ACS MARKET - Acute Coronary Syndrome Market 2015-2025

INTRODUCTION

Cardiovascular disease (CVD), including ischemic heart disease and stroke, is the leading cause of mortality in the world. The term acute coronary syndrome (ACS) applies to a spectrum of acute CVD states that are precipitated by coronary artery occlusion that results in ischemia and the necrosis of myocardial tissue. In the most modern use of the term, ACS strictly refers to a range of ischemic cardiovascular events that includes unstable angina (UA), myocardial infarction (MI), and/or death due to myocardial ischemia. In general, ACS can be viewed as the culmination of coronary artery disease (CAD), the asymptomatic build-up of atherosclerotic plaque on the walls of the coronary arteries. An ACS event is initiated upon plaque rupture triggering platelet activation and the coagulation cascade to form a thrombus on the wall of the artery that restricts blood flow. The triggering of an ACS event stemming from UA or MI initiates the acute-phase treatment setting, where therapeutic interventions are utilized to reverse and prevent the physiochemical processes that lead to coronary stenosis. The chronic-phase treatment setting, by contrast, involves secondary preventative measures that are used to prevent recurrent ACS events. The ACS therapeutic space is well-established and boasts a plethora of branded and generic drug choices to treat the major conditions associated with ACS: thrombosis (fibrinolytics, anticoagulants, and antiplatelets), hypercholesterolemia/atherosclerosis (statins and PCSK9 inhibitors), and hypertension (renin angiotensin aldosterone system [RAAS] inhibitors and beta blockers). Due to the broad range of sub-indications and available drug targets, it is evident that the ACS market is a highly lucrative area for pharmaceutical companies to invest into drug development.

THE ACS MARKET

GlobalData estimates sales of ACS therapeutics in 2015 to be approximately $7.8B across the seven major markets (7MM), which are the US, the five major European markets (5EU: France, Germany, Italy, Spain, and UK), and Japan. In the 2015 base year, 10% of market share was attributed to acute-phase sales ($714M) and 90% to the chronic phase ($7B). By 2025, GlobalData expects the ACS market to grow at a strong Compound Annual Growth Rate (CAGR) of 4.6%, reaching sales of $12.1B by the end of the forecast period. This is mainly attributed to the chronic-phase growth, which is forecast to reflect a CAGR of 5%, reaching $11.4B in sales by 2025 (94% of market share). Over this forecast, the most prominent wave of sales increase comes from the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor class, which is expected to reach $2.5B in global sales by 2025 for ACS. The launch of ETC-1002, the first-in-class lipid-lowering adenosine triphosphate-citrate lyase (ACL) inhibitor/adenosine monophosphate-activated protein kinase (AMPK) activator, is another key driver of ACS market growth, as sales are projected to peak at $767M by 2025. Moreover, an increase in the global prevalence of ACS will also cause a growth in sales, as the total ACS population in the 7MM is anticipated to reach 32,440,271 people by 2025, which represents an annual growth rate of 1.8% from 2015.

THERAPEUTIC LANDSCAPE

The launch of new drugs in the ACS space in the 5 years preceding 2015 has mostly impacted the antiplatelet arena. The most welcome additions to the antiplatelet arsenal were the new-generation antiplatelets, AstraZeneca’s Brilinta (ticagrelor), and Eli Lilly/Daiichi Sankyo’s Effient (prasugrel), which are now the two central pillars of dual antiplatelet therapy (DAPT) regimens. Brilinta, in particular, is expected to continue a robust increase in global annual sales, peaking in 2019, prior to its US patent expiry, at approximately $940M. Brilinta is positioned favorably in the first half of this forecast due to its expected launch in Japan by 2017 and its proven superiority to cornerstone antiplatelet clopidogrel. Moreover, Brilinta is the first antiplatelet approved for use longer than 1 year post-MI, and its direct competitor, Effient, is contradicted in certain high-risk patients, allowing Brilinta to maintain an excellent clinical and commercial position. It is worth noting that the most prominent barrier that will restrict the growth of the ACS market during the forecast period is the loss of patent exclusivity of these new-generation antiplatelets, Brilinta and Effient, in all 7MM by 2025. More recent antiplatelet approvals included the launches of The Medicines Company’s Kengreal (cangrelor) and Merck’s Zontivity (vorapaxar), which highlights the push in development toward antiplatelet therapeutics before 2015.

Of the numerous pathologies that manifest in the ACS population, the current late-stage pipeline is composed exclusively of lipid-altering drug candidates. As ACS is a culmination of CAD triggered by the long-term build-up of atherosclerotic plaques, lipid-altering agents that address the root cause of CAD — the cholesterol-rich coronary plaques — are among the most essential strategies for the long-term preventative treatment of ACS. Indeed, the future growth of the ACS franchise relies entirely on drugs that treat hypercholesterolemia/atherosclerosis.

The pipeline collection of promising candidates includes four major groups, three of which are first-to-market classes that are all vying for market share as adjunct therapies to the standard-of-care (SOC) statins, and for statin-intolerant patients. There are two first-in-class CETP inhibitors in the Phase II/III pipeline, Merck’s anacetrapib and Amgen’s AMG-899. However, given that three CV giants have terminated their CETP-inhibition programs in recent years, Pfizer’s torcetrapib (2006), Roche’s dalcetrapib (2012), and Eli Lilly’s evacetrapib (2015), no key opinion leader (KOL) interviewed by GlobalData showed any confidence in either drug’s chance of approval. There are two PCSK9 inhibitors, Pfizer’s bococizumab and Eli Lilly’s LY3015014, in Phase II/III development. Based on the trial progression, bococizumab will likely be the third PCSK9 inhibitor to market, followed by LY3015014, after the marketed Repatha (evolocumab) and Praluent (alirocumab). Two reconstituted human apolipoprotein A-1 (apoA-1) analogs are also in the Phase II pipeline, Cerenis Therapeutics’ CER-001 and CSL Limited’s CSL-112. KOLs believe these therapies may be useful for niche high-risk patients that have repeated re-infarctions, yet the cost and formulation (infusion) will limit use from the entire ACS population. Lastly, Esperion’s truly innovative ACL inhibitor/AMPK activator, ETC-1002, is entering Phase III development in 2016 as a low-density lipoprotein cholesterol (LDL-C) lowering therapy. KOLs believe ETC-1002 may become the SOC for statin intolerance in the future based on its current clinical profile.

The statin market represents a critical barrier to achieving blockbuster status for any of these lipid-lowering drugs. All of them will be prescribed as second-line treatments to statins, in cases of intolerance, or as adjunct treatment for patients who need additional lowering of LDL. Moreover, late in 2013, new cholesterol treatment guidelines established by the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) recommended the use of statins, and only statins, for the effective treatment of high LDL-C in ACS patients. The real-world impacts of these guidelines will play out over time, but they are likely to represent a major hurdle for up-and-coming LDL-C drugs in the ACS pipeline. In general, GlobalData believes the current ACS pipeline is relatively weak, as of the seven pipeline contenders, two of the therapies are “me-too” drugs within the PCSK9 family, yielding suboptimal innovation, and four of the drugs directly target high-density lipoprotein cholesterol, the “‘HDLC hypothesis,” which has so far not been deemed a successful strategy in improving CV outcomes.

Real opportunities exist in the ACS arena due to the launch of the revolutionary PCSK9 inhibitors, Repatha and Praluent, in 2015. According to KOLs, a large proportion of patients with clinical atherosclerotic CVD cannot reach guideline-recommended levels of LDL-C with the SOC therapies, which leads to primary or recurrent ACS events. However, these game-changing therapies both truly demonstrated their efficacy in lowering LDL-C in their pivotal Phase III trials, showing a 57% and 58% reduction in LDL-C from baseline compared to placebo for evolocumab and alirocumab, respectively. So far, the major barrier for adoption is the price of these therapies; however, once CV outcomes data for MI prevention is shown (throughout 2017), KOLs stressed that uptake will be significantly accelerated in ACS patients. Moreover, the two other PCSK9 inhibitors in the ACS pipeline, bococizumab and LY3015014, may offer further benefits to patients in terms of price and frequency of administration, respectively. The growth of the PCSK9 class, among others in the ACS pipeline, also highlights the current expansion of biologics into the ACS mainstream.

The revolutionary innovations in CV drug development in recent years cannot be denied, yet despite this and due to a persistent aging population in the 7MM, many key unmet needs exist. First, elderly patients are frequently under-represented in ACS clinical trials, leading to a lack of clinical understanding of how to treat this population segment effectively and safely. GlobalData KOLs agreed that for the entire ACS population, notable progress has been seen, yet clinical trials are focused on low-risk patient segments under the age of 75, which is a significantly smaller portion of the whole ACS patient population as the average age of primary ACS is 68 years. On a similar note, although improvements in secondary prevention of ACS have reduced the rates of mortality and morbidity in this space, repeated infarctions lead to left ventricle dysfunction, causing post-ACS patients to develop heart failure (HF). GlobalData KOLs stated that the majority of their post-ACS patients die of this comorbidity. Unfortunately, to date, no small molecule, biologic, or cell therapy has shown notable efficacy in repairing the infarcted myocardium or improving left ventricle ejection fraction to prevent HF. The last key clinical unmet need that was emphasized by all of GlobalData’s KOLs was the development of a blood-thinning agent with reduced bleeding risk; this is especially sought-after for elderly patients. However, while pushing for improved antithrombotic efficacy, as in the new generation of antiplatelets and anticoagulants, there will be an increase in patients’ bleeding risk as it is tied to the same mechanism. As such, KOLs were virtually unanimous in their skepticism that this goal is achievable. As the current state of the marketed and pipeline products stands, no therapy addresses these unmet needs, which will certainly stunt market growth as new therapies with sub-optimal efficacy improvements struggle to enter the already crowded ACS scene.

OUTLOOK

Although the ACS market is set to grow at a CAGR of 4.6%, reaching $12.1B by 2025, the potential for the market to be even more lucrative exists, especially in the sizable lipid-targeting arena. An evident trend in the ACS pipeline is the targeting of the HDL pathway. Low levels of HDL are known to be a major independent risk factor for atherosclerotic CV disease, yet specifically raising HDL is without precedent and has yet to be proven as a long-term outcome-based benefit for ACS and related events. From KOL interviews, it is increasingly evident that treating hypercholesterolemia is dependent on an array of other factors that go beyond cholesterol control by increasing HDL and lowering LDL. These other factors include the thickness of the coronary plaque, a drug’s effect on inflammatory markers, its pleiotropic role, and its ability to lower LDLC at the cellular level, which could entirely eliminate atherosclerosis. Innovation at this level is currently lacking in the lipid-lowering ACS pipeline, where achieving this scientific leap will require companies to look beyond the canonical avenues of ACS pathology to revolutionize the current landscape. This will be the determining factor toward the positive progression of the ACS market in the future.

GlobalData’s report PharmaPoint: Acute Coronary Syndrome – Global Drug Forecast and Market Analysis to 2025 (published August 2016) and other relevant topics are available at www.globaldata.com.

To view this issue and all back issues online, please visit www.drug-dev.com.

Dr. Michela J. McMullan is a Cardiovascular and Metabolic Disorders (CVMD) Analyst at GlobalData, providing expert analysis for products and companies involved in the CVMD therapeutic space, with a focus on market and therapy forecasting. Prior to working at GlobalData, Dr. McMullan earned her PhD in Pharmaceutical Chemistry from Trinity College Dublin.