Inaxaplin (VX-147): First APOL1-Targeted FSGS Candidate
Vertex's Inaxaplin (VX-147) blocks variant APOL1 channels. Phase 2a (NEJM 2023): UPCR −47.6%. AMPLITUDE Ph2/3 targets accelerated approval in APOL1-MKD.
Introduction: First Genotype-Specific FSGS Therapy
People with two APOL1 risk variants / high-risk APOL1 genotypes (G1/G1, G1/G2, G2/G2; predominantly of African ancestry) have aggressive, treatment-resistant FSGS and hypertensive nephropathy. Sparsentan and RAS inhibitors act downstream. Vertex's Inaxaplin (VX-147) is the first oral small-molecule designed to directly block the pathogenic cation channel formed by variant APOL1, and remains an investigational candidate (no FDA approval or filing as of 2026-05). Phase 2a (NEJM 2023) delivered a 13-week UPCR reduction of −47.6%, and AMPLITUDE Phase 2/3 is targeting accelerated approval[1][2].
1. Compound Profile
| Item | Detail |
|---|---|
| Generic name | Inaxaplin |
| Development code | VX-147 |
| Sponsor | Vertex Pharmaceuticals |
| Modality | Oral small-molecule, APOL1 channel inhibitor (blocks Na⁺/K⁺ cation flux) |
| Dose | 45 mg PO QD (lead-in 15 mg × 2 weeks) |
| Designations | FDA Breakthrough Therapy, FDA Rare Pediatric Disease Designation, EMA PRIME |
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2. APOL1-MKD (AMKD) Epidemiology
- APOL1 G1/G2 are common in African ancestry (selective pressure from trypanosome resistance)
- Biallelic carriers (G1/G1, G2/G2, G1/G2) have 10–30× risk of FSGS / hypertensive nephropathy / HIV-associated nephropathy[7]
- ~100,000 AMKD patients in the U.S. and Europe
- Existing therapies (ACEi/ARB/Sparsentan) target downstream pathways only; see CKD treatment landscape 2026 for context
3. Mechanism: Blocking Variant-APOL1 Pores
Wild-type APOL1 (G0) circulates and kills trypanosomes; G1/G2 variants form aberrant cation-selective pores on podocyte membranes, driving Na⁺/K⁺ dysregulation → cell swelling → podocyte death[3]. Inaxaplin directly blocks cation flux through variant APOL1 pores — the first podocyte-protective mechanism upstream of the injury cascade.
4. Clinical Evidence
4-1. Phase 2a (NCT04340362)[2]
- Design: open-label, APOL1 two-risk-allele FSGS, n=16 (13 evaluable)
- Dosing: 15 mg × 2 weeks → 45 mg × 11 weeks
- 13-week UPCR: mean −47.6% (95% CI −60.0 to −31.3)
- Safety: in this small 13-week open-label study, adverse events were mild or moderate and none led to discontinuation (small, short-term data)
- Egbuna O et al., N Engl J Med 2023;388(11):969-979 (PMID 36920755)
4-2. AMPLITUDE Phase 2/3 adaptive (NCT05312879)
- Design: placebo-controlled, APOL1 two-risk-allele non-diabetic CKD (incl. FSGS)
- Advanced to Phase 3 portion in April 2024: 45 mg vs placebo on top of SoC
- Primary: the Week 48 interim analysis evaluates UPCR % change and eGFR slope; the final efficacy analysis is anchored on eGFR slope (ClinicalTrials.gov Part A)
- Pediatric: expanding to 10–17 years
- Vertex IR (2025-09-25): enrollment of the interim-analysis cohort completed (Vertex 2025-09-25 PR)
- Positive interim → accelerated approval filing
4-3. Phase 1 Safety
- Healthy adults and renal-impaired subjects; PK/PD and no QT prolongation (PMID 38600955)
5. Regulatory
- FDA Breakthrough Therapy: APOL1 two-risk-allele FSGS (granted 2022-12-08[5])
- FDA Rare Pediatric Disease Designation: granted (pediatric AMKD)
- EMA PRIME: granted 2022-12-08[5]
- AMPLITUDE interim: interim-cohort enrollment completed 2025-09-25. Vertex's Q1 2026 update expects interim-analysis data sharing in early 2027, after the interim cohort reaches 48 weeks of treatment (full enrollment expected H2 2026); a positive readout would trigger accelerated approval filing in the U.S.
6. Competitive Landscape (FSGS / AMKD)
| Agent | MoA | Phase | Note |
|---|---|---|---|
| Inaxaplin (VX-147) | APOL1 channel block | Phase 2/3 | Genotype-specific, first-in-class |
| MZE829 (Maze) | APOL1 oral inhibitor | Phase 2 HORIZON topline positive (Mar 2026)[8] | broad AMKD uACR -35.6%, FSGS subgroup -61.8% (small); advancing to pivotal |
| Sparsentan | ETA/AT1R | FDA-approved (FSGS without nephrotic syndrome, age ≥8, proteinuria reduction) | Genotype-independent; REMS / hepatotoxicity / embryo-fetal boxed warning |
| DMX-200 (Dimerix) | CCR2 | Phase 3 (ACTION3)[8] | FSGS |
| WAL0921 (Walden) | anti-suPAR | Phase 2 basket[8] | Glomerular disease basket (incl. FSGS) |
Inaxaplin is positioned as the first disease-modifying therapy (DMT) for a kidney genotype subset, complementing proteinuria-lowering agents.
7. Preclinical & Biomarkers
- Podocyte cell models: G1/G2 podocyte swelling and death rescued by Inaxaplin
- APOL1 transgenic mice: proteinuria and glomerular injury improvement
- Biomarkers: UPCR, eGFR slope, circulating APOL1 dynamics, urinary podocyte markers
- Genotyping: APOL1 G1/G2 testing required before therapy
8. Points to Watch
- AMPLITUDE interim UPCR + eGFR slope
- Genotype testing infrastructure and reimbursement
- First-to-pivotal / first-to-approval race vs Maze MZE829 (HORIZON topline positive Mar 2026)
- Indication expansion to hypertensive and HIV-associated nephropathies
- Combination strategies with Sparsentan / SGLT2i
References
1. Vertex Pharmaceuticals. Vertex advances inaxaplin (VX-147) to Phase 3 of adaptive Phase 2/3 trial. Press release, 2024. Vertex IR / Vertex Announces Key Advancements Across Kidney Portfolio (interim cohort enrollment complete). Press release, September 25, 2025. Vertex IR
2. Egbuna O, et al. Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants. N Engl J Med. 2023;388(11):969-979. PubMed 36920755 / ClinicalTrials.gov: NCT04340362
3. Datta S, et al. APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease. J Clin Invest. 2024;134(5):e172262. PubMed 38227370 / JCI
4. AMPLITUDE — ClinicalTrials.gov: NCT05312879
5. Vertex Announces Inaxaplin (VX-147) Granted Breakthrough Therapy Designation by FDA and PRIME Designation by EMA. Press release, December 8, 2022. Vertex IR
6. Egbuna O, et al. Phase 1 Safety, Tolerability, and Pharmacokinetics of Inaxaplin. Glomerular Dis. 2024;4(1):64-73. PubMed 38600955 / PMC11006409
7. Papeta N, et al. APOL1 variants increase risk for FSGS and HIVAN but not IgA nephropathy. J Am Soc Nephrol. 2011;22(11):1991-1996. PubMed 21997397
8. Competitor trials (ClinicalTrials.gov): MZE829 HORIZON NCT06830629 / DMX-200 ACTION3 NCT05183646 / WAL0921 basket NCT06466135