6 Rare Diseases That Have New FDA-Approved Treatments

Rare Disease Day, which falls at the end of February each year, is an opportunity to take stock of advances in this space, as well as the many remaining gaps in care and treatment.

Defined as diseases that affect fewer than 200,000 people in the U.S., rare diseases collectively afflict about 350 million people worldwide, according to the National Organization for Rare Disorders. An estimated 7,000 of these conditions have been identified, and more than 90% of them have no FDA-approved treatment.

Yet progress toward developing such treatments continues, particularly among smaller companies. Here are five rare diseases that have seen drug approvals since last year’s Rare Disease Day.

Duchenne muscular dystrophy (DMD) is a relatively common rare disease, affecting about one out of every 3,600 baby boys. This X-linked genetic disease affects the dystrophin protein, a component of muscle, and causes progressive weakening of skeletal and heart muscle.

Families affected by DMD saw a spate of treatment approvals in 2023 and 2024, including Sarepta Therapeutics’ Elevidys and Catalyst Pharmaceuticals’ Agamree. The most recent was Duvyzat (givinostat), a small molecule therapy marketed by ITF Therapeutics. It targets histone deacetylases, enzymes that modulate gene and protein expression in the muscle.

“Deregulation of HDACs is a major consequence of the lack of dystrophin associated with DMD,” Matt Trudeau, head of ITF, told BioSpace in an email ahead of the FDA decision in March 2024. “We believe givinostat’s mode of action has the potential to inhibit HDAC pathological overactivity and thereby impact the cascade of events leading to muscle damage which, in turn, may counteract disease pathology and slow muscle deterioration.”

In the Phase III Epidys trial, givinostat met the primary endpoint of a change in the four-stair climb assessment from baseline to 72 weeks. Italfarmaco, the parent company of ITF which developed the drug, also reported that it showed “favorable outcomes” in key secondary measures, including on the North Star Ambulatory Assessment (NSAA), a scale that measures motor function skills. On the NSAA, patients treated with the new drug saw less worsening compared to placebo after 18 months. Givinostat was generally well tolerated, with no treatment-related severe or serious adverse events.

Metachromatic leukodystrophy (MLD) is a metabolic disease that affects one in every 100,000 live births. It is caused by a mutation in the arylsulfatase-A (ARSA) gene, which codes for an enzyme that breaks down sulfatides, and is characterized by a pathological build-up of sulfatides in the brain, liver, kidneys, spleen and other body parts. Over time this buildup can lead to organ damage and neurological issues, and patients often experience motor, behavioral and cognitive problems, as well as seizures. Most patients die within five years of disease onset.

The FDA approved the first therapy for early juvenile or early symptomatic forms of the disease, Lenmeldy (atidarsagene autotemcel), in March 2024. The gene therapy, marketed by Orchard Therapeutics, uses a patient’s own stem cells to deliver a functioning copy of the ARSA gene. Lenmeldy was also approved by the European Union in December 2020, where it is marketed as Libmeldy.

The FDA’s approval of Lenmeldy is backed by data from two single-arm, open-label trials enrolling a total of 37 pediatric MLD patients. Over a median follow-up of 6.76 years, Lenmeldy led to significantly better overall survival compared with natural history data. The gene therapy also preserved motor and cognitive function in late-infantile MLD patients. Lenmeldy’s most common adverse events were febrile neutropenia, stomatitis, respiratory tract infections and rashes.

Fewer than 1,000 people in the U.S. have been diagnosed with WHIM syndrome, according to the NIH. The condition’s name is an acronym of the four characteristics of the disease: warts, hypogammaglobulinemia (low antibody levels), infections and myelokathexis (a white blood cell disorder). The syndrome is caused by mutations in the chemokine receptor (CXCR4) gene that increase the activity level of the resulting protein.

In April 2024, the FDA approved X4 Pharmaceuticals’ Xolremdi (mavorixafor) as the first targeted treatment for WHIM. Xolremdi is an oral CXCR4 antagonist that draws white blood cells from the bone marrow into the blood to improve immune deficiencies. It is approved for patients 12 and older.

Phase III results from the 4WHIM trial of Xolremdi showed a 60% reduction in annualized infection rate compared to placebo; trial participants had less than one infection per year compared with 4.5 for the placebo group.

Teresa Tarrant, an associate professor at Duke University’s School of Medicine and lead investigator of the 4WHIM trial, told BioSpace last year that previous treatments for the disease were only supportive. “I think that for a lot of patients, the idea that there is a targeted therapy . . . something that is directly correcting the underlying problem for the individual, I think that gives them a lot of hope, a lot of optimism,” Tarrant said. “I think WHIM is going to be a poster child for rare diseases and the ability where we’re at now in modern medicine to design therapies to treat underlying genetic disorders.”

Afflicting approximately one in every 150,000 people, Niemann-Pick disease type C (NPC) is an ultrarare lysosomal storage disease that progressively impairs patients’ physical and cognitive function. It is caused by mutations in the NPC1 and NPC2 genes that hinder the body’s ability to clear cholesterol and other lipids from inside cells, leading to their pathologic build-up in the brain and other crucial organs. NPC affects patients’ speech, motor and swallowing functions. According to the FDA, patients with NPC typically live only up to around 13 years of age.

September 2024 saw not one, but two approvals of therapies for NPC. The first, Zevra Therapeutics’ Miplyffa (arimoclomol), is an oral drug approved for patients 2 years and older that is intended to be used alongside miglustat, a small molecule approved to treat the neurological manifestations of NPC. According to the company, Miplyffa activates transcriptional factors, resulting in the upregulation of coordinated lysosomal expression and regulation (CLEAR) genes.

In a clinical trial, Zevra found that Miplyffa plus miglustat stopped disease progression during 12 months of treatment, decreasing patients’ scores on an assessment of NPC symptom severity. Meanwhile, patients treated with miglustat alone experienced a progression in symptoms.

The second approval was for IntraBio’s Aqneursa (levacetylleucine) in adults and children weighing at least 15 kg. According to the company, it is not clear what Aqneursa’s target is, but it may activate cerebral glucose metabolism in the cerebellum and thus boost cerebellar activity.

A randomized, double-blinded and placebo-controlled crossover study found that during the 12-week period that patients were treated with Aqneursa, they showed better functional performance as measured by a score that assesses their gait, sitting, stance and speech. The drug was well-tolerated, with common side effects including vomiting, abdominal pain, difficulty swallowing and upper respiratory tract infections. The drug’s label includes a warning for embryo-fetal harm if used during pregnancy.

The back-to-back NPC approvals highlighted the FDA’s commitment to supporting the development of innovative therapies for rare diseases, Janet Maynard, director of the agency’s Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine, said in a statement.

Cerebrotendinous xanthomatosis (CTX) is a very rare metabolic disease, affecting just one in a million people globally. It is characterized by the inability to break down certain types of cholesterol and other lipids, leading to their toxic accumulation throughout the body, particularly in the brain and connective tissues. Patients with CTX suffer from neurological abnormalities in early adulthood, including seizures and problems with movement and speech.

Just last week, CTX got its first approved drug with the FDA’s greenlight of Mirum Pharmaceuticals’ oral therapy Ctexli (chenodiol). CTX is caused by mutations in the CYP27A1 gene, which codes for an enzyme that breaks down cholesterol into bile acids, and Ctexli replenishes the body’s levels of bile acids. This reduces the build-up of the toxic metabolites that cause the disease.

Mirum’s application for approval of the drug included data from the Phase III RESTORE study, a June 2024 readout of which showed the drug could lower bile alcohols “with high statistical significance,” the biotech said at the time. Ctexli’s benefit was 20-fold greater in magnitude than that of placebo. The most common adverse events associated with Ctexli include hypertension, muscle weakness and diarrhea, and its label includes precautions about potential liver toxicity.