May 25, 2024
Novartis' Atrasentan Shows Significant Proteinuria Reduction in Phase III Trial for IgA Nephropathy
In the ALIGN study, atrasentan, when used alongside a renin-angiotensin system (RAS) inhibitor, resulted in a notable 36.1% reduction in proteinuria compared to placebo after 36 weeks.
The activation of the endothelin A (ETA) receptor contributes to increased proteinuria in IgA nephropathy (IgAN). Atrasentan is a selective ETA receptor antagonist that aims to lower persistent proteinuria and protect kidney function across a diverse patient population.
IgAN is a complex, progressive, and rare kidney disorder that urgently needs effective targeted therapies. Approximately 30% of patients with persistent proteinuria (≥1 g/day) progress to kidney failure within a decade.
Novartis revealed the results of an interim analysis from the Phase III ALIGN study, evaluating the efficacy of atrasentan, an experimental oral selective ETA receptor antagonist, in patients with IgA nephropathy. Patients treated with atrasentan, in addition to maximum tolerated doses of a RAS inhibitor, showed a 36.1% reduction in proteinuria after 36 weeks compared to those receiving placebo plus supportive care.
Reduction in proteinuria is a known indicator of delayed progression to kidney failure and has been used as a key endpoint in IgAN clinical trials to facilitate accelerated regulatory approvals. Novartis plans to submit atrasentan for FDA approval in IgAN by the first half of 2024. The ALIGN study is ongoing in a blinded fashion, and comprehensive results, including the secondary endpoint of change in estimated glomerular filtration rate (eGFR) at 136 weeks, and data from an exploratory cohort receiving a sodium-glucose co-transporter-2 (SGLT2) inhibitor, are expected in 2026.
About the ALIGN Study
The ALIGN study (NCT04573478) is a global, randomized, multicenter, double-blind, placebo-controlled Phase III trial assessing the efficacy and safety of atrasentan versus placebo in patients with IgAN at risk of progressive kidney function loss. A total of 340 patients with biopsy-confirmed IgAN and baseline proteinuria ≥1 g/day, despite optimized RAS inhibitor treatment, were randomized to receive daily oral doses of atrasentan (0.75 mg) or placebo for about 2.5 years (132 weeks). All patients continued with a maximum tolerated and stable dose of a RAS inhibitor as supportive care, unless they were unable to tolerate this therapy. An additional cohort of 64 patients on a stable dose of SGLT2 inhibitor for at least 12 weeks was also included.
The primary endpoint is the change in proteinuria from baseline to 36 weeks, measured by the 24-hour urine protein to creatinine ratio (UPCR). Secondary and exploratory endpoints include changes in kidney function over 136 weeks, as measured by eGFR, along with assessments of safety and tolerability.
About Atrasentan
Atrasentan is an investigational oral ETA receptor antagonist currently in Phase III trials for IgAN and in early development for other rare kidney diseases. Activation of the ETA receptor is linked to increased proteinuria, kidney damage, fibrosis, and loss of kidney function in IgAN. Atrasentan is intended to complement existing supportive therapies to lower persistent proteinuria and maintain kidney function. Preclinical studies also suggest that atrasentan may reduce inflammation and fibrosis in IgAN.
About IgA Nephropathy (IgAN)
IgAN is a progressive and rare kidney disease. Each year, around 25 individuals per million globally are newly diagnosed with IgAN. Up to 30% of patients with persistent proteinuria (≥1 g/day) may develop kidney failure within 10 years. There is a critical need for effective, targeted therapies to slow or prevent the progression of IgAN to kidney failure.
May 25, 2024
Novartis Unveils Phase III Fabhalta (Iptacopan) Data in C3 Glomerulopathy (C3G) with Significant 35.1% Reduction in Proteinuria
Recent results from the Phase III APPEAR-C3G study show that Fabhalta (iptacopan) achieved a significant 35.1% reduction in proteinuria compared to placebo over six months. Additionally, there was a numerical improvement in estimated glomerular filtration rate (eGFR) over the same period. Fabhalta also demonstrated a favorable safety profile with no new safety issues.
C3G is an extremely rare kidney disorder caused by the overactivation of the alternative complement pathway, often leading to kidney failure in about 50% of patients within a decade. Currently, there are no approved treatments for this condition. Fabhalta, an oral Factor B inhibitor, targets the root cause of C3G.
Novartis presented data from the 6-month double-blind phase of the APPEAR-C3G study at the European Renal Association (ERA) Congress. Patients treated with Fabhalta plus supportive care saw a 35.1% reduction in proteinuria compared to those receiving placebo. This reduction in proteinuria, measured by the 24-hour urine protein to creatinine ratio (UPCR), is a key indicator of delaying kidney failure progression.
Fabhalta is an investigational oral Factor B inhibitor designed for adult patients with C3 glomerulopathy. The study also highlighted a numerical improvement in eGFR of +2.2 mL/min/1.73 m² over six months with Fabhalta compared to placebo. The drug's safety profile remained consistent, with no new safety concerns reported.
The APPEAR-C3G study will continue with an additional 6-month open-label period, where all patients, including those previously on placebo, will receive Fabhalta. Results from this phase will be presented at a future medical meeting.
At the ERA Congress, Novartis also shared new data from its rare disease portfolio, including findings from the 36-week interim analysis of the Phase III ALIGN study of investigational atrasentan in IgA nephropathy (IgAN), and the 9-month interim analysis of Fabhalta in IgAN from the Phase III APPLAUSE-IgAN study. Long-term 33-month efficacy and safety data for Fabhalta in C3G from a Phase II extension study, 1-year data for investigational zigakibart in IgAN, and real-world data for C3G and atypical hemolytic uremic syndrome (aHUS) were also presented.
About the APPEAR-C3G Study
The APPEAR-C3G study (NCT04817618) is a Phase III multicenter, randomized, double-blind, parallel-group, placebo-controlled trial assessing the efficacy and safety of twice-daily oral Fabhalta (200 mg) in patients with C3G. The study includes both adult and adolescent cohorts, with the adult cohort undergoing a 6-month double-blind period followed by a 6-month open-label period where all participants receive Fabhalta.
The primary endpoint for the double-blind period was the reduction in proteinuria from baseline at 6 months, as measured by the 24-hour UPCR. The primary endpoint for the open-label period is the reduction in proteinuria from baseline at 12 months for both treatment arms and the reduction from 6 to 12 months for the placebo arm. Secondary endpoints during the double-blind period include changes in eGFR, the proportion of participants achieving specific renal endpoint criteria, changes in glomerular inflammation, patient-reported fatigue scores, and assessments of safety and tolerability.
May 24, 2024
Phase 2 NOBLE Study of Pegcetacoplan Shows Positive Results at ERA Congress
Significant reductions in disease activity were observed at 12 weeks and maintained over a year in the phase 2 NOBLE study of pegcetacoplan, according to late-breaking data presented at the European Renal Association (ERA) Congress.
Sobi and Apellis Pharmaceuticals, Inc. reported encouraging one-year outcomes from their phase 2 NOBLE study, which evaluated systemic pegcetacoplan, a targeted C3 therapy, for treating post-transplant recurrence of C3 glomerulopathy (C3G) and primary immune complex membranoproliferative glomerulonephritis (IC-MPGN). The findings were shared during a late-breaking oral presentation at the ERA Congress held from May 23-26 in Stockholm, Sweden.
One-year results for 11 patients treated with pegcetacoplan revealed:
A reduction in C3c staining intensity by two or more orders of magnitude from baseline in 64% (seven) of patients.
Complete clearance of C3c deposits (zero C3c staining intensity) in 55% (six) of patients, including all three IC-MPGN patients.
Corresponding with the reduction in C3c staining, 64% (seven) of patients exhibited zero inflammation as determined by the activity score of the C3G histologic index.
Excess C3c deposits signify active disease, which can result in kidney inflammation, damage, and ultimately failure. The elimination of these deposits and the associated inflammation facilitates kidney recovery and extends kidney function. Furthermore, pegcetacoplan treatment led to sustained improvements in critical disease indicators, including proteinuria, and continued stabilization of kidney function.
The treatment was generally well-tolerated, with most adverse events being mild to moderate, consistent with previously reported outcomes.
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