Pfizer Terminates Torcetrapib Program
This article was originally published in The Pink Sheet Daily
Executive Summary
Company will investigate whether an increased risk of mortality is a class effect of CETP inhibitors.
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Pfizer terminated development of potential blockbuster cholesterol therapy torcetrapib after a data safety monitoring board found a significant imbalance in mortality during a Phase III study comparing a torcetrapib/ Lipitor (atorvastatin)combination to atorvastatin alone, the company said Dec. 2. As part of its oversight, the DSMB conducts monthly reviews of major events related to the 15,067-patient ILLUMINATE morbidity and mortality study. In its latest review, conducted Dec. 1, the DSMB saw 82 deaths in the torcetrapib/atorvastatin arm compared to 51 deaths in the atorvastatin arm, Pfizer told "The Pink Sheet" DAILY Dec. 3. The study enrolled patients deemed to be at significant risk for cardiovascular morbidity/mortality, including patients with diabetes or hypertension, or patients who had a history of heart attack or stroke. Overall, the mortality rate was lower than expected, the company says, but the study has been halted, and development of the compound terminated, because of the significant imbalance between the two arms. The prespecified boundary for the DSMB to take action was a p-value of .01 in the difference between mortalities seen in the two arms. Pfizer characterized the results as "both surprising and disappointing," and noted that the DSMB had said the study could continue after completing its most recent comprehensive quarterly review in late October. Pfizer had forecast that it would file the torcetrapib/atorvastatin combination therapy with FDA in late 2007, ahead of Lipitor's patent expiration, which could come as early as 2010, following a recent appellate court ruling (1 (Also see "Lipitor Generics Could Come 15 Months Earlier Than Anticipated After Patent Deemed Invalid" - Pink Sheet, 2 Aug, 2006.)). The company released preliminary Phase III results of the torcetrapib/atorvastatin combo in October, showing that patients on the combo product experienced an average increase in systolic blood pressure of two millimeters Hg compared to patients on atorvastatin alone. At the time, the company defended torcetrapib, saying the results were a "very early snapshot" and would not affect the CV profile of the cholesteryl-ester transfer protein inhibitor (2 (Also see "Torcetrapib Phase III Preliminary Results Offer Mixed Snapshot" - Pink Sheet, 31 Oct, 2006.)). Pfizer now says it is unsure if the increase in overall mortality can be attributed to the blood pressure rise, but plans to look at the issue in more detail in collaboration with leading experts in the field. A key area of Pfizer's investigation will relate to whether the increased risk of mortality observed in the Phase III trial is a class effect for CETP inhibitors. The company expects its investigation to take months; any significant findings will be released via a scientific presentation, Pfizer said. In a Dec. 3 statement, FDA said it "fully supports Pfizer's decision to suspend this trial." The agency said it would work with Pfizer and other sponsors developing CETP inhibitors "to ensure that appropriate protections are in place to identify any safety signals as early in the development process as possible." Other companies developing CETP inhibitors, which raise HDL cholesterol levels, include Roche, which has a Phase II compound, R1658, licensed from Japan Tobacco (3 (Also see "Roche Raises Cholesterol Profile With HDL-C Elevator From Japan Tobacco" - Pink Sheet, 20 Oct, 2004.)). As recently as Nov. 30, during Pfizer's R&D briefing, the company had said that the net benefits of the torcetrapib/atorvastatin combo "will greatly benefit patients with CV risk" (4 (Also see "Pfizer Plans Four New Products A Year Starting In 2011" - Pink Sheet, 30 Nov, 2006.)). Pfizer's decision to terminate the torcetrapib program will not affect the company's financial guidance, the company said, although it plans to accelerate previously announced efforts to cut costs and improve efficiency. - Joshua Berlin ([email protected]) |