Contradictory Study Results Increase Clopidogrel Pharmacogenomics Controversy
New study suggests that CYP2C19 loss-of-function polymorphisms are not relevant to antiplatelet drug effectiveness.
Clopidogrel, an antiplatelet agent sold as Plavix®, is widely used as a preventive medicine for a variety of cardiovascular diseases, such as heart attack and stroke. Although it has proven to be vastly popular, with worldwide sales estimated at over US$6 billion, this particular drug has seen more than its fair share of controversy.
This began when a study into the pharmacogenomics of CYP450 polymorphisms and clopidogrel obtained results suggesting that carriers of alleles conferring reduced metabolizer enzyme CYP2C19 function – approximately 20% of the population – gained less benefit from the drug than those without. Following this result, in March 2009 the US FDA announced the addition of a warning to the label of clopidogrel, alerting doctors to this issue. This would later be highlighted in March 2010 by making it a boxed warning.
Ever since the first FDA update, discussion and debate on the matter has been lively among cardiologists, a situation which seems likely to continue following the results of a recent study led by Professor Guillaume Paré (McMaster University, Ontario, Canada).
The research, funded by clopidogrel‘s marketing companies Sanofi-Aventis (Paris, France) and Bristol-Myers Squibb (NY, USA), involved genotyping over 6000 patients from two pre-existing clinical trials, Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) and Atrial Fibrillation Clopidogrel Trial with Irbesartan for the Prevention of Vascular Events (ACTIVE). Patients were grouped according to the *2, *3 and *17 SNPs of the CYP2C19 gene, and their response data was compared.
The most noteworthy results are summed up by a comment from Professor Paré “We found the previously reported genetic variants had no effect at all (for patients) in either the CURE or ACTIVE trials”. The study concludes more formally, with “Among patients with acute coronary syndromes or atrial fibrillation, the effect of clopidogrel as compared with placebo is consistent, irrespective of CYP2C19 loss-of-function carrier status”.
Expressed either way, this seems to be a confident statement on the issue of clopidogrel pharmacogenomics. Although the study noted that individuals with a gain-of-function CYP2C19 allele did indeed benefit more from treatment with clopidogrel, the overall results do seem to weaken the case for individualizing clopidogrel dosage based on the results of genetic analysis.
As if in response to the inevitable questions that will arise from this contradiction of previous results, Professor Paré acknowledged that his results were obtained from different populations than the previous study, but commented that, concerning the statistical strength of his data “…our study design was a bit stronger from an epidemiology point of view”.
It remains to be seen what the response will be to this latest development, although based on past performance, it seems unlikely that this will be the last word in the clopidogrel pharmacogenomics controversy.
Source: Paré G, Mehta SR, Yusuf S et al.: Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N. Engl. J. Med. doi: 10.1056/NEJMoa1008410 (2010) (Epub ahead of print).
KRAS Mutation Protects Cancer Cells from PI3K Mutation-Enabled mTOR Inhibitor Therapy
The use of mammalian target of rapamycin (mTOR) inhibitors as anticancer agents is currently being explored in a variety of clinical trials, although many questions regarding variable patient response remain unanswered. A recent study from a research group led by Professor Alberto Bardelli (University of Torino, Turin, Italy) has shed some light on this issue by outlining one way in which cancer cells can avoid the effects of mTOR inhibitors such as everolimus.
The phosphoinositide-3-kinase (PI3K) signaling pathway is very important for cell growth and survival, and as such is often mutated in cancer. These properties have generated a great deal of interest in PI3K and its effectors (including mTOR) as potential targets for chemotherapy.
mTOR inhibitors were initially used as immunosuppressants in transplant patients in order to reduce the problem of graft rejection, but since then interest in their anticancer capabilities has led to some mTOR inhibitors, such as everolimus and temsirolimus, being approved for use in treating certain tumor types.
The study by Professor Bardelli‘s group examined factors affecting the efficacy of everolimus in eradicating human cancer cells both in vitro and in vivo using human cancer cells in immunocompromised mice. The results indicated that the PI3K pathway mutations left cancer cells vulnerable to the effects of everolimus, but that KRAS mutations, either pre-existing or subsequently introduced, could remove this vulnerability. Subsequent testing demonstrated that removing these mutations returned the cells to their everolimus-sensitive state.
These results may have significant impact, removing some of the mystery surrounding response to mTOR inhibitors in cancer therapy. They indicate two groups of patients, one of which is more likely to respond to such treatment, and one which is much less likely to, allowing increased treatment efficiency and effectiveness.
Sources: Di Nicolantonio F, Arena S, Tabernero J et al.: Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J. Clin. Invest. 120(8), 2858–2866 (2010); Mohseni M, Ho Park B: PIK3CA and KRAS mutations predict for response to everolimus therapy: now that‘s RAD001. J. Clin. Invest. 120(8), 2655–2658 (2010).
Mouse Model of Genetic Hearing Loss Allows Easier Testing of Otoprotection Drugs
Ototoxicity, damage to the ear, is an unfortunate side effect of many important drugs. Animal models have been used to examine the effects of such examples as the antibiotics gentamicin and neomycin, and the cancer chemotherapy agents cisplatin and vinblastine sulfate, but evaluating otoprotection drugs has often been a more difficult process. Therefore, the recent announcement from the laboratory of Professor Qing Yin Zheng (Case Western Reserve University, OH, USA) of a new mouse model for hearing loss may prove to be useful to the development of new drugs in this area.
The novel mutation is called erlong, or erl, and is present in the Cdh23 gene, where it causes progressive hearing loss in the mice beginning when they are 27 days old. Although similar mutations have been found before, this one is particularly useful because, when treated with the pan-caspase inhibitor Z-VAD-FMK, cochlear outer hair cell loss (and thus, hearing loss) is significantly reduced in the mutant mice. In the words of the paper describing the study, “This is the first genetic mouse model of hearing loss shown to respond to otoprotective drug therapy”.
This, coupled with the relatively rapid onset of deafness in the mice (at 90 days old), suggests that this model may see plenty of use as a way to screen potential drugs for otoprotective effects.
Source: Han F, Yu H, Tian C et al.: A new mouse mutant of the Cdh23 gene with early-onset hearing loss facilitates evaluation of otoprotection drugs. Pharmacogenomics J. doi:10.1038/tpj.2010.60 (2010) (Epub ahead of print).
Novel BRAF Inhibitor Chemotherapy Shows High Success Rate in Melanoma
Recent Phase I trials of a novel therapeutic agent for melanoma have demonstrated high levels of effectiveness, with over 80% of the target patient group showing a response.
The drug, PLX4032, inhibits the activity of the BRAF protein, a product of the BRAF gene, which can be mutated in a wide variety of cancers. Although the frequency of mutation differs between cancer types, the majority of melanoma cases demonstrate such a mutation, and so it was this group of cancer patients that the first trials have focused on.
When detected at an early stage, melanoma is generally treated surgically with a good success rate, but once metastasis has occurred the prognosis becomes significantly worse. Only 10–20% of patients respond to the currently approved drugs for metastatic melanoma, dacarbazine and interleukin-2, and estimates for survival are generally under 9 months. Therefore, the impressive performance of the BRAF inhibitor PLX4032 at clinical trials is an encouraging development. As study leader Dr Keith Flaherty (Massachusetts General Hospital Cancer Center, MA, USA) put it, “Until now, available therapies were few and unreliable, so these findings can really change the outlook for patients whose tumors are fueled by this mutation”.
The BRAF protein is involved in cell signaling and growth, and can be involved in tumor growth when a mutation in the BRAF gene leads to its permanent activation. Although there are several potential mutations with this effect, the most common one is referred to as V600E. The role of the BRAF mutation in cancer has been known for several years now, but the development of a therapy based on this knowledge has taken time, with false starts and drug bioavailability issues delaying progress.
The recent Phase 1 trial involved a total of 87 patients, 55 at the initial dose-determination stage and an additional 32 at the follow-up stage. In total, of those patients with melanoma carrying the V600E BRAF mutation and receiving 240 mg or more of PLX4032 twice daily, 37 (81%) demonstrated a response (34 partial and three complete).
The generation of such positive results is a significant change from previous treatments for this type of cancer. In the words of Dr Flaherty, “Until now, we‘ve never had a credible first treatment option for metastatic melanoma, so this has completely transformed how we approach treatment for patients with the BRAF mutation”.
Despite concerns regarding the tendency of tumors subjected to single-agent chemotherapy to develop resistance, he remained optimistic; “Although we don‘t know how long response may last, the ability to beat this disease down in the short term will buy us time to strategize second-line therapies and design the next generation of trials”.
A Phase II clinical trial for PLX4032 has been underway since earlier this year, and a Phase III trial is currently enrolling patients. If these trials are successful, a new and significantly more effective drug may be added to melanoma chemotherapy.
Sources: Flaherty KT, Puzanov I, Kim KB et al.: Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010); Massachusetts General Hospital press release www.massgeneral.org/about/pressrelease.aspx?id=1274; Plexxikon press release www.plexxikon.com/view.cfm/78Press-Releases