Fewer HAE attacks, life quality gains seen with donidalorsen at 2 years

Interim findings in long-term extension study of treatment's use by adults

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

Share this article:

Share article via email
Two hands, a stethoscope, and some medications surround a clinical trial graph showing positive results.

Donidalorsen, an experimental treatment in the pipeline of Ionis Pharmaceuticals, continues to prevent swelling attacks when taken for up to two years, allowing a better quality of life for adults with hereditary angioedema (HAE).

These results come from an ongoing open-label extension study (NCT04307381) in HAE patients who completed a placebo-controlled Phase 2 trial, which found donidalorsen’s use significantly reduced monthly swelling attacks in just under four months.

As reported at the extension study’s one-year mark, the treatment — given as a subcutaneous (under-the-skin) injection at extended and alternative doses — is continuing to be effective, safe and well tolerated, with no serious side effects recorded in this latest interim analysis.

“We are very encouraged by the demonstrated safety, efficacy, and quality of life profile of donidalorsen,” Richard S. Geary, PhD, executive vice president and chief development officer at Ionis, said in a company press release.

Recommended Reading
A doctor holds a clipboard while consulting with a patient.

Researchers define clinically meaningful score change in angioedema test

Donidalorsen ability to prevent HAE attacks tested at varied dose schedules

“The two-year [open-label extension] results further support donidalorsen as a potentially compelling prophylactic [preventive] treatment option for patients with hereditary angioedema,” Geary said.

Results were detailed in the poster “Two-Year Analysis of the Donidalorsen Phase 2 Open-Label Extension Study in Patients With Hereditary Angioedema,” presented at the American College of Allergy, Asthma & Immunology (ACAAI) meeting held Nov. 9-13 in Anaheim, California.

The company also recently announced that top-line trial results are likely by June in its Phase 3 OASIS-HAE (NCT05139810) study in 84 adults and children with HAE, ages 12 and older. This fully enrolled and pivotal trial is testing donidalorsen, given every four or eight weeks, against a matched placebo.

“We look forward to reporting pivotal topline Phase 3 results in the first half of next year,” Geary said.

HAE results when the protein kallikrein becomes overactive, driving the production of bradykinin, a pro-inflammatory molecule. Too much bradykinin causes blood vessels to widen and leak into nearby tissues, leading to rapid swelling.

Managing HAE can be challenging due to unpredictable swelling attacks, the disease’s hallmark symptom, with patients’ varying responses to HAE treatments adding complexity. Patients often require a treatment approach tailored to their individual needs.

“Hereditary angioedema is a significant healthcare challenge for which there is an ongoing need for long-term, sustained prophylactic treatment offering patients significant efficacy and tolerability that is easy to use,” Geary said.

Donidalorsen is an antisense oligonucleotide — a synthetic (lab-made) sequence of genetic material — designed to prevent HAE attacks by lowering the levels of prekallikrein, a kallikrein precursor.

HAE swelling attacks reported to drop by 96% over two years of treatment

Of the 20 adults with HAE type 1 or 2 who took part in the Phase 2 clinical trial (NCT04030598), 17 rolled into the three-year (156 week), open-label extension study due to conclude in April 2025. Fourteen patients (82.4%) have completed two years of treatment.

Here, all received a fixed 80 mg dose of donidalorsen every four weeks for an initial 13 weeks. One month later, patients entered a flexible-dose period, being given donidalorsen at an 80 mg dose every four or eight weeks, or at a 100 mg dose every four weeks.

Over two years, a mean reduction of 96% was reported in HAE attacks. Patients, with a mean age of 39, saw their monthly swelling attack rates drop from a mean of 2.7 at the Phase 2 study’s start to 0.06. They remained attack free for 99.7% of that time.

All reported a clinically meaningful improvement in quality of life, as measured by a mean drop of 26.6 points in the Angioedema Quality of Life (AE-QoL) questionnaire, where lower scores indicate quality of life gains.

Blood levels of prekallikrein fell by more than half, declining by a mean of 57.1%, and they remained low for up to two years.

“There was a sustained reduction in plasma prekallikrein concentration,” the researchers wrote.

Injection site discoloration and a reaction were reported in two patients (11.8%). There were no serious side effects, and no treatment-emergent side effects leading to discontinuation.

“Treatment was well tolerated and resulted in no new safety signals,” the researchers wrote.

A separate analysis of the eight patients treated with 80 mg of donidalorsen every eight weeks also was presented at the ACAAI, in the poster “Two-Year Analysis of Donidalorsen Taken Every 8 Weeks (Q8W) in Patients With Hereditary Angioedema.

Five of the eight (62.5%) remained attack free across the two years. Swelling attacks fell by a mean of 82.9% over that time, with monthly attack rates dropping from a mean of 2.2 to 0.29. Mean AE-QoL scores dropped by 27.4 points, again indicating gains in life quality with continued donidalorsen treatment.

Donidalorsen recently was designed an orphan drug by the U.S. Food and Drug Administration in treating HAE. This designation aims to speed the review and potential approval of treatments for rare diseases, and confers certain benefits to therapy developers, including seven years of market exclusivity upon approval.