Swelling Attacks Down, Quality of Life Up in Donidalorsen Phase 2 Trial
Full trial results were detailed in the study, “Inhibition of Prekallikrein for Hereditary Angioedema,” published in The New England Journal of Medicine. The study was supported by Ionis Pharmaceuticals, the company developing donidalorsen.
HAE is characterized by the overactivity of the kallikrein protein, which makes a signaling molecule that promotes swelling. Donidalorsen, formerly known as IONIS-PKK-LRx, is designed to prevent HAE swelling attacks by lowering levels of prekallikrein, a kallikrein precursor.
The Phase 2 trial (NCT04030598) enrolled 20 people with HAE, ages 21–66. Two participants had HAE type 2, the rest had type 1 disease. About two-thirds were women, and all but one were white.
“The racial and ethnic group composition of our patient population does not reflect the equal distribution of hereditary angioedema with C1 inhibitor deficiency across racial and ethnic groups in the United States or Europe and is thus a limitation of the trial,” the scientists wrote.
Participants were randomly assigned to receive 80 mg of donidalorsen, or a placebo, delivered once monthly, via subcutaneous (under-the-skin) injection.
The study’s main goal was to assess the effect of treatment on swelling attack rates after 17 weeks (just under four months).
Top-line results, announced last year, showed that the goal was met. Compared with a placebo, donidalorsen lowered the number of monthly HAE attacks by 90% over the course of the study. After the second dose of the experimental therapy, attack rates fell by 97%. The number of attacks that required on-demand treatment similarly decreased, by 95% after 17 weeks.
From week five to week 17, a total of 12 out of 13 (92%) patients treated with donidarlorsen were attack-free. Treatment with donidalorsen led to a significant decrease in prekallikrein levels, which dropped by 61% by the trial’s end.
Total scores on the Angioedema Quality of Life Questionnaire decreased by a mean of 26.8 points in patients treated with donidalorsen, while scores decreased by 6.2 points for those given a placebo. Lower scores indicate better quality of life.
The most common side effects reported with donidalorsen were nausea and headache, though both were also commonly reported by those given a placebo. No participants dropped out of the study due to safety concerns, and no deaths or serious side effects were reported.
All but three of the 20 opted to enroll in an open-label extension study, where all will be treated with donidalorsen and monitored for long-term safety and efficacy outcomes.
“Because the exposure to donidalorsen in this trial was limited to four doses, we designed an open-label extension study to assess safety over a period of 156 weeks. The study is ongoing, and on the basis of medical monitoring and safety reviews, no safety signals have been observed to date,” the researchers wrote.
In a separate study, donidalorsen was used to treat three patients with HAE type 3, also known as HAE with normal C1-inhibitor, since the underlying cause of the disease is different than in types 1 or 2. Results were presented in a poster at the American Academy of Allergy, Asthma and Immunology Annual Meeting, held Feb. 25–28, in Phoenix, Arizona, and virtually.
Patients’ mean monthly rate was 4.23 swelling attacks per month before the study. This decreased by about 75%, to 1.52 attacks a month after 17 weeks on donidalorsen. The therapy was generally well tolerated in these type 3 patients.
“Positive Phase 2 data published in NEJM, along with data presented at the American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting, demonstrate that treatment with donidalorsen reduced attack frequency and disease burden of hereditary angioedema,” Kenneth Newman, MD, vice president of clinical development and leader of the immunology and pulmonology franchise at Ionis, said in a press release.
The company recently launched a Phase 3 trial called OASIS-HAE (NCT05139810) to further investigate the safety and effectiveness of donidalorsen in people with HAE types 1 or 2. The study is recruiting participants in California and Ohio.
“The promising findings from [the Phase 2 trial] are particularly encouraging as we continue to advance the Phase 3 clinical study for donidalorsen and underscore our commitment to deliver transformative treatments for patients with unmet therapeutic needs,” Newman said.