Vertex's Inaxaplin Cuts Proteinuria in Broader AMKD Populations in Phase 2b AMPLIFIED
Key Insights
Vertex reported positive Phase 2b AMPLIFIED results for inaxaplin in two APOL1-mediated kidney disease (search) populations not enrolled in its pivotal AMPLITUDE trial.
In the modest proteinuria cohort, inaxaplin 45 mg once daily reduced urine albumin-to-creatinine ratio by 42.7% at Week 13 versus baseline.
The type 2 diabetes (search) cohort showed a smaller 17.3% UACR reduction, with the confidence interval crossing zero, and UPCR fell 25.4%.
Vertex Pharmaceuticals reported positive results from the Phase 2b AMPLIFIED study of inaxaplin in people with APOL1-mediated kidney disease (search) (AMKD) and modest proteinuria, and in people with AMKD and type 2 diabetes (search). Both populations are distinct from the severe proteinuria, comorbidity-free group being studied in the company's pivotal AMPLITUDE trial.
Inaxaplin is a small-molecule inhibitor of APOL1 (search) 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 occurs in people of African ancestry who inherit two APOL1 risk variants and has no approved therapies. Current management relies on non-specific chronic kidney disease supportive care, including renin-angiotensin-aldosterone system inhibitors and sodium-glucose cotransporter-2 inhibitors, which address downstream consequences rather than the underlying genetic driver.
Trial Design and Endpoints
AMPLIFIED is a Phase 2, single-arm, open-label study evaluating a 45 mg once-daily dose of inaxaplin for 13 weeks on top of optimized standard of care. Forty-one people were enrolled and dosed across two cohorts. Cohort 1 enrolled people with AMKD and modest proteinuria, defined as a urine albumin-to-creatinine ratio (UACR) of at least 0.1 g/g to less than 0.42 g/g (N=23). Cohort 2 enrolled people with AMKD, type 2 diabetes (search) and proteinuria, defined as UACR of at least 0.1 g/g to less than 6 g/g (N=18).
The primary endpoint was mean percent change in UACR at Week 13 compared with baseline, evaluated separately for each cohort. Other endpoints included mean percent change in urine protein-to-creatinine ratio (UPCR) at Week 13 and safety. According to the pre-specified statistical analysis plan, two people, one in each cohort, who were noncompliant with treatment were excluded from the efficacy analyses. The Week 13 analyses included 18 and 14 people in cohorts 1 and 2, respectively. The 95% confidence intervals were generated post hoc.
Proteinuria Reductions by Cohort
In cohort 1, inaxaplin on top of optimized standard of care reduced UACR by 42.7% at Week 13 compared with baseline (95% CI -58.3%, -21.1%), from a mean baseline UACR of 0.28 g/g (standard deviation 0.09). UPCR fell 44.7% (95% CI -60.9%, -21.9%) from a mean baseline of 0.46 g/g (SD 0.20).
Vertex noted these results are in line with the treatment effect previously reported in the Phase 2a study of inaxaplin in AMKD with focal segmental glomerulosclerosis (search) (FSGS), which showed a UACR reduction of 43.4% and a UPCR reduction of 47.6% at Week 13. In the modest proteinuria cohort, most people were not diagnosed with FSGS.
In cohort 2, UACR fell 17.3% at Week 13 compared with baseline (95% CI -36.3%, 7.2%), from a mean baseline of 0.67 g/g (SD 0.87), with the confidence interval crossing zero. UPCR decreased 25.4% (95% CI -45.1%, 1.4%) from a mean baseline of 1.12 g/g (SD 1.51).
"These results add to the evidence base for inaxaplin and its potential as a first- and best-in-class treatment targeting the underlying cause of AMKD. The modest proteinuria cohort, which included patients with and without FSGS, delivered remarkable reductions in proteinuria consistent with the original Phase 2a study in patients with AMKD and FSGS," said Carmen Bozic, M.D., executive vice president, global medicines development and medical affairs, and chief medical officer at Vertex. "We are also excited with the treatment effect, though smaller in magnitude, in the type 2 diabetes (search) cohort. We look forward to discussing the AMPLIFIED results with regulators in the context of the AMPLITUDE pivotal study."
Safety Profile
Inaxaplin was generally safe and well tolerated across both cohorts. There were no serious adverse events related to inaxaplin, and all adverse events were mild or moderate in severity. The most common adverse event, occurring in more than 5% of subjects, was headache at 7.3%. Five people had isolated, asymptomatic transaminase elevations, which resolved.
Pivotal Program and Regulatory Path
Vertex has completed full enrollment in the Phase 2/3 AMPLITUDE study of inaxaplin in people with severe proteinuria and no other kidney disease-causing comorbidities. The trial evaluates inaxaplin 45 mg once daily orally compared with placebo, on top of standard of care. The primary efficacy endpoint for the final analysis is estimated glomerular filtration rate (eGFR) slope in patients receiving inaxaplin compared with placebo after two years of treatment.
Vertex said it is on track to share data from the pre-planned interim analysis of AMPLITUDE in early 2027, once the interim analysis cohort reaches 48 weeks of treatment. The interim analysis will assess percent change from baseline in proteinuria and eGFR slope in the pre-specified cohort. If positive, the data could form the basis for potential accelerated approval in the U.S., which would make inaxaplin the first approved therapy for AMKD.
"These results are very convincing," said Glenn Chertow, M.D., M.P.H., professor of medicine at Stanford University School of Medicine and chair of the Vertex APOL1 (search) Program Steering Committee. "These patients were already well treated with foundational chronic kidney disease therapies and treatment with inaxaplin led to additional reductions in proteinuria. As someone who treats this rapidly progressing disease where unmet need is high, I am looking forward to the AMPLITUDE interim analysis and am hopeful that we'll soon have a potentially disease-specific and disease-modifying therapy to offer to patients living with AMKD."
Disease Burden and Competitive Landscape
AMKD is a rapidly progressing, proteinuric kidney disease caused by two variants in the APOL1 (search) gene. Inherited APOL1 genetic variants cause kidney cell injury, cell death and damage to the glomeruli, which filter blood in the kidney. This leads to protein in the urine and decreased kidney function, which can lead in turn to dialysis, transplant or death. AMKD affects approximately 150,000 people in the U.S. and Europe.
The only other APOL1 (search) inhibitor with Phase 2 efficacy data is Maze Therapeutics' MZE829, which reported a 35.6% mean UACR reduction across 12 evaluable patients at 12 weeks in the open-label HORIZON trial in March 2026, with a 61.8% reduction in the FSGS subgroup. Maze has said it plans a pivotal program. Cross-trial comparisons are limited by differences in population, design and duration. Vertex separately challenged Maze's comparative efficacy claims before the National Advertising Division, which referred the matter to federal regulators after Maze declined to participate in the self-regulatory process.