Mounting Evidence: Add-on Lipid Therapies Keep On Failing For Risk Reduction
New American College of Cardiology/American Heart Association guidelines released Nov. 12 move away from numerical LDL cholesterol targets, instead focusing on reducing risk in adults most likely to benefit from treatment (see related story, Also see "Time, And Price, Are Right To Prescribe Statins To the Masses" - Pink Sheet, 2 December, 2013.). They also heavily emphasize statins as a proven mainstay of treatment and note the lack of evidence for using other lipid-modifying drugs. The conclusions come out of a long history of trials exploring the connection between various lipid parameters and cardiovascular risk, which have substantiated the value of lowering LDL and failed to confirm clinical benefit from affecting other lipid levels.
Outcomes Study	Release Date	Key Findings	Implications/Fallout
FIELD: Long-term study from Laboratoires Fournier tried fenofibrate vs. placebo in about 9,800 patients with type 2 diabetes. Patients not on statins at time of study entry, but allowed to start statins during trial.	November 2005	Fenofibrate missed primary endpoint for reducing coronary events. Total events were reduced, due to reduction in heart attacks and revascularizations.	Reporting results in the Lancet, investigators noted higher rate of statin use in placebo group may have masked fenofibrate effect. Accompanying Lancet editorial found results inconclusive.
ILLUMINATE: Study of 15,000 patients compared Pfizer Inc.’s CETP inhibitor torcetrapib with its statin Lipitor (atorvastatin) vs. Lipitor alone.	December 2006	Trial terminated after 82 deaths were reported in torcetrapib arm vs. 51 deaths for Lipitor alone. Pfizer ended development.	Raises questions about mortality as class effect. But torcetrapib had been linked to blood pressure rise, which could explain result Also see "Pfizer’s Lipitor Extension Shot Down By Failure Of Torcetrapib Silver Bullet" - Pink Sheet, 11 December, 2006.. Other big pharmas still heavily invested in CETP, but waiting for outcomes data before submitting for approval Also see "Big Pharma’s Gamble On HDL Hypothesis" - In Vivo, 23 April, 2012..
ENHANCE: 720 patients treated with high dose of Merck & Co. Inc.’s Vytorin – combination of 80 mg dose of statin Zocor and Zetia (ezetemibe) – vs. Zocor/placebo.	January 2008	Reduces LDL, triglycerides & C-reactive protein, but fails to affect atherosclerosis progression, measured by carotid intima-media thickness.	When full results are released at ACC meeting, experts urge to return to proven statins Also see "No Surprises From ENHANCE At ACC Mean Vytorin Hopes Hang On IMPROVE-IT" - Pink Sheet, 7 April, 2008.. Combined Vytorin/Zetia sales plummet from $4.6 billion in 2008 to $844 million in 2009, climbing back up to $4.3 billion in 2012. Merck shifts emphasis to IMPROVE-IT 18,000-patient outcomes trial of Vytorin due in 2014 or 2015 ([A#14130312002]). Zetia’s patent expires in 2017.
SEAS: 1,870 patients with mild-to-moderate asymptomatic aortic stenosis treated with 40 mg Zocor plus 10 mg Zetia or placebo.	September 2008	Zetia/Zocor arm cut LDL by at least 50% compared to placebo, yet missed primary composite outcome of reduced CV events. Statistically significant increase in number of cancers reported for treatment arm.	In combination with ENHANCE data, damages Zetia’s profile and contributes to decline in sales post 2008 Also see "New Look At Ezetimibe Fails To Confirm Vytorin Cancer Signal" - Pink Sheet, 1 September, 2008..
ACCORD Lipid trial: NIH-funded study of5,000+ patients with type 2 diabetes and CVD tests AbbVie Inc.’s fenofibrate TriCor with Zocor vs. Zocor alone.	March 2010	TriCor combo safe but failed primary endpoint for cutting combined rates of death, non-fatal heart attack or non-fatal stroke. Different effects for different patient groups, with women possibly harmed by the add-on but men benefiting. Also suggested possible benefit for patients with high baseline triglycerides and low HDL.	Reinforces 2005 FIELD trial, which had led to use of fibrates as add-on only in higher-risk patients Also see "Abbott's Fibrate Franchise Will Likely Remain Limited To High-Risk Patients After ACCORD" - Pink Sheet, 14 March, 2010.. Company noted that two-thirds of patients in trial would not be treated with fibrates under treatment guidelines at that time. Tricor/Trilipix franchise sales were about $1.1 billion in 2012, down 20% from $1.37 billion in 2011 and $1.35 billion in 2010. Generic Tricor entered U.S. 4Q 2012; generic fenofibrate has been on the market since 2002. Abbvie/AstraZeneca abandoned Trilipix/Crestor combo Certriad after FDA “complete response” letter in March 2010 Also see "AstraZeneca And Abbott Pull The Plug On Cardio Combination Drug" - Pink Sheet, 23 December, 2010..
AIM-HIGH: NIH-funded study of 3,400 patients with history of CV disease tests Abbvie’s Niaspan (XR niacin) as add-on to Zocor with or without Zetia. Baseline LDL controlled, HDL low, triglycerides high.	May 2011	NIH halts trial 18 months early due to lack of efficacy. Data safety and monitoring board (DSMB) notes small, unexplained increase in ischemic strokes.	Company stressed results applied only to the study population (stable, non-acute pre-existing CV disease) Also see "More Disheartening News For Abbott Cholesterol Franchise: Niaspan/Statin Study Halted Due To Lack Of Added Benefit" - Pink Sheet, 26 May, 2011.. Results damage HDL hypothesis, but lipidologists see trial as inconclusive due to small size and other design flaws, as well as early end Also see "Big Pharma’s Gamble On HDL Hypothesis" - In Vivo, 23 April, 2012.. Niaspan sales flat from 2010-2012 (from $927 million to $911 million), prior to patent expiry in 3Q 2013.
dal-OUTCOMES: Tested Roche’s CETP inhibitor dalcetrapib in 15,000 patients post-acute coronary syndrome (ACS), on top of evidence-based care.	May 2012	DSMB advises ending study due to lack of “clinically meaningful” efficacy. No safety issues reported.	Roche ends entire dal-HEART program of dalcetrapib, including two outcomes trials and four other studies. Spurs more questions about value of boosting HDL Also see "Dalcetrapib Failure Raises Yet More Questions On Value Of Tinkering With HDL Cholesterol" - Pink Sheet, 14 May, 2012.. But other CETP sponsors press on, betting on better outcomes with bigger HDL effects Also see "Merck, Lilly Vow To Press On With CETP, Despite Dalcetrapib Disaster" - Pink Sheet, 7 May, 2012..
ORIGIN: Six-year study of Pronova BioPharma ASA’s omega-3 fish oil Omacor (marketed in U.S. as Lovaza by GlaxoSmithKline PLC and other firms ex-U.S.). Tested 1g Omacor (EPA/DHA mix) daily vs. placebo on top of standard therapy in 12,500 patients at high risk for CV events, with early type 2 diabetes or pre-diabetes.	June 2012	Triglyceride levels cut; no significant effect on other lipids. Missed primary endpoint of reducing death from CV causes, and no significant effect on major vascular events. Similar adverse event rates.	Investigators noted 1 g dose may have been too low to show effect. FDA cites failed study in 2013 review of Amarin’s fish oil Vascepa, rejected for expanded label Also see "Panel To Weigh Amarin’s Expanded Vascepa Use Given Clinical Outcome Concerns" - Pink Sheet, 11 October, 2013.. GSK reported sales of £607 million ($975 million) in 2012, up 5% from 2011. Ruling in U.S. patent case in September 2013 paves way for generics.
HPS2-THRIVE:Tredaptive (extended-release niacin/anti-flushing agent laropiprant) as add-on therapy to intense background lipid-lowering in 25,000+ patients.	March 2013	Tredaptive group has raised HDL, lower LDL and lower triglycerides, but only a small, numerical reduction in CV events and many serious adverse events.	Investigators blame AEs on niacin, say add-on niacin is not healthy Also see "Tredaptive Safety Hazards Cast Shadow Over AbbVie’s Niaspan" - Pink Sheet, 18 March, 2013.. Further damages HDL hypothesis Also see "HPS2-THRIVE Post-Mortem: Lessons Learned For CV Drug Developers" - Pink Sheet, 18 March, 2013.. Merck drops U.S. development, suspends sales elsewhere.
Italian Risk and Prevention Study:Tested 1 g omega 3 (EPA/DHA) in about 12,500 patients with multiple CV risk factors, followed for five years.	May 2013	Did not reduce risk for CV death or hospitalization for CV causes compared to placebo. Nominal change in triglycerides and HDL in treatment group.	Study cited in FDA briefing documents for Amarin’s Vascepa expanded label panel review in 2013 as example of recent, failed randomized fish oil trial.
STABILITY:GSK’s Lp-PLA2 inhibitor darapladib as add-on to statins and other lipid drugs in 15,000+ patients with chronic heart disease.	November 2013	Darapladib add-on arm fails to demonstrate reduction in events. No imbalance in adverse events.	Company will analyze secondary endpoints and work to understand data better. Results still pending from second outcomes trial of darapladib for event prevention after ACS, SOLID-TIMI 52.
Source: “The Pink Sheet” archives, company websites

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