Novartis Pharma AG: Novartis atrasentan Phase III data show clinically meaningful proteinuria reduction further advancing company's IgA nephropathy (IgAN) portfolio

• In the ALIGN study, atrasentan, in addition to supportive care with a renin-angiotensin system (RAS) inhibitor, demonstrated a statistically significant 36.1% proteinuria (protein in urine) reduction vs. placebo + supportive care at 36 weeks¹
  
  
• Endothelin A (ETA) receptor activation contributes to elevated proteinuria in IgAN^2-5; atrasentan is a potent, selective ETA receptor antagonist with potential to reduce persistent proteinuria and preserve kidney function for a broad patient population¹
  
  
• IgAN is a heterogeneous, progressive, rare kidney disease with a need for effective, targeted therapies^6,7; up to 30% of patients with persistent proteinuria (=1 g/day) progress to kidney failure within 10 years⁸
  
  
• Through its rare kidney disease portfolio, Novartis is committed to exploring a range of treatment options with different modes of action to slow IgAN progression

Basel, May 25, 2024 - Novartis today presented results from a pre-specified interim analysis of the Phase III ALIGN study of atrasentan, an investigational oral selective endothelin A (ETA) receptor antagonist, in patients with IgA nephropathy (IgAN)¹. Patients treated with atrasentan, in addition to supportive care (maximally tolerated and stable dose of a renin-angiotensin system [RAS] inhibitor), achieved a 36.1% (p<0.0001) reduction in proteinuria (as measured by 24-hour urine protein to creatinine ratio [UPCR]) at 36 weeks when compared to placebo on top of supportive care¹. The results were presented during a late-breaking clinical trials session at the European Renal Association (ERA) Congress¹. The study also showed atrasentan has a favorable safety profile consistent with previously reported data^1,9.

Proteinuria reduction is a recognized surrogate marker correlating with delaying progression to kidney failure and has been used as an endpoint in IgAN clinical trials to support accelerated regulatory approvals¹⁰. US FDA submission for atrasentan in IgAN is on track for the first half of 2024.

"For those living with IgAN and their families, the disease can have a significant impact not only physically, but also mentally. When my son Eddie was diagnosed with IgAN 20 years ago, there were no FDA-approved medicines developed to treat IgAN. That was as devastating as the diagnosis itself because we felt completely in the dark about how to manage the condition," said Bonnie Schneider, Director and Co-Founder, IgAN Foundation. "It's a disease that affects people differently, and what works for one person may not work for another. We're pleased to see ongoing research into different treatments and are excited for a future where the community will have options to meet their individual needs."

The ALIGN study continues in a blinded manner, and therefore only limited interim analysis results can be presented^11,12. The final analysis, including the key secondary endpoint of change from baseline in estimated glomerular filtration rate (eGFR) at 136 weeks, and the results in participants receiving a sodium-glucose co-transporter-2 (SGLT2) inhibitor as background care in an exploratory cohort, is expected in 2026^11,12.

"ETA receptor activation causes proteinuria, which is usually one of the first clinical signs of IgAN. Patients with persistent proteinuria have a poorer prognosis and are more likely to progress to kidney failure," said Professor Hiddo Heerspink, Professor of Clinical Trials and Personalized Medicine at the Department of Clinical Pharmacy and Pharmacology at the University Medical Center Groningen and ALIGN blinded Steering Committee Chair. "We need targeted treatment options that can support patients with IgAN across the care pathway. These data from the ALIGN study further demonstrate the ability of atrasentan to significantly reduce proteinuria and, if approved, its potential to become a new foundational treatment for people living with IgAN that can be seamlessly added to current supportive therapy."

"Atrasentan has the potential to help transform how IgAN is managed for many people living with this complex illness," said David Soergel, M.D., Global Head, Cardiovascular, Renal and Metabolism Development Unit, Novartis. "Our multi-product IgAN portfolio aims to address the needs of a broad, heterogenous patient population with different modes of action to target distinct drivers of the disease, with the ultimate goal of improving patient care in this therapeutic area."

At ERA, Novartis is also presenting new data across its rare disease portfolio, including 6-month data for Fabhalta^® (iptacopan) in C3 glomerulopathy (C3G) from the Phase III APPEAR-C3G study, long-term 33-month efficacy and safety data for Fabhalta in C3G from the Phase II extension study, additional data for Fabhalta in IgAN from the 9-month interim analysis of the Phase III APPLAUSE-IgAN study, 1-year Phase I/II data for investigational zigakibart in IgAN, and data from real-world studies in C3G and atypical hemolytic uremic syndrome (aHUS)^13-16.

About ALIGN
The ALIGN study (NCT04573478) is a global, randomized, multicenter, double-blind, placebo-controlled Phase III clinical trial comparing the efficacy and safety of atrasentan versus placebo in patients with IgAN at risk of progressive loss of kidney function^11,12. In total, 340 patients with biopsy-proven IgAN with baseline total proteinuria =1 g/day despite optimized RAS inhibitor treatment were randomized to receive once-daily oral doses of atrasentan (0.75 mg) or placebo for approximately 2.5 years (132 weeks)^11,12. Patients continue receiving a maximally tolerated and stable dose of a RAS inhibitor as supportive care (unless they are unable to tolerate RAS inhibitor therapy)^11,12. An additional group of 64 patients receiving a stable dose of SGLT2 inhibitor for at least 12 weeks have also been enrolled^11,12.

The primary efficacy endpoint of the study is change in proteinuria as measured by 24-hour UPCR from baseline to 36 weeks^11,12. Secondary and exploratory objectives include evaluating the change in kidney function from baseline to 136 weeks as measured by eGFR, as well as safety and tolerability^11,12.

About atrasentan
Atrasentan is an investigational potent and selective oral ETA receptor antagonist, currently in Phase III development for IgAN and early-stage development for other rare kidney diseases^1,11,12,17. Activation of the ETA receptor contributes to elevated proteinuria, which is associated with kidney damage, fibrosis and loss of kidney function in IgAN^2-5. Atrasentan has potential to be added to current supportive therapy to reduce persistent proteinuria and preserve kidney function for a broad patient population¹. Preclinical models have also suggested that atrasentan may reduce inflammation and fibrosis in IgAN^18-21.

About IgA nephropathy (IgAN)
IgAN is a heterogeneous, progressive, rare kidney disease⁶. Each year, approximately 25 people per million worldwide are newly diagnosed with IgAN²².

Up to 30% of people who have IgAN with persistent higher levels of proteinuria (=1 g/day) may progress to kidney failure within 10 years⁸. There is a need for effective, targeted therapies for IgAN that can help slow or prevent progression to kidney failure^6,7,23.

Novartis commitment in rare kidney diseases
At Novartis, our journey in nephrology began more than 40 years ago when the development and introduction of cyclosporine helped reimagine the field of transplantation and immunosuppression. We continue today with the same bold ambition to transform the lives of people living with kidney diseases.

Through our portfolio, we are exploring potential therapeutic options to address the current unmet needs of people living with rare diseases, including IgAN, C3G, aHUS, immune complex membranoproliferative glomerulonephritis (IC-MPGN) and lupus nephritis (LN). Innovative treatment options that target the underlying causes of these diseases may preserve kidney function and help people live longer without the need for dialysis or transplantation.
???
IgAN is a heterogeneous disease presenting with a variety of clinical manifestations, phenotypes, and variable speeds of progression⁶. In addition to atrasentan, Novartis is advancing the development of two other therapies in IgAN with highly differentiated mechanisms of action: Fabhalta, an investigational oral Factor B inhibitor of the alternative complement pathway, and zigakibart, an investigational subcutaneously administered anti-APRIL monoclonal antibody, which are both in Phase III development^24-26. Through our IgAN pipeline, we are committed to creating a portfolio of innovative medicines that improve and extend the lives of people living with kidney disease.

Disclaimer
This 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," "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 press release, 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 press release 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; 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 Novartis
Novartis 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 (https://www.novartis.com/) and connect with us on LinkedIn (https://www.linkedin.com/company/novartis/), Facebook (https://www.facebook.com/novartis/), X/Twitter (https://twitter.com/Novartis) and Instagram (https://instagram.com/novartis?igshid=MzRlODBiNWFlZA==__;!!N3hqHg43uw!pjp8z253J5NjaOYrW65UbAAlHeHRdQ-w0m4ezZxEQEl0ptafXN2M99VRIk39pf49PAc8NbK93Pxp3uaSBQkAf8oEnzWXG8Sk$).

References

1. Heerspink HJL, Jardine M, Kohan D, et al. ALIGN Phase 3 Primary Endpoint Analysis: Atrasentan Shows Significant Reduction in Proteinuria in Patients with IgA Nephropathy. Presented at European Renal Association (ERA) Congress; May 25, 2024; Stockholm, Sweden.
2. Tycová I, Hrubá P, Maixnerová D, et al. Molecular Profiling in IgA Nephropathy and Focal and Segmental Glomerulosclerosis. Physiol Res. 2018;67(1):93-105. doi:10.33549/physiolres.933670
3. Lehrke I, Waldherr R, Ritz E, Wagner J. Renal Endothelin-1 and Endothelin Receptor Type B Expression in Glomerular Diseases with Proteinuria. J Am Soc Nephrol. 2001;12(11):2321-2329. doi:10.1681/ASN.V12112321
4. Zanatta CM, Veronese FV, Loreto Mda S, et al. Endothelin-1 and Endothelin A Receptor Immunoreactivity is Increased in Patients with Diabetic Nephropathy. Ren Fail. 2012;34(3):308-315. doi:10.3109/0886022X.2011.647301
5. Kohan DE, Barton M. Endothelin and Endothelin Antagonists in Chronic Kidney Disease. Kidney Int. 2014;86(5):896-904. doi:10.1038/ki.2014.143
6. Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4):S1-S276. doi:10.1016/j.kint.2021.05.021
7. Boyd JK, Cheung CK, Molyneux K, Feehally J, Barratt J. An Update on the Pathogenesis and Treatment of IgA Nephropathy. Kidney Int. 2012;81(9):833-843. doi:10.1038/ki.2011.501
8. Reich HN, Troyanov SAA, Scholey JW, Cattran DC. Remission of Proteinuria Improves Prognosis in IgA Nephropathy. J Am Soc Nephrol. 2007;18(12):3177-3183. doi:10.1681/ASN.2007050526
9. Kim SG, Inker LA, Packham DK, et al. WCN23-1126 Atrasentan for the Treatment of IgA Nephropathy: Interim Results of the AFFINITY Study. Kidney Int Rep. 2023;8(9):1902. doi:10.1016/j.ekir.2023.02.1088
10. Thompson A, Carroll K, Inker LA, et al. Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy. Clin J Am Soc Nephrol. 2019;14(3):469-481. doi:10.2215/CJN.08600718
11. ClinicalTrials.gov. NCT04573478. A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Atrasentan in Patients with IgA Nephropathy at Risk of Progressive Loss of Renal Function (ALIGN). Available from: https://clinicaltrials.gov/study/NCT04573478 (https://clinicaltrials.gov/study/NCT04573478). Accessed May 2024.
12. Lambers Heerspink H, Jardine M, Kohan DE, et al. WCN23-1085 A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Atrasentan in Patients with IgA Nephropathy - The ALIGN Study. Kidney Int Rep. 2023;8(3):S279-S280. doi:10.1016/j.ekir.2023.02.630.
13. Kavanagh D, Bomback A, Vivarelli M, et al. Efficacy and Safety of Iptacopan in Patients with C3 Glomerulopathy: Results from the Phase 3 APPEAR-C3G Trial. Presented at European Renal Association (ERA) Congress; May 25, 2024; Stockholm, Sweden.
14. Nester CM, Eisenberger U, Karras A, et al. Update to the Long-Term Safety and Efficacy of Iptacopan in C3G: 33-Month Extension Study Data from Patients Enrolled in a Phase 2 Study. Presented at European Renal Association (ERA) Congress; May 25, 2024; Stockholm, Sweden.
15. Perkovic V, Kollins D, Papachristofi O, et al. Efficacy and Safety of Iptacopan in Patients with Primary IgA Nephropathy: Interim Analysis Results of the Phase 3 APPLAUSE-IgAN Study. Presented at European Renal Association (ERA) Congress; May 25, 2024; Stockholm, Sweden.
16. Barratt J, Kooienga L, Agha I, et al. One Year of Zigakibart Treatment Shows Clinically Meaningful Proteinuria Reduction and Good Tolerability in a Phase 1/2 Study of IgA Nephropathy. Presented at European Renal Association (ERA) Congress; May 25, 2024; Stockholm, Sweden.
17. ClinicalTrials.gov. NCT04573920. A Phase 2, Open-Label, Basket Study of Atrasentan in Patients with Proteinuric Glomerular Diseases (AFFINITY). Available from: https://clinicaltrials.gov/study/NCT04573920 (https://clinicaltrials.gov/study/NCT04573920). Accessed May 2024.
18. Sasser JM, Sullivan JC, Hobbs JL, et al. Endothelin A Receptor Blockade Reduces Diabetic Renal Injury via an Anti-Inflammatory Mechanism. J Am Soc Nephrol. 2007;18(1):143-154. doi:10.1681/ASN.2006030208
19. Olson E, McConnell M, Ragan S, et al. MO264: Selective Endothelin A Receptor Antagonist Atrasentan Attenuates Mesangial Cell Injury, Proteinuria and Intra-Renal Proliferative, Inflammatory and Fibrotic Transcriptional Networks in a Rat Model of Mesangioproliferative Glomerulonephritis. Nephrol Dial Transplant. 2022;37:S3. doi:10.1093/ndt/gfac067.063
20. Cox J, Gunawan M, Wu J, et al. A Central Role of Endothelin A Receptor Activation in Mesangial Cell - Podocyte Crosstalk in IgA Nephropathy and Other Mesangio-Proliferative Glomerulopathies. Glomerular Dis. 2022;2(Suppl 1):1-78. doi:10.1159/000525410
21. King A, Oballa R, Gunawan M, et al. POS-378 Selective ETA Antagonist Atrasentan, Rapidly Reduces Albuminuria and Downregulates Intra-Renal Pro-Inflammatory and Pro-Fibrotic Transcriptional Networks in the gddY Mouse Model of Spontaneous IgA Nephropathy. Kidney Int Rep. 2021;6(4):S164. doi:10.1016/j.ekir.2021.03.396
22. McGrogan A, Franssen CF, de Vries CS. The Incidence of Primary Glomerulonephritis Worldwide: A Systematic Review of the Literature. Nephrol Dial Transplant. 2011;26(2):414-430. doi:10.1093/ndt/gfq665
23. Xie J, Kiryluk K, Wang W, et al. Predicting Progression of IgA Nephropathy: New Clinical Progression Risk Score. PLoS ONE. 2012;7(6):e38904. doi:10.1371/journal.pone.0038904
24. Novartis. Novartis completes acquisition of Chinook Therapeutics. Available from: https://www.novartis.com/news/media-releases/novartis-completes-acquisition-chinook-therapeutics (https://www.novartis.com/news/media-releases/novartis-completes-acquisition-chinook-therapeutics). Accessed May 2024.
25. Novartis. New Novartis Fabhalta® (iptacopan) data show clinically meaningful and statistically significant proteinuria reduction of 38.3% versus placebo for patients with IgA nephropathy (IgAN). Available from: https://www.novartis.com/news/media-releases/new-novartis-fabhalta-iptacopan-data-show-clinically-meaningful-and-statistically-significant-proteinuria-reduction-383-versus-placebo-patients-iga-nephropathy-igan (https://www.novartis.com/news/media-releases/new-novartis-fabhalta-iptacopan-data-show-clinically-meaningful-and-statistically-significant-proteinuria-reduction-383-versus-placebo-patients-iga-nephropathy-igan). Accessed May 2024.
26. Perkovic V, Kollins D, Renfurm R, et al. WCN24-1506 Efficacy and Safety of Iptacopan in Patients with IgA Nephropathy: Interim Results from the Phase 3 APPLAUSE-IgAN Study. Kidney Int Rep. 2024;9(4):S506. doi:10.1016/j.ekir.2024.02.1414

# # #

Novartis Media Relations E-mail: [e-mail] (mailto:[e-mail])
Central		North America
Anja von Treskow	[phone]	Michael Meo	[phone]
Anna Schäfers	[phone]	Marlena Abdinoor	[phone]
Switzerland Satoshi Sugimoto	[phone]
Novartis Investor Relations Central investor relations line: [phone] E-mail: [e-mail] (mailto:[e-mail])
Central		North America
Isabella Zinck	[phone]	Sloan Simpson	[phone]
Nicole Zinsli-Somm	[phone]	Jonathan Graham	[phone]
Imke Kappes	[phone]	Parag Mahanti	[phone]