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/day^1,2. 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] AUC_0-∞ and C_max) 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 t_1/2 and AUC_0-∞ in fed vs. fasted states and T_max was delayed in the fed state. Data combined from PK‑101 and PK-102 studies continued to reveal higher exposure (GM AUC_0-∞ and C_max) for TRM‑201 25 mg compared to VIOXX 25 mg. TRM-201 17.5 mg had slightly lower GM AUC_0-∞ but comparable GM C_max compared to the reference published literature³ and comparable AUC_0-∞ and slightly higher C_max compared to the VIOXX label. The median T_max 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 T_max. 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

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/establishing-a-scientific-bridge-to-historic-vioxx-to-enable-a-reintroduction-of-rofecoxib-pharmacokinetic-evaluation-of-trm%e2%80%91201-rofecoxib/