9 important things to know about PCSK9 cholesterol drugs
2015 has been a big year for cardiology. Attendees at this year’s American College of Cardiology (ACC) meeting, which ended recently, are still buzzing about the clinical-trial sessions highlighting the latest breakthrough in cardiology—the PCSK9 inhibitors. Cardiologists and general practitioners alike are excited about the two PCSK9 inhibitors, alirocumab and evolocumab, in late-stage clinical development, because of their ability to lower LDL-C in patients for whom other treatments have been ineffective.
Barry Mennen, MD, a Washington, DC-based practicing physician, who has been in the pharmaceutical industry for 30 years, has spent many years focusing on cardiovascular disease (CVD) and the challenge of treating patients with multiple risk factors. "This (the advent of the PCSK9 inhibitors) was one of the biggest takeaways from ACC this year," says Mennen, who attends ACC every year. "And now many practitioners are waiting for an approval so they can start treating their patients with this exciting new class of drugs."
1. What are PCSK9 inhibitors?
PSCK9 inhibitors are monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PSCK9).
2. Trade names
The trade name for evolocumab, developed by Amgen, is Repatha. The trade name for alirocumab, developed by Sanofi and Regeneron, is Praluent.
3. Mode of action
SCK9 inhibitors have a very elegant mode of action. PCSK9 itself is a protein, which plays a role in cholesterol homeostasis. Here’s how PCSK9inhibitors work: Normally LDL-C is removed from the blood when it binds to an LDL-C receptor (LDLR) on the surface of liver cells. However, when the protein PCSK9 binds to the LDLR, it stops this cholesterol-removal process by metabolizing the LDLR and breaking it up, effectively making it impossible for the LDLR to return to the surface of the cell and remove more cholesterol. By blocking that process, PCSK9 inhibitors allow LDLRs to remove more LDL-C from the body.
4. Clinical trial data
The clinical trials for each of the PCSK9 inhibitors in development were designed to evaluate the long-term safety and tolerability of evolocumab (OSLER) and alirocumab (ODYSSEY) in high CVD-risk patients with hypercholesterolemia not effectively controlled with their current lipid-modifying therapy (LMT).
Mennen says, "Findings from both studies were similar. Results were available on about 3,000 patients from the OSLER studies and about 1,500 patients from the ODYSSEY trials. Patient profiles were very similar, though patients in the ODYSSEY trials were a little older and little sicker. Also, 92% of patients in the ODYSSEY trials were white, compared with 86% of patients in the OSLER trials. Overall, however, the end results were comparable. Each drug lowered LDL-C by about 60% and decreased the rate of CVD events, including heart attack, heart failure leading to hospitalization and death, by about 50%."
5. The PCSK9 inhibitors are democratic drugs
The clinical trials for both alirocumab and evolucumab were global and included a broad cross-section of subjects—all of whom had difficult-to-treat hypercholesterolemia. The studies cut across all demographic categories, including age, race, nationality and economic status. For example, in terms of global reach, the OSLER trials enrolled 47.1% of its subjects in North America; 40.5% in Europe and 12.4% of its subjects in Asia Pacific or South Africa.
Mennen says, "The study results tell a story. This is a significant advance in dealing with a big killer and cause of morbidity worldwide."
6. The number of patients who fall into the high-risk category is larger than originally estimated
PCSK9 inhibitors will undoubtedly be a more costly treatment option than the current standard LMT, statins, which are a largely genericized class. In order to meet the risk threshold for eligibility a patient will need to suffer from familial hypercholesterolemia, which does not respond to standard therapy; have multiple risk factors, such as diabetes and a previous CVD event, in addition to hypercholesterolemia; or be intolerant of statins. According to Mennen, who has treated many of these patients through the years, this category is a significant population.
"When you add it all up, 20% to 25% of patients fall into one of those categories and can benefit from PSCK9 inhibitors," he says.
7. One side effect has generated particular concern
Overall, patients treated with PCSK9 inhibitors had higher rates of nonspecific side effects, such as arthralgia, headache, limb pain and fatigue, compared with placebo-treated patients. There were also more injection-site reactions in subjects treated with PCS9 inhibitors.
However, clinicians were most concerned about neurocognitive events. According to Mennen, "Overall, 1% to 1 ½ % of patients experienced treatment-related neurocognitive effects, mainly confusion and some memory loss. However, it’s important to note that the neurocognitive issues were not related to the amount of LDL-C decrease."
8. One of the main advantages will be ease of use
Research has shown that up to 46% of patients prescribed statins for hypercholesterolemia do not adhere to therapy, which significantly decreases the likelihood that they will achieve an optimal LCL-C of 100 mg/dL. In fact, one in ten CVD events is directly linked to nonadherence.
The advantage of PCSK9 inhibitors is that dosing will only involve a subcutaneous injection either once or twice per month. Patients will receive pre-filled syringes that they can easily administer at home. And as Mennen points out, "Sub-Q injections are much easier than intramuscular injections and patients handle them well."
9. This drug took roughly a decade to develop, from bench to bedside
Truly a remarkable feat.
During this year’s ACC, Peter Libby, MD, Mallinckrodt Professor of Medicine, Harvard Medical School, pointed out one of the most astounding features of the PCSK9 inhibitor story. The protein was discovered in 2003, and the translational research since then has been very rapid. In only 12 years, we have gone from a protein in a lab to thousands of patients in clinical trials, with likely approval this year. Moreover, this has been a collaborative effort, involving industry, academic centers, researchers around the world, federal agencies and patients.
It’s true: PSCK9 inhibitors are a game-changer and could very well change the statistics surrounding CVD mortality.