New Drugs in Hypertension

Transcription

1 New Drugs in Hypertension David Webb MD FRCP FMedSci FRSE BHF Centre of Research Excellence (CoRE), The University of Edinburgh 16 th May, 2017 Royal College of Physicians, London

2 Outline: New Drugs for Hypertension 1. Why we need new drugs? 2. Why are they hard to develop? 3. Where are the key opportunities? 4. What may emerge in the near-term?

3 ESH / ESC Guidelines The main benefits of antihypertensive therapy are due to lowering BP alone J Hypertens 2003;21:

4 ESH / ESC Guidelines The main benefits of antihypertensive therapy are due to lowering BP alone J Hypertens 2003;21: An accepted surrogate (for reducing stroke, MI and HF)

5 Do we really need new drugs? ACEIs: Captopril Enalapril Lisinopril Perindopril Quinapril Ramipril etc. ARBs: Candesartan Irbesartan Losartan Olmesartan Telmisartan Valsartan etc. Central: Methyldopa Clonidine Moxonidine Vasodilators: Hydralazine Minoxidil CEBs: Amlodipine Diltiazem Nifedipine Verapamil etc. a-blockers: Doxazosin Indoramin Prazosin Terazosin Phenoxybenzamine Phentolamine b-blockers: Atenolol Bisoprolol Metoprolol Propranolol etc. Renin inhib: Aliskiren Thiazide/like: Bendroflumethiazide Chlortalidone Hydrochlorthiazide Indapamide Metolazone etc. Loop: Bumetanide Furosemide Torasemide K+ sparing: Amiloride Triamterene Eplerenone Spironolactone

6 The life cycle of a medicine

7 The life cycle of a medicine

8 The life cycle of a medicine RoI + profit

9 The life cycle of a medicine

10 Global burden of hypertension: huge! Ezzati & Riboli et al. NEJM 2013;369:954-64

11 Global burden of hypertension: huge! Critical to: Stroke Myocardial infarction Angina pectoris Heart failure CKD progression Diabetes outcomes Ezzati & Riboli et al. NEJM 2013;369:954-64

12 Hypertension: still on the rise globally Ageing populations Obesity/diabetes epidemic Western diets now ubiquitous

13 Side effects of treatment: common ACE inhibitors: cough, renal dysfunction Beta-blockers: wheeze, cold peripheries, lassitude, exercise intolerance, bad dreams, impotence, heart block, diabetes Calcium antagonists: headaches, flushing, ankle swelling, tachycardia Diuretics: impotence, rashes, low Na+, low K+, diabetes, gout

14 Compelling indications HF: diuretic, BB, ACEI/ARB, Aldo antag Post-MI: BB, ACEI, Aldo antag High coronary risk: diuretic, BB, ACEI, Aldo antag Diabetes: diuretic, BB, ACEI/ARB, CCB CKD: ACEI/ARB Recurrent stroke prevention: diuretic, ACEI Isolated systolic HTN: CEB

15 What do we need from new approaches? Bigger effects on BP Better tolerated Better safety Better targeted Additional benefits e.g. on arterial stiffness, endothelial function, proteinuria) i.e. Bigger effects or benefits beyond BP reduction

16 New opportunities: beyond BP reduction Treatment-resistant hypertension - Manifest failure of existing therapy Diabetic nephropathy End-stage renal disease/dialysis - Direct outcome studies possible

17 Future therapies in hypertension? Endothelin receptor antagonists (ambrisentan) Phosphodiesterase type 5 inhibitors (sildenafil, tadalafil) Soluble guanylate cyclase stimulators (riociguat) Dual ECE/neprilysin inhibitors (daglutril) Dual ARB/neprilysin inhibitors (valsartan/sacubitril) New mineralocorticoid receptor antagonists (finerenone) SGLT-2 inhibitors (empagliflozin) Aldosterone synthase inhibitors (LCI 699) Xanthine oxidase inhibitors (allopurinol) AGE breakers (alagebrium)

18 Future therapies in hypertension? Endothelin receptor antagonists (ambrisentan) Phosphodiesterase type 5 inhibitors (sildenafil, tadalafil) Soluble guanylate cyclase stimulators (riociguat) Dual ECE/neprilysin inhibitors (daglutril) Dual ARB/neprilysin inhibitors (valsartan/sacubitril) New mineralocorticoid receptor antagonists (finerenone) SGLT-2 inhibitors (empagliflozin) Aldosterone synthase inhibitors (LC1699) Xanthine oxidase inhibitors (allopurinol) AGE breakers (alagebrium)

19 Future therapies in hypertension? Endothelin receptor antagonists (ambrisentan) Phosphodiesterase type 5 inhibitors (sildenafil, tadalafil) Soluble guanylate cyclase stimulators (riociguat) Dual ECE/neprilysin inhibitors (daglutril) Dual ARB/neprilysin inhibitors (valsartan/sacubitril) New mineralocorticoid receptor antagonists (finerenone) SGLT-2 inhibitors (empagliflozin) Aldosterone synthase inhibitors (LC1699) Xanthine oxidase inhibitors (allopurinol) AGE breakers (alagebrium)

20 Focus on the vascular endothelium Endothelin receptor antagonists (darusentan, atrasentan) Phosphodiesterase type 5 inhibitors (PF )

21 Targetting ET-1 in TRH

22 ET antagonists in TRH Pro: reduce blood pressure reduce arterial stiffness reduce proteinuria reduce inflammation improve endothelial function Dhaun et al., Hypertension 2008;52: Con: teratogenic (limited risk in TRH) can cause fluid retention - Use low doses, assess weight, early diuretic, BNP Weber et al., Lancet 2009;374:

23 Krum et al., New Engl J Med 1998;338: Bosentan reduces BP in primary hypertension 293 patients with mild/moderate HT Bosentan, enalapril 20mg or placebo; for 4 weeks Diastolic BP Systolic BP

24 Darusentan in TRH: DORADO Phase 2/3 Study Double-blinded RCT over 14 weeks Darusentan 50, 100 and 300mg daily Placebo control 379 patients with TRH 97% on ACEI/ARB 40% with proteinuria Co-primary endpoint: D clinic SBP & DBP Weber et al., Lancet 2009;374:

25 Darusentan in TRH: DORADO Phase 2/3 Study 60% reduction in proteinuria No change in serum K+ Modest reduction in egfr Weber et al., Lancet 2009;374:

26 Darusentan in TRH: DORADO-AC Phase 3 Study Double-blinded RCT over 14 weeks Darusentan mg daily (as per PI) Placebo and guanfacine (active) controls 849 patients (120 P; 364 D; 365 G) Co-primary endpoint: D clinic SBP & DBP Bakris et al., Hypertension 2010;56:824-30

27 Darusentan in TRH: DORADO-AC Phase 3 Study Age 63 yrs; ~45% female; 10% black; Entry clinic BP 152/88; ABPM 134/79 100% on diuretics 96% on ACEI/ARB 41% with type 2 diabetes BMI ~31 ~30% with albuminuria ~25% with CKD Bakris et al., Hypertension 2010;56:824-30

28 Darusentan in TRH: DORADO-AC Study Bakris et al., Hypertension 2010;56:824-30

29 Darusentan in TRH: DORADO-AC Study Systolic BP Diastolic BP Bakris et al., Hypertension 2010;56:824-30

30 Darusentan in TRH: DORADO-AC Study a lesson learned from the current trial is that future hypertension trials should seriously consider using change in ambulatory BP, rather than office BP, as the primary end point. Bakris et al., Hypertension 2010;56:824-30

31 Kohan et al., J Am Soc Nephrol 2011;22:763

32 Atrasentan: Phase 3 trial design Weight gain >3kg Oedema BNP >300pg/ml Heart failure STOP Double Blind Treatment Period (Estimated 425 Events) Screening Period (up to 14 Days) Run-In Period 2 weeks if receiving max tolerated labeled dose of RAS Run-In Period 4 to 12 weeks if not receiving max tolerated labeled dose of RAS 6 Week Enrichment Period Atrasentan 0.75 mg QD > 30% UACR reduction < 30% UACR reduction R R Atrasentan 0.75 mg QD (1574 subjects) Placebo QD (1574 subjects) Atrasentan 0.75 mg QD (500 subjects) Placebo QD (500 subjects) Follow-Up Period (45 Days) 2 Weeks 7 Weeks Up to 12 Weeks Randomization 48 Months Primary endpoint: Time to first occurrence of renal composite event defined as a doubling of serum creatinine, or the onset of end stage renal disease (need for dialysis or renal transplantation) Final Tx Period Visit (T48)

33 Opposites in blood vessel regulation Endothelin Vessel constricting Pro-Inflammatory Pro-clotting Nitric oxide Vessel dilating Anti-inflammatory Anti-clotting

34 Oliver et al., Hypertension 2006;48:622-7 Oliver et al., Hypertension 2010;56:62-7 Generator Cell Target Cell O 2 L-citrulline GTP cgmp NO NO-haem GC SNOs Nitrosothiols (SNO) PDE5 inhibitors

35 Brown et al., Hypertension 2014;63:5-11

36 PDE5 inhibition reduces albuminuria in diabetic nephropathy (DN) 256 patients with DN egfr UACR>300mg/g All on ACEI/ARB PF mg or placebo (3:1) Safe Well tolerated UACR reduced 16% at 12 weeks Scheele et al., JASN 2016;27:

37 Pill burden poor adherence

38 Polypills Improve adherence Generally well tolerated Reduce risk factor levels

39 Gradman AH. Lancet 2017;389: Polypills Improve adherence Generally well tolerated Reduce risk factor levels Further investigation of the paradigm of ultra-low-dose quadruple therapy for simplified treatment initiation in patients with hypertension is clearly warranted.

40 Immunisation? Tissot et al., Lancet 2008;56:824-30

41 Conclusions There are likely to be cost-effective new medicines for hypertension emerging in the next few years, either: directly for targeted high-risk groups, or indirectly through repurposing after patent expiry

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43 Are devices the way forward? Don t be seduced! The regulatory burden of evidence on safety and efficacy is much lower The placebo effect is very powerful Need randomized, blinded, placebo/sham controlled trials We mustn t rely on small studies/post-hoc analyses SYMPLICITY-3 should not be a one-off!

44 Genotype-driven treatment: uromodulin (UMOD) polymorphism UMOD (Tamm-Horsfall protein): Expressed in TAL Regulates Na+ homeostasis SNPs in GWAS linked to GFR & BP Hypothesis (BHF funded): People with uncontrolled hypertension possessing the rs aa genotype will show a sustained better response to loop diuretic (torasemide) than those possessing the G allele. Padmanabhan et al., Hypertension 2014;64:918-23

45 Conflicting interests I am a member of the DSMB for AbbVie s SONAR phase 3 study with the endothelin antagonist atrasentan in diabetic nephropathy I am President of the BPS, and a Board member of MHRA, but this talk represents my personal views, not those of these organisations I will talk about licensed medicines in indications for which they are not licensed