RARE Daily

Novartis Rare Kidney Disease Drug Meets Endpoint in Phase 2 Study

November 5, 2021

Novartis reported that a phase 2 study of its experimental factor B inhibitor iptacopan in patients with C3 glomerulopathy (C3G) met the primary endpoints in both patient cohorts in the study.

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

The data were presented at the American Society of Nephrology 2021 Annual Meeting.

“The data presented at ASN provide a detailed picture of the potential of iptacopan for the treatment of patients with C3G and, for the first time, in patients whose C3G had returned following kidney transplantation,” said lead study investigator Edwin Wong, consultant nephrologist at the National Renal Complement Therapeutics Centre, Newcastle upon Tyne NHS Foundation Trust, Newcastle University, UK. “These results are important for patients with C3G because proteinuria is a key risk predictor for kidney disease progression, and deposits of C3 protein ultimately cause inflammation and kidney damage.”

Iptacopan is a first-in-class oral therapy that targets the alternative complement pathway, one of the key drivers of complement-related renal diseases (CDRDs). It is the most advanced asset in the Novartis nephrology pipeline and has the potential to become the first targeted therapy to delay progression to dialysis in C3G. Iptacopan is currently in development for a number of CDRDs where significant unmet needs exist, including C3G, IgA nephropathy (IgAN), atypical hemolytic uremic syndrome (aHUS), and idiopathic membranous nephropathy (iMN), as well as the blood disorder paroxysmal nocturnal hemoglobinuria (PNH).

The phase 2 open-label study consisted of two cohorts. The non-randomized study evaluated the efficacy, safety, and pharmacokinetics of iptacopan in patients with C3G (cohort A) and patients who have undergone kidney transplantation and have subsequent C3G recurrence in the transplanted organ (cohort B).

The primary endpoint for cohort A was reduction in proteinuria (as measured by UPCR 24h) from baseline to week 12. The primary endpoint for cohort B was change in C3 deposit score (based on immunofluorescence microscopy) from kidney biopsy from baseline to week 12. On completion of the study, all patients had the option to receive ongoing iptacopan in a long-term extension study.

In the final analysis from the study, patients were treated with 200mg of iptacopan twice daily for 12 weeks, in addition to background therapy. Patients in cohort A (16 with C3G, but who have not had a kidney transplant [native C3G]) showed a 45 percent reduction in proteinuria (protein in urine) compared to baseline, as measured by 24-hour urinary protein to creatine ratio. Patients in cohort B (7 whose C3G had returned following a kidney transplant) showed significantly reduced C3 protein deposits compared to baseline, as measured by C3 deposit score (based on immunofluorescence microscopy) from kidney biopsy.

Additionally, both cohorts in the phase 2 study showed strong and sustained inhibition of alternative complement pathway activity and normalization of serum C3 levels over 12 weeks. In combined data from both cohorts, kidney function remained stable after 12 weeks. Previously presented data from the long-term extension study showed kidney function was maintained in the seven patients who were treated for a total of six months at that time, suggesting extended iptacopan treatment may prolong the time to, or even potentially prevent, the development of kidney failure.

Iptacopan showed a favorable safety and tolerability profile in the phase 2 final analysis, with no serious adverse events suspected to be related to iptacopan.

“C3G is a devastating disease where people can end up facing life-altering and often exhausting kidney dialysis or transplantation at a time when they might otherwise be focused on building their lives, careers, and families. With currently no approved treatments, there is a major unmet need for therapies that can delay progression to kidney failure,” said John Tsai, head of Global Drug Development and chief medical officer of at Novartis. “These data demonstrate the ability of iptacopan to strongly and specifically inhibit the key driver for C3G – the alternative complement pathway. The results also show the potential for iptacopan to provide the first targeted treatment for people living with C3G, and we are actively recruiting for our pivotal phase 3 APPEAR-C3G study.”

Author: Rare Daily Staff

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