Looking for the Common in Rare

When P.J. Brooks was working in his lab at the National Institutes of Health on two ultra-rare diseases many years ago, he came to the realization that the populations for these conditions were so small that it was unlikely that anyone would develop a treatment for them, even if they had a drug that might benefit people with the condition.

It wasn’t just those two diseases Brooks was studying, but thousands of others as well for which the same could be said as the overwhelming majority of rare diseases are what many people would consider ultra-rare.

With more than 10,000 known rare diseases, about 95 percent of which are without an approved therapy, and there are about 20 to 25 new U.S. Food and Drug Administration drugs approved each year for a rare disease, the limits of developing one drug at a time to treat these conditions become apparent. In addition to the simple math, there’s also the economic reality that ultra-rare diseases face the additional risk of being unable to attract the interest of a drug developer because a given condition may affect so few patients.

The tendency in drug development with the advent of genetic medicine has been to divide diseases into small and smaller populations by addressing their specific molecular mechanisms. While this has given rise to precision medicines, it’s also had the unintended consequence of paring down patient populations—“splitting,” rather than “lumping” as researcher sometimes term it.

The question for Brooks, who is now deputy director in the Division of Rare Diseases Research Innovation at the NIH’s National Center for Advancing Translational Sciences, is how do we get more people access to clinical trials or drugs that may benefit them if their diseases are so rare that they are of no interest to drug companies? The answer may be to look for commonalities between diseases, rather than focusing on what makes them unique. In other words, more lumping and less splitting.

Basket cases

One approach Brooks has advocated is to conduct basket trials in rare diseases. To date, basket trials have been used mostly in cancer. In a basket trial, a single experimental therapy is tested against multiple different diseases at once that may share a common molecular driver, such as a specific type of mutation.

Basket trials in rare diseases have been done, although they come with challenges. The National Center for Advancing Translational Sciences has funded two studies through a Small Business Innovation Research Cooperative Agreement to conduct clinical trials of a single drug in multiple diseases at once. Brooks was the scientific contact on the request for applicants first issued in 2022.

The program, Basket Clinical Trials of Drugs targeting Shared Molecular Etiologies (SaME) in Multiple Rare Diseases, focuses on applying a single therapy to treat multiple rare diseases. Though specific diseases may be caused by an underlying genetic mutation, different diseases may share molecular etiologies, such as triple repeat expansions, signallopathies, epigenetic dysregulation, or nonsense mutations. A single drug may be able to correct such problems even though they occur in different genes from one disease to the next.

“Originally, the idea was how do you get people into clinical trials of drugs that might benefit them even if their disease is so small that, by themselves, no one would start a trial. What would change things a lot, in addition to more people doing it, is if one of these would lead to an actual FDA drug approval,” said Brooks. “That was what made a big deal in oncology. That gave me a lot of confidence that FDA can deal with this.”

He noted that in cancer, the outcomes center on the question of whether a tumor gets bigger, smaller, or stays the same. In the case of rare diseases, there will be a need to contend with diverse clinical outcomes.

“There are ways to deal with that,” he said. “It’s not an insurmountable problem to think about diverse outcomes.”

The program has funded two rare disease basket trials that are preparing to enter the clinic. The first study focuses on two ultra-rare, maternally inherited, mitochondrial diseases: MELAS (mitochondrial encephalopathy, lactic acidosis, stroke-like episodes) and LHON-Plus (Leber’s hereditary optic neuropathy-Plus). The two conditions share an etiology that involves a defective pathway involved in ATP synthesis and results in a chronic energy deficit.

The second study involves primary immunodeficiency diseases that have activating mutations on the JAK/STAT pathway. The study will test a single drug to treat four rare immune disorders caused by defects in different but related molecular pathways involving JAK or STAT. In each case, genetic defects cause dominant activating, gain-of-function mutations that lead to early-onset autoimmunity and immune dysregulation.

A long pursuit
Brooks has long been involved in making a case for rare disease basket trials based on the etiology of diseases. In 2014, he co-authored a paper in the journal Nature Biotechnology that argued for grouping patients by molecular etiology. One example the paper used was nonsense mutations because of premature stop codons, a mutation in a gene that causes the termination of the translation of a gene into a protein. An estimated 11 percent of disease-causing mutations are nonsense mutations. There are now therapies in development that seek to correct nonsense mutations with the potential for a single drug to work across these mutations, regardless of the gene in which they occur.

Missense mutations, which result in abnormal protein folding, are another example. Proteins have three-dimensional structures and when they become improperly folded it can cause a needed protein to become unable to perform its function. Similarly, it’s possible a single drug could be developed to address this problem across genetic mutations.

More recently, Brooks co-authored a paper with other members of an International Rare Diseases Research Consortium (IRDiRC) task force that examined the feasibility of grouping rare diseases around common etiologies to conduct basket trials. That paper found that despite the promise of applying basket trials to rare diseases, its use is still limited and said collaborations between clinicians, industry, regulatory bodies, policy makers, and patients are needed to address the challenges that limit widespread development of these basket trials in rare diseases.

The paper identified key considerations for the use of a basket trial in rare diseases including whether there is sufficient understanding of the biology across multiple rare diseases, understanding of how the molecular alteration influences the natural history of the disease across the lifespan, whether there is a variable disease progression having a large spectrum of genotype–phenotype correlations, and whether patient factors in one or more sub‐groups may affect drug effectiveness.

“While there are thousands and thousands of rare diseases, when you really get down to it, the number of underlying biochemical and molecular problems is a lot smaller,” said Brooks.

Brooks thinks the idea is starting to spread through the rare disease ecosystem. When he attended the World Orphan Drug Conference earlier this year, one large drug company was discussing basket trials in the context of novel therapeutic trial approaches and had a citation to the IRDiRC paper.

Ultimately, he believes, if there are examples of successful rare disease basket trials, others will follow.

“It’s going to take a while because it is a novel approach, but what I would love see is for that to become an option for any clinical trial in rare disease—that you wouldn’t have to have a specific funding opportunity,” said Brooks. “What I would love is that it just would become one of several ways you could do rare disease clinical trials. It would be great if it became the most common way because I think that is the best way to treat the most people.”