BioPharma, Pharma

FDA nod for Novartis sets up cholesterol drug showdown with Amgen, Regeneron

Novartis drug Leqvio now has the FDA’s green light, making it the first RNA interference medicine approved for lowering cholesterol. The regulatory decision sets the stage for competition against cholesterol medicines from Amgen and Regeneron that also address liver protein PCSK9.


The FDA has approved a new cholesterol-lowering drug from Novartis that addresses the same target as two commercialized medicines from Amgen and Regeneron, but with a different approach and a key dosing advantage—just two injections per year.

The drug, inclisiran, is part of a relatively new class of genetic medicines that work by stopping production of a problem protein. In the case of the Novartis drug, which will be marketed under the name Leqvio, the target is PCSK9, a liver protein that in high amounts, impedes the body’s ability to clear low-density lipoprotein cholesterol, the “bad” form of cholesterol. Leqvio is comprised of small-interfering RNA that harnesses a cellular mechanism called RNA interference to stop a gene from producing PCSK9.

The way that Leqvio and other RNAi drugs work is sometimes referred to as gene silencing. It’s a different approach than PCSK9 inhibitors, antibody drugs that bind to this protein to block it. The FDA approved two of these drugs, Amgen’s  Repatha and Regeneron’s Praluent, in 2015. They’re both given as subcutaneous injections every two weeks or monthly. However, their high price tags made them a tough sell to payers, and revenue fell short of initial expectations. In 2018, Amgen slashed Repatha’s price by nearly 60%, making the drug available at the list price of $5,850 per year. Months later, Regeneron matched the pricing move for its PCSK9-blocking drug.

Approvals of the Amgen and Regeneron drugs cover heterozygous familial hypercholesterolemia (HeFH), an inherited disorder that causes dangerously high cholesterol levels, potentially leading to heart disease, heart attacks, and strokes. Both drugs subsequently received additional approvals for preventing heart attack and stroke.

Leqvio also treats HeFH, but its approval also includes a much larger group: those who have a buildup of cholesterol in the arteries called clinical atherosclerotic cardiovascular disease. Of the 30 million Americans diagnosed with this cardiovascular disorder, about 20 million are treated with cholesterol-lowering statin drugs, Novartis said in an investor presentation. Just 4 million of those patients achieve their cholesterol goal, leaving 16 million patients that could be treated with Leqvio. For those patients, the Novartis drug is indicated for use alongside diet and statin therapy.

Inclisiran, as Leqvio was first known, came from the labs of Alnylam Pharmaceuticals, the Cambridge, Massachusetts-based biotech that won the first-ever FDA approval of an RNAi drug, Onpattro. Alnylam licensed inclisiran to The Medicines Company, which advanced it through Phase 3 testing. MedCo was preparing to file for FDA approval in 2019 when Novartis struck a deal to  acquire the entire company for $9.7 billion.

The FDA review of Leqvio was based on results from three Phase 3 clinical trials enrolling 3,457 patients who were also receiving the maximum dose of statins that they could tolerate. The results showed that at month 17, patients treated with Leqvio had cholesterol levels reduced by 52% compared to those given a placebo.

“What we know and what the science has showed us is the lower you get the LDL cholesterol, you get more benefit in terms of cardiovascular risk reduction,” said David Soergel, Novartis’s head of global drug development cardio renal metabolism, speaking on a conference call Thursday.

The ability of Leqvio to reduce disease or lower the risk of death is still being evaluated in clinical trials. But the drug was well tolerated by patients in the studies to date. Side effects such as injection site reactions, joint pain, urinary tract infection, and diarrhea, were comparable across both arms of the studies.

Treatment with Leqvio starts with an initial dose, then another dose at three months. The twice-yearly dosing schedule begins six months later. Novartis said this schedule may help patients who have trouble with self-administered medicines or with drugs that must be taken more frequently. Novartis set a $3,250 price for each dose of Leqvio. That means in a patient’s first year of treatment, three shots will cost $9,750. After that, the annual price will be $6,500.

The Institute for Clinical and Economic Review, a drug price watchdog, concluded in January of this year that evidence for the Novartis drug offers benefit over usual care, and to be cost effective, it recommended a price in the range of $3,600 to $6,000 annually. Victor Bulto, head of Novartis Pharma U.S., said that the company is confident that the annual price is within ICRER’s range of cost effectiveness.

Leqvio’s approval comes one year after the FDA turned down Novartis’s drug application, citing manufacturing issues. Novartis said Leqvio will become available in early January. Bulto said Novartis will commercialize its new drug with the same sales force that markets its blockbuster heart failure medication,  Entresto, which has prescriber overlap with Leqvio.

“We know these customers very well and we are targeting them with a highly skilled and experienced workforce,” Bulto said.

Photo by Novartis