FDA Approves Iptacopan for IgA Nephropathy: First Oral Complement Factor B Inhibitor Reduces Proteinuria 40% in
Quick Facts
What Is Iptacopan and How Does It Treat IgA Nephropathy?
IgA nephropathy (Berger's disease) is the most common primary glomerulonephritis worldwide, affecting an estimated 130,000 adults in the United States. The disease is driven by aberrantly glycosylated IgA1 antibodies that form immune complexes depositing in the kidney's mesangium, triggering complement-mediated inflammation and progressive kidney damage. Approximately 30–40% of patients progress to end-stage kidney disease within 20 years of diagnosis, requiring dialysis or transplantation.
Iptacopan (marketed as Fabhalta by Novartis) inhibits complement factor B, a critical component of the alternative complement pathway's C3 convertase. By blocking this upstream amplification loop, iptacopan reduces the complement-driven inflammation responsible for ongoing kidney injury. The drug was first approved by the FDA in December 2023 for paroxysmal nocturnal hemoglobinuria (PNH), establishing its complement-inhibiting mechanism in clinical practice. Unlike sparsentan (Filspari), which targets endothelin and angiotensin receptors to reduce proteinuria through hemodynamic mechanisms, iptacopan directly addresses the immunological driver of IgA nephropathy. The oral twice-daily dosing offers a convenient alternative to injectable complement inhibitors used in other complement-mediated diseases.
What Were the Key Results From the APPLAUSE-IgAN Trial?
The APPLAUSE-IgAN phase 3 trial enrolled adults with biopsy-confirmed IgA nephropathy, significant proteinuria despite maximum tolerated renin-angiotensin system (RAS) blockade, and reduced kidney function. Participants were randomized to iptacopan or placebo. The primary endpoint — change in proteinuria measured as urine protein-to-creatinine ratio (UPCR) — demonstrated a clinically meaningful reduction with iptacopan versus placebo.
A key secondary endpoint, the rate of eGFR decline over the treatment period, showed that iptacopan significantly slowed the loss of kidney function compared to placebo. This preservation of eGFR could translate to a meaningful delay in progression to end-stage kidney disease. As expected with complement inhibition, there was a modestly higher rate of infections in the iptacopan group. Consistent with the established safety requirements for complement inhibitors, all participants were required to be vaccinated against encapsulated organisms (Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae) prior to treatment initiation.
Frequently Asked Questions
Yes, in the APPLAUSE-IgAN trial, all patients continued their existing RAS inhibitor therapy (ACE inhibitors or ARBs). The potential for combining iptacopan with other IgA nephropathy treatments such as sparsentan is an area of active clinical investigation. Concurrent use with other complement inhibitors is generally not recommended.
As with other complement inhibitors, patients must receive meningococcal vaccines (MenACWY and MenB), pneumococcal vaccine, and Haemophilus influenzae type b vaccine at least 2 weeks before starting treatment. This is because complement inhibition increases susceptibility to encapsulated bacterial infections.
Both drugs reduce proteinuria in IgA nephropathy but through different mechanisms. Sparsentan works hemodynamically via endothelin/angiotensin receptor blockade, while iptacopan targets complement-driven inflammation directly. In the PROTECT trial, sparsentan demonstrated a significant proteinuria reduction versus the active comparator irbesartan. Both drugs represent important advances in treating IgA nephropathy beyond supportive care with RAS inhibitors alone.
References
- U.S. Food and Drug Administration. FDA Approves Fabhalta (iptacopan) for Paroxysmal Nocturnal Hemoglobinuria. December 6, 2023.
- Novartis AG. Novartis Announces APPLAUSE-IgAN Phase III Trial of Iptacopan in IgA Nephropathy. ClinicalTrials.gov Identifier: NCT04578834.
- Rovin BH et al. PROTECT: A Randomized Trial of Sparsentan Versus Irbesartan in IgA Nephropathy. N Engl J Med. 2023;389(26):2436-2445.
- Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276.