Efficacy, tolerability, and safety of the oral phosphate binder VS-505 (AP301).

BACKGROUND: VS-505 (AP301), an acacia and ferric oxyhydroxide polymer, is a novel fiber-iron-based phosphate binder. This two-part phase 2 study evaluated the tolerability, safety, and efficacy of oral VS-505 administered three times daily with meals in treating hyperphosphatemia in chronic kidney disease (CKD) patients receiving maintenance hemodialysis (MHD). METHODS: In Part 1, patients received dose-escalated treatment with VS-505 2.25, 4.50, and 9.00 g/day for 2 weeks each, guided by serum phosphorus levels. In Part 2, patients received randomized, open-label, fixed-dosage treatment with VS-505 (1.50, 2.25, 4.50, or 6.75 g/day) or sevelamer carbonate 4.80 g/day for 6 weeks. The primary efficacy endpoint was the change in serum phosphorus. RESULTS: The study enrolled 158 patients (Part 1: 25; Part 2: 133), with 130 exposed to VS-505 in total. VS-505 was well tolerated. The most common adverse events were gastrointestinal disorders, mainly feces discolored (56%) and diarrhea (15%; generally during weeks 1‒2 of treatment). Most gastrointestinal disorders resolved without intervention, and none were serious. In Part 1, serum phosphorus significantly improved (mean change -2.0 mg/dL; 95% confidence interval -2.7, -1.4) after VS-505 dose escalation. In Part 2, serum phosphorus significantly and dose-dependently improved in all VS-505 arms, with clinically meaningful reductions with VS-505 4.50 and 6.75 g/day, and sevelamer carbonate 4.80 g/day (mean change -1.6 (-2.2, -1.0), -1.8 (-2.4, -1.2), and -1.4 (-2.2, -0.5) mg/dL, respectively). In both Parts, serum phosphorus reductions occurred within 1 week of VS-505 initiation, returning to baseline within 2 weeks of VS-505 discontinuation. CONCLUSION: VS-505, a novel phosphate binder, was well tolerated with a manageable safety profile, and effectively and dose-dependently reduced serum phosphorus in CKD patients with hyperphosphatemia receiving MHD. Clinical Trial registration number: NCT04551300.

Randomized Phase 2 Trial of Telitacicept in Patients With IgA Nephropathy With Persistent Proteinuria.

Introduction: To date, no specific therapies have been approved for immunoglobulin A nephropathy (IgAN) treatment. Telitacicept is a fusion protein composed of transmembrane activator and calcium-modulating cyclophilin ligand interactor and fragment crystallizable portion of immunoglobulin G (IgG), which neutralizes the B lymphocyte stimulator and a proliferation-inducing ligand. Methods: This phase 2 randomized placebo-controlled trial aimed to evaluate the efficacy and safety of telitacicept in patients with IgAN. Participants with an estimated glomerular filtration rate (eGFR) >35 ml/min per 1.73 m2 and proteinuria ≥0.75 g/d despite optimal supportive therapy, were randomized 1:1:1 to receive subcutaneous telitacicept 160 mg, telitacicept 240 mg, or placebo weekly for 24 weeks. The primary end point was the change in 24-hour proteinuria at week 24 from baseline. Results: Forty-four participants were randomized into placebo (n = 14), telitacicept 160 mg (n = 16), and telitacicept 240 mg (n = 14) groups. Continuous reductions in serum IgA, IgG, and IgM levels were observed in the telitacicept group. Telitacicept 240 mg therapy reduced mean proteinuria by 49% from baseline (change in proteinuria vs. placebo, 0.88; 95% confidence interval, -1.57 to -0.20; P = 0.013), whereas telitacicept 160 mg reduced it by 25% (-0.29; 95% confidence interval, -0.95 to 0.37; P = 0.389). The eGFR remained stable over time. Adverse events (AEs) were similar in all groups. Treatment-emergent AEs were mild or moderate, and no severe AEs were reported. Conclusion: Telitacicept treatment led to a clinically meaningful reduction in proteinuria in patients with IgAN in the present phase 2 clinical trial. This effect is indicative of a reduced risk for future kidney disease progression.

Spop ameliorates diabetic nephropathy through restraining NLRP3 inflammasome.

Diabetic nephropathy (DN) is one of the most common causes for end-stage renal disease without effective therapies available. NLR family, pyrin domain-containing 3 (NLRP3) inflammasome possesses a fundamental effect to facilitate the pathogenesis of DN. Unfortunately, how NLRP3 inflammasome is mediated still remains largely unclear. In the present study, an E3 ubiquitin ligase Speckle-type BTB-POZ protein (Spop) was identified as a suppressor of NLRP3 inflammasome. We first showed that Spop expression was extensively down-regulated in kidney of DN patients, which was confirmed in kidney of streptozotocin (STZ)-challenged mice and in high glucose (HG)-stimulated podocytes. Intriguingly, we showed that conditional knockout (cKO) of Spop in podocytes considerably accelerated renal dysfunction and pathological changes in the glomerulus of STZ-induced mice with DN, along with severe podocyte injury. Furthermore, Spop specific ablation in podocytes dramatically facilitated inflammatory response in glomeruli of DN mice via enhancing NLRP3 inflammasome and nuclear factor κB (NF-κB) signaling pathways, which were confirmed in HG-cultured podocytes. Notably, our findings indicated that Spop directly interacted with NLRP3. More importantly, Spop promoted NLRP3 degradation via elevating K48-linked polyubiquitination of NLRP3. Collectively, our findings disclosed a mechanisms through which Spop limited NLRP3 inflammasome under HG condition, and illustrated that Spop may be a novel therapeutic target to suppress NLRP3 inflammasome, contributing to the DN management.