Drug repurposing, the practice of finding new medical uses for existing medications, has emerged as a faster and cheaper path to treating rare diseases, but the journey from identifying a promising candidate to getting it into patients' hands remains complex and unpredictable. While the COVID-19 pandemic accelerated interest in repurposing existing drugs for new conditions, experts now face the challenge of creating sustainable systems to move these discoveries through clinical trials, regulatory approval, and commercial distribution.

What Makes Drug Repurposing Attractive for Rare Diseases?

Drug repurposing offers a compelling advantage over developing entirely new medications. Because the safety profile, pharmacology, and manufacturing processes of existing drugs are already well understood, development can be significantly faster, less costly, and less risky. This advantage is particularly valuable in rare diseases, where patient populations are small and unmet medical needs are often urgent.

A recent success story illustrates the potential. Nitisinone, originally developed as a herbicide, received FDA approval in 2025 for treating alkaptonuria, an ultra-rare metabolic disease, after 25 years of work by National Institutes of Health researchers. For young patients, this approval made it possible to slow disease progression and reduce the need for repeated joint surgeries. Other notable examples include everolimus for tuberous sclerosis complex, alpelisib for PIK3CA-related overgrowth spectrum, and sirolimus for rare vascular anomalies.

Why Do Researchers Struggle to Identify Repurposing Candidates?

Until about a decade ago, researchers lacked systematic tools to screen thousands of existing drugs for new therapeutic uses. The Broad Institute of Harvard and MIT addressed this gap in 2015 by creating the Drug Repurposing Hub, originally designed to identify cancer treatments and later expanded to cover a wider range of conditions. The Hub maintains a screening library spanning thousands of drugs and makes it available to academic researchers and nonprofits.

What makes this library particularly valuable is not just its size, but the depth of information attached to each compound. When researchers identify a promising candidate, they can immediately access key details about the drug's target, mechanism of action, approved indication, and stage of development. The library is continuously updated as drugs advance through clinical development and gain approval for new uses.

"The repurposing library is our number one used library, and not just in rare diseases. We can screen thousands to hundreds of thousands of compounds in a very robust manner," said Jaime Cheah, associate director of scientific outreach and screening at the Broad Institute's Center for the Development of Therapeutics.

Jaime Cheah, Associate Director of Scientific Outreach and Screening, Broad Institute's Center for the Development of Therapeutics

What Barriers Stand Between Discovery and Patient Access?

Even after identifying a promising drug candidate, researchers face multiple obstacles before a therapy reaches patients. These barriers span scientific, regulatory, economic, and practical domains:

• Clinical Trial Design: Conducting robust clinical trials in small patient populations typical of rare diseases requires careful study design and often takes longer than trials for common conditions.
• Regulatory Navigation: Regulatory pathways were not originally designed with drug repurposing in mind, creating confusion about which approval processes apply to repurposed drugs.
• Commercial Incentives: Industry partners must be convinced that a repurposed drug is worth taking all the way through to approval, which can be challenging when patient populations are tiny and market potential is limited.

An often overlooked step is developing an assay, or test, that can determine whether a drug produces a meaningful effect in a relevant disease model. Especially in rare diseases, such assays may not yet exist. When this is the case, the Broad Institute's Hub supports researchers in developing new testing systems from the ground up, often working with patient advocacy groups to collect cells directly from patients to create assays that more accurately reflect their condition.

How Are Stakeholders Working Together to Overcome These Challenges?

Recognizing that drug repurposing requires coordinated effort, stakeholders are increasingly collaborating to address systemic barriers. EURORDIS, a nonprofit alliance representing over 1,000 rare disease patient organizations across Europe, works closely with REMEDi4ALL, an initiative funded by the European Union to create an accessible and standardized platform covering all stages of the drug repurposing journey.

"For many rare diseases, our understanding of the underlying biology and disease mechanisms has advanced significantly in recent years. However, translating this knowledge into approved therapies remains challenging. Drug repurposing faces scientific, regulatory, economic, and practical challenges. Addressing these barriers requires greater collaboration and a shift towards more patient-centered and translational research," explained Claudia Fuchs, senior manager of drug repurposing projects at EURORDIS.

Claudia Fuchs, Senior Manager of Drug Repurposing Projects, EURORDIS

The Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP) in Hamburg also plays a key role in this ecosystem. With three repurposed drugs already in clinical stages, the institute works closely with the REMEDi4ALL network to support researchers and advocacy groups in navigating regulatory requirements and generating the evidence needed to demonstrate efficacy and safety.

Steps to Move a Repurposed Drug Toward Clinical Development

• Screen Existing Compounds: Use comprehensive drug libraries to systematically identify which existing medications might benefit patients with a specific rare disease, leveraging annotated databases that provide detailed information about each drug's properties and history.
• Develop Relevant Assays: Create or adapt disease models and testing systems that accurately reflect the condition in question, ideally using patient-derived cells to ensure the assay captures the real-world biology of the disease.
• Conduct Preclinical Research: Perform laboratory and animal studies to validate that the drug produces a meaningful effect, identify relevant biomarkers, and determine the optimal route of administration for the new indication.
• Navigate Regulatory Pathways: Work with regulatory agencies to clarify which approval processes apply to the repurposed drug and gather the specific evidence needed to support a regulatory submission.
• Design Clinical Trials: Plan and execute clinical trials appropriate for small patient populations, often requiring innovative trial designs and close collaboration with patient advocacy groups to ensure feasibility and relevance.

A recent example demonstrates the complexity of this process. Researchers at Fraunhofer ITMP discovered an unexpected new use for an investigational drug as a potential treatment for KCNQ2-related developmental and epileptic encephalopathy (KCNQ2-DEE), a rare and severe form of childhood epilepsy. While searching for compounds that could target ion channels affected by the disease, the team found that an antipsychotic drug, originally developed for a different molecular target, showed promising activity.

The challenge now is to create the conditions that allow a steady stream of repurposed therapies to reach those who need them most. This requires not just scientific innovation, but also systemic changes in how funding is allocated, how regulatory pathways are designed, and how commercial incentives are structured to support work in areas where patient populations are small but medical needs are profound.