Vertex Pharmaceuticals (Nasdaq: VRTX) reported positive Phase IIb data for inaxaplin in two APOL1-mediated kidney disease (AMKD) populations not enrolled in its pivotal trial, extending the drug's potential addressable population. Meanwhile, the company said it has completed enrollment in the Phase II/III AMPLITUDE trial, with an interim analysis expected in early 2027.
Inaxaplin is a small-molecule inhibitor of APOL1 channel function that blocks the gain-of-toxic-function activity of the APOL1 G1/G2 risk variants in podocytes, the kidney filtration cells damaged in AMKD. The disease, which affects people of African ancestry who inherit two APOL1 risk variants, has no approved therapies. Current management relies on non-specific chronic kidney disease (CKD) supportive care — renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors — that address downstream consequences rather than the underlying genetic driver.
The Phase IIb AMPLIFIED study enrolled 41 patients across two open-label cohorts: people with AMKD and modest proteinuria (urine albumin-to-creatinine ratio (UACR) ≥0.1 g/g to <0.42 g/g; N=23) and people with AMKD and type 2 diabetes (UACR ≥0.1 g/g to <6 g/g; N=18). Both populations are distinct from the severe proteinuria, comorbidity-free population being studied in AMPLITUDE. All patients received inaxaplin 45 mg once daily on top of optimized standard of care for 13 weeks.
The stronger signal came in the modest-proteinuria cohort, where mean geometric UACR fell 42.7% from baseline at Week 13 (95% CI: −58.3%, −21.1%) and UPCR fell 44.7%. Vertex said the magnitude of reduction was consistent with its earlier Phase IIa study in AMKD with focal segmental glomerulosclerosis, which showed 43.4% and 47.6% reductions in UACR and UPCR, respectively, despite most patients in the modest-proteinuria cohort not having FSGS. The effect was smaller in patients with type 2 diabetes: UACR fell 17.3% (95% CI: −36.3%, 7.2%) and UPCR fell 25.4%, with the UACR confidence interval crossing zero. The 95% confidence intervals were generated post hoc. Inaxaplin was generally well tolerated, with no drug-related serious adverse events; all adverse events were mild or moderate, headache was the most common event at 7.3%, and five patients had isolated asymptomatic transaminase elevations that resolved.
The AMPLIFIED data matter to the AMPLITUDE regulatory strategy because Vertex said it plans to discuss the results with regulators in the context of the pivotal study. Vertex said the AMPLITUDE interim analysis, which will assess percent change from baseline in proteinuria and estimated glomerular filtration rate (eGFR) slope at 48 weeks in the pre-specified cohort, could support a filing for accelerated approval in the US if positive. The final analysis primary endpoint is eGFR slope after two years of treatment.