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Treatment with monoclonal antibodies that inhibit the activity of PCSK9 was shown to significantly lower LDL cholesterol levels and have a strong cardiovascular benefit.
Important early data on PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, concurrently published in the New England Journal of Medicine(NEJM) and presented at the American College of Cardiology’s annual meeting, show that these investigational monoclonal antibodies (mAbs) significantly reduce the incidence of cardiovascular events in patients with hypercholesteremia. The drugs were also associated with an approximately 60% reduction in low-density lipoprotein (LDL) cholesterol when compared with the current standard of care, somewhat confirming fears from payers such as CVS Health and Express Scripts that these medications will be as budget-busting as recent treatments launched to treat hepatitis C.
Unlike statins, PCSK9 inhibitors are biologic mAbs. Despite this drug class difference, researchers of the NEJM study write that PCSK9 inhibitors “have the same ultimate mechanism for LDL reduction as statins-namely, by increasing LDL receptor activity on the hepatocyte surface, suggesting that PCSK9 inhibitors should similarly have a beneficial effect on cardiovascular outcomes.”
Two open-label trials (OSLER-1 and OSLER-2) for Amgen’s Repatha (evolocumab) enrolled 4465 participants over a period of 11.1 months. Upon completion of a parent trial of evolocumab, patients were randomized to receive 140 mg of evolocumab every two weeks with standard therapy, 430 mg of evolocumab every month with standard therapy, or standard therapy alone. Compared with the control group, the rate of cardiovascular events in the evolocumab groups was cut in half (0.95% and 2.18%, respectively). In addition, the participants treated with the investigational mAb experienced a 61% reduction in LDL cholesterol. There was a small increase in neurocognitive events, but these will apparently be flushed out in the FOURIER trial enrolling 27,500 participants, lead study author Marc Sabatine commented at the American College of Cardiology meeting, reports Forbes. In a related NEJM editorial, Neil J. Stone, MD, and Donald M. Lloyd-Jones, MD, wrote that while the efficacy of PCSK9 inhibitors over statins is promising, “Both studies acknowledged that specific assessments of neurocognitive function is needed.”
In another trial named ODYSSEY LONG TERM investigating Sanofi and Regeneron’s Praluent (alirocumab), a similar drug, patients (n=2341) treated with a 1-mL injection of alirocumab every two weeks experienced a 62% reduction in LDL levels when compared with placebo. Compared with those receiving placebo, the study participants also experienced fewer major adverse cardiac events (3.3% vs. 1.7%, respectively). More adverse reactions, such as myalgia, neurocognitive events, and injection-site reactions were reported in the alirocumab group than in the placebo group.
Although seemingly superior to statins, an endorsement of PCSK9 inhibitors for widespread use is premature, write Stone and Lloyd-Jones, and off-target events “can scuttle a promising drug.” However, patients who do not respond well to statins or have adverse reactions to statins could be good candidates for treatment with these mAbs, they wrote.
Now, groups like CVS Health have some early evidence about the cardiovascular benefits of these drugs. The company wrote in a Health Affairs Blog last month that the “major rub with the class though is that while there is evidence to show that this class reduces intermediate outcomes (LDL), we have limited information to date about how this class of medications will affect clinical outcomes (primarily cardiovascular events).” This new efficacy evidence could actually support the company’s assertion that "PCSK9 sales could be expected to persist and grow over time, and will likely be the highest selling class of medications in history.” Express Scripts estimates PCSK9 inhibitors will cost $10,000 a year or more per patient, which explains why Amgen’s and Sanofi/Regeneron’s products may be pitted against one another in the payer space. Praluent’s Prescription Drug User Fee Act (PDUFA) date is July 24, 2015 and Repatha’s PDUFA date is Aug. 27, 2015. Pfizer also has an oral pill and experimental vaccine targeting PCSK9 in development; this alternative administration could add a new wrinkle in the payer debate when it comes to patient adherence. Eli Lilly also has a PCSK9 product in the pipeline.