Vertex’s Inaxaplin Granted U.S. Breakthrough Therapy and EU Priority Medicines Designations
June 8, 2022
Rare Daily Staff
Vertex’s inaxaplin has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration for APOL1-mediated focal segmental glomerulosclerosis (FSGS) and Priority Medicines (PRIME) designation by the European Medicines Agency (EMA) for APOL1-mediated chronic kidney disease (AMKD).
APOL1-mediated kidney disease is a form of chronic kidney disease caused by mutations in the APOL1 gene. Approximately 100,000 people in the U.S. and Europe have two APOL1 genetic mutations and proteinuric kidney disease. People who inherit two mutations in the APOL1 gene have a course of disease that is far more aggressive than in the absence of APOL1 genetic mutations. Inherited APOL1 genetic mutations cause kidney disease through a toxic gain of function, which leads to podocyte injury. This injury disrupts filtration, resulting in proteinuria and rapidly progressive kidney disease. Progressive kidney disease can result in dialysis, kidney transplant or death. Inaxaplin is the first investigational therapy aimed at treating the underlying cause of AMKD.
Focal segmental glomerulosclerosis (FSGS) is a form of AMKD that leads to scarring of the filters in the kidneys, rendering them unable to filter blood, which can lead to kidney damage and failure. Treatment for FSGS focuses on treating the symptoms and preventing any additional scarring.
The FDA’s Breakthrough Therapy designation is intended to expedite development and review of medicines that aim to address a serious condition with preliminary clinical evidence indicating that the drug may demonstrate substantial improvement over existing treatments on one or more clinically significant endpoints. The Breakthrough Therapy designation was granted based on the phase 2 clinical study of inaxaplin in patients with APOL1-mediated FSGS.
The EMA’s PRIME designation is a regulatory mechanism that provides early and proactive support to developers of promising medicines, to optimize the generation of robust data and enable accelerated assessment so these medicines can potentially reach patients faster. The goal of PRIME is to help patients benefit as early as possible from innovative new therapies that have the potential to significantly address an unmet medical need. PRIME designation was granted based on clinical proof-of-concept data from Vertex’s phase 2 study of inaxaplin in APOL1-mediated FSGS. Inaxaplin is only the second nephrology product to be granted PRIME designation.
A randomized, double-blind, placebo-controlled phase 2/3 adaptive study of inaxaplin is ongoing and will first evaluate two doses of inaxaplin for 12 weeks to select a dose for phase 3 and subsequently evaluate the efficacy and safety of the single, selected dose in the phase 3 portion of the study.
Patients aged 18 to 60 years, with two APOL1 mutations, urine protein to creatinine ratio (UPCR) ≥0.7 g/g to <10 g/g, estimated glomerular filtration rate (eGFR) ≥25 to <75 mL/min/1.73m2 and on stable doses of standard of care medications are eligible to enroll. Approximately 66 patients are planned to be enrolled in the phase 2 dose-ranging portion of the study, and approximately 400 additional patients are planned to be enrolled in the Phase 3 portion of the study.
The primary efficacy endpoint for the final analysis is eGFR slope in patients receiving the inaxaplin selected dose compared to placebo. The secondary efficacy endpoint is time to composite clinical outcome, which will also be assessed at the final analysis and is defined as a sustained decline of ≥30% from baseline in eGFR, the onset of end-stage kidney disease (i.e., maintenance dialysis for ≥28 days, kidney transplantation, or a sustained eGFR of <15 mL/min/1.73 m2), or death. The final study analysis will occur when subjects have at least two years of eGFR data and when approximately 187 composite clinical outcomes have occurred.
The study is also designed to have a pre-planned interim analysis at Week 48 evaluating eGFR slope, supported by a percent change from baseline in UPCR in the inaxaplin arm versus placebo. If positive, the interim analysis may serve as the basis for Vertex to seek accelerated approval of inaxaplin in the U.S. for patients with AMKD.

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