Rare Disease Drug Repurposing

Treatments are urgently needed for the more than 9500 rare diseases with no US Food and Drug Administration-approved therapies. Although repurposing can be less time- and cost-intensive compared with novel drug development, hurdles have impeded systematic repurposing. Rare disease nonprofit organizations (RDNPs) are well-positioned to overcome barriers and have spearheaded rare disease repurposing efforts for decades. However, no comprehensive data are available on the state of rare disease repurposing or features of successful efforts.

To characterize the state of rare disease drug repurposing, identify factors associated with successful outcomes, and share thematic insights using the interactive Repurposing of All Drugs, Mapping All Paths (ROADMAP) Project web tool.

The ROADMAP study was a qualitative study using a mixed-methods analysis of US-based RDNP leaders and their stakeholders, including a national survey and semistructured interviews of RDNP leaders, conducted from September 29, 2021, to January 6, 2022. Surveys and interviews revealed themes associated with RDNP strategies, timelines, and support mechanisms. Data were analyzed from January 22, 2024, to April 23, 2024.

The primary survey outcome was the repurposing project stage (abandoned, early, clinical, late, or successful). Qualitative outcomes included themes characterizing repurposing experiences. Two random forest models of drug- and disease- specific as well as organization-specific variables were used to evaluate factor importance toward inferring the project stage. Orthogonal significance testing was conducted using Spearman rank correlation, and P values in each model were corrected for multiple hypothesis testing using a Benjamini-Hochberg procedure.

Representative organizations submitted survey responses, including 147 of 698 potential US-based RDNPs. The median RDNP age was 10 years (IQR, 5-20 years), and the median annual revenue was $355 390 (IQR, $90 028-$946 108). Among 34 leaders who were interviewed, representing 25 RDNPs, 23 were female (67.6%), and the RDNPs had a median age of 15 years (IQR, 6-19 years) and a median revenue of $670 719 (IQR, $193 587-$1 830 890). Among the surveyed RDNPs, 58 of 138 (42.0%) specifically identifying their involvement in repurposing supported repurposing projects, and 94 drugs were in various stages of repurposing, of which 23 met success criteria (5 with US Food and Drug Administration approval and 18 with off-label use with subjective benefit). Survey factors associated with successful outcomes included nonprofit-supported patient recruitment into trials (Gini importance, 3.90; ρ = 0.50; adjusted P < .001) and provision of nonfinancial research support (Gini importance, 0.69; ρ = 0.33; adjusted P = .02). Interview themes were synthesized into a 5-stage repurposing framework with roadblocks and recommendations that included (1) enabling drug repurposing, (2) identifying a drug therapy, (3) validating a drug therapy, (4) clinical use and testing, and (5) reaching an optimal end point for clinical practice.

The findings of this qualitative study of RDNP repurposing suggest that several opportunities were associated with successful outcomes and can be considered to optimize systematic repurposing among RDNPs, external collaborators, and policymakers with the use of an interactive tool showcasing insights to facilitate data-driven drug repurposing.