Rare Disease Drug Repurposing

Abstract

Importance: 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.

Objective: 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.

Design, setting, and participants: 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.

Main outcomes and measures: 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.

Results: 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.

Conclusions and relevance: 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.

Figure 1.. Identification of US-Based Rare Disease Nonprofit Organizations (RDNPs) and the Repurposing of All Drugs, Mapping All Paths (ROADMAP) Project Study Execution

The ROADMAP survey was administered to RDNP mailing lists and email addresses from a list of 698 US-based RDNPs that qualified for the study. This list was assembled by a team of more than 70 trained volunteers following extraction from existing lists of RDNPs and searches of public databases. The same team extracted public data from the websites of these RDNPs to characterize the surveyed cohort; 1 author (S.N.) later extracted GuideStar Pro (Candid) data on all entries. Among ROADMAP respondents, 147 unique, US-based RDNPs were represented, 25 of which participated in hour-long, semistructured interviews. Insights from interviews and survey data iteratively informed the development of a framework for data-driven drug repurposing (DDDR). NORD indicates National Organization for Rare Disorders.

Figure 2.. Case-Based Applications of the Data-Driven Drug Repurposing (DDDR) Framework

Abbreviated timelines of cases of rare disease repurposing, including the use of selumetinib in neurofibromatosis type 1 (NF1) and nitisinone in alkaptonuria (AKU), are shown. Each case highlights unique paths and considerations while repurposing a drug and the importance of drug and disease profile factors (eg, generic vs on-patent drugs, previous regulatory standards for rare disease). These paths are mapped to the themes and stages comprising a DDDR framework, conceptualizing rare disease nonprofit organization–supported repurposing experiences. CDER indicates Center for Drug Evaluation and Research; CDMRP, Congressionally Directed Medical Research Programs; CTF, Children’s Tumor Foundation; EMA, European Medicines Agency; FDA, US Food and Drug Administration; MEK, mitogen-activated protein kinase kinase; NCI, National Cancer Institute; NIH, National Institutes of Health; NTAP, Neurofibromatosis Therapeutic Acceleration Program; PN, plexiform neurofibroma.