February 1, 2011 (Vol. 31, No. 3)

As Patent-Protected Statins Fade Into Sunset, One Major Failure Hovers Ominously Over Contenders

Back in 2008, Pfizer strategically delayed generic competition for its blockbuster statin product Lipitor (atorvastatin) by some 20 months until November 2011. By settling global patent disputes with Ranbaxy Laboratories, a generic drug maker in India that had threatened to market its own version of Lipitor, Pfizer hung on to the majority of the cholesterol-lowering market.

Although most statin drugs already have generic versions, Lipitor remains widely used, especially among patients who don’t respond to the generic formulations or require a higher dose than Lipitor’s competitors offer. Lipitor became the best-selling pharmaceutical in history with 2009 sales of $11.4 billion and retained this status in 2010. The drug thus dominates the $20 billion statin market.

Statins comprise a class of drugs that lower cholesterol by inhibiting HMG-COA reductase, an enzyme that synthesizes cholesterol in the liver. By the end of 2010, branded statins remaining on the market included: Lipitor; fluvastatin (Novartis’ Lescol); lovastatin (Merck & Co.’s Mevacor and Watson Pharmaceuticals’ Altocor and Altoprev); pitavastatin (Kowa Company’s Livalo); pravastatin (Bristol-Myers Squibb’s Pravachol); rosuvastatin (AstraZeneca’s Crestor); and simvastatin (Merck’s Zocor).

Several combination preparations of a statin and another agent, such as Merck’s Vyotrin, which couples ezetimibe and simvastatin, are also available.

CETP Inhibition

So what might the next wave of successful anticholesterol agents look like? Will any achieve the therapeutic success of statins? One new class of drug candidates is cholesterol ester transfer protein (CETP) inhibitors, but there has already been one major clinical failure, with Pfizer’s torcetrapib failing in Phase III. The firm spent $800 million developing the drug, which was dubbed one of pharma’s biggest flops.

CETP normally moves cholesterol from high-density lipoproteins (HDL) to very low density or low density lipoproteins (VLDL or LDL). Inhibition of this transfer process is expected to increase HDL levels, the good cholesterol, and reduce the bad cholesterol, or LDL levels.

While Pfizer was expected to win approval for torcetrapib in 2008 and assuage declining Lipitor sales, it was forced to stop development in 2006 after the occurrence of major cardiovascular events among trial participants. The study called Illuminate involved 15,067 patients with coronary heart disease (CHD) or CHD risk equivalent (type 2 diabetes) given torcetrapib and atorvastatin or only atorvastatin.

The primary endpoint of the trial, a composite of first major cardiovascular event defined as CHD death, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina, diverged between the treatment groups early in the trial. At termination, the torcetrapib group showed a 25% increased risk over the groups that received atorvastatin alone. Overall, 82 patients taking the combination of torcetrapib and atorvastatin died compared with 51 deaths among those taking only atorvastatin.

In a post-hoc analysis of the halted trial, investigators concluded that the reasons for the adverse outcome were uncertain. They said that torcetrapib administration was associated with undesirable off-target effects that could have contributed to and increased mortality/morbidity. These included heightened blood pressure, increased sodium bicarbonate and aldosterone levels, and decreased potassium levels.

Lessons Learned

Despite torcetrapib’s failure, Pfizer’s Phase III trial suggested that CETP inhibition can raise HDL levels resulting in atherosclerosis regression. Positive trial results included a mean increase of 72.1% in HDL cholesterol (HDL-C), a mean decrease of 24.9% in LDL cholesterol (LDL-C), and a mean decrease of 9% in triglycerides compared with baseline.

The scientists found that while the majority of torcetrapib-treated patients demonstrated no regression of coronary atherosclerosis, a significant regression was observed in patients in the highest HDL-C quartile. The researchers noticed a continuous inverse relationship between HDL levels and the percent atheroma volume.

Moreover, this relationship was only clearly seen in the group receiving the CETP inhibitor, strongly suggesting that in patients achieving high HDL levels, HDL particles were functional in promoting regression of atherosclerosis, the research team concluded.

Roche’s Dalcetrapib

The investigators who conducted the post-hoc analysis said that the adverse effects were molecule specific and not related to CETP inhibition in general. This is good news for Merck & Co. and Roche, which both have CETP inhibitors in late-stage trials.

Roche says its dalcetrapib has a different profile compared to torcetrapib in terms of mechanisms of action, molecular structure, binding site, and interaction with CETP. Dalcetrapib covalently modifies a Cys-H group in the N-terminal part of the lipid-binding tunnel of CETP to induce a conformation change in the protein that promotes reverse cholesterol transport in animal models.

Data from Phase II trials of dalcetrapib alone (at doses up to 900 mg/day) or in combination with statins showed that it was generally well tolerated in patients with type II hyperlipidemia, CHD, or CHD risk equivalents. A similar incidence of adverse events (AEs) and serious AEs were seen in the dalcetrapib and placebo recipients.

In April 2008, Roche began a Phase III trial in stable coronary heart disease patients with recent acute coronary syndrome (ACS). Enrollment of approximately 15,600 patients has been completed from sites around the world. Patients are randomized to receive either dalcetrapib 600 mg or placebo daily, together with stable medication for ACS.

Merck’s Anacetrapib

In November 2010, Merck presented Phase III results of its CETP inhibitor, anacetrapib. DEFINE was an 18-month study that included more than 1,600 patients with or at high risk for CHD who were already receiving statins and were at the guideline-established LDL-C goal. The study was designed to assess the lipid-modifying efficacy, safety, and tolerability of anacetrapib 100 mg daily added to ongoing statin therapy with or without other lipid-modifying agents.

Researchers suggested that the event distribution in DEFINE yielded a predictive probability of 94% that anacetrapib would not be associated with a 25% increase in cardiovascular events seen with torcetrapib.

Merck will move forward with a four-year study to be launched in April 2011 and enroll 30,000 patients. If trial results are positive, anacetrapib may reach the market in 2015. Anacetrapib is part of a major commitment by Merck to cardiovascular disease drug development; when the large-scale study for anacetrapib is fully enrolled, the company will have some 120,000 patients in heart drug trials.

Some cardiologists believe, however, that the development of HDL therapies experienced a serious setback with termination of torcetrapib’s clinical development. Potentially because of off-target actions of torcetrapib, surrogate biomarkers intended to elucidate the impact of the drug on atherosclerosis provided an uninterpretable picture of actual effects, commented David Orloff, M.D., executive director of Medpace, in the American Journal of Cardiology.

Pfizer’s failure in spite of spending big bucks on torcetrapib calls into question the merits of increasing HDL levels as well as lowering LDL levels. Ongoing clinical trials will certainly clarify some issues, but whether they will demonstrate success and bring a new cholesterol-lowering drug to the market remains to be seen.

Patricia F. Dimond, Ph.D. ([email protected]), is a principal at BioInsight Consulting.

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