PCSK9: What you need to know

Research is progressing in biologics, particularly concerning a new class of potential cholesterol-lowering drugs which inhibit proprotein convertase subtilisin/kexin type 9, or PCSK9.

“PCSK9 development is the most exciting thing in cardiology that we’ve had in 5 or 10 years,” Stephen L. Kopecky, MD, president of the American Society for Preventive Cardiology and professor of medicine at Mayo Clinic, told Cardiology Today.

Others are enthusiastic about the improvements in LDL seen in clinical trials.

Stephen L. Kopecky

“PCSK9 inhibitors are actually able to lower LDL more effectively than the highest doses of the most powerful statins we have,” Steven E. Nissen, MD, chairman of the department of cardiovascular medicine at Cleveland Clinic and member of the Cardiology Today Editorial Board, said in an interview.

But, what do we know about this new class of drugs?

1. The drugs in development are believed to lower LDL cholesterol by inhibiting the PCSK9 enzyme.

Researchers in 2003 studied a patient with heterozygous familial hypercholesterolemia, minimal receptor function and normal LDL receptor structure. According to Evan A. Stein, MD, PhD, voluntary professor of laboratory medicine at University of Cincinnati and director of the Metabolic and Atherosclerosis Research Center in Cincinnati, the researchers noticed that when PCSK9 was increased, LDL receptors stopped functioning.

Evan A. Stein

As research moved forward, LDL receptors and PCSK9 were studied in people with naturally low LDL and low familial CVD risk. The results were compared to observations seen in people with high LDL, and it was discovered that PCSK9 binds to LDL and the LDL receptor in the bloodstream but doesn’t harm the receptor. The receptors appeared normal, but function was reduced. Eventually, it was postulated that if excess production of PCSK9 were related to variations in genetic factors causing very high cholesterol levels and early CVD, then an underexpression of PCSK9 would result in higher LDL receptor activity, lower LDL and reduced CVD risk.

“In just a few short years, we have gone from discovering a new protein, which was not thought to have any role in cholesterol metabolism, to a protein that we now know plays a critical role,” Stein said.

2. PCSK9 inhibitors are believed to cause minimal adverse events.

“Apparent safety is one of the main reasons for the strong optimism about the future of these drugs,” Sergio Fazio, MD, PhD, chief of the section of cardiovascular disease prevention at Vanderbilt University Medical Center, told Cardiology Today.

PCSK9 inhibitors are administered subcutaneously or intravenously, and data from some clinical trials show injection site irritation and minor reports of myalgia and creatinine-kinase elevation. However, in the phase 3 ODYSSEY MONO study, the PCSK9 inhibitor alirocumab (Sanofi-Regeneron) was associated with an extremely low rate of injection-site reactions, likely because of the use of a new disposable autoinjector.

“Although it is possible that some untoward effects may eventually be identified, today there are no obvious symptomatic or biochemical adverse events within the context of short clinical trials,” Fazio said.

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3. Several drugs are in or have completed phase 3 trials.

At the American College of Cardiology Scientific Sessions, held in March, the first phase 3 results were reported for alirocumab, with the ODYSSEY MONO study, and evolocumab (Amgen), with the GAUSS-2, LAPLACE-2, MENDEL-2, RUTHERFORD-2 and DESCARTES studies. According to investigator Eli M. Roth, MD, FACC, ODYSSEY MONO was the first of 14 phase 3 studies for alirocumab to have results released, and nine more of those studies are expected to be released by the end of 2014.

Eli M. Roth

ODYSSEY OUTCOMES, a phase 3 CV outcomes trial, will enroll about 18,000 patients with a recent ACS to evaluate the effect of alirocumab on the occurrence of CV events, according to a press release from Sanofi and Regeneron. Likewise, Amgen has its own phase 3 CV outcomes trial in the works for evolocumab, FOURIER, which will enroll approximately 22,500 patients with CVD, according to a company press release.

Pfizer began a phase 3 program for its PCSK9 inhibitor, bococizumab, last fall, and reported positive results from a phase 2b study at the ACC meeting.

“If this therapeutic concept gets FDA approval and reaches the market, it will transform the way we manage CV risk,” Fazio said.

4. Effects of PCSK9 are not short–lived.

Clinical trials demonstrate the therapeutic effects of PCSK9 can linger.

“The effects are long lasting. In one case, the PCSK9 inhibitor can be given once a month,” Nissen said.

Peter Libby

Peter Libby, MD, chief of the division of cardiovascular medicine at Brigham and Women’s Hospital and Cardiology Today Section Editor, said patients prefer treatment with PCSK9. “They don’t have to take pills; they don’t have to worry about skipping a dose. I think this favorable response is something we will see more of with biologic injections.”

Disclosures: Fazio reports receiving consulting fees from Merck and Sanofi/Regeneron. Kopecky reports no relevant financial disclosures. Libby is an unpaid consultant or involved in clinical trials for Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genzyme, GlaxoSmithKline, Merck, Novartis, Pfizer, ProNova and Sigma-Tau; he is also a member of scientific advisory boards for Athera Biotechnologies, BIND Biosciences, Carolus Therapeutics and Interleukin Genetics. Nissen reports working with Amgen on a trial of AMG 145; he receives no compensation for this relationship. Roth is employed by Sterling Research Group, which has received research funds and consulting fees from Amgen, Regeneron and Sanofi. Stein reports consulting fees from Amgen, Bristol-Myers Squibb, Genentech/Roche and Sanofi/Regeneron.