Genetic diseases, like cystic fibrosis and sickle cell disease, can be devastating to the people afflicted by them, but they often affect few people. The exact cutoffs vary from nation to nation, but in the United States, a rare disease is defined as one that afflicts fewer than 200,000 Americans. Most of these diseases are genetic, and nearly 85 percent of them are “ultra-rare,” with a prevalence of less than one patient for every one million people. Although each disease affects few people, the cumulative health burden of rare diseases is significant. The global prevalence of rare disorders is estimated to be between four and six percent, meaning that about 350 million people worldwide are living with a rare disease. In the US, around 7,000 known rare and ultra-rare diseases affect 30 million people.

Many of these conditions are life-threatening. For instance, cystic fibrosis can cause frequent lung infections, and sickle cell disease can cause anemia. In many cases, symptoms can progress rapidly if left untreated. However, treatment options are often limited. Most rare diseases still have no FDA-approved treatment because, for many, there are simply too few patients for drugs to be profitable. Ophir Klein, a professor of orofacial sciences and pediatrics and a clinical geneticist at the University of California, San Francisco, describes the challenge this way: “Developing therapies is expensive and time consuming, and drug companies are largely not incentivized to spend the resources needed for very small numbers of patients—the economics just don’t make sense.”

Over the past 40 years, US federal policy has aimed to improve treatment options for rare disease patients by offering private companies financial incentives and reducing testing demands. The Orphan Drug Act of 1983gave drug manufacturers development incentives and market exclusivity for “orphan drugs,” that treat rare diseases. Today, rare disease treatments represent an increasing share of new drug approvals, suggesting that these incentives are effective.

Still, patients, particularly those with ultra-rare diseases, face a number of hurdles to obtaining treatment. They are geographically dispersed, making large clinical trials impossible. The underlying mutations that cause their diseases are often variable, meaning that treatments may vary for patients afflicted with the same symptoms. Testing is often necessary for diagnosis, and disease progression can be so rapid that there is little time for treatment between diagnosis and mortality. And when treatments are available, access to drugs is often inequitable and expensive.

These challenges have required regulators, private companies, and other stakeholders to become more creative about drug development and to rethink the drug development pipeline itself.

Emerging strategies: repurposing drugs and reusing platforms

One pathway to decrease the cost of drug development for ultra-rare diseases is to repurpose existing FDA-approved drugs. Klein’s lab is currently trying to identify candidate drugs for treating MEPAN syndrome, a rare genetic neurological disorder. Recent work showed that MEPAN is caused by mutations in the gene MECR. The mutations disrupt mitochondrial fatty acid synthesis, which degrades the mitochondria—cellular components that turn oxygen into energy. The neurons that initiate movements and receive sensory information are often most affected by this degradation, and the disease leads to the progressive onset of motor and vision issues in childhood. Klein’s lab made yeast lines that carry the same MECR mutations found in patients, and they observed an expected decrease in mitochondrial activity. They then screened a panel of FDA-approved drugs and found that some drugs restored mitochondrial activity in mutant yeast. Next, they plan to determine which of these candidates improves mitochondrial activity in cells from MEPAN patients, with the eventual goal of doing a human clinical trial. For this project, Klein’s lab is collaborating with Perlara, a company that has had previous success with this repurposing approach. To find a treatment for the congenital disease PMM2-CDG, Perlara screened approved drugs in both worms and patient cells that have mutations in the gene PMM2, which plays an important role in ensuring the proper functioning of proteins. They identified the drug epalrestat, which is already approved for treatment of diabetic neuropathy in Japan.  A 40-patient phase III clinical trial is currently underway to test if epalrestat improves outcomes in PMM2-CDG patients.

Still, drug repurposing is not always the most fruitful strategy for developing ultra-rare disease treatments. In some cases, the best option for treating an ultra-rare disease involves targeting a specific mutation that is responsible for a disorder of interest. For instance, antisense oligonucleotides (ASOs) are small strands of genetic material that bind to particular sequences of RNA or DNA. Although ASOs are disease-specific, the platform, or the development and delivery methodology, for an ASO could be reused. John Massarelli, who manages a project on the Bioethics of Individualized Therapeutics (B.I.T.) in the Division of Medical Ethics at the NYU Grossman School of Medicine, says, “Due to the overwhelming number of rare genetic diseases lacking treatments, there have been efforts to repurpose existing treatments for new indications or to develop a platform approach that would enable the treatment of a variety of genetic diseases via a common therapeutic modality.”

The nonprofit n-Lorem Foundation makes individualized ASOs for ultra-rare diseases that affect between one and 30 patients. Started in 2020 by Stanley Crooke, former CEO of Ionis Pharmaceuticals, the organization’s goal is to go from disease diagnosis to drug dosing in less than one year. Currently, the FDA treats new ASOs as repurposed drugs, which helps reduce the duration of preclinical studies. However, current regulations do not permit commercialization of ASOs, so ASO therapy will continue to rely on philanthropy unless the FDA begins granting approval to ASOs as a single product.

Is this treatment or research?

Traditionally, a clear line is drawn between the evidence-gathering and patient-treatment phases of drug development. But trials for ultra-rare diseases blur the line between research and therapy, requiring new approaches to balance data collection with patient access. Multiple FDA programs grant accelerated review to important new therapies. For instance, the FDA’s Accelerated Approval program, which was first established in 1992, allowed drug companies to speed the marketing of drugs. Under the program, a drug may be approved—even if it has not yet been clinically tested—provided that preliminary study results show that the drug can address a serious, unmet medical need. Because some drugs are given marketing approval based on weaker evidence than others, advocates have called for a ‘differentiated approval‘ system in which drugs that meet a higher evidentiary standard receive a higher designation. Such distinctions could prove useful in the rare disease space, where it’s difficult for patients to know what evidence supports a treatment.

Still, patients with rare diseases often don’t have time to wait for evidence to accumulate. The line between treatment and research becomes particularly blurry when patients seek non-trial access to an investigational therapy in the “compassionate use” pathway. Most compassionate use access is though the FDA’s Expanded Access program. Patients with a life‑threatening disease and no treatment options can request pre-trial access to a therapy that shows promise.  The request has to be approved by the patient’s doctor, the drug company, and an Institutional Review Board (IRB).

However, a manufacturer is not necessarily incentivized to give pre-approval access for an ultra-rare treatment, because patients granted pre-trial access typically cannot participate in the clinical trial. Given that the patient pool for ultra-rare diseases is already so small, removing a single patient from the clinical trial would increase the chances that the trial would not generate enough evidence for approval. Moreover, negative safety data generated from a single compassionate use patient could endanger FDA approval.

One way to improve pre-trial access would be to develop standards for incorporating pre-trial data into the approval process, though doing so could be complicated. “One problem with expanded access data is that it’s inherently biased, as it is not subject to the same controls as clinical research” says Massarelli. However, the FDA is making progress in clarifying the standards for pre-trial access. Massarelli says, “The FDA is very clear about what expanded access is and what it is not. This may be a product of confusion over whether or not expanded access is research and the fact that expanded access has become increasingly used over the past two decades.”

Treating an ultra-rare genetic disease today is likely to produce information and expertise that can help patients in the future. Says Massarelli, “Although uses of expanded access are classified as one-off treatments, not research, they are part of an effort to create a new therapeutic modality, where the hope is that future patients can benefit from learnings from these early attempts.”

A Case Study

Every piece of accumulated knowledge could help treat the next patient who presents with an ultra-rare disease. But even as regulators and drug development companies seek out commonalities that can improve the chances of successfully treating patients with ultra-rare diseases, it is crucial to understand that each patient is an individual. Every case is unique. Take, for instance, the story of Mila Makovek.

In November 2016, six-year-old Mila was diagnosed with Batten disease, a rare and rapidly progressing neurodegenerative condition. Batten disease is a genetic disorder, and it has been associated with a variety of genes. Mila’s symptoms, first noticed when she was three, were typical for Batten disease: she had increasing difficulty walking and forming speech, and her vision was worsening. Following Mila’s diagnosis, her mother, Julie Vitarello, started Mila’s Miracle Foundation (MMF) to raise money for gene therapy. But first they had to identify what gene was causing Mila’s disease.

Genetic testing revealed an expected mutation in one copy of the gene MFSD8. While the exact function of MFSD8 is not known, it is likely involved in the clearance of waste products made by lysosomes, which break down old and deleterious molecules in a cell. Accumulation of these waste products—a mixture of lipids and proteins called lipofuscin—is thought to drive the disease. However, Batten disease only occurs if a mutation is present in both copies of MFSD8. The results were perplexing and left Mila’s caregivers without a clear target for gene therapy. Dr. Timothy Yu, who runs a lab at Boston Children’s Hospital and studies genetic diseases, reached out to Vitarello and offered to perform full genome sequencing. Yu and his team found that Mila’s second copy of MFSD8 had an unexpected mutation that was disrupting the gene’s RNA splicing—a crucial step in converting the information from the DNA into a functional protein.

Crucially, the FDA had recently approved nusinersen, an ASO that corrects abnormal splicing in a different disease called spinal muscular atrophy. Yu’s team realized that a similar ASO could treat the unique underlying cause of Mila’s condition. Within 6 months, Yu’s team designed multiple ASOs that bound to the problematic splicing region in Makovek’s second copy of MFSD8. They found that one of these variants, which they named milasen, was particularly effective at reducing mis-splicing in cultured skin cells from Mila.

Although Yu and his team worked as quickly as possible, Mila’s condition continued to worsen—she had as many as 30 seizures each day and had great difficulty walking. Yu successfully appealed to the FDA to reduce milasen’s required safety testing in rats from three months to one month, with the expectation that the full testing would still be completed. Yu also collaborated with TriLink BioTechnologies and Brammer Bio to manufacture milasen on an expedited timeline. Just a year after her diagnosis and 10 months after Dr. Yu’s team started work, Mila took her first dose of milasen.

In the subsequent months, Mila’s symptoms appeared to stabilize.  Her seizures became less severe and decreased to several per day, but eventually her condition deteriorated again. She died from her disease in February 2021. Nevertheless, her mother remains committed to improving access to individualized therapies. Vitarello continues to run MMF, and she helped found the N = 1 Collaborative, which promotes communication among experts who treat rare diseases with ASOs and other customizable platforms.

Meanwhile, authorities continue to try to find the balance between treatment and research and between compassion and regulation. Boston Children’s Hospital aims to use Yu’s research as a template for future rare disease patients, and it has established an oversight committee for handling cases similar to Mila’s. The FDA issued a draft guidance in 2021 that aimed to clarify the use of ASOs to treat ultra-rare diseases. These ongoing deliberations will help determine whether therapies like milasen become more widely replicated, or they remain outliers that define the limits of personalized medicine.

Photo credit: Nick Youngson Pix4Free / Creative Commons