Ionis Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) has accepted for review its New Drug Application (NDA) for donidalorsen, an investigational RNA-targeted medicine intended for prophylactic treatment to prevent attacks of hereditary angioedema (HAE) in patients 12 years and older. The FDA has set a Prescription Drug User Fee Act (PDUFA) action date of August 21, 2025.
The NDA submission is based on positive results from the pivotal Phase 3 OASIS-HAE and OASISplus studies, which evaluated monthly and bi-monthly dosing regimens, as well as data from an ongoing Phase 2 open-label extension (OLE) study. These studies demonstrated significant reductions in HAE attack rates with donidalorsen treatment.
Clinical Evidence
Data presented at the 2024 American College of Allergy, Asthma & Immunology (ACAAI) Annual Scientific Meeting highlighted that donidalorsen delivered significant and sustained reductions in HAE attacks. The ongoing Phase 2 OLE study showed 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. The majority of adverse events (AEs) were mild or moderate in severity, with injection site reactions being the most commonly reported AE. No serious treatment-emergent adverse events (TEAEs) related to donidalorsen were observed.
Addressing Unmet Needs in HAE Treatment
HAE is a rare genetic condition characterized by recurrent episodes of severe swelling (angioedema) affecting various body parts, including the hands, feet, genitals, stomach, face, and throat. It is estimated to affect over 20,000 individuals in the U.S. and Europe. While current treatments exist, many patients continue to experience breakthrough attacks, highlighting the need for more effective prophylactic options.
"Despite currently available treatments, many people living with HAE continue to experience painful and potentially life-threatening breakthrough attacks," said Brett Monia, Ph.D., chief executive officer of Ionis. "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."
Donidalorsen Mechanism of Action
Donidalorsen is an investigational RNA-targeted medicine designed to reduce the production of prekallikrein (PKK). PKK plays a crucial role in activating inflammatory mediators associated with acute HAE attacks. By reducing PKK production, donidalorsen aims to prevent HAE attacks.
Regulatory and Commercial Strategy
The FDA granted donidalorsen Orphan Drug Designation in 2023. Otsuka holds exclusive rights to commercialize donidalorsen in Europe and the Asia Pacific region and is preparing to submit a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) this year. Ionis anticipates that, pending approval, donidalorsen could be its second independent commercial launch.
