2020-10-28| R&D

Novartis’s Iptacopan Shows Promising Results as First in Class Oral Therapy for Rare Renal Disease

by Tulip Chakraborty
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By T. Chakraborty, Ph.D.

On October 26th, Novartis announced positive Phase II results for its investigational oral treatment, iptacopan (LNP023), for C3 glomerulopathy (C3G), a rare renal disease. C3G constitutes a group of conditions including high protein and blood levels in the urine, which promotes kidney malfunction. This disease affects approximately 1-2 persons in a million, and affected individuals may have particularly low levels of a protein called complement component 3 (or C3) in the blood, hence the name C3 glomerulopathy. There’s no approved therapy to date for C3G, which translates to approximately 50% of patients progressing to end-stage renal disease (ESRD) within 10 years, and 50–70% experiencing disease recurrence post kidney transplant. Thus, novel treatment options are mandated to address the disease progression of C3G.



Complement pathways form a key component of normal kidney function. Complement prevents immune complexes from accumulating as well as regulating other functions of the kidney. The spontaneous hydrolysis of C3 characterizes the alternative activation of the complement pathway. One of the key proteases to regulate this is Factor B. In C3G, with low levels of C3, inhibition of factor B may help reduce the hydrolysis of C3, thereby increasing the C3 amount in plasma.

Iptacopan is a first-in-class oral, small-molecule inhibitor of factor B. Iptacopan is also being developed to be used in other renal conditions, which are characterized by changes in complement pathway activation, including IgA nephropathy, atypical hemolytic uremic syndrome, and membranous nephropathy. The drug is also under investigation as a potential treatment for paroxysmal nocturnal hemoglobinuria (PNH) with a Phase III trial underway in PNH patients. The drug has the potential to be the first alternative complement pathway inhibitor.

John Tsai, Head Global Drug Development and Chief Medical Officer at Novartis, said, “Iptacopan is the most advanced asset in our nephrology pipeline. These data demonstrate that it has the potential to improve the lives of patients with C3G.”


About the Study

The Phase II clinical trial aimed to study the safety, efficacy, and pharmacokinetic profile of iptacopan in two separate cohorts of patients. Cohort A consisted of patients with C3 glomerulopathy, while cohort B consisted of patients who had a recurrence of C3 glomerulopathy post kidney transplant. Treatment of patients with iptacopan for 12 weeks significantly reduced proteinuria when compared to baseline.

Further, the drug also inhibited alternative complement pathway activation as well as increased C3 plasma levels. Finally, iptacopan improved renal function as measured by estimated glomerular filtration rate post 12 weeks of treatment, and this improvement was sustained in 7 patients for six months. Iptacopan had a good safety and tolerability profile in this study, with no deaths or serious adverse events. These exciting findings were presented during the virtual American Society of Nephrology (ASN) 2020 Annual Meeting.

Lead study investigator, Dr. Edwin Wong, Consultant Nephrologist at the National Renal Complement Therapeutics Centre, Newcastle upon Tyne NHS Foundation Trust, Newcastle University, commented, “Proteinuria indicates the presence of inflammation in the kidney. Results from this study demonstrate that iptacopan significantly reduces proteinuria in patients with C3G. This data also highlights iptacopan’s ability to strongly and specifically inhibit the alternative complement pathway, targeting the underlying cause of this disease and potentially providing a much-needed treatment option for C3G patients who have significant unmet needs.”

The European Medicines Agency (EMA) has granted PRIME designation for iptacopan in C3G and orphan drug designation in IgA nephropathy.


Competitors in the Market

Interestingly, Alexion pharmaceuticals, which acquired Achillion Pharmaceuticals last fall for $930 million, had their potential candidate (ALXN2040) for C3G fail in two Phase II trials conducted in July. The takeover provided Alexion with two oral small-molecule Factor D inhibitors, ALXN2040 and ALXN2050, that were the frontrunners in complement PNH and C3G. Although the top executives of Alexion were visibly excited about the drugs at the time of the acquisition, suboptimal clinical responses in the Phase II trials have not only halted global regulatory talks but also provided Alexion with challenging quarter two results. Despite the setback to ALXN2040, Alexion intends to repurpose this drug as add-on therapy in PNH patients with extravascular hemolysis in a Phase III clinical trial by the end of the year. With no other competitors in the market at the moment, Novartis should be able to cash in heavily if their therapy gets approved and provide relief to the millions of patients awaiting treatment.

Related Article: Retrophin Acquires Orphan Technologies to Develop Potential, Effective Cure for Rare Disease



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