Highlights
- BI 764198, a novel oral selective TRPC6 inhibitor, significantly increased the proportion of patients achieving a proteinuria response in focal segmental glomerulosclerosis (FSGS).
- The combined odds ratio for a ≥25% reduction in urine protein-creatinine ratio (UPCR) across all treatment doses was 4.9 compared to placebo.
- The study represents the first clinical proof-of-concept for a podocyte-targeted therapy in the treatment of FSGS.
- BI 764198 was well tolerated over 12 weeks, with adverse event frequencies comparable to the placebo group.
The Mechanistic Role of TRPC6 in Podocytopathy
Focal segmental glomerulosclerosis (FSGS) remains one of the most challenging glomerular diseases to treat, characterized by podocyte injury, segmental scarring of the glomerular tuft, and a high risk of progression to end-stage kidney disease (ESKD). While current standards of care rely heavily on blood pressure control with renin-angiotensin-system (RAS) inhibitors and non-specific immunosuppression, there has long been a search for therapies that directly target the cellular machinery of the podocyte.
The transient receptor potential cation channel, subfamily C, member 6 (TRPC6), is a non-selective cation channel located in the podocyte slit diaphragm. It plays a critical role in the regulation of intracellular calcium signaling. Clinical and experimental evidence suggests that overactivity of TRPC6—whether due to genetic gain-of-function mutations or secondary activation by inflammatory or mechanical stressors—leads to calcium overload, cytoskeletal disruption, and eventual podocyte loss. By inhibiting this channel, researchers hypothesized that BI 764198 could stabilize podocyte function and arrest the progression of proteinuric kidney disease.
Study Design and Methodology
This multicenter, Phase 2, double-blind, randomized controlled trial (NCT05213624) was designed to evaluate the safety, tolerability, and exploratory efficacy of BI 764198 in adults aged 18 to 75. The study enrolled participants with biopsy-confirmed primary FSGS or those carrying a documented disease-causing TRPC6 variant. To ensure a high-risk population was studied, participants were required to have a screening urine protein-creatinine ratio (UPCR) of ≥1.0 g/g and an estimated glomerular filtration rate (eGFR) of ≥30 mL/min per 1.73 m².
Participants were randomized in a 1:1:1:1 ratio to receive one of three doses of BI 764198 (20 mg, 40 mg, or 80 mg once daily) or a matching placebo for 12 weeks. Randomization was stratified based on the concurrent use of corticosteroids. Importantly, all participants remained on stable doses of their baseline conservative therapies, including RAS inhibitors and immunosuppressants, throughout the trial period.
The primary endpoint was the proportion of participants achieving a proteinuria response, defined as a ≥25% reduction in UPCR from baseline at week 12. Secondary endpoints focused on safety, tolerability, and the change in eGFR.
Clinical Findings: Efficacy and Proteinuria Reduction
The trial screened 139 participants, with 62 eventually receiving treatment and being included in the analysis. The cohort was predominantly male (60%), with a mean age of 40.7 years. The results indicated a clear signal of efficacy for the TRPC6 inhibitor compared to placebo.
Proteinuria Response Rates
At the end of the 12-week treatment period, the proportion of patients achieving a ≥25% reduction in UPCR was significantly higher in the BI 764198 groups compared to the placebo group (7%):
- BI 764198 20 mg: 44% (OR 10.0; 95% CI 1.6-118.1)
- BI 764198 40 mg: 14% (OR 1.5; 95% CI 0.2-19.5)
- BI 764198 80 mg: 43% (OR 6.0; 95% CI 0.9-73.6)
When all active treatment arms were combined, the response rate was 35%, yielding an odds ratio of 4.9 (95% CI 1.0-48.8) against placebo. While the 40 mg dose showed a numerically lower response than the 20 mg or 80 mg doses, the overall trend supports the therapeutic potential of TRPC6 inhibition. The wide confidence intervals reflect the exploratory nature and small sample size of this Phase 2 study, yet the magnitude of the effect in the 20 mg and 80 mg cohorts is clinically significant.
Safety and Tolerability Profile
Safety is a paramount concern for novel inhibitors. In this trial, BI 764198 was well tolerated across all dose levels. Treatment-emergent adverse events (TEAEs) were reported in 71% of the treatment group, which was identical to the 71% reported in the placebo group. Most adverse events were mild to moderate in severity. There were no meaningful differences in the frequency or nature of adverse events across the different treatment arms, suggesting that TRPC6 inhibition does not carry a significant burden of acute systemic toxicity at the doses studied.
Expert Commentary and Clinical Interpretation
The results of this trial are a landmark in glomerular disease research. For decades, the treatment of FSGS has relied on blunt instruments—prednisone, calcineurin inhibitors, and mycophenolate mofetil—which carry substantial systemic side effects and do not address the underlying molecular pathology of the podocyte. This study provides the first clinical evidence that a podocyte-targeted molecular therapy can successfully reduce proteinuria in humans.
The mechanistic plausibility of BI 764198 is strong. By selectively inhibiting TRPC6, the drug likely reduces the aberrant calcium flux that leads to foot process effacement and podocyte detachment. The rapid response observed within 12 weeks suggests that even in established disease, the podocyte remains plastic enough to respond to targeted intervention. However, the non-linear dose-response (where the 40 mg group underperformed compared to 20 mg) warrants further investigation in larger cohorts to determine the optimal therapeutic window.
Limitations of the study include its short duration (12 weeks) and small sample size, which precluded definitive conclusions regarding long-term eGFR preservation. Additionally, while the study focused on primary FSGS, the potential for TRPC6 inhibition in secondary FSGS or other podocytopathies, such as minimal change disease or Alport syndrome, remains an area of high interest.
Conclusion
BI 764198 represents a promising first-in-class selective TRPC6 inhibitor for the treatment of FSGS. By demonstrating a significant reduction in proteinuria with a favorable safety profile, this trial paves the way for larger, Phase 3 clinical trials. If these results are confirmed in longer-term studies, TRPC6 inhibition could become a foundational therapy in the management of FSGS, offering a targeted alternative or adjunct to current immunosuppressive regimens.
Funding and ClinicalTrials.gov
This study was funded by Boehringer Ingelheim. It is registered with ClinicalTrials.gov under the identifier NCT05213624.
References
Trachtman H, Kretzler M, Gesualdo L, Cross N, Workeneh B, Kaufeld J, Meijers B, Ye Z, Chen Q, Derebail VK, Ng MSY, Ji B, Lobmeyer MT, Retlich S, Licarião Rocha FT, Prasad S, Soleymanlou N. TRPC6 inhibition for the treatment of focal segmental glomerulosclerosis: a randomised, placebo-controlled, phase 2 trial of BI 764198. Lancet. 2026 Feb 7;407(10528):587-598. doi: 10.1016/S0140-6736(25)02255-X. Epub 2026 Jan 27. PMID: 41616795.
