Ionis Pharmaceuticals, Inc. announced positive results from the Phase 3 OASIS-HAE and OASISplus studies of donidalorsen in patients with hereditary angioedema (HAE) demonstrating significant and sustained reduction in mean monthly HAE attack rates and continued attack rate improvement of >90% with one year of treatment for both monthly or every two-month dosing. Patients who switched to donidalorsen from prior prophylactic treatment also showed 62% further reduction in mean monthly HAE attacks from baseline, and 84% 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.

Based on these data, Ionis is pursuing regulatory approval of donidalorsen as a potential treatment for HAE. 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, sexual, stomach, face and/orthroat. Donidalorsen is an investigational RNA-targeted prophylactic medicine designed to reduce the production of prekallikrein (PKK), interrupting the pathway that leads to HAE attacks.

In the Phase 3 OASis-HAE study, patients with HAE were treated with donidalorsen (80 mg) via subcutaneous injection every four weeks (Q4W) (n=45) or every eight weeks (Q8W) (n=23), or placebo (n=22), over 24 weeks. The study met its primary endpoint, demonstrating 81% lower monthly HAE attack rate with donidalorsen Q4W compared to placebo over weeks one to 25 (p 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. Open-Label Extension Cohort: Following completion of the placebo-controlled treatment period in OASIS-HAE, 94% 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 (n=14). As of the February 28, 2024 data cut: Attack rates continued to improve over time, resulting in 93% and 92% 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, 91% (Q4W) and 100% (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. Switch Cohort: The OASISplus switch cohort evaluated the safety and efficacy of long-term dosing of donidalorsen every four weeks in patients (n=64) 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: Patients switched to donidalorsen from prior prophylactic treatment without an increase in breakthrough attacks. Patients experienced a 62% further improvement in mean monthly HAE attack rate compared to baseline for previous prophylactic treatment. 84% 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.1 Quality of life measures also showed continued improvement, with 93% of patients reporting well-controlled disease compared to 67% at baseline with prior prophylactic treatment.

Results also demonstrated =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.