Novartis presents new long-term Leqvio®▼ (inclisiran) data demonstrating consistent safety profile and efficacy beyond six years

• Long-term safety profile data was consistent with previous findings, confirming the well-established safety profile of inclisiran.[i],[ii]
• Results from the ORION-8 open-label extension trial, which included UK patients, showed twice-yearly* inclisiran, in addition to statin therapy, provides consistent low-density lipoprotein cholesterol (LDL‑C) reduction beyond six years of treatment.1
• Eight in ten patients achieved target LDL-C threshold**, in line with previously reported Phase III data.1,2
• Inclisiran is available to NHS patients in England as part of an agreement between NHS England and Novartis to pioneer a first-of-its-kind population health management approach to address elevated LDL-C in eligible patients with ASCVD across England.

August 28, 2023 — Novartis today announced new long-term data from ORION-8, a Phase III open-label extension of ORION-9, ORION-10, ORION-11 and ORION-3 trials. The data demonstrated that with twice-yearly* dosing, inclisiran, in addition to statin therapy, provides consistent low-density lipoprotein cholesterol (LDL-C) reduction beyond six years in patients with atherosclerotic cardiovascular disease (ASCVD), increased risk of ASCVD or heterozygous familial hypercholesterolemia (HeFH)1. The results were presented in a late-breaking session at the European Society of Cardiology (ESC) Congress 2023 in Amsterdam.

ORION-8, the largest clinical trial completed to date with inclisiran, continues to support the consistent long-term efficacy, safety profile, and tolerability of inclisiran, with a total exposure of more than 8,500 patient-years during the trial’s three-year follow-up1. Patients from four previous completed Novartis trials (ORION-9, ORION-10, ORION-11 and ORION-3) received inclisiran every six months* for up to an additional three years1,[iii]. 78% (95% CI: 76.8, 80.0) of patients reached their pre-specified LDL-C targets**, and on average, LDL-C levels were reduced by approximately 49% (95% CI: 48.3, 50.4)1. These results demonstrate consistent efficacy as they are comparable to the LDL-C reductions observed at the end of the initial trials1,2,[iv]. In addition, the long-term safety data was consistent with previous findings, confirming the well-established safety profile of inclisiran1,2,4.

“The present findings from the ORION-8 trial reconfirm and extend prior observations about the safety profile and efficacy of inclisiran for people with atherosclerotic cardiovascular disease and those at risk of cardiovascular disease, in whom cholesterol levels are not adequately controlled. In the largest study presented to date with several thousand injections, we can confirm that twice yearly dosing with the first in class siRNA therapy provides sustained reductions in LDL cholesterol by approximately 49% beyond 6 years of observation. The safety profile demonstrates no new additional concerns raised during this extended period of follow up. As the senior author in this trial and lead in the ORION development programme as well as an active clinician, I am acutely aware of the unmet clinical need in our patients but also the assurance needed by the clinical community for any novel therapy. Therefore, these findings are particularly important in providing clinicians and patients with further assurance helping reduce the gap between guideline recommended care and their implementation,” said Prof Kausik Ray, MD, FMedSci, Professor of Public Health at Imperial College London and Honorary Consultant Cardiologist at the Imperial College NHS Trust.

ORION-8 is part of VictORION, a large dynamic clinical trial program co-created with healthcare partners worldwide to generate evidence on the impact of cholesterol-lowering with inclisiran. The program is enrolling over 60,000 patients, across more than 50 countries and more than 30 clinical trials[v].

“These results reaffirm our partnership-based approach with the NHS on the basis that administration through primary care could positively impact population health in the UK. This will help us to deliver our shared vision for the benefit of UK patients and contribute to reducing the considerable impact of CVD on the population,” said Gerrit Zijlstra - Novartis Country Medical Head and Chief Medical Officer, Novartis UK.

Inclisiran is the first and only small interfering RNA (siRNA) therapy to lower LDL-C. It is approved in over 80 countries, including the EU and the US[vi],[vii].

Inclisiran is licensed in the UK for use in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet:

• in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin, or
• alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated[viii].

* After an initial dose and another at three months.

** <70 mg/dL, the target for patients with ASCVD or <100mg/dL for patients with increased risk of ASCVD.

About inclisiran

Inclisiran is a subcutaneous injection given by a health care provider with an initial dose, another at three months, and then every six months6,7. As a twice-yearly, HCP-administered treatment, inclisiran may help to circumvent the challenges of treatment adherence, a common issue in cholesterol management[ix],2,[x]. Inclisiran is approved in more than 80 countries worldwide including the US and EU6,7.

Novartis has obtained global rights to develop, manufacture and commercialize inclisiran under a license and collaboration agreement with Alnylam Pharmaceuticals, a leader in RNAi therapeutics.

About ORION-8

ORION-8 (NCT03814187) is a three-year open-label extension of the placebo-controlled 18-month Phase III trials ORION-9, ORION-10, and ORION-11 and the four-year Phase II ORION-3 trial (an extension of the on-year Phase II ORION-1 trial) 3,[xi]. ORION-8 evaluated the long-term safety, efficacy and tolerability of inclisiran in 3,274 patients with atherosclerotic cardiovascular disease (ASCVD), increased risk of ASCVD (includes patients with who have comorbidities such as diabetes and hypertension) or heterozygous familial hypercholesterolemia (HeFH) and elevated low density lipoprotein cholesterol (LDL-C), despite maximum tolerated dose of LDL-C lowering therapies3. 2,446 patients completed the trial to Day 1080 (three years)1. The primary endpoint of the study was the proportion of patients achieving pre-specified LDL-C targets at the end of the study, either Day 1080 or 90 days after the last injection3. Patients received 300 mg inclisiran sodium twice yearly* (every 6 months) for up to an additional three years after baseline studies2. Adverse events at the injection site occurred in 5.9% of patients, compared with 8% in the inclisiran arm of the pooled analysis of ORION-9, ORION-10, and ORION-11 trials1,6.

About VictORION

VictORION is an innovative and robust clinical program for inclisiran, comprising more than 30 trials and enrolling over 60,000 patients in more than 50 countries worldwide5. The program is designed to expand on the foundational evidence of LDL-C reduction with inclisiran in diverse patient populations to include randomized clinical trials, implementation research, real-world evidence, and trials that aim to establish its potential benefits on cardiovascular outcomes in primary and secondary prevention. A growing number of studies are planned to generate a vast array of data with major trials such as ORION-4 (secondary prevention), V(VictORION)-2-PREVENT (secondary prevention), V-1-PREVENT (high-risk primary prevention), V-INITIATE, V-INCEPTION, V-REAL, V-DIFFERENCE, and V-PLAQUE.

About atherosclerotic cardiovascular disease (ASCVD)

Atherosclerotic cardiovascular disease (ASCVD) refers to a variety of diseases caused by the development and growth of plaques in the inner lining of the arteries[xii]. The atherosclerotic plaque is mainly composed of low-density lipoprotein cholesterol (LDL-C) which accumulates over time12. Cumulative exposure to LDL-C is proportionally related to arterial plaque growth and progression leads to subsequent risk of cardiovascular events such as a heart attack or stroke12,[xiii]. Accounting for 85% of all cardiovascular disease deaths, ASCVD is the primary cause of mortality in the European Union and its burden in the United States is greater than that from any other chronic diseases[xiv],[xv],[xvi],[xvii]. ASCVD risk-equivalent corresponds to conditions that confer a similar risk for an ASCVD event (e.g., diabetes, heterozygous familial hypercholesterolemia)9,17.

About Novartis in Cardiovascular

Cardiovascular (CV) disease is a global health crisis14,[xviii]. CV disease is the number one killer in the world14. Taking more lives than all cancers combined, it contributes to one in every three deaths globally14,18. Of all CV events, 80% can be prevented[xix]. Patients and their families deserve better, and our society deserves more.

Thanks to a combination of our legacy, global footprint and leading science, Novartis is uniquely positioned to help change this landscape. We are transforming the way we think about how CV disease is managed throughout life. Our efforts include the use of early interventions and the development of pioneering treatments that address the spectrum of CV disease, from prevention to management, as well as the creation of innovative access models. By re-writing the way we work with society, we will lead a worldwide effort to improve health outcomes and roll back the crisis of CV death.

Our goal is to bend the curve of life by reducing and stopping premature death from CV 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,” “seek,” “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 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 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 reimagining medicine to improve and extend people’s lives. We deliver high-value medicines that alleviate society’s greatest disease burdens through technology leadership in R&D and novel access approaches. In our quest to find new medicines, we consistently rank among the world’s top companies investing in research and development. About 103,000 people of more than 140 nationalities work together to bring Novartis products to nearly 800 million people around the world. Find out more at https://www.novartis.com 

In the UK, we employ approximately 1,100 people to serve healthcare needs across the whole of the UK, as well as supporting the global operations of Novartis. Since 2014, Novartis has invested over £200 million in R&D and is a leading sponsor of clinical trials, in the UK. For more information, please visit www.novartis.co.uk.

References 

1. RS Wright, FJ Raal, W Koenig, U Landmesser, LA Leiter, GG Schwartz,        A Lesogor, P Maheux, Z Talloczy, S Vikarunnessa, X Zang, KK Ray. ORION-8: Long-term efficacy and safety of twice-yearly inclisiran in high cardiovascular risk patients. Data presented at the ESC Congress on August 28, 2023. 
2. Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia. N Engl J Med. 2020;382(16):1520– 1530. 
3. ClinicalTrials.Gov. ORION-8 (NCT03814187). Accessed August, 2023. https://www.clinicaltrials.gov/study/NCT03814187
4. Ray KK, Troquay RPT, Visseren FLJ, et al. Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial. Lancet Diabetes Endocrinol. 2023;11(2):109-119. 
5. Novartis. Data on File_FUSE ID 286926.
6. Food and Drug Administration (FDA). Leqvio. Last updated July 2023. Accessed August 2023.  https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/214012s009lbl.pdf
7. European Medicines Agency (EMA). Last updated December 2020. Accessed August 2023. https://www.ema.europa.eu/en/documents/overview/leqvio-epar-medicine-overview_en.pdf
8. Electronic medicines compendium. Leqvio 284 mg solution for injection in pre filled syringe. Published July 2022. Accessed August 2023. https://www.medicines.org.uk/emc/product/12039/smpc#gref
9. Ray KK, Wright RS, Kallend D, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020;382(16):1507– 1519.
10. Lansberg P, Lee A, Lee ZV, Subramaniam K, Setia S. Nonadherence to statins: individualized intervention strategies outside the pill box. Vasc Health Risk Manag. 2018;14:91-102. 
11. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. 2017;376(15):1430-1440. 
12. Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell. 2015;161(1):161-172.
13. Ference BA, Graham I, Tokgozoglu L, Catapano AL. Impact of Lipids on Cardiovascular Health: JACC Health Promotion Series. J Am Coll Cardiol. 2018;72(10):1141-1156.
14. World Health Organization (WHO). Cardiovascular diseases (CVDs). Published June 2021. Accessed August 2023. https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)
15. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke Statistics–2012 update: A report from the American Heart Association. Circulation. 2012;125(1):e2-e220.
16. Kim H, Kim S, Han S, et al. Prevalence and incidence of atherosclerotic cardiovascular disease and its risk factors in Korea: a nationwide population-based study. BMC Public Health. 2019;19(1):1112.
17. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143-3421.
18. World Health Organization (WHO). Fact sheet. Non-communicable diseases. Published June 2018. Accessed August 2023.  https://www.who.int/news-room/fact-sheets/detail/noncommunicable-diseases
19. World Health Organization (WHO). Cardiovascular diseases: Avoiding heart attacks and strokes. Published September 2015. Accessed August 2023. https://www.who.int/news-room/questions-and-answers/item/cardiovascular-diseases-avoiding-heart-attacks-and-strokes