Most HAE Patients Treated With Donidalorsen for Year Attack Free

Extension study also supports safety of hereditary angioedema treatment

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Donidalorsen, a small molecule therapy being developed by Ionis Pharmaceuticals, continues to be safe and to prevent swelling attacks when taken for up to one year by people with hereditary angioedema (HAE), trial data show.

The open-label extension study (NCT04307381) is ongoing in patients who completed a placebo-controlled Phase 2 clinical trial (NCT04030598), in which donidalorsen was found to reduce the number of monthly swelling attacks over 17 weeks.

Seventeen of the 20 people with HAE types 1 and 2 in the Phase 2 trial opted to enroll in the extension, where all are being treated with donidalorsen for up to 157 weeks (about three years). Fifteen of them (88.2%) finished one year of treatment; two withdrew.

“Today’s data further enhance donidalorsen’s profile and potential to provide significant sustained protection from attacks for people living with hereditary angioedema,” Richard S. Geary, PhD, executive vice president and chief development officer at Ionis, said in a company press release.

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Ionis Launches Phase 3 Trial of Donidalorsen for Preventing Attacks

Donidalorsen works to lower prekallikrein levels to prevent attacks

Interim trial findings were presented in a poster at this year’s American College of Allergy, Asthma & Immunology (ACAAI) Annual Scientific Meeting, held Nov. 10–14 in Louisville, Kentucky. The poster, “Phase 2 Open-Label Extension Study With Donidalorsen Treatment in Patients With Hereditary Angioedema,” was presented by Laura Bordone, PhD, associate director of clinical development at Ionis.

Donidalorsen, formerly known as IONIS-PKK-LRx, is an antisense oligonucleotide — a short stretch of man-made DNA or RNA — that is designed to lower the levels of prekallikrein, a precursor to kallikrein.

Kallikrein is a protein that increases the levels of bradykinin, a pro-inflammatory molecule that makes blood vessels dilate and leak fluid into nearby tissues, causing them to swell.

In people with HAE, kallikrein becomes overly active and causes bradykinin to build. As a result, sudden and recurrent swelling attacks can occur anywhere in the body. By lowering prekallikrein levels, donidalorsen is expected to help prevent these attacks.

The extension study’s main goal is to monitor patients for possible treatment-related side effects. Its secondary goals are to calculate the rate of swelling attacks, measure the levels of prekallikrein in the blood, record the need for on-demand treatments, and assess quality of life.

All who completed the Phase 2 trial’s 17 weeks were eligible to enter the extension study, which has two phases.

The first phase was a 13-week fixed-dose period, with patients given 80 mg of donidalorsen given every four weeks via subcutaneous (under-the-skin) injection.

Its second phase is a flexible-dose period, with patients either continuing on 80 mg of donidalorsen every four weeks or switching to 80 mg of donidalorsen given every eight weeks — or 100 mg every four weeks — for up to week 52 (one year). A switch was possible only if a patient remained attack-free for 12 weeks or more since first entering the extension study.

After that year, patients have the option of continuing with donidalorsen for up to an additional 104 weeks.

Among the 15 people treated for one year with donidalorsen, researchers reported a mean of 0.08 swelling attacks per month, down from the 2.7 monthly attacks seen in the Phase 2 trial. Treated patients remained attack free for 99.6% of the study’s duration.

Those on donidalorsen at 80 mg every four weeks saw their swelling attacks drop by a mean of 95.3% from the start of the extension study, a baseline measure.

Eight patients switched to 80 mg of donidalorsen every eight weeks, experiencing a mean reduction of 75.6% in the rate of swelling attacks from baseline, and a mean of 0.28 swelling attacks per month. Five of these people remained attack-free for one year, while the other three switched back to 80 mg of donidalorsen every four weeks.

People given the hereditary angioedema treatment reported no serious side effects

No serious side effects were reported, and no side effects led to treatment discontinuation. All lab tests, including of kidney and liver function, came back normal. Two patients (11.8%) had an injection site reaction.

Treatment with donidalorsen “was well-tolerated with no new safety signals,” Bordone reported.

Ionis recently launched OASIS-HAE (NCT05139810), a Phase 3 clinical trial further looking into donidalorsen’s safety and effectiveness in up to 84 people, ages 12 and older, with HAE types 1 or 2. The study is recruiting patients at more than 30 locations across the U.S., Canada, Europe, and Israel.

“The positive results of the Phase 2 [open-label extension] are encouraging as we continue evaluating donidalorsen, a potential best-in-class medicine, in the ongoing OASIS Phase 3 program,” Geary said.