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Until now, Barth syndrome, a fatal genetic condition that affects the heart and muscles, was deemed untreatable. The first therapy has been greenlit by U.S. regulators, as it was able to improve muscle strength for people to be able to stand and walk more easily. But the approval of elamipretide by the FDA has not come easily for the drug developer Stealth BioTherapeutics, especially since Barth syndrome is an ultra-rare disease. The move is a big one for biopharmas focused on treating ultra-rare conditions.
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Stealth BioTherapeutics’ elamipretide gains FDA approval
Elamipretide, now known by its brand name Forzinity, is the first therapy cleared for Barth syndrome and also the first FDA-approved mitochondria-targeted therapeutic.
Elamipretide is a peptide that binds to a critical fat compound in the mitochondria called cardiolipin, which then improves the structure and function of the mitochondria. The mitochondria, which is popularly known as the powerhouse of the cell, doesn’t do its job properly in people with Barth syndrome. As mitochondrial function is linked to energy production and muscle development, Barth syndrome results in muscle weakness and cardiomyopathy, which affects the heart muscle, and when it worsens, leads to shortness of breath, feeling tired, swelling of the legs, and an eventual onset of heart failure.
In the clinic, elamipretide proved its efficacy and safety. When the drug was injected into patients, knee extensor muscle strength improved in patients, and the most common side effects were injection site reactions that were treated with oral antihistamines and topical corticosteroids.
Elamipretide was cleared under accelerated approval by the U.S. Food and Drug Administration (FDA) last week for patients with Barth syndrome who weigh more than 30 kilos.
“The approval of FORZINITY, the first treatment option for Barth syndrome and the first approved mitochondria-targeted therapeutic, is a pivotal victory for the Barth syndrome community,” said Reenie McCarthy, chief executive officer (CEO) of Stealth BioTherapeutics, in a press release. “We plan to continue providing expanded access to children weighing less than 30 kilograms who are currently receiving treatment or require emergency access, while we work with the FDA to generate data needed to expand the indication to include these children.”
Elamipretide FDA approval: the trials and tribulations of developing ultra-rare disease therapies
For Stealth to get to this point has been an onerous, decade-long journey.
It presented clinical trial results to the FDA back in 2019, which was followed by the regulator advising the company to hold another phase 3 trial before submitting their drug for approval two years later.
Stealth, however, did not abide by the FDA’s request, and went on to submit elamipretide’s application for approval without the additional phase 3 trial. This was swiftly met with a rejection letter from the FDA.
Then, Stealth resent its approval request last year, which was green lit and awarded priority review for a decision to be made by January. Come January 2025, the FDA had not made up its mind and pushed the deadline to April. Further pushing the April decision date, it ended in another denial, citing the therapy’s failure to hit a six-minute walking test score in May.
This coincided with 30% layoffs at Stealth and further halted studies, as financial troubles became apparent. It lodged another new drug application, and this time, doubled down, seeking accelerated approval.
With a new decision date attached to the application – February 2026 – the FDA hold-ups were questioned by critics. Members of Congress wrote several letters demanding clarity about the rebuff.
Critics argued that research and development in healthcare was slackening under the watch of FDA commissioner Martin Makary, who was appointed by President Donald Trump in March this year. The Wall Street Journal called it “death by bureaucracy,” claiming that the FDA was strangling elamipretide.
Possibly because of the outpouring protest from Congress, the patient community, and biopharma industry, the 2026 date was preponed to September, and ultimately resulted in a win for patients and the biotech last week.
Many of the hurdles that Stealth faced were because it was treating Barth syndrome. It predominantly affects males, as it is an X-linked genetic disorder, meaning that it is caused by a mutation on the X chromosome. The life expectancy for patients is low, 85% of deaths occurring by the age of five. It affects around one in 1,000,000 males worldwide and around 150 people in the U.S. making it an ultra-rare disease, and so, ultra-hard to treat.
Ultra-rare diseases: why are they so hard to treat?
Ultra-rare diseases affect one in 50,000 people, which makes them hard to treat. Many of these conditions are poorly understood simply because there are very few people in a region whose disease can be studied in order to be treated.
A lack of awareness makes it hard to hold clinical trials in the first place, and according to a study published in the National Library of Medicine, there are no diagnostic or therapeutic guidelines for many rare diseases, and often treatments only manage the symptoms. Therefore, it’s even more difficult for ultra-rare diseases to be spotlighted in clinical studies.
The small sample sizes act as financial deterrents for investors seeking returns, and in turn, many biopharmas stay away from the field altogether. Although the FDA passed the Orphan Drug Act in 1983, which was introduced to provide incentives to drug developers through tax credits, fee waivers, and market exclusivity to prioritize rare disease therapeutics, it hasn’t really shifted perspectives for addressing ultra-rare diseases.
That’s why elamipretide’s FDA approval is a win for the ultra-rare disease community at large.
“[The approval of elamipretide] offers hope for expedited regulatory attention to other ultra-rare diseases,” said McCarthy.
Ultragenyx’s UX111 to tackle Sanfilippo syndrome type A: how far along is it?
For an ultra-rare disease like mucopolysaccharidosis type IIIA, an approved therapy is long-awaited. Mucopolysaccharidosis type IIIA, also known as Sanfilippo syndrome type A, affects one in 50,000 to 200,000 people. In these people, many of whom are children, their bodies cannot break down a large sugar molecule called heparan sulphate because of a malfunctioning enzyme. This can lead to the damage of the central nervous system (CNS), characterized by behavioral issues such as hyperactivity and aggression, progressive cognitive decline leading to loss of speech and memory, sleep disorders, hearing loss, and difficulty walking.
California-based Ultragenyx has been developing its Sanfilippo syndrome type A candidate for a while now but was shot down by the FDA in June. Citing manufacturing issues, a complete response letter (CRL) – an FDA rejection letter – was issued by the FDA after it had secured the thumbs up from the regulator to file for approval in June last year.
Originally developed by Ohio-based Abeona Therapeutics, the candidate UX111 is an adeno-associated virus (AAV) gene therapy designed to address the underlying enzyme deficiency responsible for abnormal accumulation of heparan sulfate. The one-time therapy delivers a functional copy of the gene that codes for the SGSH enzyme to cells that then produce the enzyme that is taken up by the brain.
Despite the FDA snub, the company plans to resubmit UX111 for approval next year. Like with Stealth’s perseverance that resulted in the first therapy for the Barth syndrome community, if Ultragenyx succeeds it could mean that people with Sanfilippo syndrome type A would finally have access to treatment.
Regeneron’s garetosmab shows encouraging but mixed results for ultra-rare bone disease
Another ultra-rare disease that biotechs are trying to tackle is fibrodysplasia ossificans progressiva. The condition is characterized by the abnormal development of bone in areas of the body where bone is not normally present. This leads to the unwanted locking of joints, making movement very difficult and near impossible.
New York-based Regeneron is currently working on a therapy that aims to prevent and reduce the formation of abnormal bones in the soft tissues. Upon discovering activin as a potential therapeutic target, Regeneron designed the monoclonal antibody garetosmab, which binds and neutralizes activin to curb bone growth.
The drug reaped encouraging phase 3 results this month. It reduced lesions by 90% in both the doses that were tested. The two treatment arms had one and two new abnormal bone lesions, whereas the placebo arm reported 19 new lesions over 56 weeks in a study containing 63 adults.
While the primary endpoint was met, the secondary endpoint wasn’t in the low-dose cohort. The secondary endpoint assessed flareups and there were 53 cases of it in the low-dose arm, which was a mere 20% reduction. However, the high-dose cohort witnessed an 89% reduction compared to placebo.
This trial was a big deal for Regeneron, with safety being a top priority considering five people died in a phase 2 study that led to a pause in its development in 2020. That study concluded that the drug did not cause the deaths, however, the link wasn’t entirely ruled out.
Now, the drugmaker plans to file for approval in the U.S. by the end of this year and for global clearance by next year. If garetosmab is greenlit, it would be the second treatment for people with fibrodysplasia ossificans progressiva, following Ipsen’s Sohonos approval two years ago – a drug that has seen a 20% drop in sales this year.
Zealand Pharma’s dasiglucagon and Rezolute’s ersodetug compete in race for congenital hyperinsulinism therapies
Meanwhile, Zealand Pharma’s therapy for congenital hyperinsulinism, another ultra-rare disease, has had a bumpy ride. The Danish company’s therapy dasiglucagon was hit with a CRL last year due to manufacturing concerns the FDA had. This is the second FDA rejection, but Zealand seems staunch on getting dasiglucagon approved for congenital hyperinsulinism.
Congenital hyperinsulinism causes the pancreas to make too much insulin, resulting in extremely low blood sugar. This can lead to seizures, brain damage, and even death. It affects around one in 50,000 children, making it yet another ultra-rare disease.
While dasiglucagon, which prompts the liver to release stored sugar to the blood, is given as an emergency medicine to treat people with diabetes who experience a sudden drop in blood sugar, Zealand is seeking approval for congenital hyperinsulinism. Following the FDA rebuff last year, Zealand said that it wants to bring the therapy to newborns and children with congenital hyperinsulinism.
Zealand Pharma is racing against California-based Rezolute to bring the next congenital hyperinsulinism therapy to patients. In fact, its path to approval has just been sped up by the FDA after the regulator said that the company does not have to conduct a double-blind randomized placebo-controlled trial for its phase 3 candidate ersodetug. The monoclonal antibody binds to insulin receptors in the liver, fat, and muscle tissues to treat hypoglycemia – low blood sugar – in people with congenital hyperinsulinism.
With topline phase 3 results expected next year, Rezolute is already prepping for ersodetug‘s launch, having appointed a chief commercial officer last month.
As most people with ultra-rare diseases have limited treatment options, there is a need for new therapies that can address the root causes of many of these conditions. Despite the regulatory hurdles that ultra-rare disease therapeutics face, with many biotechs slapped with rejection letters, perseverance is key, as seen with elamipretide’s FDA approval for Barth syndrome. Whether or not all these treatments make it through, we’ll have to watch out for, but Stealth’s win sure gives hope to many.
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