Donidalorsen for hereditary angioedema

Last updated Jan. 31, 2025, by Marisa Wexler, MS
Fact-checked by Joana Carvalho, PhD

What is donidalorsen for hereditary angioedema?

Donidalorsen, formerly known as IONIS-PKK-LRx, is an antisense oligonucleotide therapy that’s being developed as a preventive, or prophylactic, treatment to reduce the rate of swelling attacks in people with hereditary angioedema (HAE). It is administered via a subcutaneous, or under-the-skin,  injection.

Ionis Pharmaceuticals, donidalorsen’s developer, has submitted an application asking the U.S. Food and Drug Administration (FDA) to approve donidalorsen as a prophylactic treatment for HAE patients 12 and older. A decision from the FDA is now expected by Aug. 21, 2025.

An application seeking donidalorsen’s approval has also been accepted for review in Europe, where Otsuka Pharmaceutical holds exclusive rights to market the therapy. Meanwhile, Theratechnologies, which owns donidalorsen’s rights in Canada, is preparing an application requesting the therapy’s approval in Canada.

Now in Phase 3 clinical testing, donidalorsen had previously received orphan drug designation for the treatment of HAE in the U.S. and EU. This designation is given to experimental treatments for rare diseases to encourage their development and facilitate their regulatory review.

Therapy snapshot

How does donidalorsen work in HAE?

HAE is characterized by recurrent swelling attacks. These generally occur due to mutations that ultimately lead to the excessive production of a signaling molecule called bradykinin. Bradykinin’s production is controlled by an enzyme called kallikrein, which is overactive in people with HAE.

Donidalorsen is an antisense oligonucleotide — a short, lab-made sequence of genetic material — that’s designed to interfere with the production of prekallikrein, a precursor of the kallikrein enzyme. By reducing the levels of prekallikrein and interfering with the pathways leading to bradykinin production, donidalorsen is expected to prevent or reduce the frequency of HAE swelling attacks.

How will donidalorsen be administered in HAE?

In a Phase 3 clinical trial involving people with HAE, donidalorsen was given by subcutaneous injection at a dose of 80 mg, every month or every two months.

Donidalorsen in HAE clinical trials

Donidalorsen has been evaluated across a range of clinical trials involving HAE patients. Ionis’ application seeking the approval of donidalorsen in the U.S. is based on data from a Phase 3 study and its ongoing open-label extension, as well as data from the open-label extension of a Phase 2 trial.

Phase 2 trial

The clinical efficacy, safety, and tolerability of donidalorsen were evaluated in a Phase 2 trial (NCT04030598) that enrolled 20 people with HAE, ages 21 to 66. Participants were randomly assigned to receive four monthly injections of 80 mg of donidalorsen or a placebo for a period of 17 weeks, or about four months.

Mean monthly rates of swelling attacks were 90% lower with donidalorsen compared with the placebo over the course of the study, the results showed. From week five to week 17, 12 of the 13 patients given donidalorsen were completely free of swelling attacks, while none of the six patients given the placebo reached the same outcome. Patients given donidalorsen also reported greater improvements in life quality compared with those given the placebo.

Most participants who completed the Phase 2 trial elected to continue receiving donidalorsen in an open-label extension study (NCT04307381), which is still ongoing.

Two-year data indicated the reduction in swelling attack rates and improvements in life quality with donidalorsen were maintained with long-term treatment. Three-year data likewise showed continual improvements in quality of life, with swelling attack rates decreasing by a mean of 96% across all patients.

OASIS-HAE Phase 3 trial

The Phase 3 OASIS-HAE trial (NCT05139810) enrolled 91 people, 12 years and older, with HAE types 1 or 2, who were experiencing recurrent swelling episodes. Participants were randomly assigned to receive subcutaneous injections of 80 mg of donidalorsen or a placebo, given every month or every other month, for about six months.

Results published in 2024 showed the trial met its main goal, with patients given donidalorsen at either dosing schedule having significantly lower rates of swelling attacks compared with those receiving the placebo. Specifically, data showed that, from study weeks one to 25, monthly treatment with donidalorsen significantly reduced mean monthly attack rates by 81% relative to the placebo.

From weeks five to 25, monthly treatment also significantly reduced monthly attack rates by 87% relative to the placebo. In that time, more than half of the patients receiving monthly treatment with donidalorsen experienced a reduction in swelling attack rates of 90% or more, and more than 4 in 5 (a total of 82%) experienced a decrease of at least 70%. In patients receiving donidalorsen every month, the rate of moderate to severe attacks dropped by 89% relative to the placebo, while that of attacks requiring on-demand treatment fell by 92%.

When given every other month, donidalorsen also reduced mean monthly attack rates, though not as dramatically as when given every month. Patients given donadilorsen also reported improvements in life quality and fewer emergency room visits compared with those given the placebo.

Ongoing trials

A Phase 3 open-label extension study called OASISplus (NCT05392114) is now evaluating the long-term safety and efficacy of donidalorsen in people with HAE types 1 or 2. The extension study is open to patients who participated in and completed OASIS-HAE, as well as individuals who had never received treatment with donidalorsen and were previously on other prophylactic therapies.

For patients who had previously taken part in OASIS-HAE, donidalorsen will be administered every month or every two months. Meanwhile, for those switching from other prophylactic therapies, donidalorsen will be given every month. The extension study is expected to run through 2027.

After completing OASIS-HAE, 94% of the patients chose to enroll in the extension study. Interim data showed that reductions in HAE attack rates observed in the main trial were sustained for up to a year in OASISplus in these patients, with mean attack rates decreasing by more than 90% in patients given either dosing schedule of donidalorsen.

Data from a subgroup of 64 patients who’d previously been on other HAE treatments showed that, after switching to donidalorsen for about four months, mean monthly HAE attack rates decreased by 62% relative to rates experienced with prior treatments. Most of these participants reported they preferred donidalorsen over their previous treatments, which included C1 esterase inhibitors, Orladeyo (berotralstat), and Takhzyro (lanadelumab).

Common side effects of donidalorsen

In a Phase 2 study, the most common side effects associated with donidalorsen were nausea and headache. Injection site reactions have also been reported in other studies. No serious side effects related to the experimental therapy were reported in the Phase 2 study or the Phase 3 OASIS-HAE trial.

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