AHA 2024: Inclisiran Shows Efficacy, Improved Adherence for Reducing LDL-C

In addition to demonstrated efficacy for the reduction of low-density lipoprotein cholesterol (LDL-C) in patients with atherosclerotic cardiovascular disease (ASCVD), inclisiran’s twice-yearly dosing schedule could significant improve patients’ treatment adherence, according to data presented at the American Heart Association (AHA) Scientific Sessions 2024.¹

Inclisiran (Leqvio; Novartis) is FDA-approved as an adjunct to diet and therapy for the treatment of primary hyperlipidemia, including heterozygous familial hypercholesterolemia, to reduce LDL-C.

“We know that LDL-C is one of the most modifiable risk factors for ASCVD, and for patients after a coronary event there is an urgency to try to reduce those cholesterol goals to their appropriate levels according to the guidelines,” Kwon said.

Data indicate that patients who do not meet LDL-C goals have a nearly 50% higher risk of cardiovascular events.² Additionally, up to 80% of patients with ASCVD remain on the same statin regimen despite having LDL-C of 70 mg/dL or higher, and patients who did achieve their LDL-C goals only maintained it for an average of 6 months.³ Furthermore, in a survey of attendees at the AHA session, respondents said patients adhere to their lipid-lowering therapy for a relatively short period, with 44% saying 6 months or less.¹

Discontinuation rates are another significant obstacle. Data published in the Journal of Clinical Lipidology show that approximately 25% to 50% of patients discontinue statin medications within 6 months to 1 year.⁴ Causes can include treatment adverse effects, frequent dosing burden, high costs, fear or avoidance of self-injections, inconvenience, lack of belief in the efficacy, challenges of polypharmacy, and intolerance.^1,4

“We talk a lot about polypharmacy, or pill burden,” Kwon said. “These are all potential factors that may influence adherence or may decrease adherence to a given therapy.”

3d image of cholesterol buildup | Image credit: © jijomathai | stock.adobe.com

With all of these obstacles in mind, Kwon said many clinicians and patients are looking for treatments with high efficacy by fewer burdens, such as reduced dosing frequency and greater affordability. Inclisiran, a first-in-class, small interfering RNA lipid-lowering therapy with proven efficacy in lowering LDL-C and twice-yearly dosing, may solve some of these challenges.¹

Notably, Kwon said inclisiran has a unique mechanism of action to lower LDL-C levels, leveraging the biologic process of RNA interference. The drug selectively targets the liver, where uptake of circulating LDL-C occurs and it reaches undetectable levels in circulation within 24 to 48 hours. The treatment works upstream to prevent formation of PCSK9 protein and has a prolonged duration of effect due to slow release into the cytoplasm of hypatocytes.¹

“[Inclisiran] is taken up into the cytoplasm slowly and that allows for a long duration of action, so that’s where the long duration of dosing comes in every 6 months,” Kwon explained.

Two phase 3 trials have been completed in patients with primary hyperlipidemia—ORION-10 and ORION-11. The ORION-10 trial included 1561 patients and was an 18-month, phase 3 trial of patients who were on maximally tolerated statin therapy with or without other lipid-modifying therapies who still required additional LDL-C reduction. The primary end point was percent change in LDL-C from baseline to day 510.⁵

The ORION-11 trial was similarly designed and included 1617 patients with ASCVD or at increased risk for ASCVD. The primary efficacy measure was percent change in LDL-C from baseline to day 510.⁵

According to results from the ORION-10 trial, LDL-C reduction with inclisiran was powerful and consistent with just 2 doses per year. Furthermore, 84% of patients achieved an LDL-C <70 mg/dL compared with 18% of participants treated with placebo. The results were similar among patients with ASCVD or increased risk of ASCVD in ORION-11.⁵ Notably, Kwon said LDL-C reduction was evident within 14 days of the initial dose.¹

In addition to these 2 trials, the ORION-8 study examined long-term efficacy and safety of inclisiran in patients with primary hyperlipidemia. Patients from the phase 3 clinical trials (ORION-9, -10, and -11) were included in ORION-8, as well as patients from the phase 2 ORION-3 trial.⁶ Kwon acknowledged that this design does have some inherent limitations such as selection bias, and comparisons can only be made with patients’ baseline levels.¹

In the ORION-8 trial, 78% of participants achieved their target LDL-C, consistent with findings from ORION-10 and -11. Study authors noted approximately 50% LDL-C reduction with inclisiran at end of study (-49% mean change in LDL-C, 95% CI: -50%, -48%).^1,6

“We do have various amounts of exposure data, so there were approximately 6.5% of patients who had exposure to [inclisiran] greater than 6 years,” Kwon said.

Inclisiran has also shown promise in real-world clinical practice settings, as studied in the V-INITIATE trial. In this study 12-month, randomized, open-label study, inclisiran was initiated immediately upon failure to achieve the 70 mg/dL LDL-C threshold and was compared with usual care.⁷ Kwon did note that usual care was left up to the discretion of clinicians, although adherence to AHA guidelines was encouraged.¹ Additionally, he said 10 patients in the usual care group received at least 1 dose of inclisiran, which could impact interpretation of the results. Discontinuation of statins was a co-primary end point, defined as discontinuation for at least 30 days before the end-of-study visit.^1,7

Findings from V-INITIATE demonstrated consistent efficacy with the pivotal trialsm including a 53% difference in LDL-C reduction between the inclisiran and usual care arms. Additionally, 82% of participants in the inclisiran arm achieved their target LDL-C level, compared with 22% in the usual care arm, which which most (73%) remained on statins alone.^1,7

“Again, this is comparison to usual care, in the real-world clinical practice setting,” Kwon said. “Usual care does not represent best practices, so we just have to understand that. But the data is consistent with prior clinical trials.”

Real-world data from US claims databases also highlight the adherence rates with inclisiran compared with LCSK9 monoclonal antibodies. According to that data, 79% of patients receiving inclisiran were fully adherent at 12 months, versus 56% of patients receiving either evolocumab (Repatha; Amgen) or alirocumab (Praluent; Regeneron).¹

A significant cause for this higher adherence is because inclisiran is administered by a health care professional, as opposed to evolocumab or alirocumab, which are self-administered. Because of this, Kwon noted that claims for evolocumab and alirocumab do not confirm self-administration and may therefore be overestimated, whereas claims for inclisiran guarantee that patients received the injection.¹

The logistics of inclisiran administration are simple, Kwon said. The approved dose is 284 mg administered subcutaneously in the abdomen, arm, or thigh. No refrigeration is required and it has a shelf-life of 3 years.¹

To further discuss logistics, presented Maisha Rudison-Bryant, executive director of cardiovascular access and reimbursement at Novartis, discussed cost management for patients, who are often concerned about the additional costs of another medication. Inclisiran is broadly covered and affordable for most patients, she said. Notably, she added that 7 out of 10 commercial insurance plans do not require a step-up from another injectable medication.¹

“That is huge for our patients because it means minimal effort, in most cases, for you and your office in trying to get access for that patient,” Rudison-Bryant said.

Additionally, she highlighted the Leqvio copay program, under which 94% of patients paid as little as $0. For patients with traditional Medicare plans, no prior authorization is required, which also accelerates the time to treatment. Some supplemental plans may require precertification or prior authorization.¹

Although many patients may receive their twice-yearly inclisiran injections from their primary care provider, alternative sites of care are often just as accessible and can reduce the workload for physicians. Rudison-Bryant noted that a small number of patients do use specialty pharmacies, but because inclisiran is a medical benefit product it is primarily administered in an alternative site or physicians’ office.¹

With highly supportive efficacy data and wide availability, inclisiran may offer patients a new way to control their LDL-C, thus reducing risks of cardiovascular events.

REFERENCES

1. Kwon D, Rudison-Bryant M. Managing LDL-C With Leqvio Inclisiran After a Recent Coronary Event: Putting Evidence Into Practice. Presented at: American Heart Association Scientific Sessions 2024. November 17, 2024.

2. High-Risk American Not Reaching LDL-C Target Have Higher Rate of Cardiovascular Events. News release. Family Heart Foundation. March 21, 2023. Accessed November 17, 2024. https://familyheart.org/high-risk-missing-ldl-c-target-higher-events

3. Fox KM, Tai MH, Kostev K, Haztz M, Qian Y, Laufs U. Treatment patterns and low-density lipoprotein cholesterol (LDL-C) goal attainment among patients receiving high- or moderate-intensity statins. Clin Res Cardiol. 2017;107(5):380-388. doi:10.1007/s00392-0170-1193-z

4. Halava H, Huupponen R, Pentti J, Kivimäki M, Vahtera J. Predictors of first-year statin medication discontinuation: a cohort study. J Clin Lipidol. 2017;10(4):987-995. doi:10.1016/j.jacl.2016.04.010

5. 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;382:1507-1519. doi:10.1056/NEJMoa1912387

6. Wright RS, Raal FJ, Koenig W, et al. ORION-8: Long-term assessment of the efficacy and safety of inclisiran in patients with high risk of cardiovascular events. Novartis. August 2023. Accessed November 17, 2024. https://www.novartis.com/sites/novartis_com/files/orion-8-long-term-assessment-of-the-efficacy-and-safety-of-inclisiran.pdf

7. Koren MJ, Rodriguez F, East C, et al. An “inclisiran first” strategy vs usual care in patients with atherosclerotic cardiovascular disease. JACC. 2024;83(20):1939-1952. doi:10.1016/j.jacc.2024.03.382