Biotech Values

[urche]

Re: Celebrex

Here is an interesting article providing background on rationale for studying COX-2 inhibitors for cancer prevention and some insights into how researchers were thinking about Celebrex as a cancer prevention drug a few years ago.
http://clincancerres.aacrjournals.org/cgi/content/full/10/11/3908

The first part of the article goes into detail about optimal design of a cancer prevention trial. Below is the relevant snip detailing work with celecoxib. Of note, the inclusion criteria makes no attempt to control for cardiovascular risk factors. Also, there is no mention of intention to assess for CV events. So, if this is one of the current newsworthy studies, it came out of a later reexamination of follow up data.To me, this adds further evidence to the thesis developing on this board that Celebrex is probably safe in conventional doses, though maybe not as safe in cancer patients.


Celecoxib.
Celecoxib has a known molecular target [cyclooxygenase (COX)-2]. Non-COX targets may also contribute to the effect. In 1999, the FDA granted accelerated marketing approval for celecoxib "to reduce the number of adenomatous colorectal polyps in FAP as an adjunct to usual care" (FDA, December 23, 1999). The rationale for testing a specific COX-2 inhibitor in FAP is based on mechanistic data, preclinical efficacy studies, as well as epidemiological and clinical intervention investigations (for recent reviews, see Refs. 71, 72, 73 ). This supporting evidence includes the observation that COX isoenzymes are overexpressed in colorectal adenomas and tumors (74, 75, 76, 77, 78, 79, 80, 81, 82) . Targeted deletion of the COX-2 gene prevents CRC in animals, and celecoxib as well as other selective COX-2 inhibitors (e.g., JTE-522, NS-398, the tricyclic methyl sulfone derivative MF tricyclic, nimesulide, and rofecoxib) are also effective in preclinical models (83, 84, 85, 86, 87, 88, 89, 90, 91) . In addition, substantial epidemiological evidence supports a 40–50% protective effect of NSAIDs (primarily aspirin) against colorectal carcinogenesis (see Refs. 40 , 41 , and 92, 93, 94, 95 , and more than 30 additional studies are reviewed in Refs. 72 , 96 , and 97 ). A number of studies have also shown that the NSAID sulindac regresses adenomas in FAP patients (reviewed in Ref. 98 ). In a recent study of 21 FAP patients, rofecoxib (25 mg once daily for 9 months) modestly reduced rectal polyp number (9.9% decrease) and size [21.7% decrease (99) ].

The Subpart H approval was based on a randomized, double-blind, placebo-controlled study of 83 FAP patients in which 400 mg twice daily celecoxib for 6 months significantly reduced adenoma number by 28% [P = 0.003 compared with the 4.5% reduction with placebo (100)]. [Could this be one of the same studies whose data was released this week?] In addition, this celecoxib dose significantly reduced adenoma burden (the sum of adenoma diameters) by 30.7% (P = 0.001 compared with the 4.9% reduction with placebo). In patients receiving 100 mg twice daily celecoxib, the reductions in adenoma number and burden were 11.9% and 14.6% (P = 0.33 and P = 0.09 for the comparison with placebo, respectively). A blinded physicians’ assessment indicated a qualitative improvement in the colon and rectum and, to a lesser extent, in the duodenum of treated subjects (101) .

Postmarketing studies to show the clinical benefit of celecoxib in FAP are ongoing. These include a two-part Phase II study to evaluate safety and FAP phenotye suppression in genotype-positive children and a Phase II study to determine whether greater efficacy against adenomas and other manifestations of FAP can be achieved by combination of celecoxib with the antiproliferative agent 2-difluoromethylornithine. A separate Phase II study is evaluating the biomarker-based efficacy of celecoxib in hereditary nonpolyposis CRC patients, a cohort for whom no data are yet available regarding the effect (adverse or beneficial) of any potential CRC chemopreventive agent.

The trial data also provided support for Phase III trials in patients with prior sporadic adenomas. As shown in Table 2 , these include three Phase III studies with celecoxib alone (400–800 mg/day); a comparable study of rofecoxib (25 mg/day) is also ongoing. In addition, a Phase III trial comparing celecoxib (400 mg/day) and selenium (200 µg/day) is under way. The end point for these trials is adenoma number at 3 years [or at 1 and 3 year(s)].




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Table 2 Ongoing Phase III studies of sporadic colorectal adenoma prevention
Eligible for these trials are subjects with 1 prior colorectal adenoma; individuals with familial cancer syndromes are excluded. Intervention arms are balanced for potential confounders (e.g., trials of celecoxib alone versus placebo stratify by concomitant cardioprotective aspirin use). A clearing colonoscopy is performed at (or within several months of) baseline, the intervention is initiated, and adenoma number is assessed endoscopically at the indicated times thereafter. Secondary end points include measures of adenoma severity (size, histological grade, and so forth) as well as drug effect markers (e.g., deoxycholic acid concentration suppression by ursodeoxycholic acid, prostaglandin reduction by cyclooxygenase-2 inhibitors).





Despite the promise of efficacy and the widespread safe use of COX-2 inhibitors, the long-term safety of celecoxib has not yet been established.[prophetic words] Like traditional NSAIDs, celecoxib is contraindicated during late pregnancy. Celecoxib also has the same renal, hepatic, and GI side effects that are also associated with aspirin and other NSAIDs (reviewed in Ref. 102 ). GI events appear to be less frequent and severe with celecoxib than with nonselective agents (103) . However, limited postmarketing data suggest a comparable renal side effect profile [2.1% and 0.8% incidence, respectively, of edema and hypertension with celecoxib (104) ]. Rare cases of acute renal failure have also been reported (105) . These effects highlight the pivotal role of COX-2-dependent prostaglandins in normal renal development and maintenance (106 , 107) .
In a large clinical trial, myocardial infarction was four times more common with rofecoxib (50 mg qd) than naproxen [500 mg bid; 0.4% versus 0.1% (108) ]. However, a recent large retrospective analysis found no increased risk of myocardial infarction among >15,000 and >12,000 short-term users of celecoxib and rofecoxib, respectively, over the age of 66 years (109) . A meta-analysis of patients in trials of COX-2 inhibitors found an annualized myocardial infarction rate of 0.8 (P = 0.02) and 0.74 (P = 0.04) for celecoxib and rofecoxib, respectively, versus 0.52 for placebo (110) . This analysis is limited by the small absolute number of cardiovascular events (<70) and confounded by statistical methodology as well as heterogeneity among the three pooled study populations (aspirin use, rheumatoid versus osteoarthritis patients versus primary prevention trial participants). Nevertheless, appropriate postapproval surveillance should continue in patients with cardiovascular risk factors.

The potential for drug-drug interactions typically presents safety concerns. Celecoxib inhibits cytochrome P-450 CYP2C9, which metabolizes a number of drugs including warfarin (111 , 112) . Lithium and fluconazole also potentially interact with celecoxib. As additional postmarketing data accrue, a more complete profile of drugs that should not be used in combination with COX-2 inhibitors will likely emerge.