Pooled Inclisiran Data: Safe LDL-Lowering, Plus Hints of Fewer CVD Events

A pooled analysis of clinical trials testing inclisiran (Novartis) confirms the agent’s potent and durable effects on LDL cholesterol and also offers a glimpse of the drug’s potential for lowering the risk of major cardiovascular events.

The analysis, which combined three phase III studies of patients with heterozygous familial hypercholesterolemia (FH) or atherosclerotic cardiovascular disease (ASCVD) treated with the twice-yearly intravenous injection of inclisiran, lowered LDL cholesterol levels by more than 50% at 17 months.

And although the study was underpowered and relatively short in duration, investigators did observe a lower rate of cardiovascular death, resuscitated cardiac arrest, nonfatal MI, and stroke among patients treated with inclisiran when compared with placebo (7.1% vs 9.4%). In this exploratory analysis, the reduction was driven by fewer nonfatal MI events in the active treatment arm (5.2% vs 7.8% with placebo).  

“LDL cholesterol-lowering is the most effective intervention to change the course of atherosclerotic cardiovascular disease and FH, yet substantial residual risk remains despite aggressive treatment with statins and other agents,” said R. Scott Wright (Mayo Clinic, Rochester, MN), who presented the study as featured clinical research during the virtual American College of Cardiology 2020 Scientific Session.

“There is a compelling need for new and novel therapies which further lower LDL cholesterol beyond what we can achieve with all oral lipid-lowering agents,” he noted.

Inclisiran, a small interfering double-stranded RNA (siRNA), has a dosing advantage over currently available monoclonal antibodies alirocumab (Praluent; Sanofi/Regeneron) and evolocumab (Repatha; Amgen) in that it requires a subcutaneous injection every 6 months. Alirocumab and evolocumab are administered every 2 to 4 weeks depending on the dose. Inclisiran can aid in adherence to lipid-lowering therapy because its administration can coincide with biannual patient visits to their doctors, said Wright.

Jennifer Robinson, MD (University of Iowa, Iowa City), the scheduled discussant following Wright’s presentation, said the early data suggest inclisiran is an effective LDL cholesterol-lowering drug with a good safety profile, but that appropriate pricing will be critical if it’s going to be prescribed (and reimbursed) should it be approved by the US Food and Drug Administration and elsewhere. 

“Of course, the issue that’s on everybody’s mind is cost because previous [agents]—the monoclonal antibodies—started at about $15,000 per year and nobody bought them,” said Robinson, referring to alirocumab and evolocumab. “They went down to $5,500 a year and still nobody is really buying them. So the question is: what is the price of inclisiran going to be? The prior ICER cost-effectiveness analysis suggests the public health pricing is about $2,200 per year. It’ll be interesting for a twice-only per year injection if they can get close to that cost.”

Only once the drug is appropriately priced can there be further conversations about aggressive cholesterol-lowering, because it’s only then that physicians and patients be able to access the drug, said Robinson. 

Getting Patients to Target

In the liver, inclisiran inhibits the production of PCSK9, a protease that binds to the LDL receptor and targets these receptors for degradation, which in turns lowers the amount of LDL cholesterol that can be removed from circulation. By blocking PCSK9 production and preventing LDL receptor degradation, inclisiran facilitates hepatic LDL clearance.  

In all three studies—ORION-9 in heterozygous FH, ORION-10 in patients with ASCVD, and ORION-11 in patients with ASCVD or ASCVD risk equivalents—patients were randomized to treatment with inclisiran or placebo and received treatment on day 1, day 90, and then every 6 months thereafter. Wright said the inclusion/exclusion criteria of these studies are “comparable and similar to what one sees with major cardiovascular and lipid trials in the modern era.”

In total, 1,827 patients were treated with placebo on top of optimal medical therapy (OMT) and 1,833 received inclisiran in conjunction with OMT. More than 92% were treated with statins, of whom 74% were receiving high-intensity statins. Roughly 15% of patients were treated with ezetimibe. In the placebo- and inclisiran-treatment arms, the mean LDL cholesterol level at baseline was approximately 110 mg/dL.

At day 510, inclisiran reduced LDL cholesterol by 55% compared with placebo (P < 0.001). Focusing on the time-averaged change in LDL cholesterol from day 90 to 540, inclisiran reduced LDL cholesterol levels by 52% compared with placebo (P < 0.001). For every 100 patients treated with a statin and inclisiran, 89 patients achieved a target LDL cholesterol of less than 100 mg/dL, 76 achieved a level less than 70 mg/dL, and 58 had LDL cholesterol levels cut to less than 50 mg/dL.

“Some clinicians worry about additional therapies lowering LDL cholesterol too much and think that an LDL less than 25 mg/dL might not be safe or necessary,” said Wright. “In our trial, only 16% of patients had an LDL less than 25 mg/dL.” In the study, PCSK9 levels were slashed by 83%, non-HDL cholesterol by 46%, apolipoprotein B by 42%, and lipoprotein(a) by 20%. In a subgroup analysis, they observed a consistent benefit in all patients, including those with mild or moderate renal impairment, but the data suggested those with the highest baseline LDL cholesterol (> 129 mg/dL) didn’t achieve quite as large a reduction in LDL cholesterol as individuals with lower levels. “This likely reflects the impact of FH in the treatment study,” said Wright.

Treatment-emergent adverse events were similar between the two therapies. They did not observe any risk of liver, kidney, muscle, or platelet toxicity, nor any signs of new, worsening, or recurrent cancer.

Costs vs Benefits: Lessons Learned?

While the cardiovascular outcomes are intriguing, a full reckoning of inclirisan’s benefits won’t be known until the completion of the ongoing, large-scale, cardiovascular outcomes trial ORION-4. Conducted by researchers from the University of Oxford, that study will randomize 15,000 patients with preexisting ASCVD and follow them for 5 years. Full results aren’t expected until 2024.   

Sekar Kathiresan, MD (Massachusetts General Hospital, Boston), another discussant following the online presentation, asked why a physician would turn to inclisiran as an add-on therapy to a secondary-prevention patient currently treated with high-intensity statins and ezetimibe instead of adding evolocumab or alirocumab, two drugs which are approved by the FDA for cardiovascular event reduction.

“I think it’s going to depend on a couple of factors,” replied Wright. “One, if you believe the data on LDL-lowering, and I do believe almost all of the secondary-prevention benefit with lipid therapies is driven by LDL cholesterol-lowering—other factors like inflammation are important, but LDL-lowering is critical—then the outcome trials should show what one would expect with LDL-lowering regardless of the therapy you give.”

What it will ultimately come down to is the relative cost and benefit of inclisiran versus the PCSK9 inhibitors. “None of us on the steering committee have any insight into pricing except the sponsor has continued to say that the lessons from the monoclonal antibodies have been learned and [inclisiran] will come out at a better value to patients,” said Wright. “If it is priced more favorably and given twice per year instead of every 2 weeks, simplicity and ease of dosing might persuade clinicians to give a try.”

Inclisiran was developed by The Medicines Company, but Novartis recently purchased the company for $9.7 billion.