What is the MOA for Fabhalta (iptacopan)?

The mechanism of action for Fabhalta (iptacopan) involves the complement system (a group of proteins that help your immune system fight infections). Fabhalta is a complement factor B inhibitor. It works to treat paroxysmal nocturnal hemoglobinuria (PNH) by stopping red blood cells from getting destroyed. This reduces anemia and the need for blood transfusions. It was recently approved for immunoglobulin A nephropathy and complement 3 glomerulopathy, where it blocks activity that causes tissue damage.

How Fabhalta (Iptacopan) Works: In-Depth Mechanism of Action

Fabhalta (iptacopan) is a first-in-class, oral factor B inhibitor designed to selectively block the alternative pathway of the complement system. At the molecular level, iptacopan binds tightly to the protease domain of factor B (CFB). By attaching to factor B, Fabhalta blocks activation of a protein called C3 in the complement system. Normally, C3 is changed into C3b. C3b has two main actions in PNH:

1. C3b tags red blood cells for destruction by phagocytes (an immune cell that ingests and kills other cells). This is known as extravascular hemolysis.
2. C3b activates other proteins that destroy red blood cells in people with PNH. Specifically, it promotes the formation of C5 convertase, which changes C5 into C5b. C5b works with other proteins (C6, C7, C8, and C9) to form a membrane attack complex (MAC). MAC is essentially a hole in the membrane of the red blood cell that causes it to die. This is known as intravascular hemolysis.

Normally, these processes are controlled by proteins called CD55 and CD59. These proteins protect red blood cells from being broken down by the immune system. People with PNH do not have enough of these proteins, causing destruction of red blood cells.

• CD55 helps lower the amount of C3 convertase, which limits the formation of C3b and MAC.
• CD59 attaches to C8 and C9, preventing the formation of MAC.

Unlike terminal complement inhibitors (e.g., eculizumab, ravulizumab), Fabhalta acts upstream to control both C3-mediated extravascular hemolysis (EVH) and terminal complement-mediated intravascular hemolysis (IVH)—critical factors in the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH) and C3 glomerulopathy (C3G).

What is Fabhalta Used For?

Fabhalta is FDA approved to treat:

• Paroxysmal nocturnal hemoglobinuria (PNH)
• Immunoglobulin A nephropathy (IgAN)
• Complement 3 glomerulopathy (C3G)

Paroxysmal Nocturnal Hemoglobinuria (PNH)

• In PNH, red blood cells are highly vulnerable to immune-mediated destruction due to the lack of protective surface proteins (CD55, CD59).
• Intravascular hemolysis (IVH) occurs when the membrane attack complex (MAC) is formed via the terminal pathway, causing direct lysis of red blood cells.
• Extravascular hemolysis (EVH) results from C3b opsonization, marking red blood cells for removal by the spleen and liver.
• By acting proximally in the alternative pathway, Fabhalta (iptacopan) controls both C3b-mediated EVH and terminal complement-mediated IVH, addressing all major sources of hemolysis in PNH.

Immunoglobulin A Nephropathy (IgAN)

• IgAN is driven by the deposition of galactose-deficient IgA1 (Gd-IgA1) containing immune complexes in the kidneys.
• These complexes locally activate the alternative complement pathway, contributing to kidney inflammation and damage.
• Fabhalta blocks this pathological activation by binding Factor B and halting the formation of the C3 convertase, thereby dampening downstream complement activity and kidney tissue injury.

Complement 3 Glomerulopathy (C3G)

• C3G features chronic, uncontrolled activation of the alternative pathway, leading to excessive C3 cleavage and deposition in the kidney’s glomeruli.
• This persistent activity results in glomerular inflammation and progressive kidney disease.
• Fabhalta disrupts the cycle by attaching to Factor B, preventing the formation of C3 convertase, reducing C3 deposition and inflammation, and slowing disease progression.

Safety and Patient Access: What to Know About Fabhalta REMS

Fabhalta carries a class-specific risk of serious infections by encapsulated bacteria (e.g., Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae). Therefore, it is dispensed only under a FDA Risk Evaluation and Mitigation Strategy (REMS). Prescribers must ensure that patients are fully vaccinated against these pathogens and receive counseling on infection symptoms before starting treatment.

Patients and providers are required to enroll in the REMS program, and ongoing antibiotic prophylaxis may be recommended if urgent dosing is needed before vaccinations are complete.

This is not all the information you need to know about Fabhalta (iptacopan) for safe and effective use and does not take the place of your doctor’s directions. Review the full product information and discuss this information and any questions you have with your doctor or other health care provider.

See also:

Drug information

• Fabhalta
• Iptacopan

Related support groups

• Fabhalta (1 questions, 3 members)
• Iptacopan (1 questions, 3 members)

Medical Disclaimer