As inclisiran, a first-in-class LDL-cholesterol lowering drug, enters the U.S. market following Food and Drug Administration approval in December 2021, several issues muddy how popular inclisiran will be in actual practice. That’s despite stellar phase 3 trial evidence for safety, tolerability, and a potent lipid-lowering effect.
The active ingredient of inclisiran (Leqvio) is a small interfering RNA (siRNA) molecule that shuts down production of the PCSK9 (proprotein convertase subtilisin/kexin type 9) protein, an enzyme that’s made and functions primarily in the liver and degrades cellular receptors for LDL cholesterol. Inhibiting PCSK9 production means LDL-cholesterol receptors accumulate and boost the ability of liver cells to pull more LDL cholesterol out of blood.
PCSK9 inhibition is the most potent LDL-cholesterol lowering method now available, and it works well in patients who have maxed out LDL reduction by diet and statin treatment. The siRNA of inclisiran is tweaked to target the molecule to the surface of liver cells following subcutaneous injection. Other modifications of the siRNA give it stability that allows twice-a-year dosing, although patients receive a third injection during their first year to hasten a maximum treatment effect.
Inclisiran’s FDA approval relied on results from three pivotal trials that together enrolled 3,660 patients with either atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or heterozygous familial hypercholesterolemia (HeFH), and LDL-cholesterol levels of at least 70 mg/dL in those with established ASCVD, or at least 100 mg/dL in other patients. (HeFH and ASCVD are the drug’s approved indications.) Pooled data from the three trials showed that inclisiran was safe and well tolerated during 18 months and produced an average LDL-cholesterol reduction after 510 days (1.4 years) of about 51% compared to baseline after correction for placebo effects (J Am Coll Cardiol. 2021 Mar 9;77 [9]:1182-93).
These data showed inclisiran was about as safe and effective for reducing LDL-cholesterol as agents from another class of PCSK9 inhibitors that rely on injected antibodies to inactivate PCSK9. Two agents from this class, alirocumab (Praluent) and evolocumab (Repatha), both came on the U.S. market in 2015. Although their performance in routine practice during the ensuing 6-plus years has been as safe and effective as what they showed in their respective registration trials, they have faced a rocky uptake road that’s been primarily hindered by the hefty price tag that both drugs carry.
Prior-authorization blues
When they first came out, evolocumab and alirocumab were burdened by annual drug costs of roughly $14,000, a fact that led to widespread prior-authorization and copay barriers set up by U.S. insurers. Although these barriers gradually lessened over time, in part aided by a substantial price cut for both drugs that led to annual drug costs more in the range of $6,000/year, they remain relatively pricey and are still not easy to start in patients because of prior-authorization requirements, said clinicians.
Recent penetration of the older PCSK9 inhibitors into eligible U.S. patients “is only about 1%-2%, based on the latest data,” said Michael H. Davidson, MD, a lipid specialist and director of Preventive Cardiology at the University of Chicago.
“We have these great, effective drugs, but they haven’t really made an impact over the past 5 years,” because of very limited uptake, a situation Dr. Davidson called “very disappointing,” during an interview.
Given this recent history, inclisiran, another expensive PCSK9 inhibitor, may face similar coverage pushback as it hits the U.S. market with a retail price, announced by its manufacturer Novartis, of $3,250/dose. This means that patients who start the drug and receive their initial dose, a second dose after 3 months, and then additional doses every 6 months, rack up a drug cost of close to $10,000 the first year on the drug and $6,500 each subsequent year.
This treatment schedule highlights the major logistical difference that distinguishes inclisiran from the antibody-based PCSK9 inhibitors, which are given by repeated subcutaneous injection every 2 or 4 weeks, usually with patients self-injecting the drugs at home. The less-frequent dosing schedule for inclisiran prompted the drug’s developers to schedule injections by a clinician in an office setting in the pivotal trials, which led to labeling for inclisiran that specifies administration only by a health care professional.