Vertex Pharmaceuticals will quickly advance an experimental drug for a genetic form of kidney disease into late-stage testing, after results from a small study surpassed the company's expectations.
The findings are early evidence for a new way of treating the condition, called focal segmental glomerulosclerosis, by targeting gene variations first identified as significant a little more than a decade ago. They're also a much-needed win for Vertex, which, despite having successfully developed four effective drugs for cystic fibrosis, has struggled to convince investors it can repeat its success in other diseases.
Focal segmental glomerulosclerosis, or FSGS, describes scarring of the kidney that impairs the organ's ability to filter blood, resulting in high levels of protein in urine. It has a range of causes, such as viral infections or drug toxicity, and is one of several ways kidney disease can develop. Patients are typically treated with blood pressure medicines and steroids, which offer limited benefit.
In 2010, a group of researchers in the U.S. and Belgium discovered that two variants in a gene called APOL1 dramatically increase the risk of kidney disease, including FSGS specifically, and can lead to more aggressive progression.
Notably, the variants, which are also associated with protection from the parasite that causes African sleeping sickness, are more commonly found in the DNA of people with recent African ancestry — an inheritance pattern that could factor into the higher rates of kidney disease among African Americans in the U.S.
Vertex's drug is designed around this research, built to target and block proteins encoded by the APOL1 gene. It's one of a handful of experimental medicines Vertex has staked its research reputation to, betting that its decades of experience and well-regarded drugmaking abilities will help it invent powerful new medicines for diseases beyond cystic fibrosis. Several recent setbacks have raised some doubts, however, and Vertex shares have lost about a fifth of their value this year.
Though Vertex still has much to prove, two of its experimental drug programs have shown signs of promise. In October, the company reported encouraging findings from the first patient given a stem cell-based diabetes treatment. And the study results released by the company Wednesday suggest that it's on the right track with APOL1 and kidney disease as well.
In the study, which enrolled 16 patients with FSGS and two APOL1 variants, treatment with Vertex's drug cut average urine protein levels by 48% after about three months. The reduction is higher than the 30% to 40% lowering analysts on Wall Street have suggested would be regarded as successful, and exceeds the "double-digit" improvement Vertex CEO Reshma Kewalramani has said the company was targeting.
Importantly for a small trial with few participants, the average measured reduction in urine protein levels fell consistently from when treatment began through week 13 of the study, according to data shared by Vertex.
Girish Nadkarni, a kidney disease doctor at Mount Sinai hospital in New York City, agreed the results showed a "significant, sustained" decline in protein levels, although he noted the small number of patients involved.
"This is a very attractive proof-of-concept study," Nadkarni added, "but it needs long-term efficacy in terms of kidney outcomes." Nadkarni has consulted for other drugmakers, but not with Vertex. He's also the cofounder of Renalytix, a kidney disease diagnostics company.
Three of the 16 patients were not included in the efficacy analysis, though, as they didn't take the required number of drug tablets over the course of the study.
No serious reactions related to Vertex's drug were reported, and all side effects observed were mild or moderate in severity, Vertex said.
Lowering elevated protein levels in the urine — known as proteinuria — is considered a surrogate marker for a drug's effectiveness: important and correlated to improved outcomes, but not equivalent to clinical benefit. It's not clear to what extent protein reduction would improve kidney function or decrease the risk of kidney failure.
Yet the Food and Drug Administration does appear open to considering the relationship between protein levels and clinical outcomes. A 2019 workshop with regulators in Europe and the National Kidney Foundation indicated that protein levels could be used as a surrogate trial goal "under certain conditions," although the group focused on a measure slightly different than the one Vertex used in its trial.
Other companies, including Pfizer and Travere Therapeutics, are developing drugs for FSGS, but aren't specifically targeting the more aggressive APOL1-driven disease. Travere, which in February reported its therapy successfully reduced protein levels in a Phase 3 study, is collecting data on kidney function after the FDA indicated its initial results weren't sufficient for an accelerated approval application.
Based on the Phase 2 data disclosed Tuesday, Vertex plans to start late-stage testing of its drug in the first quarter of next year. The company indicated it plans to target proteinuric APOL1 kidney disease more broadly, rather than FSGS alone.
"I do think they have a strong rationale for doing a much larger clinical trial," Nadkarni said.
Vertex estimates about 10,000 people in the U.S. have FSGS, compared to as many as 100,000 with proteinuric APOL1 kidney disease.
Those numbers may be high, however, according to analysts at the investment bank Stifel, who noted the issues Vertex and other drugmakers have had in enrolling trials for FSGS. As Vertex is targeting patients with two risk variants in the APOL1 gene, DNA testing is required to identify eligible patients beyond their initial diagnoses.
Note: This story has been updated with additional commentary.
Correction: A previous version of this story incorrectly identified HIV-associated nephropathy and lupus as conditions included in Vertex's estimate for U.S. prevalence of proteinuric APOL1 kidney disease.