Reformulating Rofecoxib for the Acute Treatment of Migraine

Bradford C. Sippy

Last week, the FDA granted a may proceed notification to Tremeau Pharmaceuticals for the opening of an investigational new drug application for a new formulation of rofecoxib, known as TRM-201, in the treatment of acute migraine. The development plan is expected to include a phase 3 efficacy and safety study.¹

Previously, the oral tablet therapy had been brought to market as Vioxx, by pharmaceutical company Merck. But, in 2004, the cyclooxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drug (NSAID) was voluntarily pulled from the market because of concerns that it increased the risk of cardiovascular (CV) events such as heart attack and stroke.^2,3

To find out more about this new formulation, its potential to treat acute migraine, and Tremeau’s plans for its development, NeurologyLive® inquired with Bradford C. Sippy, chief executive officer, Tremeau. He offered further details on the plans for the phase 3 study and how the company plans to address the prior safety concerns.

NeurologyLive^®: What should the clinical community know about the upcoming phase 3 study of this formulation of rofecoxib? Can any details or plans be shared at this point?

Bradford C. Sippy: Tremeau expects the phase 3 study of TRM-201 for the treatment of acute migraine to follow a design similar to that of other recently approved migraine therapies. The study is designed to consistent of two parts: a single-dose placebo-controlled efficacy portion, followed by a 3-month open-label safety extension. The study is planned to include approximately 850 patients.

This therapy had been voluntarily pulled from the market because of CV risk, why should physicians not carry that concern about those risks now?

Since Vioxx was voluntarily withdrawn by Merck in 2004, numerous independent studies have demonstrated that CV risk is a dose- and duration-dependent risk of all NSAIDs. Vioxx appeared to be an outlier because the acute pain dose (50 mg) was used off-label chronically.⁴

Tremeau intends to develop TRM-201 (rofecoxib) at an equivalent strength to Vioxx’s middle dose (25mg), which has demonstrated similar CV risk as equiefficacious doses of ibuprofen, diclofenac, and celecoxib. Furthermore, the episodic nature of a migraine indication reduces the duration-related risk that comes with chronic use of NSAIDs. Finally, migraines most commonly impact women younger than 50 years old, which is generally a population with relatively low baseline CV risk compared to other chronic NSAID populations.

What might this therapy offer from a mechanistic perspective compared with the other recent additions to the migraine treatment toolbox?

NSAIDs are often used alone or in combination with other therapies (ie, CGRPs, triptans, 5HT-1F) as the standard of care for patients with migraine. However, some people cannot or prefer not to take traditional NSAIDs because of their inhibitory effect on platelet aggregation, gastrointestinal adverse effects, or for lack of efficacy.

Rofecoxib is a once-daily product that was previously demonstrated to be highly effective in the treatment of acute migraine, regardless of whether or not there was a history of prior response to other NSAIDs. Rofecoxib has been shown to easily cross the blood-brain barrier (whereas celecoxib tablets have not) and has been shown to have no effect on platelet aggregation, even at supra-therapeutic doses. Rofecoxib was the only COX-2 selective NSAID ever approved in the United States to demonstrate a reduced risk of gastrointestinal bleeding versus a traditional NSAID.

Additionally, unlike some therapies used to treat migraine, such as opioids and lasmiditan, rofecoxib has no potential for abuse and is therefore not a controlled substance.

Finally, Tremeau’s oral tablet formulation of rofecoxib, TRM-201, has been shown to be rapidly absorbed, reaching a maximum plasma concentration (median Tmax) at two hours after dosing (versus three hours for historical VIOXX). Tremeau believes this could lead to a rapid onset of action, a critical attribute for people suffering from an acute migraine attack.

Is there anything else of note that you feel is worth informing the clinical community with regard to TRM-201 and/or Tremeau’s goals in acute migraine care?

Tremeau plans to focus on patients suffering from migraine who cannot tolerate or do not respond to traditional NSAIDs.

Transcript edited for clarity.

REFERENCES
1. Tremeau Receives May Proceed Notification From FDA For Phase III Program in Acute Migraine For TRM-201 (Rofecoxib). News release. Tremeau. June 14, 2022. Accessed June 22, 2022. https://www.biospace.com/article/releases/tremeau-receives-may-proceed-notification-from-fda-for-phase-iii-program-in-acute-migraine-for-trm-201-rofecoxib-/
2. Merck Announces Voluntary Worldwide Withdrawal of VIOXX. News release. Merck. September 30, 2004. Accessed June 22, 2022. https://www.pbm.va.gov/PBM/vacenterformedicationsafety/vioxx/DearHealthcareProfessional.pdf
3. Vioxx (rofecoxib) Questions and Answers. FDA website. Updated April 6, 2016. Accessed June 22, 2022. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/vioxx-rofecoxib-questions-and-answers
4. Boice JA, Corrigan M, Sippy BC. Diagnosing the Cardiovascular Risk of VIOXX: A Place For Rofecoxib In Pain Management. Presented at: 2022 NYAS Advances in Pain; May 3-4; New York, NY.