1 ENVOLVING THE FUTURE OF SINGLE PILL COMBINATION IN ANTIHYPERTENSIVE THERAPHY Djanggan Sargowo Shangri-La, Surabaya - Sabtu, 23 Juni 2012

2 HYPERTENSION IS A PREVALENT DISEASE AFFECTING 1 BILLION PEOPLE TODAY Wolf-Maier et al. JAMA 2003;289:2363–9 Prevalence* of HTN (%) *Among persons aged 35 – 64 years old; age and sex adjusted HTN = BP  140/90 mmHg or on treatment

3 CLASSIFICATION OF BLOOD PRESSURE IN US ADULTS: JNC VII GUIDELINES BP categorySystolic (mmHg) Diastolic (mmHg) Normal<120and<80 Pre-hypertension120–139or80–89 Hypertension, stage 1 140–159or90–99 Hypertension, stage 2  160 or  100 Chobanian et al. JAMA 2003;289:2560  72

4 JNC VII AND ESH  ESC SUMMARY : Target Blood Pressure Goals Type of hypertension BP goal (mmHg) Uncomplicated<140/90 Complicated Diabetes mellitus <130/80 Kidney disease <130/80 Chobanian et al. JAMA 2003;289:2560  72 Guidelines Committee. J Hypertens 2003;21:1011  53

5 Lifestyle modifications Chobanian et al. JAMA 2003;289:2560–72 Not at goal BP* HTN without compelling indications HTN with compelling indications Stage 1 Thiazide-type diuretics for most. May consider ACE inhibitor, ARB, β-blocker, CCB, or combination Stage 2 Two-drug combination for most (usually including thiazide-type diuretic) If not at goal, optimise dosages or add additional drugs until goal BP is achieved. Consider consultation with hypertension specialist JNC VII: ALGORITHM FOR TREATMENT OF HYPERTENSION Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACE inhibitor, ARB, β-blocker, CCB) as needed *BP goal <140/90 mmHg or <130/80 mmHg for those with diabetes or chronic kidney disease

6 Consider: BP level before treatment Absence or presence of TOD and risk factors 2-drug combination at low dose Choose between: Single agent at low dose If goal BP not achieved Previous agent at full dose Switch to different agent at low dose Previous combination at full dose Add a third drug at low dose If goal BP not achieved 2–3 drug combination 3-drug combination at effective doses ESH–ESC: ALGORITHM FOR TREATMENT OF HYPERTENSION ESH–ESC Guidelines. J Hypertens 2003;21:1779–86 Full-dose monotherapy TOD = target organ damage

7 APPROXIMATELY 73% OF EUROPEAN PATIENTS WITH HYPERTENSION REMAIN UNTREATED Wolf-Maier et al. Hypertension 2004;43:10–17 Patients (%) EnglandSwedenGermanySpainItaly

More than 60% of Patients do not Achieve BP goal of <140/90 mmHg with monotherapy Patients with BP control (%) BP < 140/90 mmHgBP < 135/85 mmHg Dickerson et al. Lancet. 1999:353:2008–

9 Also Guidelines worldwide Acknowledge That Most Patients Need Combination Therapy to Achieve BP Goals Most patients with hypertension will require two or more antihypertensive medications to achieve their BP goals –When BP is > 20/10 mmHg above goal, consideration should be given to initiating therapy with two drugs Combination treatment should be considered as first choice when there is high CV risk –i.e., in individuals in whom BP is markedly above the hypertension threshold (> 20/10 mmHg), or associated with multiple risk factors sub-clinical organ damage, diabetes, renal or CV disease Chobanian et al. JAMA. 2003;289:2560–2572; Mancia et al. Eur Heart J. 2007;28:1462–1536; download.aspx?o=CG034fullguideline (accessed January 2010); Ogihara et al. Hypertens Res. 2009;32:3–107. Many patients will require more than one drug to achieve adequate BP control –Pathophysiological reasoning suggests that adding an ACE-I/ARB to a CCB or a diuretic (or vice versa in the younger group) are logical combinations The use of two or three drugs in combination is often necessary to achieve the target BP control –A low dose of a diuretic should be included in this combination JNC VII ESH/ESC NICE The Japanese Society of Hypertension Committee for Guidelines for the Management of Hypertension 2009 JSH

10 MANAGEMENT OF HYPERTENSION: GUIDELINE RECOMMENDATIONS FOR COMBINING THERAPIES  Multiple antihypertensive agents are needed to achieve BP goals  European and US guidelines for combining antihypertensive therapies

11 BENEFITS OF FIXED-DOSE COMBINATION THERAPY  Rationale for fixed-dose combinations (FDCs): efficacy; tolerability; compliance and persistence  Beneficial impact of FDCs on compliance and persistence, and costs

12 RATIONALE FOR THE USE OF FIXED-DOSE COMBINATIONS: TOLERABILITY  Low doses of two agents often result in fewer adverse events than high doses of one agent 1,2 –Physicians may accept less than optimal BP control to minimise adverse events  Compound-specific adverse events can be attenuated, e.g. 1,2 –RAS blockers effectively blunt the metabolic effects of diuretics –RAS blockers may attenuate the oedema that is caused by calcium channel blockers (CCBs) 1 Sica. Drugs 2002;62:443  62; 2 Quan et al. Am J Cardiovasc Drugs 2006;6:103  13 FDC therapy may have an improved tolerability profile compared with its single-mechanism components 1,2

Single-Pill Combinations (SPC) significantly improve Compliance/Treatment adherence (~25%) Bangalore et al. Am J Med. 2007;120:713–719. p < Chronic disease (9 studies) Hypertension (4 studies) p < * With single-pill combination therapy vs free-drug regimens Relative reduction in non-compliance* (%)

14 21% MORE PATIENTS ARE FULLY COMPLIANT WITH FIXED-DOSE COMBINATION THERAPY THAN WITH FREE- COMBINATION THERAPY 17% Patients fully compliant (%) Patients on free combination had a higher odds ratio (OR) of being non-compliant than patients on FDC: OR 2.09 (95% CI: 1.69, 2.59) Sturkenboom et al. J Hypertens 2005;23(Suppl 2):S236 21% Months since start of therapy Cohort study of general practice research data (N=755) Fixed-dose combination therapy Co-administration of two pills

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Re-appraisal of ESH/ESC Guidelines suggests 4 Preferred Antihypertensive Drug Classes Most rational combinations Combinations used as necessary Mancia et al. Eur Heart J. 2007;28:1462–1536; Mancia et al. J Hypertens. 2009;27:2121–2158. Diuretics β-blockers α-blockers ACE-I CCB ARB 2007 Diuretics ACE-I CCB ARB ONTARGET ® ACCOMPLISH HYVET

17 CCB + ARB : The Synergies of Counter-Regulation (2) ARB  Venodilation  Attenuates peripheral oedema  Effective in high-renin patients  No effect on cardiac ischaemia ARB  RAS blockade  CHF and renal benefits MistryMistry et al. Expert Opin Pharmacother. 2006;7:575–581; Sica. Drugs. 2002;62:443–462;Sica QuanQuan et al. Am J Cardiovasc Drugs. 2006;6:103  113. Synergistic BP reduction Complementary clinical benefits BP CCB  Arteriodilation  Peripheral oedema  Effective in low-renin patients  Reduces cardiac ischaemia CCB  RAS activation  No renal or CHF benefits 17

18 RATIONALE FOR A CCB  ARB COMBINATION  The calcium channel blocker (CCB)  angiotensin receptor blocker (ARB) reduces BP by targeting two key BP effector pathways  Rationale for a CCB  ARB: tolerability and efficacy  Rationale for CCB  ARB therapy with Amlodipine/Telmisartan

19 Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:42  73 White et al. Clin Pharmacol Ther 1986;39:43  8 Gustaffson. J Cardiovasc Pharmacol 1987;10(Suppl 1):S121  31 Arterial dilation No venous dilation Fluid leakage Capillary bed PERIPHERAL OEDEMA ASSOCIATED WITH CCBS

20 COMPLEMENTARY EFFECTS OF A CCB/ARB: REDUCTION OF CCB-ASSOCIATED OEDEMA Arterial dilation (CCB and ARB) Venous dilation (ARB) Capillary bed Opie. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:42  73 White et al. Clin Pharmacol Ther 1986;39:43  8; Gustaffson. J Cardiovasc Pharmacol 1987;10(Suppl. 1):S121  31; Messerli et al. Am J Cardiol 2000;86:1182  7

Amlodipine – The longest half-life in class Based on available online product information. Plasma elimination half-life (h) Lercani- dipine Nife- dipine Nimo- dipine Nisol- dipine Nicar- dipine Felo- dipine Laci- dipine Amlo- dipine 21

Amlodipine - broadest CVP evidence and indication in class 1. Pitt et al. Circulation. 2000;102:1503–1510; 2. Nissen et al. JAMA. 2004;292:2217–2226; 3. Dahlof et al. Lancet. 2005;366:895–906; 4. Williams et al. Circulation. 2006;113:1213 –1225; 5. Leenen et al. Hypertension.2006;48:374–384. PREVENT CAD patients (≥ 30%); multicentre, randomized, placebo-controlled CAMELOT 2 1,991 CAD patients (≥ 20%); double- blind, randomized study vs placebo and enalapril 20 mg ASCOT-BPLA/CAFE 3,4 19,257 HTN patients; multicentre, randomized, prospective study vs atenolol ALLHAT 5 18,102 HTN patients; multicentre, randomized, prospective study vs lisinopril INDICATION: Hypertension Coronary Artery Disease (CAD)  Chronic Stable Angina  Vasospastic Angina (Prinzmetal’s or Variant Angina)  Angiographically documented CAD without heart failure or an ejection fraction < 40% 22

23 Telmisartan has a Unique Pharmacology Profile in its Class (ARB) … Plasma half-life (h) Burnier, Brunner. Lancet. 2000;355:637–645; Brunner. J Hum Hypertens. 2002;16(Suppl 2):S13–S16; Kakuta et al. Int J Clin Pharmacol Res. 2005;25: 41–46; Wienen et al. Br J Pharmacol. 1993;110:245–252; Song, White. Formulary. 2001;36:487–499; Asmar. Int J Clin Pract. 2006;60:315–320; Israili. J Hum Hypertens. 2000;14(Suppl 1):S73–S86; Benson et al. Hypertension. 2004;43:993–1002. Longest plasma half-life Epro- sartan Lo- sartan Val- sartan Cande- sartan Olme- sartan Irbe- sartan Telmi- sartan Volume of distribution (L) Most lipophilic (high tissue penetration) 500 Cande- sartan Epro- sartan Val- sartan Olme- sartan Lo- sartan Irbe- sartan Telmi- sartan † Active metabolite of losartan Highest selective PPARγ activation PPARy fold activation Telmi- sartan Epro- sartan Olme- sartan EXP 3174 † Cande- sartan Val- sartan Irbe- sartan Receptor dissociation half-life (min) Highest receptor affinity Lo- sartan Val- sartan Cande- sartan Olme- sartan Telmi- sartan 23

24 … is the Most Studied Amongst ARBs in Mortality and Morbidity Endpoint Trials … Number of patients 44,264 51,878 19,335 12,565 1, Schrader et al. Stroke. 2005;36:1218–1226; Parving et al. N Engl J Med. 2001;345:870–878; 4. Lewis et al. N Engl J Med. 2001;345:851–860; 5. Carson et al. J Card Fail. 2005;11:576–585; 6. Papademetriou et al. J Am Coll Cardiol. 2004;44:1175–1180; Brenner et al. N Engl J Med. 2001;345:861–869; 9. Pitt et al. Lancet. 2000;355:1582–1587; 10. Dickstein et al. Lancet. 2002;360:752–760; 11. Dahlof et al. Lancet. 2002;359:955–1003; 12. Cohn et al. N Engl J Med. 2001;345:1667–1675; Pfeffer et al. N Engl J Med. 2003;349:1893–1906; 15. Julius et al. Lancet. 2004;363:2022–2031; ,405 4,449 Val-HeFT 12 IRMA II 3 LIFE 11 ONTARGET ® 16 TRANSCEND ®16 PRoFESS ®16 NAVIGATOR 13 VALIANT 14 VALUE 15 OPTIMAAL 10 ELITE II 9 RENAAL 8 SCOPE 6 CHARM 7 MOSES 1 IDNT 4 I-Preserve 5 ROADMAP 2 Epro- sartan Lo- sartan Val- sartan Cande- sartan Irbe- sartan Telmi- sartan Olme- sartan 24

… with the broadest CV prevention indication in class (based on the ONTARGET trial program) Product information provided by EMA ( and eMC ( Lo- sartan Epro- sartan Irbe- sartan Olme- sartan Val- sartan Cande- sartan Telmi- sartan Hypertension Treatment of renal disease Prevention of stroke in LVH CV high risk Atherothrombotic CV disease such as: Coronary heart disease Peripheral vascular disease Stroke Type 2 diabetes with target organ damage Heart failure or LV dysfunction ✔✔✔✔✔✔ ✔ ✔✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔✔ Patients Based on the Data From The ONTARGET ® Trial Program 25

Telmisartan + Amlodipine ® key topics BP efficacy of Telmisartan + Amlodipine in added risk patients BP efficacy of Telmisartan + Amlodipine Safety & Tolerability of Telmisartan + Amlodipine 26

27 Telmisartan + Amlodipine : Provides consistent BP Reductions across hypertension severities 160 – < – < – < – <190 (n = 31) (n = 71 ) (n = 13) (n = 305) 1 Littlejohn et al. J Clin Hypertens. 2009;11:207–213; 2 Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10). T80/A10 Mean SBP reductions from baseline (mmHg) Baseline SBP = 140 – < – <160 (n = 39)(n = 34) Mild HTN 1 Severe HTN 2 Moderate HTN 1 27

28 Are you hungry or sleepy ???? Sciences Are you hungry or sleepy ???? Sciences

Telmisartan + Amlodipine : 80% of Maximum Effect within 2 Weeks Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10). A5 and T80/A5 for the first 2 weeks, then forced-titration to A10 and T80/A10, respectively; baseline BP = 185.4/103.2 mmHg – 37.9 mmHg – 47.5 mmHg Mean SBP (mmHg) Mean SBP reduction (mmHg) Week 8 80%* Week 2 Baseline 29

Telmisartan + Amlodipine : 83% at goal for a full 24 hour (< 130/80 mmHg) Patients achieving 24-h ABPM goal* (%) A10T80/A10 (n = 52)(n = 58) p < Littlejohn et al. J Hypertens. 2008;26(suppl 1):S494; White et al. Blood Press Monit. 2010: In press. 30

Telmisartan + Amlodipine key topics BP efficacy of Telmisartan + Amlodipine in added risk patients Safety & Tolerability of Temisartan + Amlodipine 31

Telmisartan + Amlodipine : Consistently High BP reductions in added-risk Hypertensive Patients Diabetes Obesity (BMI ≥ 30 kg/m 2 ) Metabolic syndrome*** n = 62 n = 175n = 36 Mean SBP reductions from baseline (mmHg) *Mean baseline BP = 160,7/90,5 mmHg; **Mean baseline BP = 185.4/103.2 mmHg ***Diabetes, obesity (BMI  30kg/m 2 ), and HTN T80/A10 severe HTN: SBP ≥180 – <200 mmHg 2 ** Mild-moderate HTN: SBP ≥150 – <180 mmHg 1 * 1 TEAMSTA diabetes study (data on file; Boehringer Ingelheim) 2 TEAMSTA severe HTN study (data on file, Boehringer Ingelheim) n = 320 n =

Safety & Tolerability of Telmisartan + Amlodipine Telmisartan + Amlodipine key topics 33

Decreased Glomerular pressure and filtration Amlodipine + Telmisartan L-type Ca channels Increased Glomerular pressure and filtration Amlodipine L-type Ca channels Renal Hyperfiltration Induced by Amlodipine is reduced by Telmisartan Peti-PeterdiPeti-Peterdi; Abstract ESC 2010 (submitted). 34

Telmisartan + Amlodipine : Up to 90% less edema compared to Amlodipine 10mg Littlejohn et al. J Clin Hypertens. 2009;11:207–213. A10 (n = 124) T40–80+A5 (n = 264) Patients with peripheral oedema (%) T40–80+A5–A10 (n = 543) p < –90%–71% 35

Why Telmisartan + Amlodipine, because it Combines the best in class compounds – unique PK/PD evidence – in a single-pill combination Provides powerful and ‘smart’ BP reductions and high 24h BP control including patients with added-risk such as diabetes and obese Has a safety & tolerability profile similar to placebo regardless of the Telmisartan dose being used (40 mg or 80 mg) and Telmisartan 80mg is the CV preventive dose in ONTARGET. 36

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About 50% of hypertensive patients remain uncontrolled (NHANES) -> similar results from EUROSPIRE Chobanian et al. Hypertension. 2003;42:1206–1252; Ong et al. Hypertension. 2007;49:69–75; Ostchega et al. NCHS Data Brief. 2008;3:1–38; Egan et al. JAMA. 2010;303:2043–2050. * BP control defined as BP < 140/90 mmHg; BP < 130/80 mmHg for patients with diabetes or CKD; includes treated and untreated patients, except ** (only treated patients) Percentage of population Year – – – – – – 2004 Failed to achieve BP control* 2005– 2006 ** 2007–

40 RATIONALE FOR THE USE OF FIXED-DOSE COMBINATIONS: COMPLIANCE AND PERSISTENCE  A single, once-daily pill simplifies the treatment regimen compared with agents given as separate pills –Increases convenience for patients –Reduces the pill burden  Increased convenience and lower pill burden likely to improve compliance to and persistence with antihypertensive medications –Overcomes a major barrier to effective BP control  Likely to cost less than the individual components prescribed separately Neutel. In: Oparil and Weber, eds. Hypertension. Companion to Brenner & Rector’s The Kidney. 2nd ed. Philadelphia: Elsevier Saunders, p. 522  9

41 CCB + ARB : The Synergies of Counter-Regulation (1) Synergistic BP reduction Complementary clinical benefits CCB  Arteriodilation  Peripheral oedema  Effective in low-renin patients  Reduces cardiac ischaemia CCB  RAS activation  No renal or CHF benefits BP MistryMistry et al. Expert Opin Pharmacother. 2006;7:575–581; SicaSica. Drugs. 2002;62:443–462; Quan et al. Am J Cardiovasc Drugs. 2006;6:103  113.Quan 41

42 THE CCB  ARB TARGETS TWO KEY BP EFFECTOR PATHWAYS (1) Sympathetic nervous system (SNS)  SNS activity → noradrenaline binds to α 1 -adrenergic receptors on vascular smooth muscle → vasoconstriction 1  SNS also stimulates renin secretion from the kidney, thereby activating the RAS 2  CCBs inhibit SNS-induced vasoconstriction by blocking influx of calcium ions (needed for contraction) through voltage-gated calcium channels → vasodilation 3,4  Other effects of CCBs: natriuresis; inhibition of aldosterone release; interference with angiotensin II-mediated vasoconstriction 4 1 Grassi. J Hypertens 2001;19:1713–16; 2 Mancia and Grassi. 3 Robertson and Robertson. In: Hardman JG, Limbard JG, editors-in chief. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 9th ed p. 759 – 79 4 Prisant. In: Oparil S, Weber MA, editors. Hypertension: Companion to Brenner & Rector’s The Kidney. 2nd ed p. 683–704

43 THE CCB  ARB TARGETS TWO KEY BP EFFECTOR PATHWAYS (2) Renin angiotensin system (RAS)  Release of renin catalyses conversion of angiotensinogen into angiotensin I, which is converted by ACE to angiotensin II → –Vasoconstriction; increased aldosterone and sodium/water retention; SNS activation  ARBs block the effects of angiotensin II by binding to AT 1 receptors –Arterial and venous dilation –Reduced SNS activity –Reduced secretion of aldosterone and increased secretion of sodium and water Mistry et al. Expert Opin Pharmacother 2006:7:575–81

Dzau et al. Circulation. 2006;114:2850–2870; Dzau, Braunwald. Am Heart J. 1991;121:1244–1263; Yusuf et al. Lancet. 2004;364:937–952; The ONTARGET Investigators. N Engl J Med. 2008;358:1547– Clinical Evidence With ARBs AFTER ONTARGET ® Heart failure Hypertension LIFE VALUE VALIANT CHARM Val-HeFT ELITE II CV high risk ONTARGET ® trial programme Remodelling MI and stroke Cardio/ cerebrovascular death ESRD Nephrotic proteinuria Macro- proteinuria Micro- albuminuria Endothelial dysfunction Atherosclerosis and LVH Ventricular dilation/ cognitive dysfunction CHF/ secondary stroke Risk factors: hypertension, diabetes, obesity, smoking, age 44

Telmisartan : Numerically better than Valsartan AgentBaseline BP Telmisartan+Amlodipine (all doses) 1 153/102 mmHg AgentBaseline BP Valsartan with: 2 5 mg amlodipine 10 mg amlodipine 153/99 mmHg 157/99 mmHg 1.TWYNSTA™ [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc, 2009; 2. Exforge [prescribing information]. East Hanover, CJ: Novartis Pharmaceuticals Corporation, mmHg † T40/A5T80/A5T40/A10T80/A10 SBP V160/A5V320/A5V160A10V320/A10 SBP * Indirect comparisons: study design varied; † Placebo-corrected values 45

T80/A10 BP goal rate (<140/90 mmHg) after 8 weeks (%) DiabetesObese BMI ≥ 30kg/m 2 Metabolic syndrome* * Presence of diabetes, obesity (BMI  30kg/m 2 ), and HTN (n = 23) (n = 71) (n = 13) 1 Factorial design study (data on file; Boehringer Ingelheim Pharmaceuticals, Inc); 2 TEAMSTA diabetes study (data on file, Boehringer Ingelheim) More mild systolic HTN (baseline BP 153.2/101.7 mmHg) 1 More moderate systolic HTN (baseline BP 160.7/90.5 mmHg) 2 (n = 320) Telmisartan + Amlodipine : up to 87% of added-risk hypertensive patients archive BP goal (n = 198) 46

Telmisartan + Amlodipine : Comparable Safety & Tolerability Profile of 80/5-10 and 40/5-10 combinations 1. Neldam et al. ESH 2010 poster presentation (P-95) 2. Neldam et al. ESH 2010 poster presentation (P-90) Drug related AEs Peripheral edema AEs leading to premature discontinuation Serious AEs Patients per 100 patient years T80/A5-10 1,2 (n=1008) T40/A5-10 1,2 (n=1814) AE = Adverse events 47