Narsoplimab is an investigational human monoclonal antibody being developed to address certain medical conditions. This medication is designed to interact with a specific component of the body’s immune system. As an investigational drug, it is undergoing evaluation for its effectiveness and safety.
The Complement System and Narsoplimab’s Mechanism
The complement system forms a part of the body’s innate immune defense, acting as a rapid response mechanism against invading pathogens and damaged cells. This complex network of proteins circulates in the blood and can be activated through three distinct pathways: the classical, the lectin, and the alternative pathways. While the complement system is beneficial for fighting infections, its overactivation can lead to undesirable inflammation and tissue damage.
Narsoplimab specifically targets the lectin pathway, one of these pathways. The lectin pathway is triggered when certain pattern-recognition molecules bind to specific carbohydrate patterns found on pathogens or injured host cells. A key enzyme within this pathway is mannan-binding lectin-associated serine protease-2 (MASP-2).
MASP-2 plays a central role by cleaving complement proteins C4 and C2, leading to the formation of a C3 convertase. This convertase amplifies the complement cascade, resulting in inflammation and tissue injury. Narsoplimab works by binding directly to and inhibiting MASP-2, thereby blocking this early step in the lectin pathway. This targeted inhibition aims to prevent the harmful effects of lectin pathway overactivation while leaving the classical and alternative complement pathways largely undisturbed, which are important for fighting infections.
Conditions Treated by Narsoplimab
Narsoplimab is being developed to treat several conditions linked to dysregulation of the complement system, with a primary focus on hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA). HSCT-TMA is a severe, often life-threatening complication after stem cell transplantation. It involves damage to the tiny blood vessels, leading to the formation of small blood clots, destruction of red blood cells, low platelet counts, and organ dysfunction, particularly affecting the kidneys. Endothelial cell damage, which activates the lectin pathway, is a central factor in the development of HSCT-TMA.
Narsoplimab has also been investigated for other conditions where complement system overactivation contributes to disease progression. This includes IgA nephropathy, a kidney disease where immune complexes deposit in the kidneys, causing inflammation. Atypical hemolytic uremic syndrome (aHUS), another form of thrombotic microangiopathy characterized by blood and kidney issues, has also been a focus of narsoplimab studies.
Additionally, emerging evidence suggests narsoplimab’s potential role in severe COVID-19. The SARS-CoV-2 virus can activate both the lectin and alternative complement pathways, contributing to severe inflammatory responses in some patients. Narsoplimab’s mechanism of inhibiting the lectin pathway suggests a potential benefit in mitigating complement-mediated damage in such cases.
Regulatory and Development Status
Narsoplimab has undergone significant review by regulatory bodies, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). For hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), a Biologics License Application (BLA) was submitted to the FDA. In October 2021, the FDA issued a Complete Response Letter (CRL), indicating that the application could not be approved and requested additional information. A CRL means that the FDA requires more data or clarification before it can grant approval.
Omeros Corporation, the developer of narsoplimab, resubmitted the BLA for HSCT-TMA, and the FDA accepted this resubmission for review in May 2025. A target action date for the FDA decision is set for late September 2025. The resubmission included analyses showing improved overall survival in narsoplimab-treated patients compared to an external control group. The company is also preparing a marketing authorization application (MAA) for narsoplimab in HSCT-TMA for submission to the European Medicines Agency (EMA).
Narsoplimab has received specific designations to expedite its development and review. The FDA has granted it Breakthrough Therapy designation for both HSCT-TMA and IgA nephropathy. This designation is given to drugs that treat serious conditions and show preliminary clinical evidence of substantial improvement over available therapies. The drug has also received Orphan Drug designation from the FDA for HSCT-TMA and for IgA nephropathy. Similarly, the EMA has granted Orphan Drug designation for narsoplimab for treatment in hematopoietic stem cell transplantation.
Administration and Safety Profile
Based on clinical trial data, narsoplimab is administered intravenously (IV). Patients in studies for HSCT-TMA received the drug once weekly for four to eight weeks in a clinical setting. This method ensures controlled delivery and monitoring by healthcare professionals.
The safety profile observed in clinical trials for HSCT-TMA suggests that narsoplimab is generally well-tolerated, particularly given the severe nature of the patient population. Common adverse events reported in these studies included pyrexia (fever), diarrhea, vomiting, and nausea. Other side effects included neutropenia (low white blood cell count), fatigue, and hypokalemia (low potassium levels). While some deaths occurred during the studies, these were generally attributed to complications of the underlying conditions and transplant, rather than directly to narsoplimab treatment. No increased infectious complications or major safety concerns have been consistently identified in real-world data.