Gepants

Abstract

Gepants are a new class of migraine medications effective for treating migraines when they occur. Potentially they also may have benefit for prevention. Unlike the monthly injectable monoclonal antibody preventive medications that target calcitonin gene-related peptide (CGRP), gepants will be available in pill, nasal, and orally disintegrating tablet (ODT) forms and are taken either at the start of the pain, or possibly, depending on further studies, can be taken 15-30 days per month to decrease the frequency of migraine. The first generation of gepants was evaluated over 15 years ago and was subsequently abandoned because of liver toxicity, a problem not seen in the second generation of gepants being used and studied today. There are currently 4 second generation gepants, 2 of which are available for as-needed treatment of migraine. For acute treatment, there are the FDA approved ubrogepant (brand name UBRELVY, Allergan Inc., Madison, NJ) and rimegepant in orally dissolvable form (brand name NURTEC, Biohaven, New Haven, CT). Rimegepant in tablet form was found to be effective for migraine prevention in March 2020 studies. If approved for prevention, rimegepant would be the only gepant that would have both acute and preventive indications for migraine. Vazegepant, a gepant nasal spray (Biohaven), is also in development for acute migraine treatment and not yet available. Atogepant (Allergan) is being studied exclusively for migraine prevention in a daily dose. All the gepants appear to have similar effectiveness in stopping migraine attacks and similar minimal side effects, but they come in different forms, as tablet, orally dissolvable tablet, or nasal spray. Gepants are small molecules, unlike their large injectable preventive cousins the monoclonal antibodies. The gepants are antagonists of the CGRP receptor, meaning they block the ability of CGRP to bind to the CGRP docking station, where CGRP starts up or prolongs migraine attacks. An exciting feature of gepants is that, unlike the triptan class usually used to treat a migraine, gepants do not cause constriction of blood vessels, and therefore, could be used in people who have vascular disease, heart disease, or stroke. Similar to monoclonal antibodies, there have not been any studies to determine gepant safety in pregnancy, so pregnant women or those who could become pregnant and are not using birth control should avoid these medicines. As noted above, gepants have as their target CGRP, a pain-related neuropeptide that is elevated in migraine. With so many people with migraine already taking CGRP inhibiting monoclonal antibodies, the question arises, can these people benefit from a gepant for acute use while on the injectable CGRP preventive? There are only case reports of those who have used gepants for as-needed treatment for breakthrough migraine attacks while taking the injectable monoclonal antibodies, but so far, these people reported that the gepants worked, and no problems have been identified. This is an area for future study. Although outcome data are early, a signal for worsening migraines with frequent use (sometimes called medication overuse headache or rebound) has not been seen with gepants, and this is one of the reasons this class of medications is being studied for both acute and preventive treatment of migraine. Studies have suggested that when people with migraine frequently took a gepant acutely for their migraine attacks, they actually had fewer migraines over time. This was followed by a clinical trial of rimegepant taken half of all days versus a placebo, confirming the decrease in monthly migraines days over time, that is, that rimegepant has a preventive effect, although it is not yet FDA approved for this use. In addition, a study of atogepant taken daily versus placebo also showed preventive benefit for reducing attacks of episodic migraine. As a class of medications, gepants provide a lesser likelihood of acute pain relief at 2 hours than some triptans. What gepants miss in quick onset, they may make up for in better tolerability and fewer side effects. Many people with migraine will not take triptans or dihydroergotamine (DHE) because of side effects such as neck pain, nausea, chest tightening, fatigue, muscle cramps, and dizziness. Compared with a placebo pill, gepants have about a 1% chance of causing nausea and do not show the reported triptan and DHE side effects. This gentle tolerability is a strong point of gepants. The lower rates of pain freedom at 2 hours may in part have come from study requirements that subjects not take the pill until the migraine was moderate to severe in intensity, when generally pain freedom is more difficult to achieve. It may be (although not yet proven) that gepant effectiveness would be improved by taking the tablet earlier in the headache, when pain intensity is milder. Both ubrogepant and rimegepant have been studied extensively to look for signs of liver problems. Ubrogepant 100 mg was also tested using 2 days on, 2 days off, over 2 months, and appeared to cause no lasting liver difficulty or symptoms. Both ubrogepant and rimegepant have been given to over 1200 people for use over time for their migraines without liver problems. Both appear to be free of the significant liver troubles of the earlier drugs. There are drug interaction cautions for both ubrogepant and rimegepant. They are processed through a similar liver processing pathway (CYP3A4) as a number of medications, and therefore, use of these medications could either increase or decrease the effectiveness of medications using the same pathway. Medications such as antifungal drugs and clarithromycin should be avoided when using ubrogepant or rimegepant. In those who take medications such as verapamil, fluconazole, fluvoxamine, and those who drink grapefruit juice, the dose of ubrogepant should be 50 mg. The effectiveness of gepants may be decreased with phenytoin, barbiturates, and rifampin. In pregnant and nursing animal testing at very high doses (not the doses used for people), fetal toxicity and fetal loss was noted. None of the gepants is recommended in pregnancy or when nursing. It is important to stress that ubrogepant and rimegepant are very similar. They work by the same mechanism at the same site of action, blocking the same CGRP docking station. Their effectiveness at 2 hours is almost identical. Their side effects are generally nonexistent. The only real differences are dose sizes, the fact that one cannot take a second dose of rimegepant in the same day, and the fact that ubrogepant comes as a standard tablet. Rimegepant 75 mg comes in an orally dissolvable form for acute treatment and was studied in tablet form for prevention. Ubrogepant (brand name UBRELVY, Allergan, Inc, Madison, NJ) came to market in January 2020 and is now available for the acute treatment of migraine in 50 mg and 100 mg tablets. The maximum dose in a day is 200 mg. At 2 hours, pain freedom was seen in about 20% of subjects vs a placebo rate of 12%. The absence of the most bothersome migraine symptoms was reported in about 38% of those taking the either the 50 mg or 100 mg dose vs a placebo rate of 27.8%. Pain relief was seen in 61% at 2 hours vs placebo rates of 48%. The most common side effects for ubrogepant were nausea and dizziness, neither of which rose above the placebo rates. Rimegepant (brand name Nurtec ODT, Biohaven, New Haven, CT) 75 mg is the only gepant seeking indication for both acute and preventive treatment of migraine. The acute treatment indication was approved in February 2020 by the Food and Drug Administration (FDA), while its use in migraine prevention is still being studied. Rimegepant for acute use comes in a 75 ODT, while the preventive form may be a tablet with the same dosage. The maximum dose in day is just 75 mg, with no repeat dosing approved. For acute treatment, the rimegepant ODT should ideally be taken on an empty stomach, because the benefit is delayed by 1 hour after a fatty meal, and the effectiveness is reduced in the presence of a full stomach. As noted, 1 dose is recommended to be taken in a 24-hour time period, and it is not recommended this be repeated sooner. Pain freedom at 2 hours occurred in 21% or those treated with rimegepant compared to placebo of 10.9%. As with ubrogepant, rimegepant relieved the most bothersome migraine symptom by 2 hours better than placebo. There were no serious side effects seen in studies of this gepant, and the only side effects observed by patients were nausea and urinary tract infection, seen 1% above a placebo pill. In the rimegepant preventive study, reported in March 2020, the 75 mg tablet was found to be effective for the prevention of migraine with every other day dosing. A study group of 741 patients was given either a dummy placebo tablet or rimegepant 75 mg every other day. In patients taking rimegepant with a baseline of ≥14 migraine days per month, there was a 6.4 day reduction in monthly migraine days. In those with <14 migraine days per month, there was a 4 day reduction in headache days in the rimegepant group. After this is confirmed, it is likely that rimegepant will be submitted to the FDA for approval for prevention. Rimegepant would then be the first medication approved for both acute and preventive use. For now, it has only the FDA approval for acute as-needed use. Atogepant (Allergan Inc, Madison, NJ) is in trials for the prevention of migraine. When tested in a trial for prevention of episodic migraine, there was a drop of at least 4 migraine days per month, at least a 50% drop in migraine days per month by 3 months. Fatigue, nausea, and constipation appeared to increase at the higher doses, and some side effects were noted at about 2% compared with a placebo pill. No liver abnormalities above the placebo rate were found. Again, if confirmed, atogepant daily will be for prevention of migraine. Vazegepant is not available yet, but a trial for the acute treatment of migraine was completed and was positive. Vazegepant is expected to be marketed as a nasal spray. The two expected dosages are 10 and 20 mg, and because of the nasal route, it may have a rapid onset of action. In a trial with 1,673 patients, the company announced that pain relief was observed as soon as 15 minutes and return to normal function was seen in 30 minutes. At 2 hours, 20% of subjects had pain freedom, and 42% had freedom from their most bothersome migraine symptom. These results are similar to both of the oral gepants currently available. Summary: Gepants are small molecules that block the CGRP docking station or CGRP receptor and do not cause blood vessels to narrow. Overall, they have about a 20% effectiveness for pain freedom 2 hours after taking the drug. There are 4 gepants either approved or in final studies before approval. Ubrogepant is an FDA-approved and available tablet for acute treatment of migraine. Rimegepant is an approved and available orally dissolvable tablet for acute treatment of migraine and is currently being studied in tablet form for migraine prevention. Atogepant will be for prevention only, is currently being studied in tablet form, and is not yet approved or available. Vazegepant is a nasal spray being studied for acute treatment of migraine and is not yet available or approved. All the gepants appear to have similar effectiveness, minimal side effects, and so far appear to be safe. Data suggest fewer headaches may occur with frequent use of gepants, rather than the increase in headaches seen with overuse of other acute treatments.