The oral tablet formulation of rofecoxib has been shown to reach maximum plasma concentrations at 2 hours post dose compared with 3 for the historical formulation, which the company believes can improve the time to onset of action.
The FDA has provided a may proceed notification to Tremeau Pharmaceuticals, opening an investigational new drug application for the clinical development of its formulation of rofecoxib, known as TRM-201. The development plan is expected to include a phase 3 efficacy and safety study in the treatment of acute migraine, according to a release from Tremeau.1
The investigational oral tablet therapy is a cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug (NSAID) that had previously been marketed as Vioxx by Merck, but was voluntarily pulled from the market in 2004 because of concerns that it increased the risk of heart attack and stroke.2,3
“Many patients with migraine use an NSAID for rapid relief. A treatment option such as rofecoxib, with demonstrated once-daily efficacy, a rapid onset of action, no effect on platelet aggregation, and reduced risk of GI adverse effects, could be valuable in the treatment of migraine and uniquely suited to meet the needs of the large number of patients who suffer from migraine and cannot tolerate or do not respond to traditional NSAIDs,” Charles Argoff, MD, professor of neurology, and director, Comprehensive Pain Program, Albany Medical Center, said in a statement.1
Bradford C. Sippy, chief executive officer, Tremeau, said in a statement,1 that this may proceed notification and clearance of the IND “reinforces” the company’s position on the dosing of the therapy, specifying that at the proper dose it has “no unique safety issues relative to other NSAIDs and potentially several unique benefits.”
“Our strong intellectual property position, underpinned by the recent issuance of US patents covering TRM-201’s dosage strength and its highly purified rofecoxib active ingredient, affords us the opportunity to expand our development program to help patients suffering from migraine whose needs are not satisfied by currently available NSAIDs,” Sippy said.
Merck’s decision to withdraw rofecoxib from the market in 2004 was based on data from the APPROVe trial, which ultimately revealed a risk of cardiovascular events among those with a history of colorectal ademonas.3,4 The data, published in the New England Journal of Medicine by Bresalier et al, a total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up, equaling 1.50 events per 100 patient-years. In comparison, 26 patients in the placebo group reported the same during 3327 patient-years of follow-up, equaling 0.78 events per 100 patient-years. All told, the relative risk was 1.92 (95% CI, 1.19-3.11; P = .008).4
Similarly, there was between-group separation at about the 5-month mark for the incidence of nonadjudicated investigator-reported congestive heart failure, pulmonary edema, or cardiac failure (HR, 4.61; 95% CI, 1.50-18.83). Notably, overall and cardiovascular mortality were similar between rofecoxib and placebo.4
Bresailer and colleagues wrote that “the increased relative risk became apparent after 18 months of treatment; during the first 18 months, the event rates were similar in the two groups. The results primarily reflect a greater number of myocardial infarctions and ischemic cerebrovascular events in the rofecoxib group.”
Tremeau noted in its announcement that rofecoxib has shown efficacy in treating migraine, regardless of NSAID response history, as well as an ease in crossing the blood-brain barrier without effect on platelet aggregation, “even at supra-therapeutic doses.”
Tremeau’s TRM-201 formulation has been shown to reach maximum plasma concentrations (median Tmax) at 2 hours post dose compared with 3 for historical data for the drug, which the company expressed “could lead to faster onset of action, a critical attribute for people suffering from migraine.”1
This is the second IND opened for a clinical program developing TRM-201. In December 2017, the company gained agreement with the FDA for an NDA-supporting clinical development program for a phase 3 trial of the rofecoxib formulation for the treatment of hemophilic arthropathy.5