Ionis Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for donidalorsen, an investigational RNA-targeted medicine for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients 12 years of age and older. The FDA has set an action date of August 21, 2025, under the Prescription Drug User Fee Act (PDUFA). This decision marks a significant step toward potentially providing a novel treatment option for individuals affected by this rare and potentially life-threatening genetic condition.
The FDA application was based on positive results with monthly and bi-monthly dosing in the pivotal Phase 3 OASIS-HAE and OASISplus (open label extension (OLE) and switch) studies, as well as the ongoing Phase 2 OLE study. These studies demonstrated significant reductions in HAE attack rates, highlighting the potential of donidalorsen as a prophylactic treatment.
Addressing Unmet Needs in HAE Treatment
Hereditary angioedema is characterized by recurrent episodes of severe swelling in various body parts, including the hands, feet, genitals, stomach, face, and throat. It is estimated to affect more than 20,000 patients in the U.S. and Europe. Current treatment approaches often involve prophylactic medications to reduce the frequency and severity of these attacks; however, many patients still experience breakthrough attacks, underscoring the need for more effective therapies.
Donidalorsen: A Novel RNA-Targeted Approach
Donidalorsen is designed to reduce the production of prekallikrein (PKK), a key protein involved in activating inflammatory mediators associated with HAE attacks. By targeting PKK, donidalorsen aims to interrupt the pathway that leads to these debilitating episodes. The drug's RNA-targeted mechanism represents a novel approach to HAE prophylaxis.
Clinical Trial Data and Safety Profile
Data presented at the 2024 American College of Allergy, Asthma & Immunology (ACAAI) Annual Scientific Meeting showcased significant and sustained reductions in HAE attacks with donidalorsen. The ongoing Phase 2 OLE study demonstrated an overall sustained mean reduction in HAE attack rates of 96% from baseline, maintained for up to three years. Across the Phase 3 and Phase 2 OLE studies, donidalorsen was generally well-tolerated, with most adverse events being mild or moderate in severity. Injection site reactions were the most commonly reported adverse event, and no serious treatment-emergent adverse events related to donidalorsen were observed.
Future Prospects and Commercialization
"Despite currently available treatments, many people living with HAE continue to experience painful and potentially life-threatening breakthrough attacks. Based on the totality of clinical evidence from the Phase 3 OASIS-HAE and OASISplus studies, as well as new three-year results from our Phase 2 OLE study, we believe that donidalorsen has the potential to advance the prophylactic treatment paradigm for people living with HAE," said Brett Monia, Ph.D., chief executive officer of Ionis. "With the FDA acceptance of our donidalorsen NDA, we are poised for our second independent launch next year, assuming approval, which will allow us to continue to deliver on our goal to bring a steady cadence of medicines to patients with serious diseases."
The FDA previously granted donidalorsen Orphan Drug Designation in 2023. Otsuka, which has exclusive rights to commercialize donidalorsen in Europe and Asia Pacific, is preparing to submit a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) this year. If approved, donidalorsen has the potential to be Ionis' second independent commercial launch.
