Emerging Drug List ALISKIREN by gmt42811


									Emerging Drug List
                                                                                              NO. 76 DECEMBER 2006
 Generic (Trade Name):   Aliskiren (Tekturna, formerly known as Rasilez™)

       Manufacturer:     Novartis

           Indication:   Hypertension

   Current Regulatory    A new drug application for aliskiren was submitted to the US Food and Drug
              Status:    Administration in early 2006.1 Novartis has also submitted aliskiren to the European
                         Medicines Agency.2 Aliskiren is not yet licensed in Canada.

          Description:   Aliskiren is an oral direct renin inhibitor.3,4 Many factors contribute to hypertension and its
                         related complications of stroke, coronary heart disease, cardiovascular events, and death.
                         One of these factors is the activation of the renin-angiotensin-aldosterone system (RAAS).
                         Renin inhibition, for example, by aliskiren, inhibits the conversion of angiotensinogen to
                         angiotensin I. This is the rate-limiting step in the production of angiotensin II, which is a
                         key mediator of blood pressure, body fluid volume, and vascular remodeling. One recent
                         review describes the development of oral renin inhibitors and in particular, aliskiren, which
                         was the first of these drugs to reach phase III clinical trials.5

   Current Treatment:    Long-term trials of antihypertensive therapy have yielded morbidity and mortality
                         outcomes, in addition to blood pressure control results.3 These trial-based outcomes have
                         led to evidence-based guidelines that emphasize lifestyle changes in addition to multiple
                         drug therapy for most patients.6-8 The various guidelines recommend the use of diuretics,
                         calcium channel blockers, beta blockers, angiotensin converting enzyme inhibitors (ACEIs),
                         and angiotensin II receptor blockers (ARBs).

                         ACEIs and ARBs inhibit the RAAS at different points.3,4 Hence, familiarity with drugs acting
                         on the RAAS precedes the introduction of renin inhibitors. An effective oral renin inhibitor
                         has not been marketed for the treatment of hypertension.

                 Cost:   Information on the cost of aliskiren is unavailable.

            Evidence:    The effect of aliskiren on blood pressure (BP) has been studied in two short-term phase II
                         randomized controlled trials (RCTs).9,10 The first trial, which evaluated the BP effects and
                         safety of aliskiren, was undertaken in several hospital clinics in Ireland.9 Treatment groups

                      The Canadian Agency for Drugs and Technologies in Health (CADTH)
              is funded by Canadian federal, provincial and territorial governments. (www.cadth.ca)
Emerging Drug List

                       included aliskiren (37.5 mg, 75 mg, 150 mg, and 300 mg daily) or losartan 100 mg daily for
                       four weeks. Patients were adults with mild to moderate hypertension without diabetes or
                       coronary artery disease. The efficacy endpoint, which was the change in daytime ambulatory
                       systolic BP from baseline, was reported for 197 patients. No significant BP reduction was
                       reported in the group receiving aliskiren 37.5 mg daily. Aliskiren 75 mg, 150 mg, and 300 mg
                       daily, and losartan treatment groups showed significant BP reduction relative to baseline
                       (p<0.05). Safety results were reported for all of the 226 patients who were randomized.
                       Among the 29 excluded patients, 14 had withdrawn from the trial, and an additional 15 were
                       excluded because of invalid BP monitoring.

                       The second trial, comparing BP effects and safety, included patients with mild to moderate
                       hypertension and no other cardiac risk factors in an eight-week trial.10 This trial included
                       652 patients, who were randomized, after the placebo run-in, to receive aliskiren (150 mg,
                       300 mg, or 600 mg) once daily, irbesartan 150 mg daily, or placebo. All aliskiren treatment
                       groups experienced a significant reduction in trough mean systolic BP and diastolic BP
                       compared with placebo (p<0.001). There was a significant reduction in BP in the irbesartan
                       treatment group compared with the placebo group (p<0.05). The reduction in BP was
                       significantly greater in the aliskiren 300 mg per day group compared with the aliskiren
                       175 mg per day group, with no further BP reduction in the aliskiren 600 mg per day group.
                       BP control was defined as trough mean sitting diastolic BP <90 mm Hg and systolic BP
                       <140 mm Hg. It was achieved in 20.8% of the placebo group, 33.8% of the irbesartan group,
                       37.8% of the aliskiren 150 mg per day group, 50% of the aliskiren 300 mg per day group, and
                       45.8% of the aliskiren 600 mg per day group. All treatments were significantly better than
                       placebo. Safety results were reported for all 652 patients; there were 66 patients who
                       discontinued treatment.

    Adverse Effects:   Published data are limited to the two phase II trials that have been described.9,10 In the first
                       trial, 22% to 32% of patients in each treatment group reported that they experienced
                       adverse events.9 The most common adverse events were fatigue, gastrointestinal disorders,
                       or headaches. Three patients experienced serious adverse events. One patient on aliskiren
                       300 mg daily had chest pain with electrocardiogram (ECG) changes, and another in the
                       same group collapsed and was found to be hypotensive. One patient on losartan died from
                       a ruptured aneurysm of the iliac artery.

                     The Canadian Agency for Drugs and Technologies in Health (CADTH)
             is funded by Canadian federal, provincial and territorial governments. (www.cadth.ca)
Emerging Drug List

                      In the second trial, 66 patients withdrew.10 Most of the withdrawals were due to a lack of
                      therapeutic effect (21 patients), or due to the occurrence of adverse events (18 patients).
                      Adverse events were reported in 26% to 36% of patients in each treatment group. No serious
                      adverse events were reported in the aliskiren groups. One patient, who was receiving
                      aliskiren 600 mg daily, developed abnormal liver function tests, and withdrew from the trial.

     Commentary:      The prevalence of hypertension is increasing.7 Over the next 20 years, the number of adults
                      with hypertension is expected to increase by about 60% to 1.5 billion adults globally.7 One in
                      five Canadians, and one in three Canadians who are >45 years old have hypertension.11 The
                      2006 Canadian Hypertension Society recommendations focus on concurrent cardiovascular
                      risk factors, patients’ adherence to drug therapy, and patients’ involvement in BP monitoring
                      to ensure BP control and to reduce morbidity and mortality.7 Despite the availability of many
                      well-tolerated drugs, many patients have undetected or uncontrolled hypertension.3

                      Longer-term trials that are in progress will provide information on the comparative BP
                      efficacy, cardiovascular outcomes, and safety of aliskiren.2,12,13

      References:     1.      Novartis files Rasilez in US. PharmaTimes 20 Apr 2006.
                              Available: http://www.pharmatimes.com/WorldNews/Articles/8748-Novartis-blood-

                              pressure.aspx?src=PTNews-9617 . >>

                      2.      Novartis files Rasilez in Europe. PharmaTimes 28 Sep 2006. Available:
                              http://www.pharmatimes.com/WorldNews/Articles/9617-Novartis-Rasilez.aspx .
                              <<                                                                            >>

                      3.      Peter D. Core Evidence 2005;1(1):13-22.
                      4.      Duprez DA. J Hypertens 2006;24(6):983-91.

                      5.      Staessen JA, Li Y, Richard T. Oral renin inhibitors. Lancet 2006;368(9545):1449-56.

                      6.      National Collaborating Centre for Chronic Conditions. Hypertension. Management
                              of hypertension in adults in primary care: partial update. London: Royal College of
                              Physicians; 2006. NICE CG34. Available:
                              http://www.nice.org.uk/page.aspx?o=CG034fullguideline .
                              <<                                                      >>

                      7.      Canadian Hypertension Society. CHEP recommendations for the management of
                              hypertension 2006. The bottom line version. Kingston (ON): The Society; 2006.
                              Available: http://www.hypertension.ca/chep/docs/CHEP_2006_Bottom_Line.pdf .
                                         <<                                                                      >>

                      8.      Chobanian AV, et al. JAMA 2003;289(19):2560-72.

                      9.      Stanton A, et al. Hypertension 2003;42(6):1137-43.

                      10.     Gradman AH, et al. Circulation 2005;111(8):1012-8.

                    The Canadian Agency for Drugs and Technologies in Health (CADTH)
            is funded by Canadian federal, provincial and territorial governments. (www.cadth.ca)
Emerging Drug List

                      11.       Hypertension--high blood pressure. In: HealthyOntario.com. Toronto: Ontario
                                Ministry of Health Promotion; 2004. Available:
                                http://www.healthyontario.com/Conditions/H/Hypertension___High_Blood_Pressure.htm .
                                <<                                                                                             >>

                      12.       Azizi M, et al. J Am Soc Nephrol 2004;15(12):3126-33.

                      13.       Hershey JC, et al. Drug Discov Today Ther Strateg 2005;2(3):181-5.

                      Prepared by Jan Demsey, PharmD.

                      This series highlights medical technologies that are not yet in widespread use in Canada and that may have a
                      significant impact on health care. The contents are based on information from early experience with the
                      technology; however, further evidence may become available in the future. These summaries are not intended to
                      replace professional medical advice. They are compiled as an information service for those involved in
                      planning and providing health care in Canada.

                      These summaries have not been externally peer reviewed.

                      Production of this report is made possible by financial contributions from Health Canada and the governments
                      of Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Northwest Territories, Nova
                      Scotia, Nunavut, Ontario, Prince Edward Island, Saskatchewan, and Yukon. The Canadian Agency for Drugs and
                      Technologies in Health takes sole responsibility for the final form and content of this report. The views expressed
                      herein do not necessarily represent the views of Health Canada or any provincial or territorial government.

                                                                  ISSN 1496-8398 (online only)

                    The Canadian Agency for Drugs and Technologies in Health (CADTH)
            is funded by Canadian federal, provincial and territorial governments. (www.cadth.ca)

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