Novartis’ First-in-Class Complement Factor B Inhibitor Iptacopan Demonstrates Significant Efficacy in Targeting the Root Cause of C3 Glomerulopathy

November 10, 2021 /BioValleyBIOON/ --Novartis(Novartis) recently announced the evaluationFirst-in-class oral selective Factor B inhibitor iptacopan (LNP023) meets primary endpoints in both patient cohorts in Phase 2 clinical study (NCT03832114) for the treatment of C3 glomerulopathy (C3G). These data were presented at the American Society of Nephrology (ASN) 2021 Annual Meeting.

C3G is an extremely rare and severe form of primary glomerulonephritis, characterized by dysregulation of the complement system. The annual incidence of the disease worldwide is 1-2 per million, with approximately 10,000 cases in the United States, around 10,500 cases in Europe, about 3,200 cases in Japan, and approximately 32,000 cases in China. C3G is typically diagnosed in adolescents and young adults.DiagnosisAs a result, the prognosis of this disease is very poor, with about 50% of patients progressing to end-stage renal disease (ESRD) within 10 years, and 50-70% of patients experiencing recurrence after kidney transplantation.

Iptacopan isNovartisA first-in-class oral Factor B inhibitor discovered by the Institute of Biomedical Sciences, where Factor B is a key serine protease in the alternative pathway of the complement system.Iptacopan has the potential to become the first targeted therapy to delay the progression of C3G to dialysis.In October 2021, the UK Medicines andHealth ProductsThe Medicines and Healthcare products Regulatory Agency (MHRA), the National Institute for Health and Care Excellence (NICE), and the Scottish Medicines Consortium (SMC) have jointly granted iptacopan for the treatment of C3G "Innovation Passport"Qualification."

This open-label, two-cohort, non-randomized Phase 2 study, presented at the ASN annual meeting, aims to evaluate iptacopan forC3G patients who have not yet undergone kidney transplantation (Cohort A)AndPatients who have undergone kidney transplantation and subsequently experienced C3G recurrence in the transplanted organ (Cohort B)The efficacy, safety, and pharmacokinetics. In the study, in addition to receiving background therapy, patients also received oral iptacopan (200 mg, twice daily) for 12 weeks. The primary endpoint for Cohort A was the reduction in proteinuria from baseline to Week 12 of treatment (measured by 24h UPCR). The primary endpoint for Cohort B was the change in renal biopsy C3 deposition score from baseline to Week 12 (based on immunofluorescence microscopy). After the study completion, all patients had the option to receive continued iptacopan treatment in a long-term extension study (NCT03955445).

Final analysis shows: (1)In Cohort A patients (n=16), at Week 12 of treatment, proteinuria significantly decreased by 45% from baseline (measured by UPCR 24h, p=0.0003).；（2）In Cohort B patients (n=7), at Week 12 of treatment, C3 protein deposition significantly decreased from baseline (measured by renal biopsy C3 score, p=0.0313).(Note: Cohort B enrolled 11 patients, but only 7 patients had data analysis for the primary endpoint of C3 protein deposition.)

In addition,Both cohorts demonstrated strong and sustained inhibition of alternative complement pathway activity and normalization of serum C3 levels during the 12-week treatment period.. In the pooled data of two cohorts, assessed by estimated glomerular filtration rate (eGFR),Renal function remained stable after 12 weeks.(An average increase of 1.04 mL/min compared to baseline). Previously submitted data from the long-term extension study (NCT03955445) showed that renal function was maintained in 7 patients who had been treated for a total of 6 months, suggesting thatExtended iptacopan treatment may prolong and potentially even prevent the occurrence of renal failure.。

In the final analysis, iptacopan showed good safety and tolerability, with no serious adverse events suspected to be related to iptacopan.

"The data presented at the ASN meeting provide a detailed picture of the potential of iptacopan in treating patients with C3G, as well as its potential in treating recurrent C3G after kidney transplantation," said Edwin Wong, Chief Investigator of the study and nephrologist at Newcastle University in the UK. "These results are important for patients with C3G because proteinuria is a key risk predictor of kidney disease progression, and the deposition of C3 proteins can ultimately lead to inflammation and kidney damage."

NovartisJohn Tsai, Global Head of Drug Development and Chief Medical Officer at Novartis, stated: "C3G is a devastating disease that may ultimately leave patients facing kidney dialysis or transplantation. With no approved treatments currently available, there is a significant unmet medical need for therapies that can delay the progression of kidney failure. These data indicate that iptacopan strongly and specifically inhibits the key driver of C3G — the complement alternative pathway. The results also suggest that...Iptacopan has the potential to provide the first targeted therapy for patients with C3G., we are actively recruiting patients to participate in the pivotal Phase 3appEAR-C3G Study."

Chemical Structure of Iptacopan (Source: medchemexpress.com)

Iptacopan is a first-in-class, orally administered, potent, selective, small-molecule, reversible B-factor inhibitor. The B factor is a key serine protease in the alternative pathway of the complement system.

Currently, iptacopan is being developed for the treatment of many complement-driven renal diseases (CDRD) with significant unmet medical needs, including C3G, IgA nephropathy, and atypical hemolytic uremic syndrome.UremiaSyndrome (aHUS), Membranous Nephropathy (MN), and the rare blood disease Paroxysmal Nocturnal Hemoglobinuria (PNH).

The published Phase 2 data shows: (1)Iptacopan Treatment for IgAN Reduces Proteinuria and Stabilizes Renal Function；（2）Treatment of C3G reduced the rate of estimated glomerular filtration rate (eGFR) decline and stabilized renal function.；（3）Treatment of PNH significantly reduces intravascular and extravascular hemolysis, enabling most patients to achieve rapid and sustained transfusion-free improvement.

Although Novartis has a 35-year history in kidney transplantation treatment, iptacopan is the first treatment in the renal disease pipeline to address CDRD.NovartisThe goal is to transform the treatment approach by targeting one of the key drivers of these rare and progressive diseases, which has the potential to extend the dialysis-free life of CDRD patients. (Bioon.com)

Source of Original Text:Novartis iptacopan meets primary endpoints in Phase II study in rare kidney disease C3 glomerulopathy (C3G)