Ionis Pharmaceuticals announced positive results from the Phase 3 OASISplus prospective switch study of donidalorsen in patients with hereditary angioedema (HAE), published in The Journal of Allergy and Clinical Immunology In Practice. The study demonstrated that patients who switched to donidalorsen from prior prophylactic treatments showed a 62% further reduction in mean monthly HAE attack rate from baseline, with 84% of patients surveyed reporting preference for the investigational therapy.
The New Drug Application for donidalorsen to prevent attacks of HAE in adult and pediatric patients 12 years of age and older is currently under review with the U.S. Food and Drug Administration, with a target action date of August 21, 2025.
Study Design and Patient Population
The Phase 3 OASISplus study included an open-label extension cohort of patients continuing from the OASIS-HAE trial, as well as a prospective cohort to assess patients switching from both oral and injectable long-term prophylactic treatments to donidalorsen. The switch cohort evaluated the safety and efficacy of donidalorsen administered every four weeks in patients who were previously treated with lanadelumab (n=32), C1-esterase inhibitor (n=22) or berotralstat (n=11) for at least 12 weeks prior to entering the study.
Patients entered a 10-week baseline period during which they remained on their prior HAE prophylactic therapy before switching to donidalorsen following a pre-defined specific protocol.
Efficacy Results Across Treatment Groups
After 16 weeks of treatment with donidalorsen, patients experienced a 62% overall further reduction in mean HAE attack rate compared to baseline from their prior prophylactic treatment. The reduction varied by previous therapy: HAE attack rate decreased by 65%, 41% and 73% for patients switching from lanadelumab, C1INH and berotralstat, respectively.
Patients were able to transition from their prior therapy to donidalorsen with no mean increase in breakthrough attacks observed during the switch period.
Patient-Reported Outcomes and Quality of Life
The majority (84%) of patients reported a preference for donidalorsen over their prior therapy, citing better disease control, less time to administer, and less injection site pain or reactions. More patients reported well-controlled disease (93% versus 67% at baseline) after switching to donidalorsen, as measured by the Angioedema Control Test (AECT).
The AECT is a standardized patient-reported questionnaire consisting of four questions related to the frequency, unpredictability and control of angioedema, designed to help identify patients with poor disease control. Quality-of-life measures also improved regardless of prior therapy.
Safety Profile
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. One patient discontinued due to a treatment emergent adverse event not related to donidalorsen.
Clinical Context and Mechanism of Action
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. HAE is estimated to affect more than 20,000 patients in the U.S. and Europe. Many patients continue to face unpredictable, painful breakthrough attacks, even while receiving prophylactic treatment.
Donidalorsen is an investigational RNA-targeted medicine designed to target prekallikrein (PKK), which plays an important role in activating inflammatory mediators associated with acute attacks of hereditary angioedema. By reducing the production of PKK, donidalorsen could be an effective prophylactic approach to preventing HAE attacks, if approved.
"In this study, we saw that patients were able to switch to donidalorsen from another prophylactic without an increase in attacks, and in fact, there was a reduction in mean attack rate. This translated to meaningful improvements in quality of life and disease control compared to baseline with their prior treatment," said Kenneth Newman, M.D., senior vice president, clinical development, Ionis. "The study was designed to provide patients and physicians with data to inform switching to donidalorsen, and the results support our belief that donidalorsen has the potential to be the prophylactic treatment of choice for HAE, if approved."
Ionis previously reported positive results from the Phase 3 OASIS-HAE and OASISplus studies. Data from both studies were first presented at the 2024 European Academy of Allergy and Clinical Immunology Annual Congress in Valencia, Spain, and results from OASIS-HAE were published in The New England Journal of Medicine.
