FDA agrees to review Ionis’ donidalorsen as treatment for HAE
Therapy designed to prevent swelling attacks in patients 12 and older
The U.S. Food and Drug Administration (FDA) has agreed to review an application seeking the approval of donidalorsen as a preventive treatment for swelling attacks in adults and children, ages 12 and older, with hereditary angioedema (HAE).
According to Ionis Pharmaceuticals, the company developing the therapy, the agency’s approval decision is expected by Aug. 21, 2025.
Otsuka Pharmaceuticals, which holds exclusive rights to commercialize donidalorsen in the Asia-Pacific region and Europe, is preparing a similar submission for European regulatory authorities, Ionis announced in a company press release.
The U.S. application was supported by data from the Phase 3 OASIS-HAE clinical trial (NCT05139810), the OASISplus (NCT05392114) open-label extension (OLE) study, and an ongoing Phase 2 OLE study (NCT04307381), according to Ionis.
The company presented new data from these studies late last month at the 2024 American College of Allergy, Asthma & Immunology (ACAAI) Annual Scientific Meeting. That data demonstrated that donidalorsen treatment led to significant and sustained reductions in HAE attacks, as well as improvements in quality of life, for up to nearly four years among patients.
“Based on the totality of clinical evidence from the Phase 3 OASIS-HAE and OASISplus studies, as well as new three-year results from our Phase 2 OLE study, we believe that donidalorsen has the potential to advance the prophylactic treatment paradigm for people living with HAE,” said Brett Monia, PhD, Ionis’ CEO.
Application for donidalorsen approval based on new clinical data
In HAE, genetic mutations lead to the excessive production of a signaling molecule called bradykinin that acts as the driver for the recurrent swelling attacks that characterize the condition. Although available therapies can help prevent swelling attacks, breakthrough swelling can still occur in some patients.
“Despite currently available treatments, many people living with HAE continue to experience painful and potentially life-threatening breakthrough attacks,” Monia said.
Donidalorsen is a short, lab-made molecule of genetic material, called an antisense oligonucleotide. It’s designed to reduce the production of prekallikrein, a precursor of kallikrein — an enzyme that controls the production of bradykinin. Given as a monthly subcutaneous, or under-the-skin, injection, the therapy is expected to reduce kallikrein levels, thereby bringing bradykinin’s production under control and preventing swelling attacks.
Of 20 adults with HAE who participated in a Phase 2 clinical trial (NCT04030598), 17 enrolled in its OLE and received 80 mg of donidalorsen every four weeks for the first 13 weeks, or about three months. One month later, patients were given an 80 mg dose every four or eight weeks, or a 100 mg dose every four weeks.
New data from the OLE, extending up to 196 weeks, or almost four years, was presented as a poster at the ACAAI meeting. The poster was titled “Phase 2 Open-Label Extension Of Donidalorsen In Patients With Hereditary Angioedema: A Week 196 Analysis.”
In line with the OLE’s two-year data, the mean HAE attack rate across all patients during the on-treatment period dropped from 2.7 at the start of the Phase 2 study (baseline) to 0.06 up to week 196. That represented a 96% reduction. For those treated with 80 mg every eight weeks, the attack rate dropped by 83%. Participants remained attack-free over a mean of 762 days, or about two years.
For patients with available OLE data at week 156, or three years, donidalorsen treatment improved quality of life, as indicated by a 21.3-point drop in the scores of the Angioedema Quality of Life (AE-QoL) questionnaire. Those treated every eight weeks saw similar quality of life gains.
Treatment with donidalorsen seen to improve quality of life for HAE patients
In the OASIS-HAE trial, 91 HAE patients, ages 12 and older, received 80 mg of donidalorsen or a placebo every four or eight weeks for about six months. Data showed that donidalorsen significantly outperformed the placebo in its ability to reduce HAE attack rates.
Nearly all OASIS-HAE participants (94%) entered the OASISplus OLE to receive donidalorsen once monthly or every two months.
New data were presented at the meeting in a poster titled “Donidalorsen For Hereditary Angioedema: Results From The OASISplus Open-Label Extension Study.” The results showed that reductions in HAE attack rates seen in the main trial were sustained for up to a year in OASISplus. In particular, attack rates dropped by 93% among patients receiving donidalorsen every four weeks and by 92% in those treated every eight weeks.
Similarly to the Phase 2 OLE study, participants in OASISplus showed clinically meaningful improvements in quality of life at week 24, or after about six months. This was demonstrated by a mean 28-point drop in AE-QoL scores for those on the monthly regimen, and by a mean 24-point drop for those in the eight-week regimen.
More than 90% of participants reported well-controlled disease based on Angioedema Control Test scores. This included those who initially received a placebo in OASIS-HAE and switched to donidalorsen in OASISplus.
With the FDA acceptance of our donidalorsen [application], we are poised for … [an] independent launch next year, assuming approval.
Based on scores from the hereditary angioedema quality of life (HAE-QoL) assessment, the quality of life of patients treated every four or eight weeks improved by week 24. Those who switched from a placebo and were evaluated at the OLE’s start, saw a 22-point HAE-QoL gain at week 24.
Across all three studies, donidalorsen was well-tolerated, with no serious adverse events related to the therapy being reported. Most adverse events were mild or moderate in severity, with injection site reactions being the most common.
“With the FDA acceptance of our donidalorsen [application], we are poised for … [an] independent launch next year, assuming approval,” Monia said.
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