The recently reported study linking two SNPs to reduced efficacy of a commonly prescribed cholesterol drug is likely to drive pharmacogenomics research forward in this area even as it raises questions about how pharmaceutical companies may deal with these type of data.
In the study, published in the June 16 Journal of the American Medical Association, a team from Brigham and Women’s Hospital in Boston and Variagenics genotyped 1,536 individuals who received Pravachol as part of a clinical trial (Variagenics was acquired by drug maker Nuvelo in 2002). The researchers found two SNPs in the HMG-CoA reductase gene that were significantly associated with an approximately 20-percent reduction in cholesterol levels among the participants. Pravachol, known generically as pravastatin, is made by Bristol-Myers Squibb.
One crux of the findings is that this gene is the target for all statins, so the study could have wide implications. “It’s a big study,” said Daniel Chasman, the lead author on the paper. “That means that our statistical findings are more robust than what’s been reported previously.
“Because it’s such a big study and the statistical result is so robust, I am really hopeful that it will encourage people to find a way to pull together large cohorts to do more of these kinds of studies, so we can find out how widespread genetic effects are in pharmaceutical action, and somehow get it integrated into pharmaceutical development and prescription” information, he added.
The study drew its participants from the Pravastatin Inflammation/CRP Evaluation trial, a randomized, controlled cohort study supported by Bristol-Myers Squibb.
Chasman’s research team found this association between the SNPs and reduced pravastatin efficacy after resequencing 10 candidate genes and looking for associations in 148 SNPs that are known to be involved in synthesis, absorption, and transport of cholesterol, as well as statin metabolism.
Individuals who were heterozygous for either SNP in the HMG-CoA reductase gene had a 22-percent smaller reduction in total cholesterol levels, and a 19-percent smaller reduction in low-density lipoprotein cholesterol.
Chasman cautioned, however, that the results would have to be reproduced before general conclusions could be made about the implications for statin efficacy.
Chasman also cautioned that not everyone among the 6.7 percent of the study population that was heterozygous for either SNP experienced the lowered efficacy. “So we don’t really think it’s ready for a diagnostic — certainly not based on the data that we show,” he said.
There is also a question of whether big pharma will want to sell such a diagnostic with any of its statin products. The global statin market is estimated at about $20 billion and growing, according to research firm Datamonitor. At present, five big pharmas are competing for slices of the statin pie, with Pfizer’s Lipitor (atorvastatin) alone bringing in $9.2 billion in sales during 2003. Smaller shares go to Bristol-Myers Squibb for Pravachol; Merck, for Mevacor (lovastatin) and Zocor (simvastatin); Novartis for Lescol (fluvastatin); and AstraZeneca for Crestor (rosuvastatin).
Any pharmacogenomics-based diagnostic that shows reduced efficacy of statins in some individuals could cut into this highly competitive market, unless it was accompanied by a recommendation that a higher dose of a particular statin could correct for the genetic factor that made it less effective.
In a commentary accompanying the study, Wylie Burke, of the department of Medical History and Ethics at the University of Washington, said while the results from this research “might ultimately help to differentiate the patients most likely to benefit from statin therapy from those for whom the costs and risks outweigh the benefits,” current US Food and Drug Administration regulations actually discourage drug makers from documenting “the value of pharmacogenetic testing if doing so has the potential to reduce market share.”
Burke suggested three strategies to overcome current obstacles: US federal agencies ought to collaborate with academics and payors on clinical research related to pharmacogenomics; health-care payors should “establish standards that encourage outcome-oriented pharmacogenetic research;” and the FDA must require drug makers to re-evaluate their drugs based on clinically relevant public findings and change their labels “to incorporate new information about drug safety or efficacy and the need for pharmacogenetic testing.”
Meanwhile, Chasman is leading a team looking for SNP associations in data from the Prevastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 trial. This study, conducted by the TIMI group at Brigham and Women’s Hospital, compared a 40mg/day dose of Pravachol to an 80 mg/day dose of Lipitor in certain cardiac patients. The study made headlines when results indicated that the larger dose of Lipitor was significantly more effective than the Pravachol dose, and that patients taking Lipitor had fewer heart attacks.
Chasman plans to examine the efficacy of these drugs in relation to the two SNPs found in the prior study. “We can see whether or not the genetics is correlated not only with the lowering [of] cholesterol in statin therapy, but whether or not there is association with the outcome in heart attack,” he said.
“Health care payers are increasingly insisting that innovations in health care be based on good quality evidence,” Burke told Pharmacogenomics Reporter this week. “I hope this will create the motivation needed to assure that pharmacogenetic tests are based on well-designed clinical outcome studies.”