Ionis Reports Positive Results from Studies of Donidalorsen in Patients with HAE

Rare Daily Staff

Ionis Pharmaceuticals reported positive results from the phase 3 OASIS-HAE and OASISplus studies of donidalorsen in patients with hereditary angioedema that demonstrated significant and sustained reduction in mean monthly HAE attack rates and a continued attack rate improvement of more than 90 percent with one year of treatment for monthly or every two-month dosing.

Patients who switched to donidalorsen from prior prophylactic treatment also showed 62 percent further reduction in mean monthly HAE attack rates from baseline, and 84 percent of patients who switched reported a preference for donidalorsen. Donidalorsen had a favorable safety and tolerability profile across both studies, including when self-administered via an auto-injector.

Results will be presented in three late-breaking oral presentations at the 2024 European Academy of Allergy and Clinical Immunology Annual Congress in Valencia, Spain. Based on these data, Ionis is pursuing regulatory approval of donidalorsen as a potential treatment for HAE.

Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic condition that involves recurrent attacks of severe swelling (angioedema) in various parts of the body, including the hands, feet, genitals, stomach, face and/or throat. Donidalorsen is an investigational RNA-targeted prophylactic medicine designed to reduce the production of prekallikrein (PKK), interrupting the pathway that leads to HAE attacks.

“These data underscore the potential of donidalorsen to continually improve HAE attack rates and quality of life over time, positioning donidalorsen as an attractive potential treatment option,” said Brett Monia, CEO of Ionis. “In our prospective switch cohort, patients switched to donidalorsen from another prophylactic without increased breakthrough attacks and achieved greater disease control. In fact, a majority of patients who switched reported a preference for donidalorsen.”

In the Phase 3 OASIS-HAE study, patients with HAE were treated with donidalorsen (80 mg) via subcutaneous injection every four weeks (Q4W) or every eight weeks (Q8W), or placebo, over 24 weeks.

The study met its primary endpoint, demonstrating 81 percent lower monthly HAE attack rate with donidalorsen Q4W compared to placebo over weeks one to 25, and 55 percent reduction with Q8W.

In weeks five to 25, donidalorsen Q4W significantly reduced mean monthly HAE attack rates by 87 percent compared to placebo, a key secondary endpoint. In the same time frame, treatment with donidalorsen Q4W reduced severe to moderate attacks per month by 89 percent. Donidalorsen Q4W also reduced HAE attacks that require acute therapy by 92 percent. At week 25, 91 percent of donidalorsen Q4W patients were well-controlled as measured by the Angioedema Control Test (AECT). Donidalorsen resulted in clinically significant improvement in quality of life as measured by the Angioedema Quality of Life Questionnaire (AE-QoL). Donidalorsen Q8W had a similar benefit as Q4W dosing over time on attack rate reduction and quality of life measures.

Donidalorsen was well-tolerated, with no serious treatment emergent adverse events related to donidalorsen. Most adverse events were mild or moderate in severity, and injection site reactions were the most common adverse event.

The OASISplus study included an open-label extension (OLE) cohort and a first-of-its-kind prospective cohort to assess patients switching from both newer oral and injectable long-term prophylactic treatments to donidalorsen.

Following completion of the placebo-controlled treatment period in OASIS-HAE, 94 percent of eligible patients enrolled in the OLE cohort. Participants continued to receive treatment with donidalorsen via subcutaneous injection dosed every four weeks (n=69) or every eight weeks. As of the data cut at the end of February 2024, attack rates continued to improve over time, resulting in 93 percent and 92 percent improvement from baseline measured at the start of OASIS-HAE across Q4W and Q8W, respectively.

Extended treatment resulted in further improved quality of life measures and high levels of disease control. At week 25, 91percent (Q4W) and 100 percent (Q8W) of patients reported well-controlled disease as measured by the AECT. AE-QoL scores improved by 28 points (Q4W) and 24 points (Q8W) at week 25 compared to baseline in OASIS-HAE. An improvement of 6 points is considered clinically meaningful. Safety results were consistent with findings from OASIS-HAE, with no serious safety concerns and no patient discontinuations.

The OASISplus switch cohort evaluated the safety and efficacy of long-term dosing of donidalorsen every four weeks in patients  who were previously treated with another prophylactic HAE medication (lanadelumab, berotralstat or C1-esterase inhibitor) for at least 12 weeks prior to entering the study. Patients followed a pre-defined specific protocol to transition from their prior therapy to donidalorsen. Results from a pre-defined endpoint of 17 weeks indicate that patients who switched did not have an increase in breakthrough attacks, and experienced a 62 percent further improvement in mean monthly HAE attack rate compared to baseline for previous prophylactic treatment. Some 84 percent of patients who switched reported a preference for donidalorsen over their previous treatment, citing better disease control, less time to administer, and less injection site pain or reactions. Quality of life measures also showed continued improvement, demonstrating at least an 8-point improvement in AE-QoL scores. Safety results were consistent with findings from OASIS-HAE, with no serious safety concerns. One patient discontinued due to TEAE not related to donidalorsen.

Ionis plans to file a New Drug Application this year with the U.S. Food and Drug Administration. Otsuka Pharmaceutical, which has exclusive rights to commercialize donidalorsen in Europe, is also preparing to submit a Marketing Authorization Application to the European Medicines Agency this year.

Photo: Brett Monia, CEO of Ionis