RARE Daily

Novartis Presents Promising Interim Phase 2 Data of Oral Therapy for Rare Renal Disease

October 26, 2020

Rare Daily Staff

Novartis presented positive phase 2 interim analysis results for iptacopan, an experimental oral treatment for C3 glomerulopathy at the virtually held American Society of Nephrology 2020 Annual Meeting.

C3 glomerulopathy (C3G) is an ultra-rare and severe form of primary glomerulonephritis that is characterized by complement dysregulation. It has a worldwide annual incidence of 1–2 people per million and an approximate prevalence of 10,000 in the United States.

C3G is commonly diagnosed in adolescents and young adults, causing inflammation of the tiny filters in the kidneys that remove excess fluid, electrolytes, and waste from the bloodstream and pass them into the urine. The disease has a poor prognosis with about 50 percent of patients progressing to end-stage renal disease within 10 years, and 50 to 70 percent of patients experiencing disease recurrence post kidney transplant.

Currently, there are no approved therapies specifically designed to target the underlying complement dysregulation that occurs in people with C3G. Although standard of care with antihypertensive or immunosuppressive agents and terminal complement pathway blockers are helpful in some patients, no treatment is universally effective or curative.

Novartis’ iptacopan (LNP023) is a potential first-in-class oral, potent, and selective factor B inhibitor of the complement system’s alternative pathway, targeting the underlying cause of C3G. Data from the open-label phase 2 study showed that after 12 weeks, iptacopan significantly reduced proteinuria by 49 percent compared to baseline values, as measured by 24-hour urine protein/creatinine ratio (UPCR) assessment, in twelve patients with C3G. Iptacopan strongly inhibited alternative complement pathway activity and improved plasma C3 levels. In addition, iptacopan stabilized renal function as assessed by eGFR (estimated glomerular filtration rate) at week 12 and this effect was maintained in the seven patients that were treated for a total of six months after rolling over into the long-term extension study.

“Proteinuria indicates the presence of inflammation in the kidney. Results from this study demonstrate that iptacopan significantly reduces proteinuria in patients with C3G,” said the lead study investigator, Edwin Wong, consultant nephrologist at the National Renal Complement Therapeutics Centre, Newcastle upon Tyne NHS Foundation Trust, Newcastle University. “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 phase 2 study showed Iptacopan also had a favorable safety and tolerability profile  with no deaths, no serious adverse events suspected to be related to iptacopan and no adverse events leading to treatment discontinuation.

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

Iptacopan has the potential to become the first alternative complement pathway inhibitor to slow disease progression in a number of complement driven diseases. In addition to C3G, iptacopan is in parallel development for a number of other rare renal conditions with complement system involvement where significant unmet needs exist, including IgA nephropathy, atypical hemolytic uremic syndrome and membranous nephropathy.

Novartis is also investigating iptacopan in paroxysmal nocturnal hemoglobinuria (PNH) for which it presented positive phase 2 data at the European Society for Blood and Marrow Transplantation congress in August.

The European Medicines Agency granted iptacopan a priority medicines (PRIME) designation in C3G and an orphan drug designation in IgA nephropathy (IgAN).

Iptacopan (LNP023) is a first-in-class oral, small-molecule, reversible inhibitor of factor B, a key serine protease of the alternative pathway of the complement cascade.4,5

 Photo: John Tsai, head Global Drug Development and chief medical officer at Novartis

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