New drug 'ubrogepant' may work for migraine
A new study published in the November 19, 2019 issue of JAMA shows that a newly developed small molecule drug called ubrogepant may successfully fight migraine at doses of 25 and 50 mg, with pain relief at 2 hours with both doses, while the most troublesome symptom of migraine was held off at 2 hours post-dose with the 50 mg dose. This may help millions of migraine patients to achieve pain relief and function better.
Migraine is a neurological condition characterized by headache which can last for up to 72 hours, nausea, and hypersensitivity to light and sounds. It is both common and distressing, and can hamper normal life in multiple ways, including work absenteeism, loss of productivity, difficulty with relationships, career failures, financial losses and depression. The treatment and prevention of this condition has attracted much medical interest, but the rate of success is low.
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Gepants
One new line of treatment is with the small molecule medications called gepants. These are antagonists at the calcitonin gene-related peptide (CGRP) receptor, which mediates the effects of CGRP in the pathogenesis of migraine. One of these is ubrogepant, an oral drug which can be used at doses of 25 and 50 mg.
An earlier phase 2b study showed that in doses of 25 mg, 50 mg and 100 mg, ubrogepant could relieve pain with the effect lasting at 2 hours after the dose.
The study
The current phase 3 ACHIEVE II trial is meant to show if doses of 25 mg and 50 mg are effective and safe in the treatment of acute migraine. There were almost 1,700 participants, 500 on placebo, about 560 on 25 mg ubrogepant, and about the same number on 50 mg. 86% completed the trial. The mean age was about 42 years. 90% were women, and about 60% had severe pain while 40% had moderate pain. 57% were most troubled by photophobia.
All patients were between 18 and 75 years, had a history of migraine for at least 1 year but were below 50 years at onset, had 2-8 attacks in each of 3 months preceding the study, reported migraine duration of 4-72 hours without treatment or with inadequate treatment, and had at least 48 hours in between acute attacks.
The study was carried out at multiple centers, with a double-blinded randomized placebo-controlled design. The participants were grouped by their previous response to commonly used migraine drugs called triptans, and the current use of other preventive drugs. All these drugs were prohibited while taking the trial drug – including opioids, triptans, ergot derivative, nonsteroidal anti-inflammatory drugs (NSAIDs), pain relievers, antiemetics, and proton pump inhibitors. Within these groups, they were randomly assigned to receive either placebo, 25 mg of ubrogepant, or 50 mg of the drug.
The participants took one tablet of assigned medication as early as possible when migraine struck, but at all costs within 4 hours of onset. If required, the patient could take a second dose or a rescue drug within 2-48 hours, if the headache continued or started again at moderate to severe levels.
However, within the group of patients who chose to take a second dose, in the ubrogepant 25 mg/ 50 mg arms, the participants were again randomized to placebo vs the previous dose of ubrogepant. In the placebo arms, all patients repeated the dose of placebo. A rescue medication could be taken if required 2 hours after the second dose, in any of the trial arms.
Patients who did not want to take the repeat dose could take another drug from 2-48 hours after the first dose.
They then reported medication efficacy – severity of headache pain, presence of nausea, vomiting, sound or light sensitivity from the time of dosing to 48 hours afterwards, at specified intervals. The primary outcome was pain absence at 2 hours from the first dose, and absence of the most troublesome symptom (as reported at the beginning) at 2 hours.
The findings
The study found that 21% of patients on 50 mg ubrogepant, and almost the same percentage on 25 mg ubrogepant, achieved pain relief at 2 hours, compared to 14% with placebo. The drug appeared to be most effective at 3-8 hours after intake.
The most troublesome symptom was relieved in about 39% of patients on 50 mg ubrogepant, but there was no significant difference (34% vs 27%) between the 25 mg ubrogepant and placebo arms.
Among those who took a second dose, the chances of being pain-free 2 hours after the second dose were 2.2 times higher in those who took 2 doses at 50 mg each, compared to those who took two 25 mg doses, or those who took 50 mg followed by placebo. Other secondary outcomes such as the rate of pain relief over 2-14 hours, or absence of pain over the same period, were also greater in the 50 mg group. This was also seen with respect to the absence of photophobia and phonophobia (sensitivity to light and sound, respectively). Functional improvement was also obvious at 2 and 8 hours in the 50 mg group compared to placebo.
Implications
All available evidence points to the 50 mg dose as being the most effective in the acute treatment of migraine, achieving pain relief as well as absence of the most troublesome symptom at 2 hours.
The rate of adverse effects was similar in all three groups, indicating the safety and tolerability of ubrogepant. It has no cardiovascular precautions or contraindications like the triptans or ergot derivatives. It is also free of the serious cardiovascular and gastrointestinal effects of NSAIDs. Above the age of 22, cardiovascular contraindications exist in about a fifth of all patients with episodic migraine. Thus, ubrogepant may be a good option for those who fail to achieve acute relief of migraine with current medications.
It is important to capture the full benefit of the drug using alternative outcomes such as pain relief and functional improvement at 2 hours, because it appears to be maximally effective at 3-8 hours. Moreover, participants took the drug only with moderate or severe pain, while the American Headache Society recommends that treatment begin at the first sign of headache. This was not done, so we still don’t know just how much migraine pain could be averted if ubrogepant was given early rather than relatively late, as in this study. More study over a longer term is needed to find out how ubrogepant alters nerve function during migraine, any chronic side effects, and how consistently it acts to relieve pain.
Journal reference:
Lipton RB, Dodick DW, Ailani J, et al. Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute Treatment of Migraine: The ACHIEVE II Randomized Clinical Trial. JAMA. 2019;322(19):1887–1898. doi: https://doi.org/10.1001/jama.2019.16711
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