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Rx Postmortem: Pfizer, Canadian Team to See If PGx Could Have Saved Torcetrapib

Pfizer has partnered with a pair of researchers from Génome Québec and the Montreal Heart Institute’s Pharmacogenomics Centre to investigate whether PGx could have saved the drug giant’s failed hypercholesterolemia drug torcetrapib.
“A number of good drugs are sitting on shelves for probably the wrong reasons,” Jean-Claude Tardif, one of the study’s lead investigators and director of the research center at the Montreal Heart Institute, said last week during a conference on pharmacogenomics in Montreal.
“If we were able to identify those rare patients who have significant side effects, take them out of the study, and continue in Phase III with those who are not at risk but could benefit, I think this is one way pharmacogenomics could be very informative in helping clinicians develop better clinical trials,” he added.
Tardif, who holds the Canadian Institutes of Health Research Pfizer Chair in atherosclerosis at the Université de Montréal, is currently working with Michael Phillips, director of pharmacogenomics at Génome Québec and the McGill University Innovation Center. They plan to genotype 2,000 patients who were given torcetrapib and low-dose atorvastatin in a trial designed to understand how managing lipid levels affects atherosclerotic events.
The samples are from the 15,000-patient ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events) trial, sponsored by Pfizer, which was designed to test whether patients on torcetrapib and atorvastatin would see fewer cardiovascular events than with atorvastatin alone. Upon the recommendation of an independent Data Safety Monitoring Board, Pfizer torched the clinical development of torcetrapib, a drug that cost upwards of $800 million to bring to Phase III development. 
In 2006 Pfizer killed the trial after observing a 60-percent increase in deaths among patients taking torcetrapib, a CETP inhibitor, and atorvastatin, known as Lipitor and made by Pfizer, versus those taking atorvastatin alone. The study was to run until 2009.
Tardif and Phillips plan to compare the genotypes of patients with good responses and poor responses from the perspective of HDL and LDL cholesterol levels, blood pressure, electrolyte levels, and cardiovascular outcomes.
“We’re going to try to [learn] about who are these individuals … who died because of torcetrapib, and who had strokes and myocardial infarctions as a result of this agent,” Tardif said during a talk at Pharmacogenomics Now, a conference hosted by Génome Québec and Cambridge Healthtech Institute.
He added that in his investigations he would also try to differentiate the mechanism of torcetrapib from two investigational CETP inhibitors, Roche’s dalcetrapib and Merck’s anacetrapib.
‘Missed Opportunities’
The high profile and costly failure of torcetrapib — Pfizer spent nearly $1 billion to develop the drug, expected it to generate several billion dollars in sales annually, and hoped it would insulate the company from the loss of patent exclusivity on its antidepressant Zoloft and antibiotic Zithromax — raised questions about whether big pharma’s blockbuster drug-development strategy was broken.

“There are many examples of missed opportunities for cardiovascular protection … [and] pharmacogenomics can help.”

When Pfizer halted the ILLUMINATE trial, several researchers and industry observers questioned whether pharmacogenomics could have saved the drug by identifying earlier patients most likely to see adverse events.
This is the very question that Tardif and Phillips are investigating now.
According to Tardif, the researchers will conduct a genome scan and investigate several genes of interest, including CETP, LDLR, LPC, ABCA1, ApoE, ApoA, ApoB, and ApoC, as well as a number of inflammatory genes. Tardif and Phillips have also enriched the study to look at the renin hypertensive system.
It is unclear, however, what the future for torcetrapib will be if the researchers are able to identify the genetic underpinnings of why certain patients in ILLUMINATE died or experienced cardiac events with the drug.
While companies like Pfizer are more willing to use pharmacogenomics to improve the efficacy of their drugs in certain populations and to run more efficient clinical trials, big pharma has not been overly enthusiastic about using PGx to rescue failed drugs.
On the heels of torcetrapib’s failure, and with its mega-blockbuster Lipitor expected to lose patent protection in 2011, Pfizer announced in late September that it plans to exit the cardiovascular disease space, in particular the markets for hyperlipidemia/atherosclerosis, heart failure, obesity, and peripheral arterial disease. Statins can be used in the treatment of all these conditions.
Tardif and Phillips were unavailable to comment beyond what was discussed at the conference.

“There is a need for additional drugs beyond what we have now,” Tardif said at the conference. “There are many examples of missed opportunities for cardiovascular protection … [and] pharmacogenomics can help.”

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