The COVID-19 pandemic marked a turning point for drug repurposing, bringing an approach that had long occupied a drug discovery niche into the global spotlight. The urgent need for effective therapies against an emerging viral threat drove a surge in funding, research, and development efforts, with support from regulators to identify new therapeutic uses for existing drugs
Building on this momentum, the U.S. Food and Drug Administration (FDA) is now actively involving patients, researchers, and clinicians in efforts to prioritize drug repurposing in areas where commercial incentives remain limited. This renewed interest has extended well beyond infectious disease, with a major emphasis on rare diseases
“Because the safety profile, pharmacology, and manufacturing processes of an existing medicine are often already well understood, development can be faster, less costly, and less risky than developing a completely new drug,” said Claudia Fuchs, PhD, senior manager of drug repurposing projects at EURORDIS, a nonprofit alliance that brings together over 1,000 rare disease patient organizations across Europe
“This is particularly valuable in rare diseases, where patient populations are small and unmet medical needs are often urgent. Repurposing may be especially promising for diseases with well-characterized biological mechanisms, shared molecular pathways across conditions, or strong preclinical evidence supporting a therapeutic effect.”
A recent success story in drug repurposing is nitisinone, a drug originally developed as a herbicide and later approved as a treatment for hereditary tyrosinemia type 1. After 25 years of work by National Institutes of Health (NIH) researchers, nitisinone received FDA approval in 2025 for the treatment of alkaptonuria, becoming the first targeted drug for this ultra-rare metabolic disease. For young patients, this approval made it possible to slow down 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,” Fuchs noted. “These successes illustrate how a better understanding of disease biology can help identify new uses for existing medicines and accelerate access to therapies.”
The challenge now is to create the conditions that allow a steady stream of repurposed therapies to reach those who need them most. Achieving this will require overcoming several barriers: conducting robust clinical trials in the small patient populations typical of rare diseases, navigating regulatory pathways that were not originally set up with repurposing in mind, and creating commercial incentives for industry partners to take a drug with repurposing potential all the way through to approval.
Stakeholders are increasingly coming together to address these challenges. EURORDIS works closely with REMEDi4ALL, an initiative funded by the EU to create an accessible and standardized platform covering all stages of the drug repurposing journey, from securing funding and conducting research to regulatory approval and commercial distribution
“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,” said Fuchs. “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.”
Finding a hit
One of the most crucial steps in drug repurposing is identifying which of the thousands of existing drugs might benefit patients with a given rare disease. Yet until about a decade ago, researchers largely lacked the tools to systematically screen these compounds for new therapeutic uses
In 2015, the Broad Institute of Harvard and MIT created the Drug Repurposing Hub, originally conceived to identify cancer treatments and later expanded into a wider range of indications. At the core of this initiative is a screening library spanning thousands of drugs, which the Hub makes available to academic researchers and nonprofits
“The repurposing library is our number one used library, and not just in rare diseases,” said Jaime Cheah, PhD, associate director of scientific outreach and screening at the Broad Institute’s Center for the Development of Therapeutics (CDoT). “We can screen thousands to hundreds of thousands of compounds in a very robust manner.”
What makes this library so valuable is not just its size, but the depth of annotations available for each compound. This means that when researchers find a hit, they can easily access key information about the drug’s target, mechanism of action, approved indication, or stage of development. Cheah’s team is constantly updating annotations as the drugs advance through clinical development and gain approval for additional indications, while adding new compounds to the library based on user suggestions as they become available.
“It is a continually evolving library,” said Cheah. “Because of the annotations and the overlapping modalities of the drugs, it actually opens up an unbiased ability to look at pathways that might be involved in the disease.”
A library of existing drugs is only the starting point for identifying promising candidates. An often overlooked step is an assay 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; in such cases, the Hub supports library users in developing new testing systems from the ground up. Whenever possible, they work with advocacy groups to collect cells directly from patients to develop assays that more accurately reflect their condition.
As someone who works closely with patients and their families, Cheah spends much of her time helping them understand the many steps required between identifying a promising drug candidate in the library and making a therapy available to patients. Setting clear and realistic expectations around the timeline needed to demonstrate that a drug is both safe and effective, especially when developing treatments for children, helps balance hope with the realities of the drug development process
Moving into the clinic
Although drug repurposing may shorten the journey toward bringing therapies to patients, it remains a complex undertaking. Developers must carefully consider every step involved, from designing assays and validating results to conducting preclinical research, identifying relevant biomarkers, or even adjusting the route of administration depending on the target indication
“Even if someone can identify a hit compound, they may not really know how to get it into the clinic and into the hands of patients,” said Philip Gribbon, PhD, head of discovery research and managing director of the Hamburg location at the Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP)
With three repurposed drugs already in clinical stages, Fraunhofer ITMP works closely with the REMEDi4ALL network to tackle the broad challenges of moving repurposed drugs toward clinical development. Together, they support researchers and advocacy groups in navigating regulatory requirements and generating the evidence needed to demonstrate the efficacy and safety of potential repurposed therapies before they can reach patients
Last year, Gribbon and colleagues published the discovery of 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 compound had previously been tested in Phase III clinical trials as a treatment for schizophrenia, but never made it to the market.
Gribbon is now working to access existing clinical data that could inform future clinical studies of KCNQ2-DEE. Much of his time is spent reaching out to pharmaceutical companies to encourage the sharing of data from drugs they worked on in the past, with the goal of helping to repurpose those compounds for new indications. This work highlights the critical need for researchers and industry partners to align priorities and set up incentives that support data sharing and advance promising drug candidates toward new treatments.
Putting the needs of patients first should remain the shared goal guiding all stakeholders through the drug discovery and development process. “You don’t work with indications, you work with people,” said Gribbon. “We’re really doing this work in order to directly benefit patients who have a significant unmet need where there’s no other treatments available and there are no re
Keeping patients front and center
Nina Frost’s daughter Annabel had her first neurological episode in the delivery room. Two years later, she was diagnosed with alternating hemiplegia of childhood (AHC), an ultra-rare genetic disorder with devastating symptoms resulting from ion imbalances within neurons. Together with her husband, Frost created a nonprofit foundation called Hope for Annabel in 2017 to develop therapeutics for her condition, which was later renamed RARE Hope as the scope scaled to serve a broader range of rare diseases.
“We’ve seen how other families in our situation with rare diseases get thrown into this world with no re Hope, we thought this is something that we can extrapolate across conditions and to benefit more people.”
Advocacy groups like RARE Hope are essential drivers of drug discovery and repurposing efforts, helping researchers define unmet needs, facilitate clinical trial recruitment, design meaningful study endpoints, and provide feedback based on first-hand experience. In many cases, they drive research by funding early-stage preclinical studies and helping de-risk a promising candidate before larger public or private investment becomes available. These patient organizations often foster collaboration among relevant stakeholders, including researchers, clinicians, regulators, industry, and funders, playing a pivotal role in accelerating the drug development pipeline.
“When we started, there were lots of siloed research efforts across different universities that weren’t necessarily communicating with each other,” said Frost. “Over the years, we’ve built this wonderful network of collaborators who really understand the benefit of harnessing each other’s work.”
After completing an MPhil in history and beginning her career in management consulting, Frost now leads an international research program for AHC that brings together multiple patient organizations from around the world. This program has built a large portfolio of research and development projects, spanning mechanistic studies, a patient history database, the validation of new preclinical models, and the development of cutting-edge gene editing and antisense oligonucleotide therapies. In parallel, drug repurposing remains a priority for the foundation because of its potential to reach patients faster than traditional drug discovery.
Going forward, the goal for RARE Hope is to continue expanding its scope to benefit more rare conditions that have historically been neglected by conventional drug development approaches. “We’re looking for ways to harness shared biology across disorders to look for biomarkers and repurposed drugs in parallel,” said Frost. “Finding a way to pool that data and look for drug candidates to treat more patients at once is a big opportunity for the future.”
Giving medicines a second life
As researchers, patient organizations, regulators, and industry come together to bring repurposed drugs to patients in need, the field has seen massive growth in recent years. Advances in artificial intelligence (AI) are expected to accelerate this growth by enabling researchers to analyze increasingly large and complex datasets, allowing them to prioritize the most promising candidates for experimental testing
“The advent of AI is making it much easier to do these kinds of screens,” said Alex Burgin, PhD, senior director at CDoT. AI is now being used to annotate the Drug Repurposing Hub’s library with information from curated sources and to analyze imaging data generated during screening assays. Burgin also highlighted how advances in genetic engineering and the steady integration of AI over the past decade have significantly expanded the Hub’s drug repurposing efforts.Similarly, the Fraunhofer ITMP is recruiting data scientists and developing agentic AI tools to search through public databases to generate hypotheses that researchers can then test and validate. By helping scientists prioritize compounds with a higher chance of success before running more complex, costly, and time-consuming assays, these tools can make drug repurposing workflows faster and more efficient. Gribbon believes that successful drug repurposing will ultimately depend on combined expertise in informatics, experimental biology, and clinical research, with each discipline informing and strengthening the others.
“In the field of drug repurposing, AI is increasingly enabling the analysis and integration of vast amounts of biological, clinical, and real-world data,” Fuchs added. “However, it is important to mention that AI does not replace experimental and clinical validation; it helps prioritize candidates. Rigorous preclinical and clinical studies remain essential to demonstrate safety and efficacy. AI should be viewed as a powerful tool to complement, rather than replace, scientific and clinical expertise.”
As technology continues to improve, the field’s biggest challenge will be the shift from identifying promising candidates to translating them into approved therapies for patients in need. “Over the next decade, I expect drug repurposing to become more systematic, data-driven, and collaborative,” said Fuchs. “To fully realize this potential, we need sustainable incentives, patient involvement from the earliest stages, and clearer pathways to translate promising evidence into accessible treatments for people living with rare diseases.”
Clara Rodríguez Fernández is a science journalist specializing in biotechnology, medicine, deeptech, and startup innovation. She previously worked as a reporter at Sifted and editor at Labiotech, and she holds an MRes degree in bioengineering from Imperial College London
News & FeaturesArtificial intelligenceBiomarkersCOVID-19Drug discoveryDrug RepurposingEncephalopathyRare diseasesSchizophreniaUnited States Food and Drug Administration
