Atrasentan (Vanrafia): ETA-Selective Oral Drug for IgAN
Novartis Atrasentan (Vanrafia): ETA-selective IgAN drug. ALIGN UPCR -36.1% FDA accelerated 2025. Week 136 eGFR +2.39 p=0.057; 2026 traditional filing.
Introduction: An Add-On to Sparsentan-Era IgAN Therapy
In IgAN, Sparsentan (ETA/AT1R dual antagonist) established an ETA/AT1R dual-antagonist option used instead of background RAS blockade. Novartis (ex-Chinook) takes a different, selective approach: ETA-selective blockade built on optimized RAS inhibition, with an SGLT2i-treated cohort supporting add-on use in that subgroup, via Atrasentan (ABT-627 / Vanrafia). ALIGN Phase 3 showed a 36-week UPCR between-group reduction of −36.1%, earning FDA accelerated approval (proteinuria reduction in primary IgAN) on April 2, 2025[1][2]. Note that, at approval, it is not established whether Vanrafia slows kidney function decline.
Subsequently, the Week 136 eGFR change-from-baseline confirmatory analysis (reported February 13, 2026) showed a Vanrafia-vs-placebo difference of +2.39 ml/min/1.73m² (2-sided p=0.057), narrowly missing the pre-specified α=0.05 threshold. At Week 132 (end of treatment), the SGLT2i co-treated subgroup showed a larger difference of +2.59 ml/min/1.73m² (nominal p=0.039). Novartis plans to submit for traditional approval in 2026 based on this total evidence package[6]. This article covers the ALIGN/AFFINITY data, MoA differentiation vs Sparsentan, and the competitive landscape.
1. Compound Profile
| Item | Detail |
|---|---|
| Generic name | Atrasentan |
| Brand name | Vanrafia |
| Development code | ABT-627 (Abbott origin) |
| Sponsor | Abbott → AbbVie → Chinook → Novartis (acquired Aug 2023, up to USD 3.5B) |
| Modality | Oral small-molecule, ETA-selective antagonist (>1,800× vs ETB) |
| Dose | 0.75 mg PO QD |
| Approval | FDA accelerated approval 2025-04-02 (proteinuria reduction in adults with primary IgAN at risk of rapid progression, generally UPCR ≥1.5 g/g; kidney-function benefit not yet established in the label) |
| Safety | Boxed warning: embryo-fetal toxicity (pregnancy contraindicated; contraception before/during/2 weeks after treatment). No REMS, but liver-enzyme, fluid-retention, and anemia monitoring required |
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2. Endothelin Pathway in IgAN
ET-1 acts on ETA receptors on glomerular endothelium, mesangial cells, and podocytes, driving mesangial contraction/proliferation, podocyte injury, and vasoconstriction — leading to proteinuria and eGFR decline. Immune-complex stimulation elevates ET-1 in IgAN. ETB mediates NO/natriuretic protection, so ETA selectivity narrows the side-effect spectrum while preserving renal benefit.
3. Mechanism: Differentiation from Sparsentan
| Agent | Target | Relation to RASi | Trade-off |
|---|---|---|---|
| Atrasentan | ETA only | Add-on | Stacks on existing SoC; modest monotherapy UPCR; boxed warning (fetal toxicity) |
| Sparsentan | ETA + AT1R dual (DEARA) | Used instead of background RASi | Strong monotherapy; REMS for hepatotoxicity, fetal toxicity |
4. Clinical Evidence
4-1. ALIGN Phase 3 (NCT04573478)[3]
- Design: International DB-placebo-controlled, IgAN with UPCR ≥1 g/g on max-tolerated RASi
- Interim (Week 36, main stratum n=270): UPCR change Atrasentan −38.1% vs placebo −3.1%, between-group −36.1% (95% CI −44.6 to −26.4, p<0.001)
- Confirmatory Week 136 eGFR change from baseline (reported 2026-02-13)[6]: between-group difference +2.39 ml/min/1.73m² (2-sided p=0.057) — narrowly missed the pre-specified α=0.05. At Week 132 (end-of-treatment), the SGLT2i co-treated subgroup showed +2.59 ml/min/1.73m² (nominal p=0.039); Week 136 is an off-treatment measurement 4 weeks after end-of-treatment, designed with expected wash-out
- Safety: Fluid retention 11.2% vs 8.2%; no HF cases; transient transaminase elevations; anemia (mean Hb −0.7 g/dL, 12% with >2 g/dL drop); possible decreased sperm counts. Embryo-fetal toxicity carries a boxed warning
- Heerspink HJL et al., N Engl J Med 2025;392(6):544-554 (PMID 39460694, Epub 2024-10-25, print 2025-02-06)
4-2. AFFINITY Phase 2 (NCT04573920)[7]
- Basket: IgAN / FSGS / Alport / DKD+SGLT2i (initiated by Chinook Therapeutics; sponsorship transferred to Novartis Pharmaceuticals after the August 2023 acquisition). Interpret as an open-label, small, exploratory cohort
- IgAN cohort: 24-week UPCR −54.7%; 79% (15 of 19 patients) with >40% reduction (Chinook ASN 2022)
- No treatment-related SAEs; minimal BP / BNP / weight effect
4-3. FDA Accelerated Approval (2025-04-02)
- Basis: ALIGN 36-week UPCR (interim 135/135)
- Indication: proteinuria reduction in adults with primary IgAN at risk of rapid progression (generally UPCR ≥1.5 g/g); kidney-function benefit not established in the label
- Confirmation: Week 136 eGFR change from baseline reported 2026-02-13 (diff +2.39 p=0.057; Week 132 +2.59 p=0.039 in SGLT2i sub) → traditional approval filing planned 2026
5. Regulatory
- FDA: 2025-04-02 (Vanrafia, US). Continued approval may be contingent upon verification of clinical benefit in a confirmatory trial
- China: accelerated approval in 2025 (proteinuria reduction in adults with IgAN)[6]
- EMA / PMDA: public information limited; EU pediatric PIP in place
- Full approval: Week 136 eGFR change from baseline reported 2026-02-13 (diff +2.39 ml/min/1.73m² p=0.057) + Week 132 supportive data (diff +2.59, nominal p=0.039 in SGLT2i subgroup)[6] → Novartis plans a traditional-approval filing in 2026 (the FDA approval letter lists confirmatory-trial study completion in May 2026 and final report submission in September 2026). FDA expected to judge on total evidence package (UPCR + eGFR + safety)
6. Competitive Landscape (IgAN)
| Agent | MoA | FDA Status | Primary EP |
|---|---|---|---|
| Sparsentan | ETA/AT1R dual | Full approval | UPCR −50% |
| Atrasentan | ETA-selective | Accelerated Apr 2025 | UPCR −36.1% between-group |
| Iptacopan | Factor B | Accelerated Aug 2024 | UPCR −38.3% at 9 months + 49.3% slowing of eGFR decline at 24 months |
| Sibeprenlimab | anti-APRIL | Accelerated Nov 2025 | UPCR −51.2% |
| Atacicept | BAFF/APRIL | Phase 3 (ORIGIN) | UPCR −46% |
| Finerenone | nsMRA | Approved (DKD/HFpEF) | eGFR slope |
| Budesonide-MR | Gut steroid | Full approval | UPCR |
7. Preclinical & Biomarkers
- gddY IgAN mice: rapid albuminuria reduction, renal inflammation/fibrosis transcriptome reversal, FR-PTEC gene expression normalization (Chinook ASN 2022 poster/preclinical)
- Biomarkers: UPCR, eGFR slope, plasma/urinary ET-1, BNP (fluid monitoring)
8. Points to Watch
- Traditional approval filing (2026) — how FDA evaluates the borderline Week 136 p=0.057 result together with Week 132 supportive data and UPCR in the total evidence package
- EMA / PMDA filings trajectory
- Combination trials with Iptacopan / Sibeprenlimab / Finerenone
- Expansion to FSGS / Alport / DKD (AFFINITY cohorts)
- Real-world choice vs Sparsentan: REMS burden vs add-on simplicity
References
1. Novartis. FDA grants accelerated approval to Vanrafia (atrasentan) for primary IgA nephropathy. April 2, 2025. Novartis
2. FDA. VANRAFIA (atrasentan) Prescribing Information. 2025. FDA Label
3. Heerspink HJL, et al. Atrasentan in Patients with IgA Nephropathy (ALIGN). N Engl J Med. 2025;392(6):544-554. PubMed 39460694 / ClinicalTrials.gov: NCT04573478
4. Novartis completes acquisition of Chinook Therapeutics. August 11, 2023. Novartis
5. Kohan DE, et al. Role of the endothelin axis in proteinuric kidney disease. Kidney Int Rep. 2023. PMC10658204
6. Novartis. Vanrafia Phase III data support slowing of kidney function decline in patients with IgA nephropathy. Press release, February 13, 2026. Novartis
7. AFFINITY: A Basket Study of Atrasentan in Patients With Proteinuric Glomerular Diseases. ClinicalTrials.gov: NCT04573920 (open-label exploratory Phase 2; IgAN 24-week data presented at Chinook ASN 2022)