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PCSK9 inhibitors poised for breakthrough as new cholesterol-lowering therapy
New research in biologics is getting closer to finding an alternative to statins. At the forefront are drugs in development that inhibit proprotein convertase subtilisin/kexin type 9, or PCSK9.
Inhibition of the enzyme PCSK9 is believed to reduce LDL levels in a safe and effective manner, with minimal adverse effects. This therapy has garnered attention at recent cardiology conferences, including at the American College of Cardiology Scientific Sessions in March and American Heart Association Scientific Sessions last November. Clinical trial data have documented substantial LDL reductions in patients with hypercholesterolemia and familial hypercholesterolemia in combination with statins or administered alone.
Stephen L. Kopecky, MD, president of the American Society for Preventive Cardiology, discussed the excitement surrounding PCSK9 inhibitor development.
Mayo Clinic; reprinted with permission
“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 the Mayo Clinic in Rochester, Minn., said in an interview.
Cardiology Today asked experts about the history of PCSK9, current data and the need for new drugs that target LDL.
PCSK9 in the spotlight
The story began in 2003.
“The clue to the potential role of PCSK9 was the result of careful work by a group of doctors in France who were studying a patient with heterozygous familial hypercholesterolemia. Researchers measured the receptor function and found it to be minimal, but when they studied the structure of the LDL receptors they were normal. They noticed an increase in an unknown protein they called PCSK9 and found that when this protein was increased it stopped the LDL receptors from functioning,” 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, told Cardiology Today.
Researchers hypothesized that if there were a genetic abnormality related to overproduction of PCSK9, called a gain-of-function mutation, causing very high cholesterol levels and early CVD, then there would be a genetic abnormality for underexpressed PCSK9, creating an environment of increased LDL receptor activity, very low levels of LDL and no risk for CVD.
Evan A. Stein
Examination of a large heart disease program led to the discovery of a group of patients with very low LDL levels, present in other family members, who also had a marked absence of CVD. Sure enough, these patients were shown to have defects in PCSK9.
An important discovery in 2006 was that PCSK9 in the bloodstream, not inside the liver, binds to the LDL receptor along with LDL without destroying the receptor. “It then targets PCSK9 like a traffic cop, directing the receptor for destruction, rather than recycling it,” Stein said.
“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.
One thought was that if PCSK9 could be prevented from binding to the LDL receptor, then the receptor could work more efficiently and thus lower LDL levels. The goal then became discovering methods to inhibit the action of PCSK9.
Today, antibodies that inhibit PCSK9 are in advanced clinical trials, most completing phase 2 and entering phase 3. While FDA approval is still a few years away, many experts believe PCSK9 inhibitors provide the most promising alternative to lowering cholesterol since the development of statins 30 years ago.
Steven E. Nissen
“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. “And, the effects are long lasting. In one case, the PCSK9 inhibitor can be given once a month.”
“If this therapeutic concept gets FDA approval and reaches the market, it will transform the way we manage CV risk,” Sergio Fazio, MD, PhD, chief of the section of cardiovascular disease prevention at Vanderbilt University Medical Center, told Cardiology Today.
Available data
A number of PCSK9 inhibitors are being tested in trials, including AMG 145 (Amgen), SAR236553/REGN727 (Sanofi/Regeneron Pharmaceuticals) and RN316 (Pfizer). Additional candidates are in development by Roche/Genentech and Lilly, among others.
The recent American Heart Association Scientific Sessions featured a late-breaking clinical trials session dedicated to novel treatments for managing lipid disorders, with particular focus on anti-PCSK9 monoclonal antibodies.
Recent phase 2 data from the RUTHERFORD trial demonstrated LDL reductions of up to 56% when AMG 145 was administered subcutaneously every 4 weeks in combination with statin therapy, with or without ezetimibe (Zetia, Merck), in patients with heterozygous familial hypercholesterolemia. At 12 weeks, LDL was reduced by 43% with a 350-mg dose and 55% with a 420-mg dose. In the GAUSS trial, statin-intolerant patients with hypercholesterolemia experienced reductions in LDL of up to 51% with AMG 145. At 12 weeks, mean LDL decreased 41% with a 280-mg dose, 43% with a 350-mg dose, 51% with a 420-mg dose and 63% with a 420-mg dose. Phase 2 results from the LAPLACE-TIMI 57 and MENDEL trials recorded LDL reductions of up to 66% and 53%, respectively, in hypercholesterolemic patients taking AMG 145 once monthly or every 2 weeks in conjunction with statins or alone. AMG 145 is currently in phase 3 trials, according to Scott M. Wasserman, MD, FACC, executive medical director at Amgen.
Early data from phase 2 trials of the monoclonal antibody SAR236553/REGN727 describe significant reductions in LDL in healthy volunteers and patients with heterozygous familial hypercholesterolemia or nonfamilial hypercholesterolemia. Phase 2 results demonstrate greater reductions in LDL at 12 weeks when subcutaneous injections of SAR236553/REGN727, once monthly (up to 48%) or every 2 weeks (up to 78%), were added to varying doses of atorvastatin, compared with atorvastatin alone.
ODYSSEY OUTCOMES, a phase 3 CV outcomes trial, will enroll about 18,000 patients with a recent ACS to evaluate the effect of SAR236553/REGN727 on the occurrence of CV events. With the start of this study, which announced enrollment in November, eleven trials are recruiting in the global ODYSSEY program, according to a company press release.
In other phase 2 research, Pfizer’s RN316 reduced LDL levels by 46% to 56% in patients already taking high-dose statins. The drug was administered intravenously once every month.
Looking ahead, phase 3 and future studies will focus on testing these PCSK9 inhibitors and others in large patient populations.
A promising alternative
Sergio Fazio
PCSK9 inhibitors are a promising alternative for the many patients who are intolerant to statins.
“It’s important to have another tool to get patients to target cholesterol levels when statins cannot be used,” Fazio said.
Many experts interviewed by Cardiology Today expressed excitement about the lack of serious adverse events associated with the PCSK9 inhibitors thus far. The drugs are administered subcutaneously or intravenously, and some studies have reported irritation at the injection site and small reports of myalgia and creatinine-kinase elevation signals.
“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. “Apparent safety is one of the main reasons for the strong optimism about the future of these drugs.”
The costs of these biologics remain to be studied.
Peter Libby
In an interview, Peter Libby, MD, chief of the division of cardiovascular medicine at Brigham and Women’s Hospital and Cardiology Today Section Editor, said patients seem satisfied with antibody therapies such as the PCSK9 inhibitors in his experience thus far. “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.”
“Ten years ago, this protein was unknown. This is one of the fastest movements of a therapeutic concept from biologic discovery to drug development and it’s pleasing to see such a large portfolio of phase 3 trials,” Fazio said.
Disclosure: 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. Stein reports consulting fees from Amgen, Bristol-Myers Squibb, Genentech/Roche and Sanofi/Regeneron. Wasserman is executive medical at Amgen.