RARE Daily

Vertex Reports Positive Results from Phase 2 Study of VX-147 in APOL1-Mediated FSGS

December 1, 2021

Vertex Reports Positive Results from Phase 2 Study of VX-147 in APOL1-Mediated FSGS

Rare Daily Staff

Vertex Pharmaceuticals reported that a phase 2 proof-of-concept study in patients with APOL1-mediated focal segmental glomerulosclerosis, its experimental therapy VX-147 on top of standard of care achieved a statistically significant, substantial, and clinically meaningful mean reduction of 47.6 percent in the urine protein to creatinine ratio (UPCR) at Week 13 compared to baseline and was well tolerated.

These results provide the first clinical evidence and proof-of-concept that an oral small molecule APOL1 inhibitor can decrease proteinuria in patients with APOL1-mediated kidney disease. Based on these results, Vertex plans to advance VX-147 into pivotal development in APOL1-mediated kidney disease, including focal segmental glomerulosclerosis (FSGS), in Q1 2022.

APOL1-mediated kidney disease is a form of chronic kidney disease caused by variants of the APOL1 gene. More than 100,000 people in the U.S. and Europe have two APOL1 genetic variants and proteinuric kidney disease. People who inherit two risk variants in the APOL1 gene have a course of disease that is far more aggressive than in the absence of APOL1 genetic variants. Inherited APOL1 genetic variants 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.

Focal segmental glomerulosclerosis (FSGS) is a type of kidney disorder that is characterized by scar tissue that forms in some of the glomeruli in the kidney. FSGS may cause non-specific signs and symptoms, including protein in the urine, elevated levels of creatinine, and swelling. In many cases the cause of FSGS cannot be determined. Some cases are thought to be associated with congenital kidney defects, urine backing up into the kidneys, obesity, obstructive sleep apnea, sickle cell anemia, or viruses (e.g., HIV). The goal of treatment is to control symptoms and prevent chronic kidney failure. Even with treatment, many people with FSGS progress to kidney failure within 5 to 20 years.

“This approach has tremendous potential as it targets the underlying genetic driver of kidney disease in these patients,” said Glenn Chertow, professor of Medicine, Stanford University School of Medicine, and chair of the Vertex APOL1 Program Steering Committee. “These data demonstrate the potential of VX-147 as a targeted treatment for a patient population at unusually high risk of progression to kidney failure.”

A total of 16 patients were enrolled in the study. According to the pre-specified statistical analysis plan, three patients who were noncompliant with treatment were not included in the primary efficacy analysis. In the 13 evaluable patients, treatment with VX-147 on top of standard of care resulted in a rapid, statistically significant, and clinically meaningful mean change in proteinuria from baseline of 47.6 percent following 13 weeks of treatment. Reduction in proteinuria was observed early and continued throughout the 13-week treatment period. Results were consistent regardless of baseline proteinuria or background therapy.

There were no treatment discontinuations due to adverse events (AEs), and there were no serious adverse events considered related to study drug. All AEs were mild or moderate in severity. The most common AEs (occurring in greater than 15 percent of subjects) were headache, back pain and nausea.

“VX-147 is the first investigational treatment targeting the underlying cause of APOL1-mediated kidney disease. These results demonstrate that inhibition of the APOL1 protein can substantially reduce proteinuria in patients with two APOL1 genetic variants, FSGS and significant proteinuria,” said Carmen Bozic, executive vice president of global medicines development and medical affairs, and chief medical officer at Vertex. “We are working with urgency to advance this molecule into pivotal development with the goal of bringing this first-in-class therapy to the more than 100,000 patients in the U.S. and Europe living with APOL1-mediated kidney disease.”

The phase 2 open-label, single-arm study evaluated the efficacy, safety, and pharmacokinetics of VX-147 in patients with APOL1-mediated FSGS. Patients with biopsy confirmed FSGS, two APOL1 genetic variants, proteinuria defined by at least 0.7 g/g in the UPCR and an estimated glomerular filtration rate (eGFR) of at least 27 mL/min/1.73 m2 were eligible for enrollment in the study. Patients were on a stable standard-of-care regimen, which could include an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), immunosuppressants and/or low doses of corticosteroids.

Patients were treated with VX-147 for a total of 13 weeks. The primary endpoint was percent change from baseline in UPCR at Week 13. The secondary endpoints were safety and pharmacokinetics. In addition, there is a 28-day safety follow-up period after the last dose of treatment and an optional off-treatment follow-up period of up to 12 weeks after the last dose of treatment. The study is ongoing for these follow-up periods.

Photo: Carmen Bozic, executive vice president of global medicines development and medical affairs, and chief medical officer at Vertex

Stay Connected

Sign up for updates straight to your inbox.