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This year, the American Heart Association (AHA) Scientific Sessions were held in Chicago, Illinois, from November 15 to 19. Of all of the late-breaking clinical trials presented at AHA 2014, the IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) study of Merck’s low-density lipoprotein cholesterol (LDL-C)-reducing drugs-the statin, Zocor (simvastatin), and the fixed-dose combination, Vytorin (ezetimibe/simvastatin)-stole the show.
This year, the American Heart Association (AHA) Scientific Sessions were held in Chicago, from November 15 to 19. Of all of the late-breaking clinical trials presented at AHA 2014, the IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) study of Merck’s low-density lipoprotein cholesterol (LDL-C)-reducing drugs-the statin, Zocor (simvastatin), and the fixed-dose combination, Vytorin (ezetimibe/simvastatin)-stole the show.1,2 The IMPROVE-IT results were presented during a packed plenary session on Monday, November 17, by Dr. Christopher Cannon of Boston’s Brigham and Women’s Hospital. IMPROVE-IT demonstrated, for the first time, that a nonstatin, LDL-C-lowering drug, Zetia (ezetimibe), was able to prevent cardiovascular (CV) events, such as myocardial infarction and stroke, via an incremental reduction in LDL-C when added to statin secondary prevention therapy. Unlike statins, which halt the endogenous production of cholesterol in the liver, Zetia blocks the uptake of dietary cholesterol in the gastrointestinal tract. Although the reduction in the CV event rate, which was only 2%, was referred to as “modest” ad nauseam for the duration of the convention, the statistics supporting this figure were robust and clear, arguably making the study among the most influential in the history of LDL-C drug research.
IMPROVE-IT was conducted over the course of 9 years, spanning nearly the entirety of Vytorin and Zetia’s patent exclusivity periods, which are due to terminate in the United States in 2016. Since the results were announced, there has been intense debate regarding the impact that IMPROVE-IT will have on the sales and regulatory status, not only of Zetia and Vytorin, but of future LDL-C-lowering therapies. This is not without good reason; the late-stage pipeline and the FDA review docket are flush with novel LDL-C-lowering drug candidates.3 Perhaps the most hotly anticipated of these are the proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9 mAbs). The PCSK9 mAbs reduce LDL-C by preventing the degradation of LDL receptors, the “molecular filters” in the liver that remove LDL-C from the circulation. Two PCSK9s are currently vying for first-to-market status: Amgen’s evolocumab and Sanofi/Regeneron’s alirocumab. A central, unavoidable aspect of IMPROVE-IT that will directly impact the future of the PCSK9s was the study’s validation of the LDL hypothesis: the theory that LDL-C is a causative agent of cardiovascular disease (CVD) and that its reduction with aggressive drug therapy can prevent CV events. The IMPROVE-IT study established that LDL-C reduction, in and of itself, leads to the prevention of CV events, a property that can no longer be considered unique to the statins. The fact that this precedent was set with Zetia, a drug that, on average, produces a 20% reduction in baseline LDL-C, is tremendously important for the PCSK9s, which routinely demonstrate LDL-C reductions that range from 40% to 60%.
Important results from the phase 3 clinical trial programs for alirocumab and evolocumab, termed ODYSSEY and PROFICIO, respectively, were also reported at the AHA meeting. The results from ODYSSEY were especially prominent, with the presentation of the ODYSSEY ALTERNATIVE study, given by Dr. Patrick Moriarty of the University of Kansas, playing lead-in for the IMPROVE-IT presentation during Monday’s session. This was particularly appropriate, as ODYSSEY ALTERNATIVE compared LDL-C reductions between once-daily 10 mg Zetia and twice-monthly 75 mg or 150 mg subcutaneous (SC) alirocumab, in high-risk, statin-intolerant patients. The differences between the drugs were stark. Zetia reduced baseline LDL-C by 15%, whereas alirocumab reduced it by 45% (P<0.0001).4,5 These results were akin to those observed in the GAUSS-2 study of evolocumab, which were previously reported.6
The discussions sparked by the panelists following the presentation of ODYSSEY ALTERNATIVE were as interesting as the data itself. First and foremost was the unanimous acknowledgement that, even though alirocumab performed remarkably with regard to LDL-C reduction, long-term, IMPROVE-IT-like, CV-outcomes studies will be needed before broad uptake of the PCSK9s will be seen in the clinic. Dr. Sidney Smith of the University of North Carolina at Chapel Hill, who chaired the session, noted that alirocumab showed “tremendous promise,” then continued, following a conspicuous pause, saying, “…we need the outcomes…, but [this is] very exciting.” A chuckle reverberated through the lecture hall as countless heads nodded in agreement. When asked about how his patients responded to the self-administered SC dosing of alirocumab, Dr. Moriarty said they were willing to do whatever it took to control their LDL-C. The statin-intolerant patients in the study had established CVD, and were said to be “ecstatic” about the drug because most had never achieved their LDL-C goals with anything else. In this study, 42% of the patients on alirocumab achieved an LDL-C of ≤70 mg/dL, compared with only 4% in the group on Zetia. Dr. Moriarty noted that, particularly during the open-label portion of the study, the patients “keep coming back [for alirocumab],” thrilled that there was finally an effective drug for their condition that they could tolerate.
The IMPROVE-IT session at the AHA meeting was, in many ways, representative of the LDL-C-lowering space at large. On the one hand, IMPROVE-IT revealed that LDL-C reduction is key in preventing CV events, thus validating the LDL-C hypothesis and supporting the use of nonstatin drugs-in this case, Zetia-to achieve these important clinical goals. On the other hand, the session was a reaffirmation of the central importance of the outcomes-based, randomized, controlled trial in the clinical decision-making process. For the PCSK9s, this is likely to mean that their LDL-C-reducing ability will be sufficient for FDA approval, a direct positive result stemming from IMPROVE-IT. The clinical community, however, will likely be inclined to wait for the culmination of the major PCSK9 outcomes studies-alirocumab’s ODYSSEY OUTCOMES and evolocumab’s FOURIER-before clinicians prescribe the PCSK9s broadly, that is, not just in patients who are statin intolerant and at high CV risk. ODYSSEY OUTCOMES is slated to conclude in January 2018, with FOURIER concluding in December 2017.
Clinical considerations aside, IMPROVE-IT established that the use of Vytorin could achieve very low levels of LDL-C (53.7 mg/dL in the Vytorin group) at an annual treatment cost of approximately $2,350. The PCSK9s, although astonishingly effective at providing comparably low levels of LDL-C, are biologics. In fact, their market entry would mark the first time that biologics of any kind could be used to treat CV patients en masse over the long term. It is expected that these truly novel biologic medications would command biologic-level pricing, which is likely to fall into the $10,000 to $20,000/year range. Now, recalling that Vytorin and Zetia could face generic competition by 2016-the first PCSK9s are likely to launch in mid-to-late 2015-the price difference between the 2 competing therapy options becomes even more stark. As a cardiologist, do you prescribe the time-tested, scientifically established, low-cost treatment for your hard-to-treat patients, or do you go with the new, high-priced biologic? The answer will be the latter only in cases in which there are no other options, that is, in statin-intolerant, high-CV-risk patients, who are essentially patients like those in the ODYSSEY ALTERNATIVE study.
So, what does this mean for the sales of the drugs in question? Without a doubt, IMPROVE-IT ensured that Vytorin and Zetia will, first, continue to be sold-period. Second, it ensures that these drugs will have staying power, both pre- and post-patent expiry. Last, it means that, at least initially, the PCSK9 market size will be small, potentially confined to the roughly 5% of patients who are truly statin intolerant.7 How will this impact the bottom line for the PCSK9s? At biologic-level pricing, a small patient share still equals blockbuster-level sales. Therefore, if ODYSSEY OUTCOMES and FOURIER prove that the PCSK9 mAbs can deliver concrete outcomes benefits, as IMPROVE-IT did, albeit it “modestly,” for Vytorin and Zetia, then the sky’s the limit.
Dr Dimise is an analyst on the Cardiovascular and Metabolic Disorders team at GlobalData in Boston. He recently published a report and market forecast on acute coronary syndrome therapeutics. He is currently completing a comprehensive review and forecast covering the dyslipidemia market.
1. Blazing MA, Giugliano RP, Cannon CP, et al. Evaluating cardiovascular event reduction with ezetimibe as an adjunct to simvastatin in 18,144 patients after acute coronary syndromes: final baseline characteristics of the IMPROVE-IT study population. Am Heart J. 2014;168(2):205–212.
2. Merck and Co., Inc. Vytorin (ezetimibe/simvastatin) significantly reduced cardiovascular events more than simvastatin alone in patients presenting with acute coronary syndromes in the investigational IMPROVE-IT study. Press release. November 17, 2014. http://www.mercknewsroom.com/news-release/prescription-medicine-news/vytorin-ezetimibesimvastatin-significantly-reduced-cardiovas. Accessed December 2, 2014.
3. Hajhosseiny R, Sabir I, Khavandi K, Wierzbicki AS. The ebbs and flows in the development of cholesterol-lowering drugs: prospects for the future. Clin Pharmacol Ther. 2014;96(1):64–73.
4. Moriarty P, Jacobson T, Bruckert E, et al. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: Design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J Clin Lipidol. In press.
5. Regeneron Pharmaceuticals, Inc. Regeneron and Sanofi announce new results from six phase 3 trials showing that alirocumab significantly reduced LDL cholesterol. Press release. November 19, 2014. http://newsroom.regeneron.com/releasedetail.cfm?ReleaseID=883807. Accessed December 2, 2014.
6. Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2541–2548.
7. Ahmad Z. Statin intolerance. Am J Cardiol. 2014;113(10):1765–1771.