Cardiovascular Disease: Recent Drug Advances and Impending Risks

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1 Brochure More information from Cardiovascular Disease: Recent Drug Advances and Impending Risks Description: There are nearly 300 medicines in clinical development to treat cardiovascular disease. This new research report examines in detail the key areas of the cardiovascular (CV) market, gathering inside opinion of cardiologists, to highlight the dynamic changes that are underway in this multibillion dollar marketplace. Successful players will, necessarily, need to cannibalise their existing cardiovascular franchises in order to limit the impact of generic erosion when their patents expire, whilst at the same time investing in alternative therapies with better, more efficacious outcomes. This is a significant challenge given the high barrier to entry and unmet clinical needs. Not only is cardiovascular disease a Silent Killer, it is also a commercial time bomb where the risk/reward ratio for any company willing to participate needs to be carefully considered. This report provides you with a systematic appraisal into the current and future CV market, including... - A detailed review of the leading brands and how they are being positioned in the market, in addition to the potential impact of generics - Assessment of key products in development, identifying Ones to Watch in late-stage clinical development where proof of concept data has been established - Review of products that are Waiting in the Wings in early-stage clinical development where Point-of-Care data is being gathered - Analysis of the potential of Long Shots which represent new and innovative products where the scientific rationale has yet to be fully tested ANTILIPIDEMICS The lowering of bad cholesterol or low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs) has been shown to reduce the chance of a heart attack and death in people who have an elevated risk of developing heart disease or who already have heart disease. Several drug classes are currently available to treat a range of lipid disorders; each has a different mechanism of action, safety profile and impact on blood lipid profiles to different degrees. Key drugs covered by the report include: - Leading brands - Lipitor (Pfizer), Crestor (AstraZeneca), Livalo (Kowa and Partners), etc... - Recent generics - Atorvastatin, etc Alirocumab (Sanofi/Regeneron Pharmaceuticals), AMG 145 (Amgen), Anacetrapid (Merck & Co), etc RG 7652 (Roche), RN-316 (Pfizer), DRL (Dr Reddy), etc... - Long shots - ALN PCS (Alnylam/The Medicine Company), etc... Key Questions Answered - Why are statins the gold stand in lipid lowering therapies and which is the most effective at lowering LDL-C? - Will AstraZeneca s Crestor win its fight for supremacy before generic rosuvastatin reaches the market? - Why are PCSK9 inhibitors important to cardiologists and which drugs are leading the field? - Kynamro approved in the US but not in Europe: what next? - What new HDL-C modulating therapies are in development? - What new products are in development from BMS/Simcere; Dr Reddy and DezimaPharma? ANTICOAGULANTS Anticoagulant therapy is the mainstay for the prevention and treatment of thrombotic complications. Doctors commonly give patients anticoagulation therapy during invasive procedures such as angioplasty or coronary stents as well as during elective knee and hip replacement surgery and abdominal surgery where there is an increased risk of blood clots. In addition, patients with an increased risk of thrombosis and/or thromboembolism such as those with acute coronary syndrome (ACS), those suffering with atrial fibrillation

2 (AF; an erratic heart beat) or those with a history of stroke, are often treated with anticoagulant medicines to improve clinical outcomes. Key drugs covered by the report include: - Leading brands - Coumadin (Bristol-Myers Squibb), Praxada (Boehringer Ingelheim), Xarelto (Bayer/Johnson & Johnson), etc... - Recent generics - Clopidogrel, Enoxaparin sodium, etc Otamixaban (Sanofi), Vorapaxar (Merck & Co.), etc Betrixaban (Portola Pharmaceuticals) - Long shots - EP (EndotisPharma), etc Just some of the key questions answered include: - Have the new OAPs changed the treatment paradigm for patients at high risk from stroke? - Will Effient maintain its head start or will the TRIOLOGY ACS trial cause it to stumble? - What warfarin alternatives have entered the market? - Boehringer Ingelheim s Pradaxa is first to the market but what safety issues have been flagged up? - Why has GlaxoSmithKline's Arixtra failed to impress? - What new anticoagulant drug classes are in development and who is leading the field? ANTIHYPERTENSIVES High blood pressure or hypertension is a highly prevalent cardiovascular risk factor which is associated with an increased risk of heart attack and stroke. The renin-angiotensin-aldosterone system (RAAS) is widely accepted as the key pathway in the regulation of blood pressure and body volume and has been the target for a cocktail of antihypertensive drugs that include angiotensin receptor blockers (ARBs), angiotensinconverting-enzyme (ACE) inhibitors, aldosterone antagonists and more recently the direct renin inhibitors (DRIs). Key drugs covered by the report include: - Leading brands - Avapro (Sanofi/Bristol-Myers Squibb), Diovan (Novartis), Edarbi (Takeda), etc... - Recent generics - Irbesartan, etc LCZ696 (Novartis), etc DSP-9599 (Dainippon Sumitomo Pharma), etc... - Long shots - DARA (Retrophin), etc... Just some of the key questions answered include: - What impact have generics had on the sale of Avapro? - Why have Diovan generics been slow off the mark and have pill combinations offered any protection? - Will Takeda s Edarbi become the new gold standard in a market dominated by generics? - Why has Tekturna not lived up to its promise, do direct renin inhibitors have a future? - What innovative DRIs are in clinical development? - What new drug classes are next in line to transform the antihypertensive market? Contents: Scope of the report Catalyst About the author SECTION 1: ANTILIPIDEMICS Introduction - where we are now? What is the gold standard lipid lowering therapy? Which statin is most effective at lowering LDL-c? What impact has generic atorvastatin had on Lipitor? What impact has generic Lipitor had on statin prescriptions? Will AstraZeneca s crestor win the fight for supremacy?

3 When will generic rosuvastatin reach the market? Is statin safety really an issue? can Livalo differentiation itself from the pack? Statins - Market forecasts New drugs on the block Approach 1: LDL-C reducing therapies: Drug class 1: PSCK9 inhibitors can new LDL-c reducing therapies supersede statins? Why are pcsk9 inhibitors important to cardiologists? Alirocumab (Sanofi/regeneron pharmaceuticals) Sanofi s comprehensive trial program Corporate strategy AMG 145 (Amgen) Amgen s comprehensive trial program Corporate strategy rg 7652 (roche) rn-316 (pfizer) Long shots ALN pcs (Alnylam/the Medicine company) PCSK9 inhibitors - Market forecasts Approach 1: LDL-C reducing therapies: Drug class 2: Apo B modulators Sanofi s Kynamro approved in the US but not in Europe: what next? Why have Mtp inhibitors established a niche in hofh patients? Juxtapid (Aegerion pharmaceuticals) Apo B modulators - Market Forecasts Approach 2: HDL-C modulating therapies: Drug class 3: CETP inhibitors Is hdl-c elevation a feasible alternative to LDL-c lowering strategies in lipid control? Does niacin have a future following the withdrawal of Merck s tredaptive? What new hdl-c modulation therapies are in development? can the new cept inhibitors succeed where others have failed? Anacetrapid (Merck) evacetrapid (eli Lilly) DrL (Dr reddy) BAY (Bayer healthcare AG) BMS (Bristol-Myers Squibb/Simcere pharmaceutical Group) DeZ-001 (Dezima pharma) Long shots Ath03 (AffiriS AG) CETP inhibitors - Market forecasts Approach 2: HDL-C modulating therapies: Drug class 4: Apo A-1 mimetics Are apoliproprotein A-I enhancing agents commercially viable? rvx-208 (resverlogix) reverse D-4f (Abbott/Arisaph pharmaceuticals) Apo A-1 enhancing compounds, what the future holds (market forecasts) Antilipidemics overall conclusions SECTION 2: ANTICOAGULANTS Introduction - where we are now Oral anticoagulant agents Which warfarin alternatives have entered the market? to bleed or not to bleed that is the question? Boehringer Ingelheim s pradaxa is first to market... but safety issues have been flagged up? When will BI seek approval for pradaxa in the long-term prevention of recurrent Vtes? Xarelto is second to market... but Bayer s expectations are high

4 Why has Xarelto had a mixed response from regulators in AcS patients? explorer program underway to fuel future growth pfizer/bms eliquis potentially has a "best in class" profile Seeking to file for new indication by end of 2013 can Daiichi-Sankyo s Lixiana gain a foothold in the oral factor Xa market Oral anticoagulants - Market forecasts Parenteral anticoagulants Lovenox biosimilars are encroaching on the market Why has GSK s Arixtra failed to impress? Parenteral anticoagulants - Market forecasts Oral antiplatelet agents have the new oaps changed the treatment paradigm for patients at high risk from stroke? Will effient maintain its head start or will the triology AcS trial cause it to stumble? can AstraZeneca get Brilinta back on track? Oral antiplatelet agents - Market forecasts New drugs on the block Approach 1: Anticoagulant therapies: Drug Class 1: Factor Xa inhibitors otamixaban (Sanofi) Betrixaban (portola pharmaceuticals) Long shot ep (endotis pharma) Factor Xa inhibitors - Market forecasts Approach 1: Anticoagulant therapies: Drug Class 2: ultra LMWHs Long shots Adomiparin (Momenta pharmaceuticals) Ultra LMWH - Market forecasts Approach 2: Antiplatelet therapies: Drug Class 3: P2Y inhibitors cangrelor IV (the Medicine company) P2Y inhibitors - Market forecasts Approach 2: Antiplatelet therapies: Drug Class 4: PAR1 inhibitors Vorapaxar (Merck) PAR1 inhibitors - Market forecasts Anticoagulant overall conclusions SECTION 3: ANTIHYPERTENSIVES Introduction - Where we are now the hypertension market is driven by generics Avapro s has witnessed aggressive generic erosion But why have Diovan generics been slow off the mark? Will takeda s edarbi become the new gold standard? Why has tekturna not lived up to its promise? Antihypertensives - Market forecasts New drugs on the block Approach 1: RAAS modulators: Drug Class 1: Oral direct renin inhibitor Vtp (Vitae pharmaceuticals) Direct renin inhibitors - Market forecasts Approach 1: RAAS modulators: Drug Class 2: Dual acting compounds LcZ696 (Novartis) Long shot DArA (retrophin) Dual acting compounds - Market forecasts Approach 1: RAAS modulators: Drug Class 3: sgc stimulators riociguat (Bayer) cgs stimulator - Market forecasts Approach 1: RAAS modulators: Drug Class 4: NRP-A agonist

5 Long shots pl-3994 (palatin technologies) NRP-A agonist - Market forecasts Antihypertensives overall conclusions APPENDIX 1 Mechanism of pcsk9 inhibitors APPENDIX 2 Alirocumab clinical trial data APPENDIX 3 AMG 415 clinical trial data APPENDIX 4 Mechanism of cetp inhibition APPENDIX 5 Ancetrapid s clinical trial data APPENDIX 6 evacetrapid clinical trial data APPENDIX 7 Mechanism of apoa-1 mimetic APPENDIX 8 the coagulation cascade APPENDIX 9 cangrelor IV clinical trial data APPENDIX 10 the renin-angiotensin-aldosterone system (raas) METHODOLOGY primary research Secondary research ACRONYMS REFERENCES ENDNOTES List of Tables Table 1: Cardiovascular agents by category Table 2: Lipid-lowering agents, mechanism of action, safety profile and lipid profile Table 3: Leading statin drugs and combinations Table 4: Statins on LDL-C reduction and use in moderate to high risk patients with lipid disorders Table 5: Lipitor s sales decline, (sales US$mn) Table 6: Crestor s sales being challenged, (sales US$mn) Table 7: Statin sales forecast (US$mn), Table 8: Strategies and targets to modulate LDL-C levels Table 9: PCSK9 inhibitors in development Table 10: PCSK9 inhibitor sales forecast (US$mn), Table 11: Lipid lowering effects of Juxtapid Table 12: Novel developmental candidates in early stages of development Table 13: Apo B modulator sales forecast (US$mn), Table 14: Strategies and targets to modulate HDL-C levels Table 15: CETP inhibitors in development Table 16: Potency and efficacy of leading CETP inhibitors, (% change) Table 17: CETP inhibitor sales forecast (US$mn), Table 18: Apo A-1 enhancing drugs in development Table 19: Apo A-I enhancing agent sales forecast (US$mn), Table 20: Summary of approved and new drugs in development Table 21: Commonly prescribed anticoagulant agents, mechanism of action and safety profile Table 22: New oral anticoagulants, approval in patient populations Table 23: Headline results from Phase III trials of new anticoagulants versus warfarin in AF Table 24: Oral anticoagulant sales forecast (US$mn), Table 25: Forecast for leading parenteral anticoagulants (US$mn), Table 26: Oral anticoagulants potential patient populations Table 27: Leading OAP drug sales forecast (US$mn), Table 28: Novel factor Xa inhibitors

6 Table 29: Factor Xa inhibitors sales forecast (US$mn), Table 30: Novel ultra LMWH Table 31: Ultra LMWH sales forecast (US$mn), Table 32: Novel antiplatelet agents in development Table 33: P2Y inhibitor sales forecast (US$mn), Table 34: Novel PAR1 inhibitors in development Table 35: PAR1 inhibitors sales forecast (US$mn), Table 36: Summary of approved and new drugs in development Table 37: Commonly prescribed antihypertensive agents, mechanism of action and safety profile Table 38: Leading ARBs and generic availability Table 39: Avapro s sales, (sales $mn) Table 40: Diovan sales, (sales US$mn) Table 41: Tekturna fixed combinations Table 42: Leading ARB sales forecasts (US$mn), Table 43: DRI sales forecast (US$mn), Table 44: Novel DRIs in clinical development Table 45: DTI inhibitors sales forecast (US$mn), Table 46: Novel dual acting compounds in clinical development Table 47: Dual acting compounds sales forecast (US$mn), Table 48: sgc stimulators sales forecast (US$mn), Table 49: NRP-A agonist sales forecast, Table 50: Summary of approved and new antihypertensive drugs in development Table 51: Summary of DFI11565 trial data in primary hypercholesterolemia patients at 12 weeks Table 52: Summary of trial data in hefh patients at 12 weeks Table 53: Summary of LAPLACE-TIMI 57 data in 631 primary hypercholesterolemia patients at 12 weeks Table 54: Summary of MENDEL data in primary hypercholesterolemia at 12 weeks Table 55: Summary of RUTHERFORD data in hefh patients at 12 weeks Table 56: Summary of GUASS data in patients intolerant to statins at 12 weeks Table 57: Summary of anacetrapid monotherapy data (change from baseline) at 24 weeks Table 58: Summary of evacetrapid monotherapy data (change from baseline) at 24 weeks Table 59: Summary of evacetrapid combination data (change from baseline) at 24 weeks List of Charts Figure 1: Medicines under development of heart disease and stroke Figure 2: Sanofi/Regeneron s comprehensive alirocumab Phase III program Figure 3: Amgen s comprehensive AMG 145 Phase III program Figure 4: Xarelto s EXPLORER program Figure 5: Oral antiplatelet market by region, 2012 Figure 6: Oral antiplatelet market by volume, 2012 Figure 7: Oral antiplatelet market, market share of leading agents in leading markets, 2012 Figure 8: Medicines under development of heart disease and stroke Figure 9: Medicines under development of heart disease and stroke Figure 10: Schematic mechanism of action of PCSK9 in the liver Figure 11: Schematic mechanism of action of CETP inhibitors Figure 12: Schematic mechanism of action of Apo A-1 enhancing agents Figure 13: Schematic of clotting cascade and site of action of approved anticoagulant drugs Figure 14: Schematic of the renin-angiotensin-aldosterone system Ordering: Order Online - Order by Fax - using the form below Order by Post - print the order form below and send to Research and Markets, Guinness Centre, Taylors Lane, Dublin 8, Ireland.

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