|
|
Aliskiren, the first direct renin inhibitor for treatment of hypertension: The path of its development M Jadhav1, C Yeola2, G Zope1, A Nabar21 Department of Infectious Diseases (MUHS), Seth GS Medical College and KEM Hospital, Parel, Mumbai, India 2 Department of Cardiology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.93250
Standard treatments available today for treating hypertension is diuretics, β-blockers, angiotensin converting enzyme inhibitors (ACEs), angiotensin receptor blockers (ARBs), calcium channel blockers, a-blockers, vasodilators, and centrally acting drugs. It is difficult to achieve the optimized renin angiotensin aldosterone system suppression with currently available antihypertensive agents, because ACE inhibitors, ARBs, and diuretics all activate the compensatory feedback mechanism that increases renin release and increase plasma renin activity. The first orally active direct renin inhibitors (DRIs) were developed in 1980s, including enalkiren, remikiren, and zankiren. However, poor absorption from the gastrointestinal tract, less bioavailability (<2%), short half life, and low potency hindered the development of these compounds. Aliskiren is the first DRI for the treatment of hypertension. Aliskiren is designed through a combination of molecular modeling techniques and crystal structure elucidation. Aliskiren effectively reduces the blood pressure as a mono therapy as well in combination therapy. Keywords: Aliskiren, direct rennin inhibitor, hypertension
According to recent studies across the world, one billion adults have hypertension (333 million in economically developed and 639 million in economically developing countries), with the highest prevalence being noted in Eastern Europe and the Latin American/Caribbean region. More than 80% of the world's population lives in economically developing countries. [1] The meta-analysis of eight studies carried out between 1995 and 2002 gives a prevalence rate of hypertension in urban areas as 16.4%, and in rural areas as 15.7%] The details can be seen in [Table 1]. [2] Standard treatments available today for treating hypertension is diuretics, β-blockers, angiotensin converting enzyme Inhibitors (ACEs), angiotensin II receptor blockers (ARBs), calcium channel blockers, α-blockers, vasodilators, and centrally acting drugs. [3] The drugs from the class of ACE inhibitors and ARBs act by interfering with angiotensin or aldosterone. These drugs do not block the renin-angiotensin-aldosterone system (RAAS) completely. [4] It is difficult to achieve the optimized RAAS suppression with currently available antihypertensive agents, because ACE inhibitors, ARBs, and diuretics all activate the compensatory feedback mechanism that increases renin release and increase plasma renin activity (PRA). [5],[6] ACE inhibitors cause an increase in PRA and angiotensin I, which is then converted to angiotensin II by both remaining unblock ACE and by ACE independent pathways. [7] ARBs and diuretics increase PRA, angiotensin I, and angiotensin II. [8] Hence physicians have been looking for a drug which directly inhibits the renin. The first orally active direct renin inhibitors (DRIs) were developed in 1980s, including enalkiren, remikiren, and zankiren. However, poor absorption from the gastrointestinal tract, less bioavailability (<2%), short half life, and low potency hindered the development of these compounds. [9]
Aliskiren is the first in a new class of orally effective, nonpeptide, low molecular weight, and DRI for the treatment of hypertension. Aliskiren is designed through a combination of molecular modeling techniques and crystal structure elucidation. Aliskiren in combination is a potent and specific inhibitor of human renin with fewer adverse events. [10] Combination of ARBs and DRI could offer improved RAAS blockade by acting both at the receptor level and at the first step of cascade [11] [Figure 1].
Aliskiren is supplied as a 150 or 300 mg tablet designed for oral administration. The recommended initial dose of the drug is 150 mg once daily. In patients who do not have adequately controlled blood pressure, the daily dose may be increased to 300 mg. [12] In one study, the addition of the cardiovascular medicine aliskiren to standard therapy for patients recovering from a heart attack showed some positive effects in helping limit changes in the heart's shape and function, but did not demonstrate a statistically significant benefit. The 36-week study involving 820 patients, all of whom had evidence of impaired left ventricular function, assessed changes in left ventricular end systolic volume (LVESV) through echocardiograms from the baseline to the study end. A small numerical reduction in cardiac volume (LVESV, 0.99 ml) was seen in patients receiving aliskiren and standard therapy compared to those given standard therapy only; however, this was not statistically significant. Patients who received aliskiren also showed a higher rate of hyperkalemia. [13] In another study, aliskiren treatment gives significant reduction in albuminuria by 48% compared with placebo but not significantly different from irbesartan treatment. It lowers the urinary albumin excretion rate (UAER) by 58% and their combination treatment reduces albuminuria by 71% compared with placebo, significantly more than with either monotherapy. [11] ASPIRE HIGHER is the largest ongoing cardio-renal outcomes program studying Rasilez (aliskiren) and direct renin inhibition in a variety of kidney and heart diseases, including diabetic kidney disease and heart failure. The ASPIRE HIGHER clinical trial program has now expanded to involve more than 35,000 patients in 14 trials including three new mega-trials: ALTITUDE including 8600 patients with type 2 diabetes at high risk for cardiovascular and renal events; ATMOSPHERE conducted in patients with acute and chronic congestive heart failure; APOLLO including elderly patients with or without high blood pressure and other risk factors. In addition to these mega-trials, the ASPIRE HIGHER program includes a comprehensive range of short-to-medium term studies to assess the potential organ protection benefits of Rasilez across a broad range of cardio-renal conditions including heart failure, postacute coronary syndromes, post-MI, left ventricular hypertrophy, coronary artery disease, and diabetic nephropathy. [14] Circulating natriuretic peptides (NPs) are released from ventricular myocardium in response to increased wall stress and when elevated in patients with acute coronary syndrome (ACS) are associated with a three-to five-fold higher risk of death or heart failure compared with patients with low concentrations. Aliskiren in combination with valsartan will reduce the NPs. [15] Aliskiren shows antiproteinuric effects, which alone or in combination can contribute to delaying the progression of kidney disease. [16] Aliskiren is a well-tolerated antihypertensive drug with a safety profile similar or superior to those of other antihypertensive drugs. [17] Hence the more research is needed to study the various actions of aliskiren. Historical development The first evidence of the existence of renin was presented over 100 years ago. However, the importance of renin and the renin-angiotensin system in the pathogenesis of cardiovascular disease was only fully realized in the 1970s. It was another 20 years before the first inhibitors of renin were available for clinical research. [18] The first orally active compounds were developed in the 1980s, and included substances such as enalkiren and zankiren, both from Abbott, CGP38560A from Ciba-Geigy (now Novartis), and remikiren from Roche. [9] Aliskiren was discovered in Ciba-Geigy (now Novartis, Basel, Switzerland) through a combination of molecular modeling and crystallographic structure analysis. Alice Huxley, who was the project manager of aliskiren at the time, started her own company in 1998 to work on the drug. The synthetic pathway at that time was not suitable for large-scale manufacturing and the compound was out-licensed to Speedel AG (Basel, Switzerland) where a new cost-effective manufacturing method for aliskiren (SPP 100) was developed and preclinical and early clinical testing successfully performed. In 2002, Novartis then licensed back aliskiren from Speedel and conducted phase 3 trials that led to the approval in 2007. [19] During all this period, clinical studies showed that aliskiren is as efficient as the other antihypertensive drugs, while preclinical studies showed that, in genetically modified rats, aliskiren is efficient in healing the cardiovascular damage associated with angiotensin II. At its 257 th meeting on 04 April 2008, the Australian Drug Evaluation Committee recommended approval of a submission from Novartis Pharmaceuticals Pvt Ltd to register the trade names Rasilez and Enviage film-coated tablets, both containing the new chemical entity aliskiren 150 and 300 mg [Table 2] and [Table 3]. [20]
Preclinical development In 2005 Pilz et al. [21] studied that aliskiren, a human DRI, ameliorates cardiac and renal damage in double-transgenic rats. Six-week-old double transgenic rats (dTGR) were matched by albuminuria (2 mg per day) and divided into five groups. Untreated dTGR were compared with aliskiren (3 and 0.3 mg/kg per day) treated and valsartan (10 and 1 mg/kg per day) treated rats. Treatment was from week 6 through week 9. At week 6, all groups had elevated systolic blood pressure (BP). Untreated dTGR showed increased BP (202±4 mmHg), serum creatinine, and albuminuria (34±5.7 mg per day) at week 7. At week 9, both doses of aliskiren lowered BP (115±6 and 139±5 mmHg) and albuminuria (0.4±0.1 and 1.6±0.6 mg per day) and normalized serum creatinine. Although high-dose valsartan lowered BP (148±4 mmHg) and albuminuria (2.1±0.7 mg per day), low-dose valsartan reduced BP (182±3 mmHg) and albuminuria (24±3.8 mg per day) to a lesser extent. Mortality was 100% in untreated dTGR and 26% in valsartan (1 mg/kg per day) treated rats, whereas in all other groups, survival was 100%. dTGR treated with low-dose valsartan had cardiac hypertrophy (4.4±0.1 mg/g), increased left ventricular (LV) wall thickness, and diastolic dysfunction. LV atrial natriuretic peptide and myosin heavy chain mRNA, albuminuria, fibrosis, and cell infiltration were also increased. In contrast, both aliskiren doses and the high-dose valsartan lowered BP to a similar extent and more effectively than low-dose valsartan. It was concluded that in dTGR, equieffective antihypertensive doses of valsartan or aliskiren attenuated end-organ damage. Thus, renin inhibition compared favorably to angiotensin receptor blockade in reversing organ damage in dTGR. A summary of studies on preclinical development of aliskiren are provided in [Table 2]. In 2005 Wood et al. [22] studied that aliskiren, a novel, orally effective renin inhibitor, lowers blood pressure in marmosets and spontaneously hypertensive rats. They report the results of animal experiments performed in marmosets and rats in order to characterize aliskiren before its recent investigation in humans . The effects of aliskiren were investigated in sodium-depleted marmosets (oral dosing) and in spontaneously hypertensive rats (dosing via subcutaneous osmotic minipumps). Blood pressure (BP) and heart rate were measured by radio telemetry. In sodium-depleted marmosets single oral doses of aliskiren (1-30 mg/kg) dose-dependently lowered BP. At a dose of 3 mg/kg, peak effects were observed 1 h after dosing (−30±4 mmHg, n=6) and the response persisted for more than 12 h. A single oral dose of 3 mg/kg aliskiren was more effective than the same dose of either remikiren or zankiren, two orally active renin inhibitors previously tested in humans. Aliskiren (10 mg/kg) was at least as effective as equal doses of the AT1-receptor blocker valsartan or the angiotensin-converting enzyme inhibitor benazepril. In spontaneously hypertensive rats, aliskiren dose-dependently (10-100 mg/kg per day) decreased BP. Aliskiren also potentiated the antihypertensive effects of low doses of valsartan or benazeprilat (1 or 3 mg/kg per day). They concluded that aliskiren is an orally effective, long-lasting renin inhibitor that showed antihypertensive efficacy in animals superior to previous renin inhibitors and at least equivalent to angiotensin-converting enzyme inhibitors and AT1-receptor blockers. In 2008 Lu et al. [23] studied that renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice. To determine the effects of renin inhibition on atherosclerosis, they administered the novel renin inhibitor aliskiren over a broad dose range to fat-fed LDL receptor-deficient (Ldlr-/-) mice. In this study, aliskiren was administered at three different doses to produce increasing systemic inhibition of renin. Aliskiren produced no changes in body weight, plasma cholesterol concentrations, plasma aldosterone concentrations, or lipoprotein-cholesterol distribution in Ldlr-/- mice. All doses of aliskiren increased plasma renin concentrations. Renin inhibition resulted in striking reductions of the atherosclerotic lesion size in both the aortic arch and the root. To determine the role of macrophage-derived angiotensin in the development of atherosclerosis, they transplanted renin-deficient bone marrow to irradiated Ldlr-/- mice and observed a profound decrease in the size of atherosclerotic lesions. They concluded that renin-dependent angiotensin production in macrophages does not act in an autocrine/paracrine manner. Furthermore, in vitro studies demonstrated that coculture with renin-expressing macrophages augmented monocyte adhesion to endothelial cells. They found that renin inhibition profoundly decreased lesion development in mice. In 2009 Stucchi et al. [24] studied that aliskiren reduces body weight gain, adiposity, and plasma leptin during diet-induced obesity. They determined the effect of chronic treatment with the renin inhibitor, aliskiren, in a model of diet-induced obesity in mice, on: (i) body weight, adipose tissue weight and plasma leptin; (ii) food intake and caloric efficiency; and (iii) angiotensin II (Ang II) in adipose tissue. Four-week-old mice (n=40) received aliskiren 50 mg/kg/day; 6 weeks. Animals were given either a low-fat (10% kcal from fat) or a high-fat diet (45% kcal from fat) during this period. Food-intake and body-weight variation were monitored during treatment. In addition, to a decrease of PRA, aliskiren reduced body-weight gain, adipose pads, and plasma leptin concentration, independent of the diet. In adipose tissue, local concentrations of Ang II were also reduced by aliskiren. They concluded that aliskiren limited the gain of adiposity in young mice. These effects were accompanied by reduced plasma leptin levels. As Ang II favors differentiation of adipocytes, it is possible that the decreased adipose tissue was linked to changes in the adipocyte size and number. Clinical development In 2008, Parving et al., [25] studied that renoprotective effects of dual blockade of the RAAS by adding treatment with aliskiren, an oral DRI, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy. This was a multinational, randomized, double-blind study. Out of 805 patients, 599 patients were randomized. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin to creatinine ratio by 20% (95% confidence interval, 9-30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). They concluded that aliskiren may have renoprotective effects that are independent of its blood pressure lowering effect in patients with hypertension, type-2 diabetes, and nephropathy who were receiving the recommended renoprotective treatment. A summary of studies on clinical development of aliskiren are provided in [Table 3]. In 2008 Dietz et al. [26] studied the effects of the DRI aliskiren and atenolol alone or in combination in patients with hypertension. This was a double-blind, multicentre trial. A total of 694 patients with hypertension (mean sitting diastolic blood pressure ≥95 and <110 mmHg) were randomized to once daily aliskiren 150 mg (n=231), atenolol 50 mg (n=231) or the combination (150/50 mg; n=232) for 6 weeks, followed by a further 6 weeks on double the initial doses of aliskiren and atenolol. They assessed the efficacy and tolerability of study treatments and measured the plasma rennin activity (PRA) in a subset of patients. At week 12 endpoint, aliskiren, atenolol, and aliskiren/atenolol lowered systolic and diastolic BP from the baseline by 14.3/11.3, 14.3/13.7, and 17.3/14.1 mmHg, respectively. Aliskiren, atenolol, and aliskiren/atenolol reduced geometric mean PRA from the baseline by 65%, 52%, and 61%, respectively. In patients with moderate or high baseline PRA (≥0.65 ng/ml/hour), PRA was reduced to low levels (<0.65 ng/ml/hour) at week 12 endpoint in a greater proportion of patients receiving aliskiren (11/15 patients, 73.3%) or aliskiren/atenolol (18/23, 78.3%) than with atenolol (10/21, 47.6%). They concluded that direct renin inhibition with aliskiren may be an appropriate substitute for β-blocker treatment in patients with uncomplicated hypertension. Aliskiren also represents an attractive option for dual therapy with atenolol to improve systolic BP/pulse pressure reductions and BP control with maintained tolerability compared with atenolol alone. In 2008 McMurray et al. [27] studied the effects of the oral DRI aliskiren in patients with symptomatic heart failure. They took patients with New York Heart Association class II-IV heart failure, current or past history of hypertension, and plasma brain natriuretic peptide (BNP) concentration >100 pg/mL who had been treated with an ACE inhibitor (or ARB) and β-blocker were randomized to 3 months of treatment with placebo (n=146) or aliskiren 150 mg/day (n=156). Plasma N-terminal (NT) pro-BNP rose by 762±6123 pg/mL with placebo and fell by 244±2025 pg/mL with aliskiren (P=0.0106). BNP and urinary (but not plasma) aldosterone were also reduced by aliskiren. They concluded that addition of aliskiren to an ACE inhibitor (or ARB) and β-blocker had favorable neurohumoral effects in heart failure and appeared to be well tolerated. In 2009 Anderson et al. [28] studied that comparative effects of aliskiren based and ramipril based therapy on the renin system during long-term treatment and withdrawal in patients with hypertension. This was a randomized, double-blind trial. After that 842 patients (mean sitting diastolic blood pressure 95-109 mmHg) were randomized to aliskiren 150 mg or ramipril 5 mg. Dose titration and hydrochlorothiazide addition were allowed after week 6 and 12, respectively, for inadequate BP control. BP reductions were independent of baseline PRA at week 12, were greater with aliskiren than ramipril-based therapy at week 26 (17.9/13.3 vs. 15.2/12.0 mmHg, P<0.05) and persisted for longer after stopping aliskiren. Aliskiren-based therapy reduced geometric mean PRA (-63%, P<0.05; n=103), while ramipril-based therapy increased PRA (+143%, P<0.05; n=100) at week 26; PRC increased in both groups (aliskiren: +224% [n=33], ramipril: +145% [n=39], both P<0.05). Four weeks after stopping aliskiren-based therapy, PRA remained 52% below the pre-treatment baseline; PRA returned to baseline 2 weeks after stopping ramipril-based therapy. They concluded that PRA reductions persisted 4 weeks after stopping aliskiren, suggesting an inhibitory effect beyond the elimination half-life of the drug. In 2009 Solomon et al. [29] studied the effects of direct rennin inhibitor aliskiren, ARBs losartan, or both on left ventricular mass in patients with hypertension and left ventricular hypertrophy. They screened totally 1104 patients and out of that 465 patients were randomized. Among that 154 were on aliskiren (300 mg) treatment, 152 on losartan (100 mg) treatment, and 154 on aliskiren/losartan combination treatment. The primary objective was to compare change in LV mass index from the baseline to follow-up in the combination and losartan arms; the secondary objective was to determine whether aliskiren was noninferior to losartan in reducing the LV mass index from the baseline to follow-up. Systolic and diastolic blood pressures were reduced similarly in all treatment groups (6.5±14.9/3.8±10.1 mmHg in the aliskiren group; 5.5±15.6/3.7±10.7 mmHg in the losartan group; 6.6±16.6/4.6±10.5 mmHg in the combination arm; P<0.0001 within groups, P=0.81 between groups). The LV mass index was reduced significantly from the baseline in all treatment groups (4.9, 4.8, and 5.8 g/m 2 reductions in the aliskiren, losartan, and combination arms, respectively; P<0.0001 for all treatment groups). The reduction in the LV mass index in the combination group was not significantly different from that with losartan alone (P=0.52). They concluded that aliskiren was as effective as losartan in promoting LV mass regression. Reduction in LV mass with the combination of aliskiren plus losartan was not significantly different from that with losartan monotherapy, independent of blood pressure lowering. These findings suggest that aliskiren was as effective as an ARB in attenuating this measure of myocardial end-organ damage in hypertensive patients with LV hypertrophy. In 2009 Persson et al., [11] studied the renal effects of aliskiren compared with and in combination with irbesartan in patients with type 2 diabetes, hypertension, and albuminuria. The objective was to investigate whether the antiproteinuric effects of the DRI aliskiren is comparable to that of irbesartan and the effect of the combination. This was a double-blind, randomized, crossover trial. After a 1-month washout period, 26 patients with type 2 diabetes, hypertension, and albuminuria (>100 mg/day) were randomly assigned to four 2-month treatment periods in random order with placebo, 300 mg aliskiren once daily, 300 mg irbesartan once daily, or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. Aliskiren treatment reduced albuminuria by 48% (95% CI: 27-62) compared with placebo (P<0.001), not significantly different from the 58% (42-79) reduction with irbesartan treatment (P<0.001 vs. placebo). Combination treatment reduced albuminuria by 71% (59-79), more than either monotherapy. They concluded that the combination of aliskiren and irbesartan is more antiproteinuric in type 2 diabetic patients with albuminuria than monotherapy.
Aliskiren is the first drug in a class of DRI. Aliskiren effectively reduces the blood pressure as a mono therapy as well in combination therapy. From the above clinical and preclinical studies, aliskiren showed renoprotective effects; prevents myocardial end organ damage, and various other effects. These effects of aliskiren are needed to be studied in more detail. Looking to the various clinical and preclinical studies, it is evident that very few studies were conducted in Indian population, so it is advisable to perform clinical studies in Indian population to evaluate safety and efficacy of aliskiren.[33]
The authors would like to acknowledge and express their obligation to their colleagues Dr. Sagar Thakkar, Dr. Sachin Upasani and Dr. Pravita Yadav for both general support and encouragements during this project.
[Figure 1]
[Table 1], [Table 2], [Table 3]
|
|
|||||||