Results from 2 pooled post-hoc analyses of phase 3 ORION-9, -10, and -11 trials evaluating inclisiran (Novartis) demonstrated the treatment was well-tolerated and effective at sustaining reduction in low-density lipoprotein cholesterol (LDL-C) when used with other lipid-lowering therapies, regardless of patients’ age and gender. The trials were designed to evaluate the impact of age and gender on the efficacy and safety of the drug.

Inclisiran is a potential first-in-class small interfering RNA (siRNA) for hyperlipidemia in adults with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia. During the trials investigating its efficacy and tolerance among patients, inclisiran was administered to patients in the first and third months of the trial, and then additionally every 6 months up to month 17.

“High LDL-C and other risk factors for ASCVD, as well as the potential for treatment side effects, may increase with age and differ by gender,” said Kausik Ray, MD, ORION-11 trial principal investigator, professor of public health at Imperial College London, and honorary consultant cardiologist at the Imperial College Healthcare NHS Trust, in a press release. “These data are important as they show that inclisiran, as a siRNA, has the potential to provide consistent efficacy and tolerability despite the cholesterol-lowering treatment challenges posed by age and gender with 2 doses a year after the initial dosing regimen on day 1 and month 3.”

In the analysis of the results of the ORION phase 3 trials, inclisiran was found to provide similar LDL-C reductions at 50.6% from baseline compared to placebo for both women and men among the more than 3600 patients who participated. In the second pooled analysis, results demonstrated that patients in 3 age categories who were treated with inclisiran all achieved similar LDL-C reductions of approximately 51% (−51.3% <65 years; −49.9% ≥65 years to <75 years; −51.0% ≥75 years). In both analyses, inclisiran was well-tolerated among patients.

“Whether you look at it from an age or a gender perspective, inclisiran analyses continue to show consistency with effective and sustained LDL-C reduction lasting over the dosing interval,” said David Soergel, MD, global head of cardiovascular, renal, and metabolic drug development at Novartis, in the press release. “As we move forward in our journey to reimagine treatment for ASCVD, these data analyses reinforce the potential of inclisiran as a first-in-class siRNA treatment to transform LDL-C management with two doses a year, following the initial dose and another dose at 3 months, and a positive tolerability profile.” 

Following these positive results, the Committee for Medicinal Products for Human Use of the European Medicines Agency presented a positive opinion on the treatment on October 16, 2020, recommending inclisiran be granted marketing authorization. A final regulatory decision in Europe is expected by December 2020. Additionally, the FDA has taken inclisiran under review.

New Novartis analyses for investigational inclisiran demonstrate consistently effective and sustained LDL-C reduction at month 17, regardless of age and gender. East Hanover, NJ: Novartis Pharmaceuticals Corporation; November 13, 2020. Accessed November 20, 2020.