Recently approved by the European Medicines Association, and currently under review by the US Food and Drug Administration, inclisiran, a first-in-class small interfering RNA (siRNA) treatment, impressively improved primary hyperlipidemia, regardless of patients’ age and gender. Physician’s Weekly talked with ORION-11 trial principal investigator Dr. Kausik “Kosh” Ray, a professor at the Department of Public Health and Primary Care at Imperial College London, UK, and cardiologist at the Imperial College NHS Trust.

 The results from 2 pooled post-hoc analyses of the phase 3 ORION-9, -10, and -11 trials (NCT03397121, NCT03399370, and NCT03400800, respectively) were presented at the American Heart Association Scientific Sessions 2020 [1, 2]. These analyses evaluated the impact of age and gender on the efficacy and safety of inclisiran in sustaining reduction in low-density lipoprotein cholesterol (LDL-C) when used in combination with other lipid-lowering therapies.

Inclisiran is a first-in-class siRNA for hyperlipidemia in adults with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia. Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin–kexin type 9 (PCSK9), and previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing [3]. The safety and efficacy of inclisiran was published earlier this year in the New England Journal of Medicine for patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose [4]. During the ORION series of trials, inclisiran was administered to patients in the first and third months of the trial, and then additionally every 6 months up to month 17.

In the  first analysis of looking at gender, inclisiran was found to provide similar LDL-cholesterol reductions at 50.6% from baseline compared to placebo for both women and men among >3,600 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-cholesterol reductions of approximately 51%. Specifically, a reduction of  51.3% was observed in patients <65 years; a reduction of 49.9% was observed in patients 65 to <75 years, and a reduction of 51.0% was also seen in patients ≥75 years. In both analyses, inclisiran was well-tolerated among patients.

 

Physician’s weekly asked principal investigator Prof Kausik Ray (Imperial College London, UK) for his perspective:

“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. 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.”

“We know that older patients have a higher absolute risk of cardiovascular events. We also know that older patients often cannot tolerate effective doses of statins, and  yet the guidelines have moved, particularly for those highest-risk patients, to recommend lower and lower LDL targets. The reality is that means you are going to have to think about combination therapies, particularly among these groups of patients, it is important to show a treatment can be effective but also safe. And as with the overall population, older patients form an important subgroup that showed that inclisiran was effective, and that the LDL-lowering was essentially the same irrespective of age. Likewise, the safety profile was similar. For patient populations such as these, often with comorbidities and polypharmacy, sometimes unable to collect refills and prescriptions, it is beneficial  to know now that an injection that is going to be given twice a year would provide effective coverage. ”

“With respect to gender, in many of the practice-changing studies, women often tend to be underrepresented –yet they have a very high burden of cardiovascular disease. We know that the symptoms in women are sometimes atypical for cardiovascular disease. There is a lot of data that suggests that women receive less evidence-based treatment, and they could run into issues because they are perhaps not managed as aggressively as men. ”

Women are an important subgroup to show that the treatment effects are consistent. For example, we know that muscle symptoms are more frequently reported amongst women, which indicates  that their LDL cholesterol levels tend to be higher. The attending physician will be more likely to need to think about add-on treatment. Being able to show similar efficacy and a similar safety profile is really important in these 2 patient groups who are often underserved.”

Can you comment on the subtypes of lipoproteins that are being modulated?

“If you think about how the drug works and it basically increases clearance of apoB-containing lipoprotein. By lowering PCSK9, the life cycle of the LDL receptor is extended. So just like the effects of statins and PCSK9 monoclonals, one would expect similar reductions in adipogenic proteins, and these would be non-HDL and Apo B. If you get about 50% lowering of LDL, you get about a 46% lowering of non-HDL and you get about a 42% lowering of that apoB. We have also seen a really very modest lowering of the LP(a), on the order of about 25%. There are no clinically relevant increases in HDL, and there is a trend towards lower triglycerides, but this is very similar to what we see with the monoclonals, for example. C-reactive protein levels do not change.”

 

References:

  1. Wright RS, Ray KK , et al. Efficacy and safety of inclisiran according to sex: a pooled analysis of phase III studies (ORION 9, 10 And 11). ePoster presentation (P2253) at: AHA Scientific Sessions; November 2020.
  2. Wright RS, Ray KK et al. Efficacy and safety of inclisiran according to age: a pooled analysis of Phase III studies (ORION 9, 10 And 11). ePoster presentation (P2250) at: AHA Scientific Sessions; November 2020.
  3. Ray KK et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. 2017 Apr 13;376(15):1430-1440.
  4. Ray KK, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020 Apr 16;382(16):1507-1519.