Nov 04, 2021
  • Statistically significant and clinically important reductions in proteinuria were achieved for the primary endpoint for patients with C3G1
  • Additionally, statistically significant reduction in C3 protein deposits were achieved in the same study in a cohort of patients whose C3G recurred following kidney transplantation1
  • No current approved treatments exist for C3G – a rare and often progressive disease that often affects adolescents and young adults and frequently progresses to kidney failure2-4
  • Novartis is rapidly advancing clinical development of iptacopan to potentially address several complement-driven renal diseases (CDRDs) with high unmet need, as part of our wider commitment to cardiovascular, renal and metabolic disease; pivotal Phase III APPEAR-C3G study is actively recruiting

Basel, November 04, 2021 — Novartis today announced that a Phase II study of investigational iptacopan (LNP023) – a first-in-class, oral, selective factor B inhibitor – in patients with C3 glomerulopathy (C3G) met primary endpoints in both patient cohorts1. The data were presented at the American Society of Nephrology (ASN) 2021 Annual Meeting.

In the final analysis from the open-label, two-cohort Phase II study (NCT03832114), patients were treated with 200mg of iptacopan twice daily for 12 weeks, in addition to background therapy1. Patients in cohort A (16 with C3G, but who have not had a kidney transplant [native C3G]) showed a significant 45% reduction in proteinuria (protein in urine) compared to baseline, as measured by 24-hour urinary protein to creatine ratio (UPCR 24h; P=0.0003)1. 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 (P=0.0313)1.

“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.”

Additionally, both cohorts of this Phase II study showed strong and sustained inhibition of alternative complement pathway activity and normalization of serum C3 levels over 12 weeks1. In combined data from both cohorts, kidney function remained stable after 12 weeks, as assessed by estimated glomerular filtration rate (eGFR, average increase of 1.04 mL/min compared to baseline)1. Previously presented data from the long-term extension study (NCT03955445) showed kidney function was maintained in the seven patients that 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 failure5,6.

Iptacopan showed a favorable safety and tolerability profile in the Phase II final analysis, with no serious adverse events suspected to be related to iptacopan1.

“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 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 III APPEAR-C3G study.”

*11 patients were recruited into cohort B, but only 7 patients had data to analyze for the C3 protein deposits primary endpoint.

About the study
NCT03832114 is a Phase II, open-label, two cohort, non-randomized study evaluating the efficacy, safety and pharmacokinetics of iptacopan in patients with C3 glomerulopathy (C3G) (cohort A) and patients who have undergone kidney transplantation and have subsequent C3G recurrence in the transplanted organ (cohort B)1,7. The primary endpoint for cohort A was reduction in proteinuria (as measured by UPCR 24h) from baseline to week 121,7. The primary endpoint for cohort B was change in C3 deposit score (based on immunofluorescence microscopy) from kidney biopsy from baseline to week 121,7. On completion of the study, all patients had the option to receive ongoing iptacopan in a long-term extension study (NCT03955445)1.

About iptacopan
Iptacopan is an investigational, first-in-class, orally administered factor B inhibitor of the alternative complement pathway, targeting one of the key drivers of CDRDs8-10. 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 C3G9. Discovered at the Novartis Institutes for BioMedical Research, 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).

Phase III studies in IgAN (APPLAUSE-IgAN) and aHUS (APPELHUS), and a Phase II study in iMN, are actively recruiting. Two Phase III studies in PNH (APPLY-PNH and APPOINT-PNH) are also actively recruiting. Based on disease prevalence and positive data from Phase II studies, iptacopan has received EMA PRIME designation for C3G, orphan drug designations from the FDA and EMA in C3G and PNH, EMA orphan drug designation in IgAN, and FDA Breakthrough Therapy Designation in PNH.

While Novartis has a 35-year history in kidney transplantation treatments, iptacopan is the first treatment in the nephrology pipeline addressing CDRDs. Our aim is to transform treatment by targeting one of the key drivers of these rare and often progressive diseases and, in doing so, potentially extend dialysis-free life for people with CDRDs8-10.

About  C3 glomerulopathy (C3G) and complement-driven renal diseases (CDRDs)
In C3G, an overly-active alternative complement pathway – part of the innate 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)2,4,11-13. This triggers inflammation and glomerular damage that results in proteinuria (protein in urine), hematuria (blood in urine) and reduced kidney function2,4,11-13. Approximately 50% of C3G patients progress to kidney failure within 10 years of diagnosis2,3,13,14. Among patients who have undergone kidney transplantation, disease recurrence is not uncommon, with one study seeing an estimated 30% and 70% risk of transplant loss at 5 and 10 years, respectively2,13,14-16.

Each year, there are approximately 1-2 new cases of C3G per million people worldwide17. People with C3G have reported that their symptoms limit their physical and functional ability to perform day-to-day activities and also cause emotional stress18.

CDRDs, which include C3G, are thought to arise from an overactivation of the alternative complement pathway, which creates inflammation and leads to tissue and kidney damage9,19-21. CDRDs mainly affect teenagers and young adults and can progress to kidney failure, which requires dialysis or transplantation and can lead to premature death2-4,19-21.

There is a need for effective and well-tolerated, targeted therapies for C3G that can delay disease progression.

This media update contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this media update, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this media update will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this media update as of this date and does not undertake any obligation to update any forward-looking statements contained in this media update as a result of new information, future events or otherwise.

About Novartis
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  2. Smith RJH, Appel GB, Blom AM, et al. C3 glomerulopathy - understanding a rare complement-driven renal disease. Nat Rev Nephrol. 2019;15(3):129-143.
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