Phase II results for Pfizer's torcetrapib in combination with Lipitor (atorvastatin) reveal a 61% increase in HDL cholesterol for the combined atherosclerosis therapy.

Torcetrapib, a cholesterol ester transfer protein inhibitor being developed for use in combination with Lipitor (ultimately as a fixed-dose single pill), entered Phase III trials at the end of 2003.

Pfizer is understood to be spending upwards of $800 mil. on the development program, which it has described as the largest ever undertaken by the pharmaceutical industry. The company's gamble on the drug includes a $90 mil. manufacturing facility being built in Ireland.

Pfizer hopes the Lipitor-torcetrapib combination will become the preferred therapy because of its effect on "good" HDL cholesterol in addition to "bad" LDL cholesterol, which is targeted by the statins. While statins also raise HDL-C, it is generally only by a moderate 5% to 10%.

Analysts predict that if the combined therapy is proven effective, sales could eventually top Lipitor's, which posted $5.8 bil. in the U.S. and $9.2 bil. worldwide in 2003 as the world's top-selling pharmaceutical. The combination could come to market by 2008; Lipitor patent exclusivity expires in 2010.

The Phase II results, reported in the April 8 issue of The New England Journal of Medicine, are the first published clinical trial data for combination use with Lipitor.

In the trial, 19 subjects with low levels of HDL cholesterol received placebo for four weeks followed by 120 mg torcetrapib once-daily for four weeks; nine of the subjects simultaneously received 20 mg daily of Lipitor. Six of the subjects who did not take Lipitor participated in a four-week extension phase where they received 120 mg of torcetrapib twice daily.

HDL-C increased by 46% (compared to placebo) in the group that received only torcetrapib, and by 61% in the group that received torcetrapib plus Lipitor. For the twice-daily torcetrapib subgroup, HDL-C increased by 106%. A significant LDL-C decrease of 17% was observed only for the torcetrapib-Lipitor combination group.

The study reports that "torcetrapib, alone or in combination with atorvastatin, resulted in no clinically significant changes in vital signs, serum chemical values, or hematologic values."

Although no serious adverse events were reported, 17 treatment-related AEs (only two of which occurred on placebo) were reported by 13 out of the 19 patients. AEs included headache, dyspepsia, herpes simplex and sweating.

Pfizer's Phase III program apparently involves two two-year pivotal trials in 886 patients; the trials are designed to measure the effectiveness of Lipitor-torcetrapib at preventing progression of coronary atherosclerosis compared to Lipitor alone. The first study will measure changes in carotid artery thickening through ultrasonography; the second will measure plaque regression through intravascular ultrasound.

However, Pfizer is understood to be using a lower torcetrapib dose of 60 mg daily in the Phase III trials due to unexplained cases of hypotension seen at doses higher than 120 mg BID. Given the dose-response relationship demonstrated in Phase II, it is possible that the 60 mg dose will produce a smaller effect than that seen with the higher doses.

Although Pfizer appears confident that the surrogate endpoints in the pivotal trials will be acceptable to FDA for initial approval, it is likely the company will pursue, or has already begun, long-term morbidity and mortality outcome trials to solidify its market position.

If torcetrapib is approved without any major safety issues, it would be the first marketed drug to substantially raise HDL-C levels without the tolerability problems of drugs such as Kos' Niaspan (niacin), which also targets HDL-C. Pfizer should thus be able to successfully differentiate the Lipitor-torcetrapib combo from Kos' Advicor , which combines niacin and lovastatin (Merck's Mevacor ).

HDL-C levels, which are strongly correlated with positive cardiovascular outcomes, are becoming the primary target of the next generation of lipid-lowering agents.

The other CETP inhibitor in development, Japan Tobacco's JTT-705, is in Phase II. The NEJM article takes a jab at JT's agent, declaring that torcetrapib 120 mg twice daily in Phase II "raised HDL levels to a level three times as high as did [900 mg of] JTT-705" in a reported study in slightly hyperlipidemic patients.

- Alla Rutstein Bobbitt

Pfizer's Lipitor-Torcetrapib Phase II Results Show HDL-LDL Double-Punch

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