Novartis phase III APPEAR-C3G study of iptacopan to treat C3 glomerulopathy meets primary endpoint

Novartis announced positive topline results from the six-month, double-blind period of the phase III APPEAR-C3G study of iptacopan for the treatment of patients with C3 glomerulopathy (C3G). The study met its primary endpoint, with iptacopan (200 mg twice daily) demonstrating superiority compared to placebo in providing clinically meaningful and statistically significant proteinuria (protein in urine) reduction on top of background therapy at six months1. The safety profile of iptacopan was consistent with previously reported data.

The data will be submitted for presentation at an upcoming medical meeting and discussed with global health authorities anticipating potential regulatory submissions in 2024. The APPEAR-C3G study continues for a six-month, open-label period, in which all patients receive iptacopan, including those previously receiving placebo. In addition, enrollment is ongoing in a separate cohort of adolescent patients with C3G.

“People living with C3 glomerulopathy have no approved treatment options indicated for this progressive disease, posing many challenges and uncertainty for these mostly young patients,” said Shreeram Aradhye, M.D., president, development and chief medical officer, Novartis. “These positive results demonstrate the potential of iptacopan to provide clinically meaningful benefit in C3G and add to our growing body of evidence that supports its use across multiple complement-mediated diseases.”

Iptacopan, which is also being investigated in other complement-mediated diseases, recently achieved positive interim results in IgA nephropathy (IgAN). On December 5, 2023, the FDA approved iptacopan, under the brand name Fabhalta, as the first oral monotherapy for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH), and it is currently being reviewed by the EMA for the same indication.

APPEAR-C3G (NCT04817618) is a phase III multicenter, randomized, double-blind, parallel group, placebo-controlled study to evaluate the efficacy and safety of twice-daily oral iptacopan (200 mg) in C3G patients. In addition to the announced topline results for adult patients with C3G, enrollment is ongoing in a separate cohort of adolescent patients with C3G. The study comprises a six-month double-blind period where patients were randomized 1:1 to receive iptacopan or placebo on top of background therapy, followed by a six-month open-label period where all patients receive iptacopan (including those who were previously on placebo) on top of background therapy.

The primary endpoint for the six-month double-blind period was proteinuria reduction at six months as measured by urine protein to creatinine ratio (UPCR). The primary endpoint for the open-label period is proteinuria reduction at 12 months (both treatment arms) and a comparison between proteinuria reduction at 6 and 12 months (placebo arm). Secondary endpoints include change in estimated glomerular filtration rate (eGFR), proportion of participants meeting composite renal endpoint criteria (=15% reduction in eGFR and =50% reduction in UPCR), change in glomerular inflammation (as measured by disease total activity score in a renal biopsy), change in patient reported fatigue (as measured by FACIT-Fatigue score), and safety and tolerability.

C3 glomerulopathy (C3G) is an ultra-rare, progressive complement-mediated kidney disease that initially presents in mostly children and young adults. Each year, approximately 1-2 people per million worldwide are newly diagnosed with C3G, a form of membranoproliferative glomerulonephritis (MPGN).

In C3G, overactivation of the alternative complement pathway – part of the immune system – causes deposits of C3 protein to build up in kidney glomeruli (a network of blood vessels that filter waste and remove extra fluids from the blood). This triggers inflammation and glomerular damage that results in proteinuria (protein in urine), hematuria (blood in urine) and reduced kidney function. Approximately 50% of C3G patients progress to kidney failure within 10 years of diagnosis, at which point they will require dialysis and/or kidney transplantation, with over 55% of patients with C3G experiencing disease recurrence post-transplant.

Iptacopan is an oral, Factor B inhibitor of the alternative complement pathway.

Discovered at Novartis, iptacopan recently demonstrated clinically meaningful and highly statistically significant proteinuria reduction in patients with IgA nephropathy (IgAN) at the interim analysis in the Phase III APPLAUSE-IgAN study (NCT04578834). Iptacopan is also being investigated in phase III studies for atypical hemolytic uremic syndrome (aHUS) (APPELHUS [NCT04889430]) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) (APPARENT [NCT05755386]). On December 5, 2023, the FDA approved iptacopan, under the brand name Fabhalta, as the first oral monotherapy for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH), and it is currently being reviewed by the EMA for the same indication.

Based on disease prevalence, unmet needs and data from phase II studies, iptacopan has received FDA Breakthrough Therapy Designation in C3G and PNH, orphan drug designations from the FDA and EMA in PNH and C3G, EMA PRIME designation for C3G, and EMA orphan drug designation in IgAN25-28.

Chronic kidney disease (CKD) affects 1 in 10 people worldwide. People living with CKD may ultimately progress to kidney failure, requiring maintenance dialysis and/or kidney transplantation. 

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