IgA Nephropathy Clinical Trial Landscape

Why IgA nephropathy trial monitoring is essential in 2026

IgA nephropathy (Berger's disease) is the most common primary glomerulonephritis worldwide, affecting approximately 1.3 million patients. Until 2021, no disease-modifying therapy existed and standard of care was limited to supportive RAS blockade and corticosteroids. The past four years have seen a transformation: three distinct mechanisms have now reached approval in the US, and the Phase 3 pipeline remains among the most active in all of nephrology.

This rapid approval pace creates a complex and fast-moving competitive landscape. For nephrology pharma teams, investors, and clinicians, tracking IgAN trial activity is no longer optional — the landscape changes quarterly. Key signals to monitor include:

• New Phase 3 completions and readouts — multiple ongoing confirmatory and expansion trials with eGFR and proteinuria endpoints
• Combination therapy trials — pairing approved mechanisms (e.g., budesonide + sparsentan, atrasentan + APRIL blocker)
• Pediatric and early-stage trials — IgAN diagnosed in childhood or early adulthood; earlier intervention hypothesis now being tested
• Biomarker-stratified enrollment — Gd-IgA1 levels, Oxford classification (MEST-C score), and eGFR slope as stratification and enrichment tools
• Complement pathway programs — iptacopan and other lectin/alternative pathway inhibitors targeting downstream mesangial injury

Phase 3 IgA nephropathy pipeline (2025–2026)

The IgAN Phase 3 pipeline in 2026 contains more concurrent programs than any other nephrology indication — 12 distinct trials from 9 sponsors spanning 6 distinct mechanisms. Key trials by mechanism:

Complement C5 vs. Factor B: two different bets on the same pathway

Both iptacopan (Factor B, Novartis) and ravulizumab (C5, Alexion/AstraZeneca) are in Phase 3 IgAN trials — representing competing hypotheses about where in the complement cascade intervention is most effective for mesangial injury.

Iptacopan blocks upstream at Factor B — inhibiting the alternative pathway amplification loop before the C3 convertase forms. This prevents both C3 and C5 cleavage and does not rely on a terminal complement blockade. Its oral dosing is a major commercial advantage over intravenous C5 inhibitors.

Ravulizumab blocks downstream at C5 — the same mechanism approved for PNH and atypical HUS. Long-acting IV infusion every 8 weeks. C5 inhibition prevents membrane attack complex formation but leaves upstream complement deposition (C3b) intact, which may be relevant for mesangial injury biology.

The IgAN complement competition mirrors the PNH landscape: terminal C5 inhibition (ravulizumab, eculizumab) preceded Factor B inhibition (iptacopan), but in PNH, Factor B added protections against extravascular hemolysis that C5 inhibitors lacked. In IgAN, neither mechanism has published Phase 3 data yet — the readout will be a defining data point for complement inhibitor platform companies across the entire glomerulonephritis space.

Next-generation approaches: siRNA and plasma cell depletion

Beyond APRIL/BAFF blockade and complement inhibition, two emerging mechanisms represent the next frontier in IgAN:

Sefaxersen (Roche) — RNA interference targeting the galactosylation defect

Sefaxersen (RO7434656) uses small interfering RNA (siRNA) to silence C1GALT1, the enzyme responsible for adding galactose to IgA1's O-glycans. In IgAN, C1GALT1 is underactive, producing the galactose-deficient IgA1 (Gd-IgA1) that drives autoantibody formation. Rather than blocking APRIL/BAFF upstream of Gd-IgA1 production, sefaxersen corrects the structural glycosylation defect directly. Phase 3 trial (NCT05797610) enrolls patients at high risk of progression. If successful, this approach addresses the molecular root cause of IgAN rather than its downstream consequences — a conceptually distinct strategy from all currently approved therapies.

Felzartamab (Biogen) — anti-CD38 plasma cell depletion

Felzartamab is an anti-CD38 monoclonal antibody that depletes CD38-expressing plasma cells — the cells that produce the pathogenic Gd-IgA1 and autoantibodies in IgAN. CD38 is expressed on long-lived plasma cells in the bone marrow, not just circulating B cells, which means felzartamab may deplete the disease-causing cell population more completely than APRIL/BAFF blockers that act upstream. Anti-CD38 antibodies (daratumumab, isatuximab) are approved in multiple myeloma; Biogen is applying this mechanism to autoimmune glomerulonephritis. Phase 3 (NCT06935357) is actively recruiting, making felzartamab one of the most mechanistically novel programs in the IgAN field.

Understanding the IgAN pathogenesis cascade — why so many mechanisms work

IgA nephropathy results from a multi-step pathogenic cascade, which explains why so many mechanistically distinct therapies are showing Phase 3 activity:

• Step 1 — Gd-IgA1 overproduction: Mucosal B cells in the gut-associated lymphoid tissue (GALT) produce galactose-deficient IgA1 (Gd-IgA1). APRIL and BAFF drive this overproduction. Budesonide (Tarpeyo) targets the GALT to reduce mucosal IgA1 production; sibeprenlimab and atacicept block APRIL/BAFF directly.
• Step 2 — Autoantibody formation: Circulating Gd-IgA1 triggers production of IgG/IgA autoantibodies that recognize its aberrant galactose-deficient hinge region, forming pathogenic IgA immune complexes.
• Step 3 — Mesangial deposition: IgA immune complexes deposit in the glomerular mesangium, activating mesangial cells and triggering complement. Complement inhibitors (iptacopan) target this step.
• Step 4 — Glomerular injury: Mesangial complement activation drives cytokine release, proteinuria, and progressive scarring. Endothelin-A receptor antagonists (atrasentan, sparsentan) reduce proteinuria and renal injury at this level.

Because each step is a distinct intervention point, combination trials pairing, for example, an APRIL blocker with an endothelin antagonist — addressing both upstream Gd-IgA1 overproduction and downstream proteinuria — are now being designed. The next wave of Phase 3 trials will increasingly test combinations rather than single agents.

Complement inhibition: the iptacopan story

Iptacopan (LNP023, Novartis) is an oral inhibitor of complement Factor B, blocking the alternative pathway amplification loop at the mesangial level. Its approval in paroxysmal nocturnal hemoglobinuria (PNH) in 2023 validated the oral Factor B inhibitor mechanism; the Phase 3 APPLAUSE-IgAN trial is testing whether the same pathway drives enough disease in IgAN to produce clinically meaningful proteinuria reduction and eGFR preservation.

The APPLAUSE-IgAN readout is one of the most watched in nephrology for 2026. If complement Factor B inhibition produces proteinuria reductions comparable to approved agents, it would provide a fourth mechanistically distinct approved therapy and potentially valuable combination partner. For companies developing complement inhibitors across indications — hemolytic anemias, C3 glomerulopathy, lupus nephritis — the iptacopan IgAN data is a major signal for indication expansion.

APRIL/BAFF pathway: the upstream IgA-reducing approach

Sibeprenlimab (VIS649) specifically blocks APRIL, reducing Gd-IgA1 production directly. Phase 2 data showed 48% reduction in proteinuria versus placebo — a larger effect than approved ETA antagonists. The VISIONARY Phase 3 trial is fully enrolled and data are expected in 2026, making this one of the most important near-term IgAN readouts.

Atacicept (Vera Therapeutics) blocks both APRIL and BAFF via a TACI-Fc fusion protein. Vera's ORIGIN Phase 3 trial showed rapid and deep reductions in Gd-IgA1 and proteinuria in Phase 2, and the Phase 3 primary endpoint is eGFR slope — the most clinically meaningful long-term endpoint and the gold standard regulators want to see.

The competition between sibeprenlimab (anti-APRIL only) and atacicept (anti-APRIL + anti-BAFF) represents one of the most important mechanism-of-mechanism questions in nephrology: does dual APRIL/BAFF blockade add incremental benefit over APRIL alone?

Who monitors IgA nephropathy clinical trials

• Nephrology pharma BD teams — tracking competitive programs across endothelin, complement, and APRIL/BAFF mechanisms; monitoring new registrations for partnership and licensing intelligence
• Nephrologists at academic medical centers — identifying Phase 3 trial enrollment opportunities for patients with progressive IgAN; staying current on mechanism-based treatment sequencing
• Nephrology investors — monitoring Phase 3 data milestones for Vera Therapeutics, Travere, Calliditas, Vertical Biosciences; APPLAUSE-IgAN readout timing for Novartis
• CROs specializing in renal disease — identifying new Phase 2/3 IgAN trial registrations before they reach public databases; understanding enrollment competition between concurrent trials
• Complement inhibitor platform companies — tracking iptacopan results and new registrations to validate complement's role across glomerular diseases
• Patient advocacy (NephCure, PKD Foundation) — keeping IgAN patients informed about available trials and emerging treatment options

What we monitor for IgA nephropathy

• Condition keywords: "IgA nephropathy", "IgAN", "Berger disease", "Berger's disease", "mesangial IgA deposition", "IgA glomerulonephritis"
• Mechanism keywords: "APRIL", "BAFF", "TACI", "atrasentan", "sparsentan", "budesonide", "iptacopan", "sibeprenlimab", "atacicept", "complement Factor B", "alternative pathway"
• Phase filter: Phase 1 for early competitive intelligence, Phase 3 for registration-enabling trials
• Sponsor filter: Industry only (Novartis, Travere, Vera, Otsuka, Calliditas, Vertical Biosciences) or all including academic
• Status filter: Recruiting only for actionable trial enrollment; or all active for competitive landscape tracking

Related nephrology clinical trial monitors

• Chronic kidney disease (CKD) clinical trials — overlapping GFR progression endpoints, RAS blockade, oral GLP-1, and cardiorenal outcomes programs
• Amyloidosis clinical trials — related rare kidney disease pipeline; overlapping nephrology patient population
• Lupus clinical trials — overlapping lupus nephritis programs; shared APRIL/BAFF pathway targets (belimumab)
• Complement inhibitor clinical trials — iptacopan, ravulizumab, and Factor B vs. C5 competition across IgAN, PNH, and gMG
• Atrial fibrillation clinical trials — DOAC-related renal endpoints and anticoagulation in CKD

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