The product of a joint development programme between US drug development company Pozen and GSK, Treximet is a novel combination therapy consisting of sumatriptan and naproxen sodium in a single tablet for the treatment of acute migraine.

Following completion of pivotal Phase III trials on the new combination therapy, the companies filed for regulatory approval with the US Food and Drug Administration (FDA), receiving a letter of approval for Treximet in June 2006. However, because Pozen’s initial response to the letter was incomplete the FDA requested additional information in December 2006, thus delaying Treximet’s final approval.

The company re-filed with the FDA and was given approval for the drug in April 2008, for treatment of migraine in adults with acute migraine attacks.

This was an important development for Pozen given its previous failure to secure FDA approval for its earlier combination migraine therapy, metoclopramide plus naproxen sodium (MT100).

The triptan era

Introduced into clinical practice in the early 1990s, the triptan class of drugs were a major advance in the treatment of acute migraine. Triptans, of which GSK’s sumatriptan was the first to be approved, are selective 5-HT1 agonists and specific anti-migraine medicines. They are considered among the most effective agents for relieving symptoms of an acute migraine attack.

Sumatriptan, for example, is often used in the initial headache phase of a migraine attack and to ameliorate other symptoms. It can be administered orally, intranasally or by subcutaneous injection, and is considered preferred therapy for migraine patients who are refractory to simple analgesics.

Seven triptans are available for the treatment of acute migraine. They include:

  • Sumatriptan
  • Rizatriptan
  • Zolmitriptan
  • Naratriptan
  • Almotriptan
  • Frovatriptan
  • Eletriptan.
“Pozen was given approval for Treximet in April 2008, for treatment of migraine in adults with acute migraine attacks.”

Triptans are believed to induce vasoconstriction of the cartoid arterial circulation, which dilates during a migraine attack. In addition, they may act at synapses of the trigeminal nerve to reduce neuronal firing and inhibit release of neurotransmitters that cause vasodilation. They are effective against not only headache but also associated symptoms of nausea, photophobia and phonophobia.

Triptans are contraindicated in patients with ischaemic heart disease and unstable angina. They should not be given concomitantly with ergotamine, a drug also used in the treatment of migraine.

Combination therapy for migraines

Triptans, described above, and non-steroidal anti-inflammatory drugs (NSAIDs) are both widely used in the treatment of acute migraine for the relief of pain and other symptoms. Combining a triptan and NSAID in a single tablet has the potential to provide greater symptom relief than therapy with either drug alone.

Sumatriptan acts primarily to restore normal tone to dilated blood vessels, while NSAIDs block the effects of inflammatory mediators such as prostaglandins and thus provide an additional
route to pain relief.

With Treximet, sumatriptan and the NSAID naproxen sodium are combined in a single tablet using GSK’s RT Technology. This produces a rapidly dissolving oral formulation that is readily absorbed into the patient’s bloodstream producing a fast onset of
drug action, a prerequisite for effective symptom relief.

Treximet efficacy – pivotal phase III studies

Promising results from a Phase II trial on combination therapy had been confirmed in two pivotal Phase III trials. In the earlier Phase II double-blind, placebo-controlled trial involving 972 patients with acute migraine, concomitant use of a triptan and NSAID produced a more rapid onset of action and longer duration of pain relief than either triptan monotherapy or placebo.

Among patients in the dual treatment arm, 65% experienced pain relief within two hours of dosing compared with 49% and 27% of those on triptan monotherapy or placebo respectively. Pain relief within two hours of dosing is regarded as the gold standard for efficacy and the basis on which acute migraine therapies are approved.

“In Phase III trials Treximet demonstrated superior pain relief within two hours of dosing in comparison with the individual agents and placebo.”

In both pivotal Phase III trials, Treximet demonstrated superior pain relief within two hours of dosing in comparison with the individual agents (sumatriptan and naproxen) and placebo. All other regulatory endpoints were met with respect to placebo.

meet regulatory requirements, any new combination drug, such as Treximet, must demonstrate superiority over the individual components of the combination.

In addition to the Phase III clinical trials, Pozen also conducted a one-year open-label study to assess the long-term safety of Treximet as a treatment for acute migraine. The study enrolled 565 patients who were treated for about 24,500 migraine attacks with Treximet. In patients who completed the study, five migraine attacks were treated each month with Treximet.

Marketing commentary

Affecting up to 10% of the general population, migraine is a common condition. It is classed as a primary headache, a group that also includes cluster and tension-type headaches. First-line treatment of migraine still focuses primarily on the use of simple analgesics and NSAIDs, although they are not specific anti-migraine therapies and thus carry the risk of rebound headache.

Combining a NSAID with a specific anti-migraine triptan, however, has potential to offer relief of migraine symptoms over and above those achieved with either class of drug alone. Patients with migraine often have a variable response to treatment and so the availability of a new treatment option such as Treximet may expand treatment options.

Under the terms of their agreement, Pozen was responsible for pre-clinical, clinical, and regulatory development of Treximet, while GSK’s responsibilities included drug formulation, manufacturing and commercialisation.