高血圧治療薬のパイプライン分析

Overview

Introduction

Analysis of key late stage developmental therapies in the anti-hypertensives market.

• It is no longer possible to identify one particular class of drugs as the current gold-standard treatment in hypertension.
• While many physicians remain frustrated by the limited capability of individual antihypertensive agents to lower blood pressure to target levels, there is no superclass on the horizon with the ability to treat hypertension effectively using monotherapy. Instead, the solution will lie in physicians' acceptance of the need to use effective drug combinations earlier in treatment and the wider issue of patient education and involvement in therapy decisions.
• The need to address risk factors beyond hypertension, in particular raised lipids, has led to a demand for combination therapies that can treat more than one risk factor at a time. Antihypertensive combinations, both with and without a statin, are likely to be common in the future.
• BMS's vasopeptidase inhibitor Vanlev (omapatrilat) had demonstrated the greatest antihypertensive efficacy among novel compounds in recent years, giving rise to the development of several other potential members in this class. However, it appears that fear of litigation surrounding the potential for angioedema has restricted further progress of this class.
• Despite continued research into logical hypertension targets such as endothelin and vasopressin, the potential for any of these agents to be successful in the treatment of essential hypertension appears limited.
• The only agent likely to significantly challenge the unbridled growth of the ARBs during the forecast period will be Novartis's oral renin inhibitor, aliskiren. While renin inhibition has long been a logical therapeutic objective, formulation difficulties had kept it an elusive goal until now. Its intervention in the familiar renin angiotensin aldosterone system (RAAS) at a point earlier than both ACE inhibitors and ARBs may mean it will offer superior blockade of the RAAS than either class without the bradycardia-related side effects of ACE inhibitors.

TABLE OF CONTENTS

ABOUT DATAMONITOR HEALTHCARE

• About the Cardiovascular pharmaceutical analysis team

CHAPTER 1 EXECUTIVE SUMMARY

• Scope of the analysis
• Datamonitor insight into the hypertension market
• It is no longer possible to identify one particular class of drugs as the current gold-standard treatment in hypertension.
• While many physicians remain frustrated by the limited capability of individual antihypertensive agents to lower blood pressure to target levels, there is no superclass on the horizon with the ability to treat hypertension effectively using monotherapy. Instead, the solution will lie in physicians' acceptance of the need to use effective drug combinations earlier in treatment and the wider issue of patient education and involvement in therapy decisions.
• The need to address risk factors beyond hypertension, in particular raised lipids, has led to a demand for combination therapies that can treat more than one risk factor at a time. Antihypertensive combinations, both with and without a statin, are likely to be common in the future.
• BMS's vasopeptidase inhibitor Vanlev (omapatrilat) had demonstrated the greatest antihypertensive efficacy among novel compounds in recent years, giving rise to the development of several other potential members in this class. However, it appears that fear of litigation surrounding the potential for angioedema has restricted further progress of this class.
• Despite continued research into logical hypertension targets such as endothelin and vasopressin, the potential for any of these agents to be successful in the treatment of essential hypertension appears limited.
• The only agent likely to significantly challenge the unbridled growth of the ARBs during the forecast period will be Novartis's oral renin inhibitor, aliskiren. While renin inhibition has long been a logical therapeutic objective, formulation difficulties had kept it an elusive goal until now. Its intervention in the familiar renin angiotensin aldosterone system (RAAS) at a point earlier than both ACE inhibitors and ARBs may mean it will offer superior blockade of the RAAS than either class without the bradycardia-related side effects of ACE inhibitors.
• Summary
• Key metrics

CHAPTER 2 PATIENT POTENTIAL

• Definition of hypertension
• A cardiovascular risk factor
• Chronic asymptomatic condition
• Attractive target for R&D
• Additional indications
• Segmentation of hypertension
• Diagnostic criteria
• Markers of hypertension
• Systolic blood pressure
• Diastolic blood pressure
• Systolic-diastolic hypertension
• Pulse pressure
• Isolated systolic hypertension (ISH)
• Which markers are most important?
• Target organ damage
• Screening
• Measuring blood pressure
• Hypertension subtypes
• Hypertension in African-American patients
• Patients with diabetes or renal insufficiency
• Elderly hypertensives
• Epidemiology of hypertension
• Prevalence of hypertension
• Methodology
• US
• Japan
• France
• Germany
• Italy
• Spain
• UK
• Summary
• Unmet needs in hypertension
• Environmental unmet needs
• The need for earlier use of combination therapy
• Greater availability of logical two- and three-drug combinations
• Increased diagnosis and treatment of ISH
• Greater patient involvement in therapy
• Clinical unmet needs
• Ability to reduce SBP more effectively with a single agent
• Treatment that targets several risk factors at once
• Ability to reduce microalbuminuria and LVH
• Other potential unmet needs
• Overall assessment criteria
• Comparators used to assess each criterion

CHAPTER 3 R&D APPROACH

• Definition of current comparator therapy
• Is there a gold standard in hypertension?
• Selecting a suitable comparator
• Classification of pipeline products
• Launched product classes
• Diuretics
• MECHANISM OF ACTION
• USE IN MONOTHERAPY
• VALUABLE IN COMBINATION THERAPY
• WIDELY, THOUGH DECREASINGLY, USED IN HEART FAILURE
• LEADING DIURETICS
• Beta blockers
• MECHANISM OF ACTION
• CARDIOSELECTIVITY
• INTRINSIC SYMPATHOMIMETIC ACTIVITY (ISA)
• LIPID SOLUBILITY
• DOMINATED ANTIHYPERTENSIVE THERAPY IN THE 1980S
• Centrally acting agents
• RARELY USED DUE TO POOR SIDE-EFFECT PROFILES
• Alpha blockers
• MAINLY USED FOR BENIGN PROSTATIC HYPERPLASIA
• POOR SIDE-EFFECT PROFILE
• SELECTIVE ALPHA BLOCKERS - MORE POTENT AND BETTER TOLERATED
• ALLHAT TRIAL - A MAJOR SETBACK FOR ALPHA BLOCKERS
• Calcium channel blockers
• MECHANISM OF ACTION
• SALES DRIVEN BY ADDITIONAL INDICATIONS
• PFIZER'S NORVASC LEADS THE MARKET
• ACE inhibitors
• MECHANISM OF ACTION
• SIDE-EFFECT ADVANCE ON OLDER DRUGS
• A RANGE OF ADDITIONAL INDICATIONS
• LOSING PATENT PROTECTION
• Angiotensin II receptor blockers (ARBs)
• MECHANISM OF ACTION
• SIDE EFFECTS COMPARABLE TO PLACEBO
• NOVARTIS'S DIOVAN LEADS THE MARKET
• Developmental product classes
• Neutral endopeptidase inhibitors (NEPs)
• Vasopeptidase inhibitors
• Neutral peptidase/endothelin converting enzyme inhibitors
• Endothelin receptor antagonists
• THE ENDOTHELIUM
• ENDOTHELIN: A POTENT VASOCONSTRICTOR
• Oral renin inhibitors
• AGE crosslink breakers
• Sodium/potassium ATPase modulators
• Clinical trial design in hypertension
• Mortality endpoints
• Adequately powered
• Significant numbers of each sub-population
• Use of the gold standard as comparator drug
• Morbidity endpoints
• Use of surrogate markers
• Key research impacts on hypertension
• Outcome-based endpoints
• Impact of clinical trial duration on R&D budget

CHAPTER 4 HYPERTENSION PIPELINE ANALYSIS

• Pipeline overview
• Key companies involved in the hypertension pipeline
• Novartis
• Focused portfolio
• Focused approach to launch
• Novel, yet realistic, commercial approach
• Speedel
• Cherry picking
• Leader in oral renin inhibitors

CHAPTER 5 DRUGS ACTING ON RENIN ANGIOTENSIN SYSTEM

• Vasopeptidase inhibitors
• Overview of vasopeptidase inhibitors
• Pipeline summary
• Vanlev
• Profile
• Clinical trial data
• OMAPATRILAT VERSUS LISINOPRIL
• OCTAVE STUDY
• FDA ADVISORY COMMITTEE DECISION
• CLINICAL TRIALS SINCE OCTAVE
• Marketing factors
• Patient potential
• SWOT analysis
• Unmet needs analysis
• Forecast to 2012
• AVE 7688
• Profile
• Clinical trials
• Marketing factors
• Patient potential
• VEP inhibitors in early-stage development
• 796406
• Recently discontinued VEP inhibitors
• Fasidotril
• PROFILE
• CLINICAL TRIAL DATA
• MARKETING FACTORS
• PATIENT POTENTIAL
• Sampatrilat
• MDL 100240
• Gemopatrilat
• Z13752A (GW 660511X)
• Conclusions for VEP Inhibitors
• NEP/ECE inhibitors
• SLV306
• Profile
• Clinical trial data
• Patient potential
• Marketing factors
• SWOT analysis of class
• Oral renin inhibitors
• Pipeline summary
• Aliskiren (SPP100)
• Profile
• Clinical trial data
• PHASE I
• PHASE IIA
• PHASE IIB
• Marketing factors
• Patient potential
• SWOT analysis
• Unmet need analysis
• Forecast to 2012
• Other oral renin inhibitors
• Angiotensin receptor blockers (ARBs)
• Pipeline overview
• Pratosartan
• Profile
• Clinical trials
• Patient potential
• SWOT analysis
• Unmet needs assessment
• Forecasts
• ACE inhibitor/calcium channel blocker combinations
• Pipeline overview
• Lercanidipine/enalapril combination
• Profile
• Clinical trials
• Marketing factors
• Patient potential
• SWOT analysis
• Unmet need analysis
• Forecast
• Summary forecast of key pipeline products acting on renin angiotensin system

CHAPTER 6 DRUGS NOT ACTING ON RENIN ANGIOTENSIN SYSTEM

• Calcium channel blockers
• Pipeline overview
• Clevelox (clevidipine)
• Profile
• Clinical trial data
• Marketing factors
• Patient potential
• SWOT analysis
• Unmet needs assessment
• Forecast
• S-amlodipine
• Profile
• Clinical trial data
• Marketing factors
• Patient potential
• SWOT analysis
• Unmet needs analysis
• Forecast
• Discontinued calcium channel blockers
• Lemildipine
• Oxodipine
• AGE crosslink breakers
• Pipeline overview
• ALT-711 (alagebrium chloride)
• Profile
• Clinical trial data
• PRECLINICAL STUDIES
• PHASE II STUDIES
• FUTURE STUDIES
• Marketing factors
• Patient potential
• SWOT analysis
• Summary of class
• Na+/K+ ATPase inhibitors
• Pipeline overview
• PST 2238
• Profile
• Clinical trials
• Patient potential
• Marketing factors
• SWOT analysis
• Unmet needs assessment
• SWOT analysis
• Endothelin receptor antagonists
• Pipeline overview
• ERAs in Phase III for indications other than hypertension
• Sitaxsentan
• Tezosentan
• Ambrisentan
• ERAs in Phase II development for hypertension
• Darusentan
• PROFILE
• CLINICAL TRIALS
• MARKETING FACTORS
• PATIENT POTENTIAL
• SPP301
• PROFILE
• CLINICAL TRIALS
• MARKETING POTENTIAL
• ERAs in Phase I
• TBC3711
• J104132
• SB234551
• Phase I ERAs no longer in development
• PD-180988 (CI-1034)
• SWOT analysis
• Other novel drugs in Phase II and above
• Pipeline overview
• MC-4232 (Cardoxal)
• Profile
• Clinical trials
• Marketing factors
• Patient potential
• Summary forecasts of pipeline antihypertensives not acting via the RAAS

CHAPTER 7 KEY PHASE I COMPOUNDS

• Pipeline overview
• Angiotensin vaccine
• PMD 3117
• Profile
• Clinical trials
• Marketing factors
• Patient potential
• SWOT analysis

APPENDIX

• Contributing experts
• Bibliography
• Epidemiology
• Epidemiology Internet resources
• Clinical trial data
• Report methodology
• About Datamonitor
• About Datamonitor Healthcare
• Datamonitor Healthcare's research and analysis methodologies
• Datamonitor Healthcare's therapy area capabilities
• About the Cardiovascular analysis team
• Disclaimer

List of Tables

• Table 1: Prevalence of hypertension in the seven major markets (000s), 2004-12
• Table 2: Key global parameters of hypertension, 2004-12
• Table 3: Global antihypertensive market value, 2003
• Table 4: Pipeline drugs in development for hypertension 2004
• Table 5: Forecast key products in hypertension pipeline ($m), 2005-12
• Table 6: European Society of Hypertension definitions and classification of blood pressure levels
• Table 7: ESH stratification of cardiovascular risk based on blood pressure and other factors
• Table 8: BHS guidelines, 2004
• Table 9: JNC VII: categories of hypertension
• Table 10: JNC VII: recommended treatment for hypertension
• Table 11: JNC VII: recommended treatment for compelling indications
• Table 12: Blood pressure thresholds (mmHg) for definition of hypertension based on different types of measurement
• Table 13: Prevalence of hypertension in the seven major markets (000s), 2003-12
• Table 14: Unmet need comparators selected for baseline drug performance with weighting and score
• Table 15: Quantitative measures used for clinical efficacy endpoints
• Table 16: Pipeline drugs in development for hypertension 2004
• Table 17: Pipeline drugs in development for hypertension that act via the RAS 2004
• Table 18: Key products in R&D pipeline for the vasopeptidase inhibitor class, 2004
• Table 19: Risk of angioedema observed in the OCTAVE trial
• Table 20: Assumptions and factors influencing Vanlev's sales forecast
• Table 21: Key NEP/ECE products in the R&D pipeline 2004
• Table 22: Key products in R&D pipeline for the oral renin inhibitor class, 2004
• Table 23: Baseline clinic blood pressures and heart rates, and changes from baseline with treatment
• Table 24: baseline demographics aliskiren vs. irbesartan
• Table 25: Assumptions and factors influencing aliskiren's sales forecast
• Table 26: Key products in R&D pipeline angiotensin II receptor blockers
• Table 27: Assumptions and factors influencing pratosartan's sales forecast
• Table 28: Key ACE inhibitor combinations in late-stage R&D pipeline, 2004
• Table 29: Assumptions and factors influencing lercanidipine/enalapril combination sales forecast
• Table 30: Forecast key pipeline antihypertensive products acting on RAS ($m), 2005-12.
• Table 31: Pipeline drugs in development for hypertension, 2004
• Table 32: Key calcium channel blockers in late-stage R&D pipeline, 2004
• Table 33: Assumptions and factors influencing Clevelox's sales forecast
• Table 34: Assumptions and factors influencing S-amlodipine's sales forecast
• Table 35: Key products in the R&D pipeline 2004 AGE crosslink breakers
• Table 36: Clinical trial summary ALT-711
• Table 37: Results of Phase IIa study in vascular compliance
• Table 38: Sodium/potassium ATPase inhibitors in development for the treatment of hypertension, 2004
• Table 39: Key products in R&D pipeline for the endothelin receptor antagonists class, 2004
• Table 40: Key novel agents in development, Phase II and above, 2004.
• Table 41: Forecast key products in hypertension pipeline
• Table 42: Key Phase I R&D products in hypertension pipeline 2004.

List of Figures

• Figure 1: Key impacts on the hypertension market to 2012
• Figure 2: Overview of hypertension pipeline by phase and company, 2004
• Figure 3: Clinical and environmental unmet needs in hypertension
• Figure 4: Greatest unmet environmental needs in hypertension 2004
• Figure 5: Greatest clinical unmet needs in hypertension 2004
• Figure 6: Baseline for drug comparison
• Figure 7: ACE inhibitors and angiotensin II receptor blockers: mechanism of action
• Figure 8: Clinical trial design criteria in hypertension
• Figure 9: Breakdown of Novartis turnover by therapy area, 2003
• Figure 10: Mechanism of action of classes acting on RAS and NEP system
• Figure 11: Octave trial design
• Figure 12: BMS therapeutic focus, 2003
• Figure 13: SWOT analysis of vasopeptidase inhibitors
• Figure 14: Vanlev unmet needs analysis
• Figure 15: Global sales forecast for Vanlev ($m), 2006-12
• Figure 16: Fasidotril placebo-controlled trial, Laurent et al. 2000
• Figure 17: SWOT analysis for VEP inhibitors
• Figure 18: SWOT analysis neutral endopeptidase and endothelin converting enzyme inhibitors
• Figure 19: Aliskiren vs. losartan trial design, Stanton et al., 2003.
• Figure 20: 24-hour ABPM results aliskiren vs. losartan
• Figure 21: Aliskiren vs. irbesartan trial design
• Figure 22: Reduction in mean sitting SBP from baseline at week eight; aliskiren vs. irbesartan
• Figure 23: SWOT analysis for aliskiren
• Figure 24: Aliskiren unmet needs analysis
• Figure 25: Global sales forecast for aliskiren ($m), 2007-12
• Figure 26: SWOT analysis for Pratosartan
• Figure 27: Pratosartan unmet needs assessment
• Figure 28: Global sales forecast for pratosartan ($m), 2006-12
• Figure 29: SWOT analysis for Recordati CCB/ACE-I combination
• Figure 30: Unmet needs analysis Recordati lercanidipine/enalapril combination
• Figure 31: Global sales forecast for lercanidipine/enalapril combination ($m), 2005-12.
• Figure 32: SWOT analysis for Clevelox
• Figure 33: Unmet needs assessment Clevelox
• Figure 34: Global sales forecast for Clevelox ($m), 2008-12
• Figure 35: SWOT analysis for S-amlodipine
• Figure 36: S-amlodipine unmet needs analysis
• Figure 37: Global sales forecast for S-amlodipine ($m) , 2008-12
• Figure 38: Trial design for Phase IIa study in hypertension with arterial stiffening, Kass et al,. 2001
• Figure 39: SWOT analysis alagebrium chloride
• Figure 40: Alagebrium chloride unmet needs assessment
• Figure 41: SWOT analysis Na+/K+-ATPase modulators
• Figure 42: SWOT Analysis for PST 2238
• Figure 43: SWOT analysis endothelin receptor antagonists (ERAs)
• Figure 44: The action of Protherics' angiotensin I vaccine
• Figure 45: SWOT analysis angiotensin vaccine