IgA nephropathy went from “ACE inhibitor and hope” to nine drug classes in under five years. This page organises that landscape the only way it makes sense — by which hit of the four-hit model each agent interrupts, and by which compartment it actually reaches. Two of the four hits still have no agent at all.
How to use this section
Start with the four-hit map below. The two interactive tools let you toggle agents and watch the consequences: the interactive map covers all four hits — B-cell compartments, class switching and glomerular hemodynamics in one view. The mechanism review is the full PMID-anchored treatment of the BAFF/APRIL axis.
The Four-Hit Model, and What Reaches Each Hit
Hit 1 — Galactose-deficient IgA1 production
Mucosal B cells in gut-associated lymphoid tissue and Waldeyer's ring produce IgA1 whose hinge-region O-glycans lack terminal galactose. TGF-β directs the switch to IgA; APRIL supplies the CD40-independent switch signal. This is the source, and it sits in tissue.
| Agent | Target | Status | Reaches GALT? |
|---|---|---|---|
| Nefecon / TARPEYO | Targeted-release budesonide, ileal delivery | FDA approved | ✅ by design |
| Sibeprenlimab (VOYXACT) | anti-APRIL | Accelerated approval, Nov 2025 | ✅ ligand is systemic |
| Zigakibart | anti-APRIL | Phase 3 (BEYOND) | ✅ |
Hits 1 + 2 — Production and autoantibody
Hit 2 is the anti-glycan IgG and IgA autoantibody response against the Gd-IgA1 neoepitope. Agents that act on B-cell survival or the plasma cell address both hits at once.
| Agent | Target | Status | Reaches the plasma cell? |
|---|---|---|---|
| Atacicept (TRUTAKNA) | TACI-Fc — BAFF + APRIL | Accelerated approval, Jul 2026 | ✅ both ligands |
| Telitacicept | TACI-Fc — BAFF + APRIL | Phase 3 (TELIGAN) | ✅ |
| Felzartamab | anti-CD38 | Phase 2a (IGNAZ) | ✅ directly |
| Mycophenolate | IMPDH-II, antiproliferative | KDIGO 2025: Chinese patients | ❌ post-mitotic |
| Rituximab | type I anti-CD20 | Failed RCT | ❌ CD20-negative |
| Obinutuzumab | type II anti-CD20, glycoengineered | Case series, n=3 | ❌ CD20-negative |
Why three agents with real B-cell activity still fail
**Rituximab** depletes circulating CD20+ B cells completely and reaches neither the GALT source nor the plasma cell, which has shed CD20. In the randomized trial, serum Gd-IgA1 and its autoantibodies **did not change at all**.
**Mycophenolate** blocks lymphocytes that are *dividing*. The long-lived plasma cell is post-mitotic and does not use the de novo purine pathway, so the established secreting pool is untouched. Its record fits that ceiling — a large benefit in Chinese cohorts that has not reproduced in Western ones.
**Obinutuzumab** reaches tissue more deeply than rituximab and still cannot touch a CD20-negative plasma cell. It fixes one of the two failures.
The common lesson: **B-cell activity is not the target. The pathogenic protein is.**
Hit 3 — Immune-complex formation and mesangial deposition
No agent targets Hit 3
There is no drug that prevents Gd-IgA1 and anti-glycan antibody from forming complexes, and none that blocks mesangial deposition. Hit 3 is addressed only indirectly, by lowering the concentration of the reactants upstream. That is the structural argument for treating Hit 1 hard.
Hit 4 — Complement activation and glomerular injury
| Agent | Target | Status | Key result |
|---|---|---|---|
| Iptacopan (FABHALTA) | Complement factor B, alternative pathway | FDA approved | eGFR slope −3.10 vs −6.12 mL/min/yr; kidney-failure composite HR 0.57 |
| Sparsentan (FILSPARI) | Dual endothelin ETA + AT1 | FDA approved | Chronic 2-yr slope −2.7 vs −3.8 vs active comparator |
| Atrasentan | Selective ETA | FDA approved | Proteinuria reduction (ALIGN) |
| SGLT2 inhibitors | Proximal Na/glucose, tubuloglomerular feedback | Guideline-supported add-on | DAPA-CKD IgAN subgroup HR 0.29 |
| ACE inhibitor / ARB | AT1, efferent tone | Foundation | Every trial enrols on top of this |
The Target Has Moved
KDIGO 2025 shifted the proteinuria goal to <0.5 g/day, ideally <0.3, superseding the older <1 g/day. That reframes what the new agents actually buy: a 46% reduction from the ORIGIN 3 baseline of 1.5 g/g lands near 0.8 g/g — still above goal, and inside a band carrying hazard ratios of 1.7 to 4.0 for progression.
Clinical Pearl — the guideline does not yet endorse these drugs
KDIGO 2025's list of therapies that reduce pathogenic IgA production contains targeted-release budesonide, reduced-dose corticosteroids, and mycophenolate in Chinese patients. **No BAFF or APRIL agent appears on it** — both approvals postdate the guideline. Prior-authorization arguments should rest on the label indication and the trial data, not on KDIGO.
Verdict: What Works, What Does Not, and On What Evidence
Tiered by endpoint quality, not by effect size. Proteinuria reduction and preserved kidney function are different claims, and several agents have only the first.
Tier 1 — Proven on kidney function or a hard composite
| Agent | Endpoint | Result |
|---|---|---|
| Iptacopan (FABHALTA) | 24-month eGFR slope and kidney-failure composite | Slope −3.10 vs −6.12 mL/min/1.73m²/yr (difference 3.02, 95% CI 2.02–4.01, p<0.001). Composite 21.4% vs 33.5%, HR 0.57 (0.40–0.81). Serious infections 6.7% vs 2.1%. |
| Nefecon / TARPEYO | 2-year time-weighted average eGFR | Difference 5.05 mL/min/1.73m² (95% CI 3.24–7.38, p<0.0001) after a 9-month course with 15 months off drug. |
| Sparsentan (FILSPARI) | Chronic 2-year eGFR slope vs active comparator | −2.7 vs −3.8 mL/min/1.73m²/yr (difference 1.1, 95% CI 0.1–2.1, p=0.037). Composite kidney failure not significant — 18/202 vs 26/202, RR 0.7 (0.4–1.2). |
| SGLT2 inhibitors | Composite kidney outcome, IgAN subgroup | DAPA-CKD prespecified IgAN subgroup (n=270): HR 0.29 (0.12–0.73); eGFR decline −3.5 vs −4.7 mL/min/yr. |
| ACE inhibitor / ARB | Foundation | Not re-litigated. Every modern trial enrols on top of maximally tolerated RAS blockade; the comparator arms are already treated. |
Tier 2 — Proteinuria surrogate; kidney-function data pending or not peer-reviewed
| Agent | Result | What is missing |
|---|---|---|
| Sibeprenlimab (VOYXACT) | 51.2% placebo-adjusted proteinuria reduction at 9 months (96.5% CI 42.9–58.2) | eGFR slope is the key secondary and reads out at trial completion. Approved under accelerated approval. |
| Atacicept (TRUTAKNA) | 41.8-point placebo-adjusted proteinuria difference at week 36; 104-week topline reports slope −0.6 vs −5.6 and composite HR 0.24 | The two-year result currently exists as a sponsor press release, not a peer-reviewed publication. Accelerated approval. |
| Telitacicept | 55.0% relative proteinuria reduction at 39 weeks (95% CI 47.6–61.3) | Interim analysis; no slope data. |
| Atrasentan | Proteinuria reduction (ALIGN) | No completed chronic slope against an active comparator. |
| Felzartamab (anti-CD38) | Phase 2a: UPCR −29.5% at 9 months in the 9-dose arm, sustained to 24 months | Phase 2a, n=54. Mechanistically the most direct route to the plasma cell; unproven at scale. |
Tier 3 — Failed, population-restricted, or unproven
| Agent | Verdict | Why |
|---|---|---|
| Rituximab | Does not work | Randomized trial, n=34. B cells fully depleted; eGFR, proteinuria, Gd-IgA1 and anti-Gd-IgA1 all unchanged. Wrong compartment, and the output cell is CD20-negative. |
| Mycophenolate | Population-restricted | Large benefit in Chinese cohorts (composite aHR 0.23, 95% CI 0.09–0.63); not reproduced in Western populations. KDIGO 2025 restricts the suggestion accordingly. Benefit is withdrawal-dependent — eGFR loss went from 2.9 to 6.1 mL/min/yr after stopping. |
| Obinutuzumab | Unproven | Three-patient uncontrolled case series in refractory disease. Deeper tissue depletion than rituximab, but still cannot reach a CD20-negative plasma cell. |
| Belimumab | Not studied | No IgA nephropathy dataset exists. Included in the interactive tools for mechanistic contrast only. |
| Systemic corticosteroids | Effective but toxic | Reduce kidney failure, at the cost of serious infections and deaths. Reserved for aggressive disease; KDIGO 2025 suggests reduced-dose regimens. |
Clinical Pearl — the pattern across all three tiers
Every agent in Tier 1 either **reaches the mucosal source** (Nefecon), or **acts downstream of deposition** on hemodynamics and complement (sparsentan, SGLT2i, iptacopan). Every agent in Tier 3 acts on B cells in the **circulating or proliferating** compartment — the one that is easy to measure and not where the disease is.
The Tier 2 agents are the interesting case: they neutralise a **soluble ligand** rather than deplete a cell, so they have no tissue-penetration problem at all. Whether that converts a strong surrogate into preserved kidney function is the question the confirmatory readouts will answer.
In This Section
| Resource | What it covers |
|---|---|
| The Pharmacology and Immunotherapy of IgAN — interactive | Fourteen agents, four hits, three linked panels: B-cell compartments and the GALT source, class-switch recombination with measured immunoglobulin effects, and the glomerulus — the animated hemodynamics simulator from the creatinine and GFR lecture, extended with atrasentan, sparsentan and ERA plus SGLT2 inhibitor. |
| APRIL and BAFF/APRIL Inhibition — mechanism review | The full PMID-anchored treatment: receptor specificity, memory B-cell sparing, plasma-cell redundancy, vaccine and mucosal consequences, and why anti-CD20 fails. |
| IgA Nephropathy — clinical overview | Presentation, diagnosis, Oxford MEST-C risk stratification, case-based learning and self-assessment. |
| From Pathogenesis to Precision Medicine — student handout | The same pathophysiology pitched for students and trainees. |
| IgA Nephropathy: A Patient’s Guide | Plain-language version for the clinic. |
Related material elsewhere on the site: albuminuria and proteinuria measurement and GFR estimation in the CKD module; endothelin antagonism in resistant hypertension in the hypertension module.