Inaxaplin (VX-147): First APOL1-Targeted Drug for FSGS/AMKD
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
APOL1 G1/G2 risk allele carriers (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 to directly block the pathogenic cation channel formed by variant APOL1. 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, 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
- ~100,000 AMKD patients in the US
- 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: mostly mild-moderate AEs; no serious signals
- 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: 48-week UPCR % change + eGFR slope
- Pediatric: expanding to 10–17 years
- 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
- EMA PRIME: granted
- AMPLITUDE interim: expected 2026 (per Vertex communications)
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) | Direct competitor |
| Sparsentan | ETA/AT1R | Approved (FSGS in review) | Genotype-independent |
| DMX-200 (Dimerix) | CCR2 | Phase 3 (ACTION3) | FSGS |
| WAL0921 (Walden) | anti-suPAR | Phase 2 | FSGS candidate antigen |
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-in-class race vs Maze MZE829
- 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
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. Giovinazzo JA, et al. APOL1 variant-induced cation channel activity and podocyte injury. J Clin Invest. 2023. JCI
4. AMPLITUDE — ClinicalTrials.gov: NCT05312879
5. Vertex. Phase 1 Safety and Tolerability of Inaxaplin. 2024. PMC11006409