Narsoplimab: Targeting MASP-2 to Advance Therapies in Immune-Mediated Disorders

Narsoplimab is a human monoclonal antibody that targets MASP-2, a key enzyme in the lectin pathway of the complement system.

Narsoplimab inhibits MASP-2, blocking the activation of the lectin complement pathway and reducing inflammatory damage in immune-mediated diseases.

It has been studied in IgA nephropathy, HSCT-TMA, and other inflammatory conditions, with emerging evidence in COVID-19-related trials.

Narsoplimab has received Breakthrough Therapy designation, but full FDA approval is pending further data and regulatory review.

Recent trials explore its use in IgA nephropathy (IgAN), COVID-19, and transplant-associated thrombotic microangiopathy (HSCT-TMA).

Narsoplimab (OMS721) is a pioneering monoclonal antibody that targets MASP-2 (mannan-binding lectin-associated serine protease-2), a crucial enzyme in the lectin pathway of the complement system. The complement system plays an essential role in innate immunity, helping the body eliminate pathogens and damaged cells. However, overactivation—especially in the lectin pathway—can lead to inflammatory and thrombotic damage in various diseases. Narsoplimab uniquely inhibits MASP-2, effectively halting the lectin pathway while leaving the classical and alternative pathways intact. This selective action preserves immune defense against infections while preventing harmful overactivation.

Developed by Omeros Corporation, Narsoplimab is the first therapeutic specifically designed to block MASP-2. It has been studied in a range of complement-mediated conditions, including IgA nephropathy (IgAN)—a kidney disease driven by immune complex deposition—and hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), a life-threatening complication characterized by endothelial injury and microvascular thrombosis. Its potential has also been explored in COVID-19, where complement activation contributes to severe lung and vascular inflammation.

What sets Narsoplimab apart from broader complement inhibitors is its targeted approach, which avoids compromising the entire complement cascade. This makes it particularly appealing for chronic inflammatory conditions and for immunocompromised patients where preserving infection-fighting ability is critical.

Clinical studies have shown encouraging signs of efficacy, including reduced proteinuria in IgAN and improved survival in HSCT-TMA. Regulatory submissions are ongoing, and the drug has received FDA Breakthrough Therapy designation. With a unique mechanism and expanding clinical relevance, Narsoplimab represents a novel class of immunomodulatory therapy with high translational potential.

Narsoplimab exerts its therapeutic effect by selectively inhibiting MASP-2 (mannan-binding lectin-associated serine protease-2), the key effector enzyme in the lectin pathway of the complement system. The complement cascade is a critical component of the innate immune system, and the lectin pathway is specifically activated by the recognition of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) on microbial or stressed host cells. Once triggered, MASP-2 cleaves complement proteins C4 and C2, initiating the formation of the C3 convertase, which amplifies the cascade, leading to inflammation, opsonization, and membrane attack complex (MAC) formation.

By binding to and inhibiting MASP-2, Narsoplimab interrupts this cascade at a very early step. This inhibition prevents the downstream generation of inflammatory mediators and reduces complement-mediated tissue damage, particularly in sensitive vascular beds. Importantly, it does so without affecting the classical or alternative pathways of complement activation—pathways essential for immune surveillance and pathogen clearance. This pathway-specific selectivity allows Narsoplimab to maintain a strong safety profile while delivering targeted anti-inflammatory benefits.

In conditions such as hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) and IgA nephropathy (IgAN), overactivation of the lectin pathway contributes to endothelial injury, microvascular thrombosis, and organ dysfunction. Narsoplimab’s ability to suppress this pathogenic activation offers a novel approach to disease modification.

Furthermore, in models of viral infections, including COVID-19, Narsoplimab has shown promise in dampening hyperinflammation, highlighting its potential in treating a broad range of immune-mediated diseases driven by complement dysregulation.

Narsoplimab (OMS721) is being explored across a spectrum of diseases where lectin pathway activation and complement dysregulation play central roles in disease pathology. Its selective MASP-2 inhibition offers a novel, targeted strategy for modulating inflammation and preventing tissue damage without compromising immune surveillance.

IgA Nephropathy (IgAN)

IgA nephropathy is one of the most common causes of glomerulonephritis and chronic kidney disease globally. It is marked by immune complex deposition—specifically IgA-containing immune complexes—in the renal glomeruli, leading to inflammation, proteinuria, and progressive loss of kidney function. The lectin pathway has been implicated in amplifying this inflammatory response. In a Phase 2 clinical trial, Narsoplimab significantly reduced proteinuria, a key marker of disease activity, while maintaining stable renal function. These encouraging results have laid the groundwork for ongoing Phase 3 trials, aimed at confirming long-term efficacy and safety in a larger patient population.

HSCT-Associated Thrombotic Microangiopathy (HSCT-TMA)

HSCT-TMA is a rare but often fatal complication of hematopoietic stem cell transplantation, driven by endothelial injury, complement activation, and microvascular thrombosis. With no approved therapies, Narsoplimab represents a significant advancement. It has shown strong preliminary efficacy in improving survival rates, reducing organ damage, and improving laboratory markers of TMA. These findings earned Narsoplimab FDA Breakthrough Therapy designation, accelerating its development pathway.

COVID-19 and Systemic Inflammatory Syndromes

Excessive complement activation contributes to endothelial dysfunction and cytokine storm in severe COVID-19 cases. Narsoplimab was included in the I-SPY COVID trial to assess its ability to mitigate this immune overactivation. While full data is pending, this application highlights the broader relevance of MASP-2 inhibition in systemic inflammatory and infectious diseases.

A biosimilar is a biologic product that is highly similar to an already approved reference biologic, with no clinically meaningful differences in safety, purity, or potency. In research, biosimilars offer a cost-effective and accessible alternative for studying drug mechanisms and responses.