Tremeau Pharmaceuticals, Inc Concord, MA, United States
Judith Boice1, Travis Helm1, Maria Bermudez2, Mark Corrigan1 and Bradford Sippy1, 1Tremeau Pharmaceuticals, Inc, Concord, MA, 2Clinical Pharmacology of Miami, LLC, Miami, FL
Background/Purpose: TRM-201 (rofecoxib) is a cyclooxygenase-2 (COX-2) selective inhibitor being developed for the treatment of hemophilic arthropathy (HA) and acute migraine. Previously marketed as VIOXX, rofecoxib is a once-daily treatment which has been shown to be effective for numerous indications including OA and RA. Rofecoxib has no effect on platelet aggregation, a reduced risk for GI adverse events compared with traditional NSAIDs, and a similar CV risk to other NSAIDs at doses ≤25 mg/day1,2. VIOXX was voluntarily removed from the market in 2004 by the original sponsor. There are no FDA approved rofecoxib-containing products commercially available with which to conduct a comparative bioavailability or bioequivalence study. The pharmacokinetics (PK) of single doses of TRM-201 were evaluated in healthy subjects to identify a dose that would provide comparable exposure to 25 mg of VIOXX (rofecoxib).
Methods: Studies TRM-201-PK-101 (PK-101) and TRM-201-PK-102 (PK-102) were single-center, open-label PK studies assessing single doses of TRM-201. The studies were methodologically designed to be highly consistent with the most robust published PK study of VIOXX3 and also to be compared to the VIOXX label (i.e., historic data). Study PK-101 assessed 25 mg of TRM-201 with a two-period crossover design in 53 subjects; a food-effect sub-study in 16 of these subjects was also conducted. Study PK-102 was a four-period crossover design in 24 subjects assessing TRM-201 doses of 12.5 mg, 17.5 mg, 20 mg and 25 mg under fasted conditions. Study PK-102 was designed to combine data from both PK‑101 and PK‑102 studies.
Results: In study PK‑101, exposure (geometric mean [GM] AUC0-∞ and Cmax) was substantially higher for TRM‑201 versus VIOXX 25 mg in the historic data. The magnitude of the difference in exposure between TRM-201 25 mg and VIOXX 25 mg was not accounted for by any demographic variables. Consistent with historic data, TRM‑201 had similar t1/2 and AUC0-∞ in fed vs. fasted states and Tmax was delayed in the fed state. Data combined from PK‑101 and PK-102 studies continued to reveal higher exposure (GM AUC0-∞ and Cmax) for TRM‑201 25 mg compared to VIOXX 25 mg. TRM-201 17.5 mg had slightly lower GM AUC0-∞ but comparable GM Cmax compared to the reference published literature3 and comparable AUC0-∞ and slightly higher Cmax compared to the VIOXX label. The median Tmax for TRM-201 was 2 hours compared to 3 hours for the published literature3. TRM-201 was well tolerated in both studies.
Conclusion: TRM-201 achieves comparable exposure at a lower nominal dose (17.5 mg) compared to the historic data for 25 mg of the previously marketed rofecoxib (VIOXX), with a shorter Tmax. These data suggest that TRM-201 has a higher bioavailability and is more rapidly absorbed than VIOXX. The 17.5-mg dose of TRM-201 is currently being evaluated in a Phase III study in hemophilic arthropathy and a Phase III program in acute migraine is being planned. Additional development programs are under consideration.
References: 1. US FDA, VIOXX (Rofecoxib) USPI 2016 2. McGettigan P, et al. PLoS Med 2011:8(9): e1001098 3. Schwartz j, et al. Clin Drug Invest 2003; 23 (8): 503-509
Disclosures: J. Boice, Tremeau Pharmaceuticals, Inc.; T. Helm, Tremeau Pharmaceuticals; M. Bermudez, None; M. Corrigan, Tremeau Pharmaceuticals, Tremeau Pharmaceuticals; B. Sippy, Tremeau Pharmaceuticals.
