NEWS & ANALYSIS FROM THE ANALYST’S COUCH Trends in the market for antihypertensive drugs M. Adam Ali, Salman Rizvi and Basharut A. Syed Red fabric chair by Hugh Threlfall/Alamy Stock Photo Hypertension, or prolonged and persistent has been disappointingly low and most patients monotherapies, as the dosage of each active elevation in blood pressure, is one of the who are treated with existing monotherapies ingredient in the FDC pill is lower than most important risk factors for mortality fail to achieve target blood pressure. the dosage of the respective drug when and morbidity due to cardiovascular Reflecting the issues with existing prescribed as monotherapy. Moreover, the disease. An estimated one billion people are monotherapies and the challenges of prescription of a single FDC aids compliance affected by hypertension worldwide and the developing antihypertensive drugs with new when compared with the prescription of condition accounts for more than half of the mechanisms of action, many companies multiple monotherapies. This can lead to 17 million deaths caused by cardiovascular have focused on developing fixed-dose indirect cost savings owing to the prevention disease each year. Approximately 5% of combinations (FDCs) of two or more of hospitalization and direct cost savings in hypertensive patients have an underlying agents, and dozens of such FDCs have the form of lower prescription costs. From a cause (for example, kidney disease) for their been approved in the past 15 years. There commercial perspective, this approach has disease, but the vast majority are diagnosed are several advantages to formulating also provided companies with an opportunity with ‘essential hypertension’ with unknown antihypertensive drugs as FDCs. Data from to introduce new branded antihypertensive aetiology. Pulmonary arterial hypertension clinical trials show that the ARB valsartan products and reduce the impact of generic (PAH) is a subtype of hypertensive disease in and the CCB amlodipine have a synergistic entries on their franchises. the arteries connecting the right side of the effect in reducing the peripheral oedema While FDCs have dominated recent drug heart to the lungs. It can be associated with associated with the use of CCBs alone when development efforts for hypertension in other conditions, including connective tissue formulated as an FDC. The use of FDCs can general, there has been more innovation with disease, and it has been the focus of efforts to also reduce the side effects of the individual drugs for PAH. The pioneering endothelin ▶ develop PAH-specific interventions. Table 1 | Selected late-stage antihypertensive products Current therapies Drug Developers MOA Status US guidelines encourage physicians to put Candesartan cilexetil/nifedipine Bayer ARB/CCB Phase III recently diagnosed patients with hypertension on the DASH (Dietary Approaches to Stop Fimasartan/amlodipine Boryung Pharmaceutical ARB/CCB Phase III Hypertension) diet, which can lower blood Fimasartan/hydrochlorothiazide Boryung Pharmaceutical/ ARB/diuretic Phase III pressure within 2–3 weeks. When patients Stendhal Mexico do not achieve adequate reductions in blood Telmisartan/chlorthalidone HanAll Biopharma ARB/diuretic Phase III pressure, pharmacological intervention is Telmisartan/amlodipine/ Boehringer Ingelheim ARB/CCB/ Approved required. First-line agents include various hydrochlorothiazide diuretic (Japan) drugs that have been generic for many years, Telmisartan/amlodipine/ Yuhan ARB/CCB/ Phase III such as the vasodilating agents hydralazine and chlorthalidone diuretic minoxidil, the thiazide diuretics hydrochloro- Azilsartan/amlodipine/ Takeda ARB/CCB/ Phase III thiazide and chlorthalidone, the beta-blockers hydrochlorothiazide diuretic atenolol and metoprolol, and angiotensin- Losartan/atorvastatin Yuhan/HanAll Biopharma ARB/statin Pre- converting enzyme inhibitors (ACEIs) such registration as captopril and enalapril. More recently Valsartan/pitavastatin JW Pharmaceutical ARB/statin Phase III approved drugs, such as the calcium channel Candesartan cilexetil/rosuvastatin Alvogen ARB/statin Phase III blockers (CCBs) amlodipine and nifedipine, and angiotensin II receptor blockers (ARBs) Valsartan/amlodipine/rosuvastatin CJ Healthcare ARB/CCB/statin Phase III such as valsartan, telmisartan, irbesartan and Amlodipine/celecoxib Kitov Pharmaceuticals CCB/NSAID Phase III olmesartan, are also now generic. The most CS 3150 Daiichi Sankyo MRB Phase III recent approval of a drug in a new class was HCP 1401 and HCP1305 Hanmi Pharmaceutical Other FDCs Phase III the direct renin inhibitor, aliskiren (Tekturna; Bardoxolone methyl Reata Pharmaceuticals/ AIM agent Phase III Novartis), in 2007. Kyowa Hakko Kirin Many of these drugs are limited by issues Esuberaprost Lung Biotechnology Prostaglandin Phase III including side effects, poor bioavailability receptor agonist and lack of applicability across a range of Nitric oxide inhalation (INOpulse) Bellerophon Therapeutics sGC stimulant Phase III hypertensive patient groups. Despite the global AIM, antioxidant inflammation modulator; ARB, angiotensin II receptor blocker; CCB, calcium channel burden of hypertension, the number of novel blocker; FDC, fixed-dose combination; MOA, mode of action; MRB, mineralocorticoid receptor blocker; drugs reaching the market in the past decade NSAID, nonsteroidal anti-inflammatory drug; sGC, soluble guanylate cyclase. NATURE REVIEWS | DRUG DISCOVERY ADVANCE ONLINE PUBLICATION | 1 ©2017 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. NEWS & ANALYSIS FROM THE ANALYST’S COUCH ▶ receptor antagonist bosentan (Tracleer; 2015 15% 32% 2020 16% Actelion) was approved in 2001, and has 30% been followed by the second-generation 5% drugs ambrisentan (Letairis; Gilead) ARBs in 2007 and macitentan (Opsumit; Gilead) in 6% US $28.2 US $24.9 17% FDCs 2013. Two phosphodiesterase 5 inhibitors billion billion CCBs first approved for erectile dysfunction, β-blockers sildenafil (Revatio; Pfizer) and tadalafil ACEIs 12% 7% Diuretics (Adcirca; United Therapeutics/Eli Lilly), 9% were approved for PAH in 2005 and 2009, 17% 3% Others respectively. The soluble guanlyate cyclase 13% 18% stimulator riociguat (Adempas; Bayer) Figure 1 | Global sales of antihypertensive drugs. In 2015, angiotensin II receptor blockers was approved for PAH and also chronic (ARBs) comprising several leading brands (such as Benicar (olmesartanNature medoxomil; Reviews Daiichi | Drug Sankyo),Discovery thromboembolic pulmonary hypertension Diovan (valsartan; Novartis) and Micardis (telmisartan; Boehringer Ingelheim)) led the market, in 2014, and the prostacyclin receptor followed by fixed-dose combinations (FDCs). The ‘others’ category includes endothelin receptor agonist selexipag (Uptravi; Actelion/Nippon antagonists such as Tracleer, Opsumit (bosentan and macitentan, both Actelion) and Letairis (ambrisentan; Gilead). All drug classes, except FDCs, represent sales of monotherapies. Shinyaku) was approved for PAH in 2015. ACEIs, angiotensin-converting enzyme inhibitors; CCBs, calcium channel blockers. Late-stage pipeline Most late-stage antihypertensive drugs in Several ARB/statin FDCs, which Esaxerenone is a selective nonsteroidal the pipeline (TABLE 1) consist of dual or triple could tackle the related conditions of mineralocorticoid receptor blocker that combinations involving an ARB. Phase III hyperlipidaemia and hypertension, are also has the potential to treat several conditions, trials are under way for candesartan cilexetil/ in the later stages of the pipeline. The most including hypertension, heart failure and nifedipine (Bayer) and fimasartan/amlodipine advanced is HanAll’s losartan/atorvastatin diabetic nephropathy. Daiichi Sankyo (Boryung Pharmaceutical), both of which FDC pill, which is at the pre-registration initiated phase III trials in Japan comparing are FDCs of an ARB and a CCB. Recent stage in South Korea and in phase II trials esaxerenone with the antimineralocorticoid results from the DISTINCT trial show that in the United States. The tablet formulation eplerenone (Inspra; Pfizer) in September 2016. candesartan cilexetil/nifedipine is more of losartan/atorvastatin provides staggered Late-stage PAH-specific products include effective than nifedipine monotherapy release of both drugs, making side effects less bardoxolone methyl (Reata Pharmaceuticals), and that it has greater efficacy in lowering likely and increasing compliance. Two other esuberaprost (Lung Biotechnology) and blood pressue across various ethnic groups. dual combinations, valsartan/pitavastatin Bellerophon Therapeutics’ INOpulse inhaled Another FDC in phase III development (JW Pharmaceuticals) and candesartan delivery of nitric oxide. contains a combination of fimasartan and cilexetil/rosuvastatin (Alvogen), are also in hydrochlorothiazide (Boryung/Stendhal phase III trials. Meanwhile, CJ Healthcare Market indicators Mexico). The presence of fimasartan — an has two ARB/CCB/statin triple combinations The global market for antihypertensive drugs ARB with selectivity for angiotensin II type 1 in development, differing only in the statin generated revenues worth US$28.2 billion in (FIG. 1) (AT1) receptor subtype — in this FDC offsets used. Valsartan/amlodipine/rosuvastatin is in 2015 , but for the period 2013–2015, the increase in plasma renin activity due to phase III trials while valsartan/amlodipine/ the market contracted, with an associated the hydrochlorithiazide. This combination atorvastatin is in phase I trials.