Drug Repurposing May Benefit Rare Disease, Considerations, and Caveats

February 06, 2023 - The Orphan Drug Act of 1983 defines a rare disease as a medical condition that impacts less than 200,000 people in the United States. Despite the restrictive nature of this definition, the Genetic and Rare Diseases Information Center of the NIH estimates that roughly 7,000 known rare diseases affect nearly 10% of the population in the US. Drug repurposing may benefit rare diseases by providing more treatment options. With many potential benefits, researchers and advocates for drug repurposing must understand the considerations and caveats associated with this pharmaceutical practice.

Rare Disease Research

According to the National Organization for Rare Diseases (NORD), approximately 95% of rare diseases do not have a treatment. As a result, the Rare Genomics Institute estimates that rare diseases account for 35% of deaths in the first year of life, and 30% of patients with a rare disease in childhood will not live to the age of five.

The jarring statistics around rare diseases have made them a particular area of interest for researchers and healthcare professionals — especially those who encounter patients with rare diseases. Despite the sparked interest in rare diseases, they present unique challenges throughout the research and drug discovery process.

“One of the first challenges with rare diseases is that they're rare, and so there will be fewer patients, fewer samples, and more limited resources to do research,” explained David Fajgenbaum, MD, MBA, MSc, cofounder of Every Cure, assistant professor of medicine, Translational Medicine & Human Genetics, founding Director of the Center for Cytokine Storm Treatment & Laboratory (CSTL), and associate director of Patient Impact, Orphan Disease Center, University of Pennsylvania. “Further, because these diseases are rare and little work has been done, there's very little understanding, in many cases, around the basic mechanisms underlying these diseases.”

In addition to the challenges with gathering information, Fajgenbaum notes that there are additional layers of difficulty in incentivizing drug companies and manufacturers to develop drugs for this disease. He notes that being able to tack a high price onto the drugs may provide an incentive in some cases; however, if the drug already exists and can be sold in a cheap, generic form, many companies have no incentive to fund studies researching the medication.

“There are diseases, like systemic sclerosis or Castleman's, where there's an apparent mechanism showing that a drug could be useful, but there's no financial incentive for a company to come in and do the work,” said Fajgenbaum.

“In any case, developing a new drug is extremely challenging. But, when considering rare diseases, it's even more challenging,” added Michelle Longmire, MD, CEO and co-founder of Medable. “Companies aren't developing drugs where there is no financial incentive, but when a patient is living with that condition, that's an irrelevant point. They want a cure or treatment. Most importantly, they want to live.”

Drug Repurposing

Longmire and Fajgenbaum — and their respective organizations — have collaborated extensively to develop solutions for these challenges associated with rare diseases. Through clinical data, research, and personal experiences, the two collaborators have landed on a shared understanding of drug repurposing as a tool to expand rare disease treatment and research.

“Drug repurposing is the fancy term used to describe taking a drug that was made for one thing and finding new uses for it,” explained Fajgenbaum. “Often, when people hear repurposing, they think that the first purpose was the best, but that's not necessarily the case. It's just the first purpose that that company decided to take.”

He explained that once developed, some drugs may have better or more significant purposes than the one for which it was initially intended. Fajgenbaum adds that the first step of drug repurposing is to make drug–disease matches. For example, Every Cure finds drug–disease matches through knowledge graphs that generate scores linking drugs and diseases.

“There are 3,000 FDA-approved drugs and 12,000 human diseases, meaning there are 36 million drug–disease links,” emphasized Fajgenbaum. “The first step is determining the strongest drug disease links and validating them in the laboratory or using real-world data.” Sometimes, real-world data can be gathered if patients are already exposed to the drug, allowing researchers to collect early data on whether or not the medication is promising.

Drug Repurposing in Clinical Trials

Clinical trials are one of the pillars of the pharmaceutical industry in the US. The FDA uses clinical trial data to approve or deny approvals on certain drugs. While similar to clinical trials for new medications, drug repurposing clinical trials have some unique benefits and challenges.

“One of the challenges of a clinical trial is that it tends to be very cost-intensive,” noted Longmire. “With that said, the clinical trial process around a repurposed drug isn't that different, but in terms of the evidence, researchers want to prove that it is efficacious and positively impacts the patient.”

The upside of these clinical trials is that the drugs are known to be safe, alleviating one of the financial burdens. Longmire explained that safety monitoring can be a significant financial burden during clinical trials; however, safety data already exists for repurposed drugs. 

“Of course, we're always looking for safety, but the majority of the effort is to show that this drug has an impact on this disease from an efficacy perspective,” reiterated Longmire. “That’s a critical differentiator when looking at the investments needed to bring value for these patients and understand if these will make patients healthier living with these conditions.”

Decentralized Clinical Trials

Considering the rarity of these diseases and the difficulty researchers may have finding participants for studies and clinical trials, remote or decentralized clinical trials are a natural solution to existing conflicts.

“One of the advantages of decentralized clinical trials is that we can connect with a patient regardless of where they are,” noted Longmire. Decentralized clinical trials can remove the barrier of geography, a significant historical barrier throughout clinical trials.

“Through remote clinical trials, researchers are connecting with patients in their own homes and their own communities,” added Longmire. With existing safety data, trials on repurposed drugs are the perfect fit for decentralized clinical trial models.

Additionally, remote clinical trials can help ensure that the study population accurately reflects the patient population by including participants from all backgrounds. Across the US, clinical trial diversity — or lack thereof — has been a critical concern for many clinicians. 

“Only 7% of research participants come from a diverse background as a general broad look at the problem. With that said, decentralized clinical trials will open up that access point,” explained Longmire.

Barriers to Drug Repurposing

Although drug repurposing theoretically has many benefits for patients, several barriers prevent it from becoming widely used. Fajgenbaum explains that the unavailability of a central database, the current pharmaceutical business model, and a lack of government oversight all present barriers to drug repurposing.

“There is no database that tracks all potential uses of all drugs. There's not even a good database that tracks all drug approvals,” said Fajgenbaum. He explained that people, including researchers and medical professionals, often have to do a lot of digging to get data on a specific drug.

Another challenge preventing the practice of drug repurposing from becoming more widespread is the current pharmaceutical business model. Longmire and Fajgenbaum emphasized that, when the drug is cheap and the disease is rare, the profitability for pharmaceutical companies is not favorable, disincentivizing them from enhancing research.

Fajgenbaum explained that while a pharmaceutical company could put money into drug repurposing trials if the same drug and dose exist in a generic form, any pharmacist can give the patient a generic form instead of the brand name. As a result, pharmaceutical companies will have put a lot of time and money into finding a new use for the drug, and the branded version won’t sell.

“That's where researchers and healthcare providers have to be creative,” said Fajgenbaum. “We have to be creative because I don't know how to make the math add up to persuade a company to do a trial if the disease is rare and the drug is cheap. If we can do a clinical trial efficiently and effectively with a safe drug, then we can change the paradigm and make sure that that patient gets the drug and all patients of that disease get the drug, whether or not we're able to incentivize a company.”

Fajgenbaum explained that another barrier to the widespread use of drug repurposing is that no federal governing organization ensures that all drugs are used for every disease they can benefit from.

“That might be surprising to some people because we think about FDA as being the gatekeeper in terms of being the regulators. They’re deciding what gets approved and what doesn't,” he explained. “But the problem is they're only responsible for deciding what gets approved among the things presented to them.”

Addressing Barriers to Drug Repurposing

As part of the suggestions provided by Longmire and Fajgenbaum, Fajgenbaum recommended building a database to compile potential matches, as Every Cure is doing.

“This is an obvious place where the government could lean in to build that central harmonized data infrastructure, which is something we're building through Every Cure, and we're excited to partner with federal partners,” he said.

Fajgenbaum also believes there are ways to adjust the business model, incentivizing companies to partake in drug repurposing. One example he notes is providing manufacturers and pharmaceutical companies with vouchers for doing this kind of work.

“The world that we're trying to create is a world where every drug approved for one thing is also approved and used for all the other things it can help,” commented Fajgenbaum. “We should be in a world where, if it's at a pharmacy, it can be used for everything it can help. It's not just one drug, one disease, but it's one drug, all diseases possible.”