[BLOG] The acute coronary syndrome pipeline: Novel therapies targeting unmet needs in niche patient populations

Dimise

Heart disease is consistently ranked among the leading causes of mortality in the United States and in the world, an unfortunate statistic that has historically remained steadfastly unchanged.^1,2 Acute coronary syndrome (ACS), an all-encompassing term describing the spectrum of life-threatening events that includes myocardial infarction and unstable angina, represents one of the most sudden, severe, and common manifestations of heart disease. It is expected that in 2014, over 500,000 Americans will suffer an incident ACS event for which they will need to be hospitalized.^3,4 Among these individuals, roughly 10% to 20% are likely to experience a recurrent event that will result in rehospitalization.^5,6 Fortunately, due to advances in interventional cardiology (eg, coronary angioplasty and stenting) and decades of pharmaceutical drug development, the likelihood of surviving ACS has increased. This advance has occurred, however, with a concomitant uptick in the burden of chronic, post-ACS conditions, such as atrial fibrillation (AF), which further increases the rate of repeat hospitalizations.^7,8

Not surprisingly, the treatment costs associated with ACS and its various comorbidities are astoundingly high. A 2005 study of 13,731 managed care patients who had suffered an incident ACS event revealed a $309 million price tag, or roughly $2300 per patient per month, for less than a year of ACS-related care.⁹ Importantly, the bulk of these costs-over 90%-were attributed to hospital-related expenses, with less than 10% stemming from pharmacy costs.⁹ In addition, a 2013 study of 37,911 managed care patients with ACS claims determined that workers missed an average of 60 and 398 days of work due to short- and long-term disability, respectively, costing employees an average of $2,263 and $20,609 in lost wages, and employers $7,943 and $52,473 in lost productivity.¹⁰ Further, the researchers determined that the average total cost of ACS care per employee was $8170, but only $625 of this expense was attributed to prescription drug costs.¹⁰

The current ACS treatment landscape consists predominantly of the following drug classes:

·       Statins, for reducing elevated levels of low-density lipoprotein cholesterol (LDL-C), the major causative agent of atherosclerosis

·       Blood thinners, to prevent or reverse the formation of blood clots

·       Antihypertensives, for controlling high blood pressure

Although these drugs are widely considered to be safe and effective by practicing physicians, the rate of incident and recurrent ACS is still unacceptably high. Thus, new therapeutic options are needed to address the unmet needs and shortcomings stemming from the current selection of therapies. As the economic analyses highlighted earlier demonstrated, drugs that can prevent hospitalizations for either incident or recurrent ACS will reduce the economic and disease burden for patients, and will also significantly reduce costs to employers and managed care providers.

The current late-stage pharmaceutical pipeline contains several first-in-class drugs with the potential to improve outcomes for patients who are at risk of experiencing an ACS event.³ One highly anticipated class of LDL-C-lowering therapies is the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, monoclonal antibodies that will represent the first biologic therapies to enter the ACS mainstream treatment paradigm.¹¹ Amgen’s PCSK9, evolocumab, and Sanofi and Regeneron’s alirocumab are locked in a tight race for regulatory approval, with launch dates in the United States possible as early as the second half of 2015. Two blood thinners, Merck’s protease-activated receptor-1 (PAR-1) inhibitor, Zontivity (vorapaxar), and Janssen’s factor Xa inhibitor Xarelto (rivaroxaban), exploit novel drug targets that block the platelet activation and coagulation pathways, respectively.¹²

The PCSK9s prevent the degradation of LDL-C receptors in the liver, thereby increasing the body’s ability to filter LDL-C from blood. Clinical trial results have mounted over the last year that illustrate the impressive ability of these new therapies to safely and effectively lower blood levels of LDL-C. Importantly, the PCSK9s have performed well for patients who are either intolerant to statins (~5%) or in whom statins alone are insufficient to achieve LDL-C goals. It is anticipated that these drugs will enter the market to serve this particular patient niche. As with other biologics, the PCSK9s are expected to carry a significant price tag, similar to other mainstream biologics, such as Humira (adalimumab)-far above and beyond that of the statins-a factor that will allow the statins to maintain their primacy in the LDL-C-lowering field overall.

The new blood-thinning therapies, Zontivity and Xarelto, are likely to serve patients who are at a particularly high risk for recurrent ACS events. Xarelto, which is already FDA approved for multiple indications (including AF), has yet to achieve approval for ACS. Given the large phase 3 clinical trial program (EXPLORER) in which it is currently engaged, however, it is likely to achieve this label expansion within the next 4 to 5 years. Once this occurs, Xarelto will be the natural choice for patients suffering from AF who have a history of ACS. Zontivity, which was FDA approved in May 2014, differs from the clopidogrel class of antiplatelet blood thinners in that it is recommended for use beyond the 1-year post-ACS window. With these new therapy options, physicians will need to be judicious when considering their approach to clot prevention, as excessive blood thinning can cause life-threatening bleeding. Indeed, Zontivity is contraindicated in patients with a history of stroke due to the rate of adverse bleeding events observed in clinical trials.¹³

The PCSK9s, evolocumab and alirocumab, and the new blood thinners, Xarelto and Zontivity, are representative of a new trend in ACS treatment and reflect a shift in pharmaceutical development in general. They target niche patient populations and are unlikely to completely supplant established therapies. The PCSK9 inhibitors will be welcome alternatives to statins for patients who cannot tolerate these traditional ACS drugs. The blood thinners Zontivity and Xarelto will serve patients who are at high risk of recurrent ACS events, and will be well received in cases in which multiple ACS comorbidities need to be managed. Ultimately, if these therapies can prevent ACS events from occurring within their target patient groups, the relatively low costs associated with drug treatment will far outweigh the economic and health-related burdens that ACS hospitalization presents for patients, employers, and healthcare providers.

Mr Dimise is an analyst on the Cardiovascular and Metabolic Disorders team at GlobalData in Boston, where he recently completed an in-depth report covering marketed and pipeline therapies for acute coronary syndrome.

References

1.     Hoyert DL. 75 years of mortality in the United States, 1935–2010. NCHS data brief, No 88, Hyattsville, MD: National Center for Health Statistics; 2012.  http://www.cdc.gov/nchs/data/databriefs/db88.pdf. Accessed August 12, 2014.

2.     World Health Organization (WHO) (2014). World health statistics 2014. Geneva, Switzerland: World Health Organization; 2014.  http://apps.who.int/iris/bitstream/10665/112738/1/9789240692671_eng.pdf?ua=1. Accessed August 12, 2014.

3.     PharmaPoint Report: Acute coronary syndrome – Global drug forecast and market analysis to 2023. London, UK: GlobalData; July 2014.

4.     Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics–2014 update: a report from the American Heart Association. Circulation. 2014;129(3):e28–e292.

5.     Menzin J, Wygant G, Hauch O, et al. One-year costs of ischemic heart disease among patients with acute coronary syndromes: findings from a multi-employer claims database. Curr Med Res Opin. 2008;24(2):461–468.

6.     Thune JJ, Signorovitch JE, Kober L, et al. Predictors and prognostic impact of recurrent myocardial infarction in patients with left ventricular dysfunction, heart failure, or both following a first myocardial infarction. Eur J Heart Fail. 2011;13(2):148–153.

7.     Rogers WJ, Frederick PD, Stoehr E, et al. Trends in presenting characteristics and hospital mortality among patients with ST elevation and non-ST elevation myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006. Am Heart J. 2008;156(6):1026–1034.

8.     Chen SY, Crivera C, Stokes M, et al. Outcomes associated with comorbid atrial fibrillation and heart failure in medicare beneficiaries with acute coronary syndrome. BMC Health Serv Res. 2014;14(1):80–88. 

9.     Etemad LR, McCollam PL. Total first-year costs of acute coronary syndrome in a managed care setting. J Manag Care Pharm. 2005;11(4):300–306.

10.  Page RL 2nd, Ghushchyan V, Gifford B, et al. The economic burden of acute coronary syndromes for employees and their dependents: medical and productivity costs. J Occup Environ Med. 2013;55(7):761–767.

11.  Poirier S, Mayer G. The biology of PCSK9 from the endoplasmic reticulum to lysosomes: new and emerging therapeutics to control low-density lipoprotein cholesterol. Drug Des Devel Ther. 2013;7:1135–1148.

12.  Shimada YJ, Giugliano RP. Emerging antithrombotic drugs for acute coronary syndrome. Expert Opin Emerg Drugs. 2013;18(3):307–318.

13.  Morrow DA, Braunwald E, Bonaca MP, et al; TRA 2P–TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012;366(15):1404–1413.