Ziltivekimab reduced inflammatory biomarkers associated with atherosclerosis in people with chronic kidney disease in phase 2 trial

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May 17, 2021, 12:30 ET

PLAINSBORO, N.J., May 17, 2021 /PRNewswire/ -- Novo Nordisk today presented results from RESCUE, a phase 2 randomised, double-blind, placebo controlled clinical trial assessing the effect of once-monthly, investigational ziltivekimab, an interleukin-6 (IL-6) inhibitor, on biomarkers of inflammation. The trial showed a significant reduction of multiple inflammatory biomarkers associated with atherosclerosis in people with advanced chronic kidney disease (CKD) and elevated high-sensitivity C-reactive protein (hsCRP), representing high cardiovascular risk. The data were announced today at the virtual American College of Cardiology's (ACC) 70th Annual Scientific Session¹ and simultaneously published in The Lancet².

Atherosclerosis is the major cause of cardiovascular disease (CVD), including heart attack and stroke³. Atherosclerosis is characterised by the build-up of fats, cholesterol and other substances in the artery walls that results in vessel narrowing and reduced blood flow³. Chronic inflammation contributes to the development and progression of atherosclerosis⁴, and biomarkers for inflammation, such as hsCRP, can be used to predict cardiovascular risk⁵.

The RESCUE trial met its primary endpoint, showing that after 12 weeks, median levels of hsCRP were significantly reduced with ziltivekimab compared with placebo (77%, 88% and 92% reduction in those receiving 7.5 mg, 15 mg and 30 mg of ziltivekimab, respectively, compared to 4% for placebo). The proportion of people achieving both a greater than 50% reduction in hsCRP and hsCRP levels of less than 2 mg/L, a secondary endpoint, was also significantly higher with ziltivekimab than placebo (66%, 80% and 93% in those receiving 7.5 mg, 15 mg and 30 mg of ziltivekimab, respectively, compared to 4% for placebo). Dose-dependent reductions were also observed for four additional inflammatory biomarkers (fibrinogen, serum amyloid A, haptoglobin and secretory phospholipase A2). Treatment emergent adverse events were considered to be mild, moderate, or severe and were similar between the placebo and ziltivekimab groups. Ziltivekimab was generally well tolerated, with no unexpected side effects².

"In the RESCUE trial, ziltivekimab showed significant reductions in inflammatory biomarkers associated with atherosclerosis, including hsCRP," said Paul M. Ridker, director of the Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, US. "Chronic inflammation is common in people with chronic kidney disease and puts them at increased risk of cardiovascular events, such as heart attack and stroke."

CVD is the number one cause of morbidity and mortality globally⁶. It is responsible for one-third of all deaths worldwide, 85% of which are caused by heart attack and stroke3. Furthermore, approximately half of all deaths in people with CKD are due to CVD-related complications⁷, meaning those with CKD are more likely to die from CVD than progress to end-stage renal disease⁸.

"We are very encouraged by these promising phase 2 data, which is an important step towards a new potential anti-inflammatory treatment approach for people living with atherosclerotic CVD and CKD," said Martin Holst Lange, executive vice president for Development at Novo Nordisk. "Based on these results, we are planning to progress ziltivekimab to a large-scale phase 3 cardiovascular outcomes trial to further assess its potential, as we continue to advance our commitment in cardiovascular disease."

About the RESCUE trial⁹
RESCUE is a phase 2, randomised, double-blind, placebo-controlled clinical trial assessing the effect of once-monthly subcutaneous ziltivekimab on biomarkers of inflammation in people with advanced CKD and elevated hsCRP. The study, which enrolled 264 participants, was designed to assess if ziltivekimab can safely and effectively reduce levels of inflammatory biomarkers relevant to atherosclerosis. The pre-specified primary endpoint was change in hsCRP after 12 weeks of treatment, with additional data on safety and other inflammatory biomarkers (fibrinogen, serum amyloid A, haptoglobin and secretory phospholipase A2) collected over 24 weeks of treatment.

About investigational ziltivekimab
Ziltivekimab is a fully human monoclonal antibody designed to lower systemic inflammation through inhibition of IL-6 (a pro-inflammatory cytokine with a causal role in atherosclerosis). With its extended half-life technology, ziltivekimab has been designed to enable once-monthly administration by subcutaneous (SC) injection. Ziltivekimab is being developed by Novo Nordisk following the acquisition of Corvidia Therapeutics, announced in June 2020.

About atherosclerotic cardiovascular disease (ASCVD) and CKD
Globally, 700 million people live with CKD, and this number is increasing6. Renal impairment is associated with chronic inflammation¹⁰, which is recognised as a critical driver of ASCVD¹¹. Atherosclerosis, defined as the build-up of fats, cholesterol, and other substances in artery walls in the form of plaques, can lead to obstruction of arterial blood flow3. Elevated hsCRP levels are a biomarker for inflammation and can be used to predict the risk of cardiovascular events such as heart attack and stroke^4,12. Despite guideline-recommended cardiovascular risk factor management, a high risk for cardiovascular events remains⁴.

About Novo Nordisk
Novo Nordisk is a global healthcare company that's been making innovative medicines to help people with diabetes lead longer, healthier lives for 95 years. This heritage has given us experience and capabilities that also enable us to help people defeat other serious diseases including obesity, hemophilia and growth disorders. We remain steadfast in our conviction that the formula for lasting success is to stay focused, think long-term and do business in a financially, socially and environmentally responsible way. With U.S. headquarters in New Jersey and production and research facilities in six states, Novo Nordisk employs nearly 6,000 people throughout the country. For more information, visit novonordisk.us , Facebook , Instagram and Twitter.

References

1.	Ridker P, Devalaraja M, Baeres F, et al. Effects Of Interleukin-6 Inhibition With Ziltivekimab On Biomarkers Of Inflammation Among Patients At High Risk For Atherosclerotic Events. Presented during the American College of Cardiology's 70th Annual Scientific: Late-breaking abstract 21-LB-20783-ACC.

2.	Paul M Ridker, Matt Devalaraja, et al. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. The Lancet, Published Online May 17, 2021 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00520-1/fulltext

3.	Herrington W, Lacey B, Sherliker P, Armitage J, Lewington S. Epidemiology of Atherosclerosis and the Potential to Reduce the Global Burden of Atherothrombotic Disease. Circulation Research. 2016; 118(4): 535-546

4.	Lawler PR, Bhatt DL, Godoy LC et al. Targeting cardiovascular inflammation: next steps in clinical translation. European Heart Journal. 2021. 42(1):113–131.

5.	Pfutzner A, Forst T. High-sensitivity C-reactive protein as cardiovascular risk marker in patients with diabetes mellitus. Diabetes Technology & Therapeutics. 2006; 8(1):28-36.

6.	World Health Organization. Cardiovascular diseases. Available from: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds). Last accessed: April 2021.

7.	GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet. 2020; 395:709-733.

8.	Keith DS, Nichols GA, Cullion CM, Brown JB, Smith DH. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Archives of Internal Medicine. 2004;164(6):659-663.

9.	ClinicalTrials.gov. Trial to Evaluate Reduction in Inflammation in Patients With Advanced Chronic Renal Disease Utilizing Antibody Mediated IL-6 Inhibition (RESCUE). Available from: https://clinicaltrials.gov/ct2/show/NCT03926117. Last accessed: April 2021.

10.	Oberg BP, McMenamin, Lucas FL, McMonagle E, Morrow J, Ikizler TA, Himmelfarb J. Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease. Kidney International. 2004; 65(3):1009-1016.

11.	Alani H, Tamimi A, Tamimi N. Cardiovascular co-morbidity in chronic kidney disease: Current knowledge and future research needs. World Journal of Nephrology. 2014; 3(4):156-168.

12.	Faxon DP, Fuster V, Libby P et al. Atherosclerotic Vascular Disease Conference: Writing Group III: pathophysiology. Circulation. 2004; 109:2617.