Vertex Drug Shows Promise in Rare Kidney Disease IgA Nephropathy

Rare Daily Staff

An experimental therapy from Vertex Pharmaceuticals significantly reduced key markers of kidney damage in people with IgA nephropathy, a rare autoimmune disease that can lead to kidney failure, according to interim phase 3 trial results.

IgA nephropathy, also known as IgA nephritis, is a chronic kidney disease in which the immune system makes abnormal antibodies that deposit in the kidneys’ filtering units. These deposits cause inflammation and scarring, which over time can reduce how well the kidneys filter waste from the blood. The condition is the most common form of primary inflammatory kidney disease, and many patients gradually worsen, with a large share eventually reaching end-stage kidney disease or dying within 20 years of diagnosis without effective treatment.

Vertex’s povetacicept is a lab-engineered fusion protein designed to dial down overactive immune B cells thought to drive IgA nephropathy. It blocks two immune-signaling proteins, BAFF and APRIL, which normally help B cells survive and make antibodies but are abnormally elevated in several autoimmune kidney diseases. By inhibiting both signals, povetacicept seeks to stop production of the faulty IgA antibodies that lodge in the kidneys.

The U.S. Food and Drug Administration has granted povetacicept Breakthrough Therapy designation and is reviewing portions of Vertex’s biologics license application under a rolling, accelerated process. Vertex said it plans to finish that application by the end of March and is using a priority review voucher that could shorten the FDA review time from 10 months to six months. If approved, the company plans to launch povetacicept as an at-home autoinjector given once monthly.

The phase 3 RAINIER trial is a global, randomized, double-blind, placebo-controlled study testing povetacicept 80 milligrams given every four weeks on top of standard care in adults with IgA nephropathy. In a preplanned interim analysis at 36 weeks, 199 patients from the main cohort were evaluated for how much their 24-hour urine protein-to-creatinine ratio — a key measure of protein leakage that signals kidney damage — changed from baseline. Patients who received povetacicept saw protein in the urine drop by 52 percent from baseline, translating into a statistically significant and clinically meaningful 49.8 percent reduction compared with those on placebo.

The trial also met both of its main secondary goals. Levels of a disease-driving antibody form called galactose-deficient IgA1 fell by 77.4 percent from baseline with povetacicept, while they rose 9.1 percent in the placebo group, for a 79.3 percent reduction versus placebo. Among patients who had blood in the urine at study entry, 85.1 percent of those on povetacicept had their hematuria resolve, compared with 23.4 percent on placebo, a 61.7 percentage-point improvement. In an exploratory measure tied to treatment targets in international kidney guidelines, 42.2 percent of povetacicept-treated patients achieved very low levels of protein in the urine, versus 6.2 percent on placebo.

Povetacicept was generally safe and well tolerated in the interim analysis. In the main safety population of 557 patients, about three-quarters in each group reported at least one side effect, most of which were mild or moderate. Serious side effects occurred in 3 percent of patients on povetacicept and 4.3 percent on placebo, with the same low rate of serious infections in both groups and no deaths. Injection-site reactions were more common with povetacicept but were nonserious and mild or moderate, and immune responses against the drug did not appear to affect its effectiveness or safety profile.

“The phase 3 RAINIER 36-week interim analysis results in IgAN are remarkable. With its clinical profile, dosing and administration advantage, and breadth of potential indications, povetacicept demonstrates best-in-class potential and establishes renal medicine as Vertex’s fourth franchise alongside cystic fibrosis, hematology, and acute pain,” said Reshma Kewalramani, president and CEO of Vertex. “As a nephrologist, I am struck by the rapid, deep, and sustained response to povetacicept, as well as the consistency of benefit across all subgroups. These results are important for patients with IgAN and also bring us one step closer to realizing povetacicept’s pipeline-in-a-product promise.”