British Medical Groups Express Concern About Inclisiran Rollout

The British Medical Association (BMA) and the Royal College of General Practitioners (RCGP) are raising concerns about the use and planned rollout of the LDL cholesterol-lowering medication inclisiran (Leqvio; Novartis), particularly around the absence of long-term outcomes and safety data.

The groups are also worried about the additional resources that will be needed in a primary-care setting “to deliver this novel drug at a time of unprecedented demand and shortages in workforce,” according to a position statement released recently.

European regulators approved inclisiran for lowering LDL-cholesterol levels in patients with hypercholesterolemia or mixed dyslipidemia in late 2020. Early this year, the UK government, the National Health Service (NHS), and Novartis agreed to an undisclosed discount to make the drug broadly available at the population level. In England, the National Institute for Health and Care Excellence (NICE) has concluded that at its presently discounted price, inclisiran is cost-effective in selected secondary prevention patients, and has suggested that the drug may be administered—the biologic is given as an injection twice yearly—in primary-care settings by general practitioners.

While the RCGP and BMA “fully support innovation” and population health-based approaches to care, they are concerned about the rollout of inclisiran, which is a “black triangle drug.” That is a designation given to any new medication approved for the first time and shows the drug is subject to increased monitoring from regulatory agencies. While waiting for long-term outcomes data, as well as better evidence of safety, the RCGP and BMA suggest physicians focus on all available treatment options, like lifestyle changes, high-intensity statin therapy, ezetimibe, and—where appropriate—injectable therapies.

The RCGP and BMA remind physicians that “if you initiate inclisiran in primary care, as the decision maker, you take full responsibility for the prescribing.”

At present, inclisiran is not approved in the US. In late 2020, the Food and Drug Administration passed on approving the drug after problems were discovered in one of the European manufacturing plants. These problems have since been corrected and the company is expecting an announcement from the FDA on January 1, 2022.   

It’s Cheap and the Government is on Board

Kausik Ray, MD (Imperial College London, England), who has been involved in several studies testing inclisiran, suspects the concerns about safety and efficacy won’t gain too much traction. All of the LDL-lowering therapies, including statins, ezetimibe, and the two PCSK9 inhibitors, were approved before the major cardiovascular outcomes trials were completed, he noted. None of these drug classes had long-term safety data at the time of launch either.

He acknowledged that primary-care physicians are extremely busy, but said there is interest on their part for initiating treatment. Of the logistical concerns raised by the RCGP and BMA, such as the capacity of family doctors to administer inclisiran, Ray said things will likely settle down after some of the early “back and forth” gets worked out. Based on some of the early projections, and with the discount between the NHS and Novartis, it’s thought that as many as 300,000 people in the UK, mostly in the primary-care setting, could be treated with inclisiran.

Inclisiran is a small interfering RNA (siRNA) agent that inhibits the production of PCSK9, which is a protease that binds to the LDL receptor and targets it for degradation. By blocking the production of PCSK9, the LDL receptors can bind to LDL cholesterol and clear it through the liver, thereby reducing serum LDL levels. The monoclonal antibodies alirocumab (Praluent; Sanofi/Regeneron) and evolocumab (Repatha; Amgen), which are injected once or twice per month depending on the dose, have a different mechanism of action in that they bind to free plasma PCSK9 and promote its breakdown.

Inclisiran has been tested in several phase III clinical trials for the reduction of LDL-cholesterol levels in patients prescribed maximally tolerated statin therapy. Trials include ORION-9, which tested inclisiran in patients with familial hypercholesterolemia, ORION-10, a study of patients with atherosclerotic cardiovascular disease (ASCVD), and ORION-11, which tested the drug in patients with ASCVD or ASCVD-risk equivalents. In those studies, the mean placebo-adjusted reduction in LDL cholesterol was approximately 50%.

The ORION-4 study, led by researchers at the University of Oxford in collaboration with the TIMI Study Group, is the major cardiovascular outcomes trial currently underway. In this 15,000-patient trial, investigators are studying whether the addition of inclisiran to guideline-directed medical therapy lowers the risk of major adverse cardiovascular events (coronary heart disease death, MI, stroke, or urgent revascularization) in patients with ASCVD. Results are expected in 2026.