRIME; gene therapy; orphan designation; orphan medicinal product; prevalence; rare diseases; regulatory incentives; viral vector-based medicines.

Graphical abstract

Figure 1

Distribution of conditions for viral vector-based gene therapy products submitted for orphan medicinal product designation Analysis of the proportion of applications per therapeutic area. The total number of OD applications was 114.

Figure 2

Characteristics of the orphan medicinal products in EU and in other regions (A) The sponsor at the time of initial OD was classified in 4 different categories. Data shown as percentage. (B) Distribution of the type of sponsor per year at the time of initial OD. (C) Proportion of OD applications categorized according to the prevalence of the orphan condition. (D) Comparative table showing viral vector-based orphan designated products, as shown in the Community Register (after COMP/EMA opinion) and in the FDA (for the United States), for the period 2016–2021. No gene therapy medicinal products obtained OD in Japan, from January 1, 2016, until July 31, 2018 (no updates are available after this date).

Figure 3

In-depth analysis of the products assessed by the COMP (A) Distribution per year of viral-based vectors used for gene replacement purposes in OD applications between 2016 and 2021. (B) Proportion of OD applications regarding the treatment modality (in vivo/ex vivo). (C) Number of viral-based vectors used per treatment modality. (D) AAV serotype distribution per year. The term “others” encompass novel serotypes such as serotype 2.5T, 2.7m8, 3B, Anc80, HSC15, hu37, hu68, LK03, PTC3, rh10, rh74, and S3.

Figure 4

Use of regulatory incentives (A) Proportion of orphan designated medicines which have received PA during the product development. (B) Proportion of orphan medicinal products that have been included in the PRIME scheme. (C) Comparative table of the number of scientific advice and PRIME applications per type of sponsor. (D) Percentage of transfers of the initial OD. Some transfers could be ascribed to Brexit and are shown as a separate category. (E) Distribution of the transfers of the ODs according to the source and destination.