Positive results from OASIS-HAE and OASISplus studies of investigational medicine donidalorsen in patients with hereditary angioedema.- IONIS Pharma

Patients who switched to donidalorsen from prior prophylactic treatment also showed 62% further reduction in mean monthly HAE attack rates 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.

Results will be presented in three late-breaking oral presentations at the 2024 European Academy of Allergy and Clinical Immunology (EAACI) Annual Congress in Valencia, Spain and OASIS-HAE results were published in The New England Journal of Medicine (NEJM).

"We're delighted by the results from the OASIS clinical program, which we believe position donidalorsen to advance the prophylactic treatment paradigm for people living with HAE. Despite currently available therapies, people living with HAE still face significant disease burden and new prophylactic treatments are needed," said Brett Monia, Ph.D., chief executive officer of Ionis. "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. 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. We thank the patients, families and clinicians who participated in these important studies. Based on these results, Ionis will pursue regulatory approval for donidalorsen, and we look forward to launching it as part of our growing independent commercial pipeline, if approved."

OASIS-HAE Study Results In the Phase III 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. i. 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<0.001), and 55% reduction with q8w (p="0.004)." ii. in weeks five to 25, donidalorsen q4w significantly reduced mean monthly hae attack rates by 87% (p><0.001) compared to placebo, a key secondary endpoint. a. in the same time frame, treatment with donidalorsen q4w reduced severe to moderate attacks per month by 89% (p><0.001). b. donidalorsen q4w also reduced hae attacks that require acute therapy by 92% (p><0.001). iii. at week 25, 91% of donidalorsen q4w patients were well-controlled as measured by the angioedema control test (aect). a.donidalorsen resulted in clinically significant improvement in quality of life as measured by the angioedema quality of life questionnaire (ae-qol) iv.donidalorsen q8w had a similar benefit as q4w dosing over time on attack rate reduction and quality of life measures. v. donidalorsen was well-tolerated, with no serious treatment emergent adverse events (teaes) related to donidalorsen. most adverse events (aes) were mild or moderate in severity, and injection site reactions were the most common ae. one patient in the donidalorsen q8w group discontinued based on investigator recommendation due to patient noncompliance and a teae.>

OASISplus Study Results – Open-Label Extension and Switch :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: i. 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. ii. Extended treatment resulted in further improved quality of life measures and high levels of disease control. a. At week 25, 91% (Q4W) and 100% (Q8W) of patients reported well-controlled disease as measured by the AECT. b. 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. iii. 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: i. Patients switched to donidalorsen from prior prophylactic treatment without an increase in breakthrough attacks. ii. Patients experienced a 62% further improvement in mean monthly HAE attack rate compared to baseline for previous prophylactic treatment. iii. 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. iv. 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 inAE-QoL scores. v. Safety results were consistent with findings from OASIS-HAE, with no serious safety concerns. One patient discontinued due to TEAE not related to donidalorsen.

"People living with HAE are facing a lifelong battle, and I see that impact firsthand in my practice. It's critical for treatment options to have lasting, durable efficacy," said Marc Riedl, M.D., M.S. clinical director, U.S. HAEA Angioedema Center; clinical service chief, Division of Allergy & Immunology, University of California, San Diego. "The OASISplus study demonstrated patients are able to change therapy to donidalorsen without the risk of increased breakthrough HAE attacks while continuing to improve in measures of quality of life and disease control."

"The comprehensive OASIS clinical program demonstrates how donidalorsen can potentially address key concerns patients may experience with currently available treatment options," said Kenneth Newman, M.D., senior vice president of clinical development at Ionis. "Donidalorsen significantly reduced HAE attack rates, and with the simplicity of monthly or every two-month self-administration via autoinjector, we believe that donidalorsen has a unique profile that may address the needs of people with HAE."

Ionis plans to file a New Drug Application this year with the FDA) marking progress toward the goal of launching our second wholly owned medicine. Otsuka Pharmaceutical Co., Ltd., 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.

See- "Efficacy and Safety of Donidalorsen for Hereditary Angioedema"- Authors: Marc A. Riedl, M.D., Raffi Tachdjian, M.D., M.P.H., William R. Lumry, M.D., Timothy Craig, D.O., Gül Karakaya, M.D., Asli Gelincik, M.D., Marcin Stobiecki, M.D., Ph.D., +11, for the OASIS-HAE Team. Published May 31, 2024 vDOI: 10.1056/NEJMoa2402478.