Drug repurposing in rare diseases | A new DREAMS-supported study published in Drug Discovery Today examines what happens between clinical evidence and regulatory approval, revealing persistent barriers in the translation of repurposed drugs for rare diseases.
Drug repurposing starts from a relatively simple idea: finding a new therapeutic use for a drug that has already been approved or investigated for another indication.
For rare diseases, the approach is particularly relevant. Around 95% of rare diseases still lack an approved therapy, according to the new study, and developing treatments is complicated by small and geographically dispersed patient populations, clinical heterogeneity, limited biomarkers and the economics of developing medicines for very small populations.
Repurposing can build on existing pharmacological and safety data, potentially reducing some of the time, cost and risk associated with developing a medicine from scratch. But a promising clinical result does not automatically translate into an approved treatment.
A new study supported by the DREAMS project has examined that gap.
Published in Drug Discovery Today, “Bridging the translational gap in drug repurposing for rare diseases: clinical success versus regulatory conversion” maps 47 clinical trials of repurposed drugs for rare diseases and tracks how often clinical evidence ultimately translated into marketing authorisation.
For 46 of the 47 trials analysed, the target disease had no curative treatment available at the time of the study.
What happens after a repurposed drug shows promise?
The researchers identified 47 clinical trials investigating already-authorised compounds for new rare disease indications.
Most were relatively advanced studies. Almost half were Phase II or II/III, close to 30% were Phase III, and 73% used randomised designs. Neuromuscular and neurogenetic disorders represented the largest diagnostic group in the analysis, accounting for 34% of the studies. Another 34% targeted ultra-rare conditions.
Of the 38 trials that had been completed at the time of the analysis, 25, or 66%, met their predefined primary or key secondary endpoints.
But that figure requires some caution.
The authors describe the 66% as an upper-bound estimate, partly because two-thirds of the studies in the overall cohort were identified through web-based searches, where positive findings can be disproportionately represented. The result also varied considerably according to study design: 56% of randomised/blinded trials met the efficacy criteria, compared with 85% of open-label or non-blinded studies.
The regulatory picture was different again.
Only 15 of the 38 completed studies, or 39%, achieved marketing authorisation from at least one of the two regulatory agencies examined. Twelve received EMA authorisation and 12 FDA approval, while nine, 24%, were authorised by both.
When the researchers restricted the analysis to the 34 completed Phase II-IV trials, 44% had achieved marketing authorisation from at least one agency.
The figures reveal the central issue explored by the study: evidence of efficacy and regulatory conversion are two different milestones in the drug repurposing pathway.
The “Sponsor gap”
One of the clearest patterns appeared when the researchers examined who sponsored the trials.
Academic organisations accounted for 64% of the 47 studies analysed. Yet among completed studies, 18% of academic-sponsored trials achieved marketing authorisation from at least one agency, compared with 69% of industry-sponsored trials.
Industry was responsible for 75% of the studies obtaining EMA authorisation and 67% of those obtaining FDA approval.
The distinction became even more pronounced when the researchers looked at who ultimately held the European marketing authorisations. Three academically sponsored trials were associated with EMA approvals, but in each case the Marketing Authorisation Holder was an industry entity. As a result, industry held all 12 EMA marketing authorisations in the cohort.
The authors describe this imbalance as a “Sponsor gap”.
The study does not establish that industry sponsorship itself causes regulatory success. Instead, the authors discuss several structural factors that may help explain the difference, including access to late-stage development funding, regulatory expertise, lifecycle ownership and commercial incentives.
They also acknowledge a potential selection effect: industry may preferentially invest in candidates that are already at a later stage of development, patent-protected or considered commercially attractive.
Patents are only part of the picture
Intellectual property is another important factor.
83% of the compounds included in the study were off-patent. Without sufficient commercial protection, the authors explain, promising compounds can become what they describe as “regulatory orphans”, lacking the financial incentive needed to support costly clinical validation and regulatory development.
But patent status alone did not explain the differences observed between academic and industry-sponsored programmes.
Even among off-patent compounds, industry-sponsored programmes achieved approval more than three times as often as academic-sponsored ones: 54% compared with 15%.
This suggests that the translational gap identified in the study extends beyond intellectual property alone, involving the wider infrastructure and incentives needed to take a programme through late-stage development.
The same evidence can face different regulatory pathways
Another challenge is that regulatory outcomes are not necessarily identical across jurisdictions.
The study documents several cases in which the EMA and FDA reached different outcomes for repurposed medicines.
Idebenone, for example, has been authorised by the EMA for Leber hereditary optic neuropathy since 2015, while the FDA issued a Complete Response Letter in February 2026 and the drug is not currently approved in the United States for that indication.
For alpelisib, the FDA granted accelerated approval for PIK3CA-related overgrowth spectrum based on single-arm data and real-world evidence, while the European marketing authorisation application was withdrawn.
The paper also examines regulatory differences involving miglustat, bosentan, sodium phenylbutyrate and imatinib.
These individual cases illustrate how differences in regulatory pathways, evidentiary requirements and benefit-risk assessments can contribute to different outcomes.
The authors therefore highlight early engagement with regulators, including mechanisms such as EMA-FDA Parallel Scientific Advice, as one possible way to better align development strategies.
A second gap: finding the evidence
The study uncovered another challenge before regulatory translation even enters the picture: identifying drug repurposing research in the first place.
Only six of the 47 studies, 12%, were initially identified through conventional bibliographic database searches using standard repurposing terminology.
Ten were found through clinical trial registries. The remaining 31 studies, 66%, were identified through web-based searches or grey literature.
The authors describe this as a “visibility gap”.
Relevant evidence can remain dispersed across trial registries, meeting abstracts, institutional communications and other sources rather than being consistently indexed as drug repurposing research in conventional scientific databases.
This fragmentation makes it harder to build a complete picture of what has already been tested, including negative or discontinued studies. Indeed, the authors acknowledge that the 47 studies should be considered a representative cross-section rather than an exhaustive census of clinical drug repurposing activity in rare diseases.
How can the translational gap be narrowed?
The study does not point to a single solution. Instead, it identifies opportunities across different stages of the development pathway.
Earlier in that pathway, more physiologically relevant patient-derived models and AI-driven approaches could strengthen candidate identification. The authors note that advances in areas such as protein structure prediction, virtual screening, multi-omics and systems biology are expanding the ways in which potential repurposing opportunities can be identified.
Further along the pathway, innovative clinical trial designs, earlier regulatory engagement, stronger academic-industry partnerships and better incentives for off-patent compounds could help promising programmes progress towards marketing authorisation.
For ultra-rare diseases, the paper also discusses the potential of N-of-1 trials, which can use patient-specific molecular information and functional screening to match authorised drugs to an individual patient. None of the 47 studies analysed used an N-of-1 design, however, and the authors note that these approaches also challenge regulatory frameworks designed around larger-scale validation.
Several initiatives are already addressing different parts of this landscape. The study highlights REMEDi4ALL, the EMA’s Medicine Repurposing Pilot and PRIME, alongside European research consortia including REPO4EU, SIMPATHIC and DREAMS.
Taken together, the analysis points to substantial therapeutic potential, but also persistent friction between clinical research and regulatory translation.
Moving a repurposed drug forward requires more than identifying a promising candidate or generating positive clinical evidence. It also requires the development capacity, regulatory expertise, incentives and partnerships needed to turn that evidence into an authorised indication.
A DREAMS-supported study
The study was supported by DREAMS – Drug REpurposing with Artificial intelligence for Muscular disorderS, funded by the European Union’s Horizon Europe research and innovation programme under Grant Agreement No. 101080229.
Several of its authors are directly involved in DREAMS. Lead author Wael Khazen, a clinical scientist and senior clinical project manager at AFM-Téléthon, is an active member of the consortium and contributes to the design of innovative clinical trials. Alexandre Méjat, Head of the International Scientific Networks Department at AFM-Téléthon, leads DREAMS Work Package 6, which focuses on the clinical translation of repurposed therapies.
The publication also acknowledges members of the DREAMS Clinical Expert Committee and the project coordinator for their insights and contributions.
By quantifying what happens between clinical investigation and regulatory authorisation, the study provides evidence on a critical part of the wider drug repurposing pathway: how promising research can move towards formal approval in rare diseases.
Read the full publication
Bridging the translational gap in drug repurposing for rare diseases: clinical success versus regulatory conversion
Authors: Wael Khazen, Arnaud Valent, Samantha Parker, Solange Corriol-Rohou, Teresinha Evangelista, Xavier Nissan and Alexandre Mejat
Journal: Drug Discovery Today
Year: 2026
DOI: 10.1016/j.drudis.2026.104807
Read the publication in Drug Discovery Today →
