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Ionis Pharmaceuticals, a California company that pioneered a whole class of RNA-targeted medicines, reported on Friday that a pair of late-stage trials showed that its experimental therapy for hereditary angioedema benefitted patients — including those taking drugs currently on the market.
In one of the Phase 3 trials, dubbed OASIS, patients with hereditary angioedema, a rare disease characterized by severe bouts of swelling, were given injections of donidalorsen either monthly or every two months. Those in the former group had an 81% lower monthly rate of swelling attacks after 25 weeks than patients given a placebo, while the reduction compared to placebo was 55% for those treated every two months.
The other study, OASISplus, found that donidalorsen’s benefits deepened and converged after up to an additional year of treatment, with swelling attack rates dropping by 92% to 93% regardless of how often patients were dosed. Notably, this study also tracked patients who switched over to donidalorsen from existing therapies meant to prevent swelling attacks, including drugs sold by Takeda and BioCryst Pharmaceuticals. Patients who switched to the Ionis drug saw their swelling attack rates drop by 62% compared to previous treatment.
Both studies found that the injection was safe and well-tolerated, with no patients discontinuing treatment due to serious adverse events. Ionis will share additional results on Friday during three presentations at the meeting of the European Academy of Allergy and Clinical Immunology in Spain.
The company plans to use the findings to apply for Food and Drug Administration approval by the end of this year. Japanese pharma firm Otsuka, which has a deal with Ionis to commercialize donidalorsen in Europe, plans to file for marketing approval there this year.
Ionis, founded in 1989, has spearheaded the push to develop genetic medicines for genetic diseases. The company is best known for Spinraza, a drug for spinal muscular atrophy, a deadly neurological disease that attacks nerve cells controlling speech, movement, and breathing. The treatment, sold by Biogen, is now a blockbuster.
The company’s new challenge: proving it can replicate that success and showing it can successfully commercialize drugs on its own.
“We think donidalorsen has the potential to be the treatment of choice for prophylactic treatment for hereditary angioedema,” said Brett Monia, CEO of Ionis.
Hereditary angioedema, or HAE, is a rare genetic disease that affects about 1 out of every 50,000 people, including more than 20,000 people in the U.S. and Europe. Patients don’t make enough of a protein called C1 inhibitor, a molecule that helps suppress inflammation. Without this key regulator, a cascade of proteins activates, causing blood vessels to spill fluid into surrounding tissues and causing dramatic swelling often mistaken for an allergic reaction. These swelling attacks can be deadly when they choke off a patient’s airways and can also affect the intestines, leading to gut-wrenching abdominal pain and nausea.
“It’s a disease that jumps on patients very spontaneously, it’s unpredictable. They get these attacks that can be extremely severe and debilitating, that put them in an ICU,” Monia said. “They can be fatal if it’s not treated aggressively.”
Biopharma companies have taken intense interest in developing HAE therapies. The most commonly prescribed treatment to quell a swelling attack is icatibant, a generic injected medicine, but Massachusetts biotech KalVista Pharmaceuticals is developing an oral drug and announced results from a successful late-stage trial in February.
There are also multiple products that help prevent swelling attacks. The leading preventive treatment, Takhzyro, brought in around $1 billion in sales for Takeda in 2023. BioCryst won approval for Orladeyo, an oral preventive therapy, in 2020. And Intellia Therapeutics is working on a CRISPR-based treatment and announced encouraging initial results in 2022.
About 70% of HAE patients in the United States are already on a preventive treatment, Monia said, but he still sees an opening for Ionis, a $5.4 billion company headquartered in the Southern California city of Carlsbad. In the trial that supported Takhzyro’s approval, a biweekly injection led to a 87% reduction in the rate of HAE attacks compared to placebo, and a monthly injection cut attacks by 73%. If Ionis could offer similar benefits with less frequent dosing, Monia argued, it would have a shot at convincing patients to switch to its therapy.
Donidalorsen is a genetic therapy made of modified RNA hitched to a sugar molecule that directs the drug to the liver. Once there, it gets absorbed by liver cells and blocks the production of prekallikrein, a protein that plays a key role in the relay race of inflammatory signals that drive HAE swelling attacks.
In addition to reducing monthly HAE attack rates, the drug reduced attacks severe enough to require acute therapy by 92% among patients injected monthly.
The OASIS study found that 91% of patients treated monthly had well-controlled disease based on responses to a standard questionnaire. Among patients who switched from another prophylactic treatment to donidalorsen in the OASISplus study, 93% reported well-controlled disease after switching, compared to 67% at baseline.
Ninety patients participated in Oasis, 62% of whom were female. The study was not racially diverse, as 93% of those enrolled were white. Researchers have flagged a dearth of diversity in past HAE trials, too, even though the disease appears to affect different races equally.
Ionis shared topline results from Oasis in January, but that brief announcement did not include specifics on the degree to which its drug reduced swelling attacks. The company also did not share results from OASISplus.
In a January note to investors, Leerink Partners market analyst Mani Foroohar estimated that the drug’s probability of winning regulatory approval was 90% given the topline announcement. Consensus estimates from analysts forecast sales increasing from $51 million in 2025 to $485 million in 2030, according to Visible Alpha.
If approved by the FDA, donidalorsen could turn out to be the biotech’s second solo launch. Last September, Ionis announced positive late-stage data for olezarsen, a drug for familial chylomicronemia syndrome, a rare and serious disease that prevents the body from breaking down fats. The biotech is awaiting an FDA decision this year on that medication.