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Pictured: Novartis office in Marburg, Germany/iStock, TBE Novartis on Monday released topline results from the Phase III APPEAR-C3G study showing that its oral factor B inhibitor iptacopan significantly reduced protein in the urine of patients with C3 glomerulopathy, an ultra-rare and progressive kidney disease. In APPEAR-C3G, twice-daily treatment with 200-mg iptacopan—when given on top of background therapy—led to a “clinically meaningful and statistically significant” improvement in proteinuria after six months, according to Novartis’ announcement. Iptacopan’s safety pro the study was consistent with prior studies. C3 glomerulopathy (C3G) is characterized by the underlying hyperactivation of the alternative complement pathway. As a result of this hyperactivation, C3 protein deposits and accumulates in the kidney glomeruli, which in turn gives rise to kidney damage, impaired kidney function and the presence of protein and blood in urine. Iptacopan addresses the underlying pathology of C3G by inhibiting factor B, which is a central player in the alternative complement cascade. “These positive results demonstrate the potential of iptacopan to provide clinically meaningful benefit in C3G and add to our growing body of evidence that supports its use across multiple complement-mediated diseases,” Novartis CMO Shreeram Aradhye said in a statement. Novartis did not reveal specific data in Monday’s announcement but said that it will submit the findings for presentation at an upcoming medical congress. The pharma will also discuss its data with global health authorities, building up to potential regulatory filings in 2024. APPEAR-C3G will continue into its six-month, open-label phase where all patients will receive iptacopan, including those being treated with placebo. Novartis is also running a separate cohort testing iptacopan in adolescents with C3G. Beyond C3G, Novartis is also trialing iptacopan in IgA nephropathy (IgAN). In October 2023, the company said that topline data from its Phase III APPLAUSE-IgAN study demonstrates strong reductions in proteinuria in IgAN patients, as compared with placebo. Regulatory submissions for this indication are also slated next year. Monday’s late-stage win comes days after iptacopan secured the FDA’s approval for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a rare blood disease characterized by anemia and thrombosis. Iptacopan carries the brand name Fabhalta in that indication. Novartis on Monday also posted 48-week data from the APPLY-PNH study, demonstrating the durable efficacy and long-term safety of Fabhalta in this indication. Patients who had received continuous treatment with Fabhalta saw consistently high levels of hemoglobin and were able to avoid undergoing blood transfusions. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Analysts at Jefferies have pegged the sales potential of Novartis' newly approved Fabhalta (iptacopan) at $3.6 billion. The company is working quickly to gain new indications in complement-mediated kidney diseases. Less than a week after gaining its first of what it hopes are several FDA approvals for its oral Factor B inhibitor Fabhalta (iptacopan) for blood disorders, Novartis has presented promising data from a trial in another indication. Without revealing numbers, Novartis said that the APPEAR-C3G phase 3 study of patients with C3 glomerulopathy (C3G) demonstrated that iptacopan provided clinically meaningful and statistically significant reduction in proteinuria (protein in the urine) compared to placebo after six months of use. C3G is one of the rarer complement-mediated kidney diseases that Novartis hopes to address with iptacopan. Within 10 years of diagnosis, approximately 50% of those with C3G have kidney failure. There are no treatments that address the underlying cause of C3G. Last week, the FDA signed off on Fabhalta, making it the first oral monotherapy to treat paroxysmal nocturnal hemoglobinuria (PNH). In APPEAR-C3G, patients received background therapy, with those in the experimental arm taking twice-daily 200 mg doses of iptacopan. The trial met its primary endpoint with the safety profile measuring up to previous studies of iptacopan, Novartis said. The study will continue for six more months, with all patients receiving ipactopan, including those who were on placebo. During this open-label period, proteinuria reduction at 12 months will be the primary endpoint. A comparison of proteinuria reduction for 12 months versus six months also will be measured. Secondary endpoints include the change in estimated glomerular filtration rate (eGFR), the proportion of participants meeting the composite renal endpoint criteria, change in glomerular inflammation and change in patient-reported fatigue. Because C3G often strikes younger people, Novartis also is enrolling adolescent patients in a separate study. Novartis will review the results with regulators around the world to generate potential submissions in 2024, it said. At an upcoming medical meeting, the company will provide detailed stats for APPEAR-C3G. The disease is an overactivation of the alternate complement pathway, which is part of the immune system, and causes protein buildup in the kidney. It is diagnosed in 1-2 people per million around the world, presenting mostly in children and young adults. Treatments aim to control blood pressure, cholesterol and proteinuria. Patients who have heart failure require dialysis and/or kidney transplant, with 55% of transplant patients having recurrence of the disorder. The trial results are more positive momentum for iptacopan, which has been dubbed “a pipeline in a pill” by analysts at ODDO BHF. Analysts at Jefferies have pegged iptacopan’s peak sales potential at $3.6 billion. The biggest opportunity for Novartis with the treatment is in primary immunoglobulin A neuropathy (IgAN), also known as Berger’s disease. Data released in October from the phase 3 study showed that iptacopan hit its pre-specified interim endpoint with significant proteinuria reductions, putting it on course for a potential fast-track approval in 2024. Other indications Novartis is investigating for iptacopan include atypical hemolytic uremic syndrome (aHUS) and immune complex membranoproliferative glomerulonephritis (IC-MPGN).

Ad hoc announcement pursuant to Art. 53 LR Phase III APPEAR-C3G study met its primary endpoint, demonstrating superiority of iptacopan vs. placebo in proteinuria reduction at six-month analysis1; the safety profile of iptacopan was consistent with previously reported data1-3 C3 glomerulopathy (C3G) is an ultra-rare complement-mediated kidney disease, with approximately 50% of patients progressing to kidney failure within 10 years of diagnosis4-7; currently no treatments address the underlying cause of C3G7-9 Novartis plans to review results with global health authorities to enable potential submissions in 2024; data will be submitted for presentation at an upcoming medical meeting Iptacopan demonstrated positive Phase III results in IgA nephropathy (IgAN) at the interim analysis and a late-stage development program is ongoing across four investigational indications10-14 Basel, December 11, 2023 — Novartis today announced positive topline results from the six-month, double-blind period of the Phase III APPEAR-C3G study of iptacopan for the treatment of patients with C3 glomerulopathy (C3G)1. The study met its primary endpoint, with iptacopan (200 mg twice daily) demonstrating superiority compared to placebo in providing clinically meaningful and statistically significant proteinuria (protein in urine) reduction on top of background therapy at six months1. The safety profile of iptacopan was consistent with previously reported data1-3. The data will be submitted for presentation at an upcoming medical meeting and discussed with global health authorities anticipating potential regulatory submissions in 2024. The APPEAR-C3G study continues for a six-month, open-label period, in which all patients receive iptacopan, including those previously receiving placebo12,15. In addition, enrollment is ongoing in a separate cohort of adolescent patients with C3G12,15. “People living with C3 glomerulopathy have no approved treatment options indicated for this progressive disease, posing many challenges and uncertainty for these mostly young patients,” said Shreeram Aradhye, M.D., President, Development and Chief Medical Officer, Novartis. “These positive results demonstrate the potential of iptacopan to provide clinically meaningful benefit in C3G and add to our growing body of evidence that supports its use across multiple complement-mediated diseases.” Iptacopan, which is also being investigated in other complement-mediated diseases, recently achieved positive interim results in IgA nephropathy (IgAN)10. On December 5, 2023, the FDA approved iptacopan, under the brand name Fabhalta®, as the first oral monotherapy for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH), and it is currently being reviewed by the EMA for the same indication16-17. About the study APPEAR-C3G (NCT04817618) is a Phase III multicenter, randomized, double-blind, parallel group, placebo-controlled study to evaluate the efficacy and safety of twice-daily oral iptacopan (200 mg) in C3G patients12,15. In addition to the announced topline results for adult patients with C3G, enrollment is ongoing in a separate cohort of adolescent patients with C3G12,15. The study comprises a six-month double-blind period where patients were randomized 1:1 to receive iptacopan or placebo on top of background therapy, followed by a six-month open-label period where all patients receive iptacopan (including those who were previously on placebo) on top of background therapy12,15. The primary endpoint for the six-month double-blind period was proteinuria reduction at six months as measured by urine protein to creatinine ratio (UPCR)12,15. The primary endpoint for the open-label period is proteinuria reduction at 12 months (both treatment arms) and a comparison between proteinuria reduction at 6 and 12 months (placebo arm)12,15. Secondary endpoints include change in estimated glomerular filtration rate (eGFR), proportion of participants meeting composite renal endpoint criteria (≤15% reduction in eGFR and ≥50% reduction in UPCR), change in glomerular inflammation (as measured by disease total activity score in a renal biopsy), change in patient reported fatigue (as measured by FACIT-Fatigue score), and safety and tolerability12,15. About C3G C3 glomerulopathy (C3G) is an ultra-rare, progressive complement-mediated kidney disease that initially presents in mostly children and young adults4-6,18. Each year, approximately 1-2 people per million worldwide are newly diagnosed with C3G, a form of membranoproliferative glomerulonephritis (MPGN)4. In C3G, overactivation of the alternative complement pathway – part of the 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)4,7,18-20. This triggers inflammation and glomerular damage that results in proteinuria (protein in urine), hematuria (blood in urine) and reduced kidney function4,7,18-20. Approximately 50% of C3G patients progress to kidney failure within 10 years of diagnosis, at which point they will require dialysis and/or kidney transplantation6-7, with over 55% of patients with C3G experiencing disease recurrence post-transplant21-24. About iptacopan Iptacopan is an oral, Factor B inhibitor of the alternative complement pathway17. Discovered at Novartis, iptacopan recently demonstrated clinically meaningful and highly statistically significant proteinuria reduction in patients with IgA nephropathy (IgAN) at the interim analysis in the Phase III APPLAUSE-IgAN study (NCT04578834)10. Iptacopan is also being investigated in Phase III studies for atypical hemolytic uremic syndrome (aHUS) (APPELHUS [NCT04889430]) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) (APPARENT [NCT05755386])13-14. On December 5, 2023, the FDA approved iptacopan, under the brand name Fabhalta®, as the first oral monotherapy for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH), and it is currently being reviewed by the EMA for the same indication16-17. Based on disease prevalence, unmet needs and data from Phase II studies, iptacopan has received FDA Breakthrough Therapy Designation in C3G and PNH, orphan drug designations from the FDA and EMA in PNH and C3G, EMA PRIME designation for C3G, and EMA orphan drug designation in IgAN25-28. Novartis and renal Chronic kidney disease (CKD) affects 1 in 10 people worldwide29. People living with CKD may ultimately progress to kidney failure, requiring maintenance dialysis and/or kidney transplantation30-31. At Novartis, our mission in nephrology began 40 years ago with transplantation and immunosuppression. Our commitment continues today through our aim to transform the lives of people living with kidney diseases by investigating new options that may slow kidney disease progression and extend dialysis-free life. We are committed to advancing the development of our renal portfolio, exploring potential therapeutic options to address the current unmet need for people living with C3G, IgAN, IC-MPGN, lupus nephritis and aHUS. DisclaimerThis press release 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,” “plans,” “may,” “could,” “investigational,” “progressing,” “development,” “upcoming,” “ongoing,” “aim,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for iptacopan, or regarding potential future revenues from iptacopan. 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 iptacopan 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 iptacopan will be commercially successful in the future. In particular, our expectations regarding iptacopan 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; 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 press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise. About NovartisNovartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people’s lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 250 million people worldwide. Reimagine medicine with us: Visit us at https://www.novartis.com and connect with us on LinkedIn, Facebook, X/Twitter and Instagram. References Novartis data on file.Novartis iptacopan meets primary endpoints in Phase II study in rare kidney disease C3 glomerulopathy (C3G). Novartis. Accessed December 6, 2023. https://www.novartis.com/news/media-releases/novartis-iptacopan-meets-primary-endpoints-phase-ii-study-rare-kidney-disease-c3-glomerulopathy-c3gWong E, Nester C, Cavero T, et al. Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy. Kidney Int Rep. 2023;8:2754-2764.Schena FP, Esposito P, Rossini M. A Narrative Review on C3 Glomerulopathy: A Rare Renal Disease. Int J Mol Sci. 2020;21(2):525.Smith RJ, Alexander J, Barlow PN, et al. New Approaches to the Treatment of Dense Deposit Disease. J Am Soc Nephrol. 2007;18(9):2447-2456.Martin B, Smith RJH. In: Adam MP, Ardinger HH, Pagon RA, et al. C3 Glomerulopathy. GeneReviews® [Internet]. Updated 2018. University of Washington, Seattle; 1993-2022.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.Goodship TH, Cook HT, Fakhouri F, et al. Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy: Conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int. 2017;91(3):539-551.Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276.Novartis investigational iptacopan Phase III study demonstrates clinically meaningful and highly statistically significant proteinuria reduction in patients with IgA nephropathy (IgAN). Novartis. Accessed December 6, 2023. https://www.novartis.com/news/media-releases/novartis-investigational-iptacopan-phase-iii-study-demonstrates-clinically-meaningful-and-highly-statistically-significant-proteinuria-reduction-patients-iga-nephropathy-iganNovartis Pharmaceuticals. Study of Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients (APPLAUSE-IgAN). clinicaltrials.gov. Accessed December 6, 2023. https://clinicaltrials.gov/study/NCT04578834Novartis Pharmaceuticals. Study of Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy. (APPEAR-C3G). clinicaltrials.gov. Accessed December 6, 2023. https://clinicaltrials.gov/study/NCT04817618Novartis Pharmaceuticals. Efficacy and Safety of Iptacopan (LNP023) in Adult Patients With Atypical Hemolytic Uremic Syndrome Naive to Complement Inhibitor Therapy (APPELHUS). clinicaltrials.gov. Accessed December 6, 2023. https://clinicaltrials.gov/study/NCT04889430Novartis Pharmaceuticals. Study of Efficacy and Safety of Iptacopan in Participants With IC-MPGN (APPARENT). clinicaltrials.gov. Accessed December 6, 2023. https://clinicaltrials.gov/study/NCT05755386Bomback AS, Kavanagh D, Vivarelli M, et al. Alternative Complement Pathway Inhibition With Iptacopan for the Treatment of C3 Glomerulopathy-Study Design of the APPEAR-C3G Trial. Kidney Int Rep. 2022;7(10):2150-2159.Novartis receives FDA approval for Fabhalta® (iptacopan), offering superior hemoglobin improvement in the absence of transfusions as the first oral monotherapy for adults with PNH. Novartis. Accessed December 6, 2023. https://www.novartis.com/news/media-releases/novartis-receives-fda-approval-fabhalta-iptacopan-offering-superior-hemoglobin-improvement-absence-transfusions-first-oral-monotherapy-adults-pnhIptacopan Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corp; December 2023.Medjeral-Thomas NR, O'Shaughnessy MM, O'Regan JA, et al. C3 Glomerulopathy: Clinicopathologic Features and Predictors of Outcome. Clin J Am Soc Nephrol. 2014;9(1):46-53.Ravindran A, Fervenza FC, Smith RJH, Sethi S. C3 Glomerulopathy Associated with Monoclonal Ig is a Distinct Subtype. Kidney Int. 2018;94(1):178-186.Caravaca-Fontán F, Lucientes L, Cavero T, Praga M. Update on C3 Glomerulopathy: A Complement-Mediated Disease. Nephron. 2020;144(6):272-280.Servais A, Noël LH, Roumenina LT, et al. Acquired and Genetic Complement Abnormalities Play a Critical Role in Dense Deposit Disease and Other C3 Glomerulopathies. Kidney Int. 2012;82(4):454-464.Zand L, Lorenz EC, Cosio FG, et al. Clinical Findings, Pathology, and Outcomes of C3GN after Kidney Transplantation. J Am Soc Nephrol. 2014;25(5):1110-1117.Regunathan-Shenk R, Avasare RS, Ahn W, et al. Kidney Transplantation in C3 Glomerulopathy: A Case Series. Am J Kidney Dis. 2019;73(3):316-323.Caravaca-Fontán F, Polanco N, Villacorta B, et al. Recurrence of Immune Complex and Complement-mediated Membranoproliferative Glomerulonephritis in Kidney Transplantation. Nephrol Dial Transplant. 2023;38(1):222-235.Novartis investigational oral therapy iptacopan (LNP023) receives FDA Breakthrough Therapy Designation for PNH and Rare Pediatric Disease Designation for C3G. Novartis. Accessed December 6, 2023. https://www.novartis.com/news/media-releases/novartis-investigational-oral-therapy-iptacopan-lnp023-receives-fda-breakthrough-therapy-designation-pnh-and-rare-pediatric-disease-designation-c3gNovartis announces European Medicines Agency (EMA) has granted orphan drug designation for iptacopan (LNP023) in IgA nephropathy (IgAN). Novartis. Accessed December 6, 2023. https://www.novartis.com/news/media-releases/novartis-announces-european-medicines-agency-ema-has-granted-orphan-drug-designation-iptacopan-lnp023-iga-nephropathy-iganNovartis received European Medicines Agency (EMA) PRIME designation for iptacopan (LNP) in C3 glomerulopathy (C3G). Novartis. Accessed December 6, 2023. https://www.novartis.com/news/media-releases/novartis-received-european-medicines-agency-ema-prime-designation-iptacopan-lnp-c3-glomerulopathy-c3gNovartis data on file.National Kidney Foundation. Global Facts: About Kidney Disease. Accessed December 6, 2023. https://www.kidney.org/kidneydisease/global-facts-about-kidney-diseaseNHS. Kidney Disease. Accessed December 6, 2023. https://www.nhs.uk/conditions/kidney-disease/National Kidney Foundation. Chronic kidney disease (CKD). 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