Rimegepant for preventing migraine

Migraine attacks usually last between 4 hours and 72 hours. They involve throbbing head pain of moderate-to-severe intensity, which can be highly disabling. The patient experts explained that migraine is an individual condition in terms of triggers and presentation. They noted that migraines are often accompanied by nausea, vomiting, dizziness, and sensitivity to light, sound and smells. Migraine can adversely affect quality of life, affecting people's ability to do their usual activities, including work. A patient expert highlighted that migraine has a large emotional and psychological burden on the day-to-day lives of those affected. In response to consultation, NICE received comments from the public, carers and patients with migraine, who explained that they can feel isolated, dismissed, and treated as responsible for their condition. They described a migraine as an invisible disability that affects all aspects of life including work, education, finances, mental health, social activities, and family. The Migraine Trust also commented that people with migraine are stigmatised, partly because of a lack of understanding about the condition and effective treatments, and the perceived effect on work productivity. Migraine can be classified as episodic or chronic, based on the frequency of headaches. Episodic migraine is defined as fewer than 15 headache days a month. Chronic migraine is defined as 15 or more headache days a month with at least 8 of those having features of migraine. The patient experts explained that the severity of the condition can vary over time, so the distinction between chronic and episodic is not clear cut. This appraisal considers rimegepant within its marketing authorisation for preventing episodic migraine. Preventing chronic migraine was not considered because it is not within rimegepant's marketing authorisation. In the first appraisal consultation document, NICE considered rimegepant for both its indications, preventing and treating migraine. In response to consultation, NICE received comments saying that the committee needed to consider the interplay between the acute and preventative indications and the effect of this on the treatment pathways. Comments explained that this is because the acute and preventative indications have distinct populations with only a small overlap. Comments also highlighted that there is a potential for misuse of rimegepant. For example, some people prescribed it for preventing migraine might take it when they have an acute migraine. The committee acknowledged these comments and considered each indication separately. Rimegepant for acute treatment is recommended in NICE's technology appraisal guidance on rimegepant for treating migraine. The committee concluded that migraine is a debilitating condition that substantially affects physical, social, psychological, and professional aspects of life.

The aim of preventative treatment is to reduce the frequency, severity or duration of migraine and improve quality of life. A 50% reduction is considered clinically meaningful in episodic migraine. The committee was aware that there is a range of oral preventative treatments that people with at least 4 migraine days per month would try before moving onto a different type of treatment. These include topiramate, propranolol and amitriptyline. The clinical experts noted that rimegepant would usually be offered after 3 preventative oral treatments had not worked, or the person cannot tolerate them. Available fourth-line treatments on the NHS are the injectable monoclonal antibodies erenumab, fremanezumab and galcanezumab. The committee also noted NICE's recently published technology appraisal guidance on eptinezumab for preventing migraine. But because eptinezumab was not recommended for routine use at the time of its decision making, it was not considered a comparator for rimegepant. Consultation comments said that there is a high unmet need for new treatment options and that existing treatments do not work for many people. Comments noted that some people try medicines not licensed for migraine, such as opioids. The committee concluded that at least 3 oral preventative treatments should be tried before other treatments are considered.

The company proposed rimegepant as a preventative treatment for episodic migraine in adults who have at least 4 and fewer than 15 migraine attacks per month, and whose symptoms have not responded to at least 3 preventative treatments, which is narrower than the marketing authorisation. The company considered that rimegepant would likely be used in NHS clinical practice at this point. The company positioned rimegepant alongside erenumab, fremanezumab and galcanezumab. But the committee noted the licensed indication of the comparators is for migraine days per month. This differs slightly from the rimegepant indication, which is for the number of migraine attacks per month. This is because a migraine attack can last more than 1 day (see section 3.1) so a person can have more than 4 monthly migraine days (MMDs) but could still have fewer than 4 attacks per month. The committee concluded that erenumab, fremanezumab and galcanezumab are the most appropriate comparators. Also, it concluded that any recommendation would not be based on migraine days per month because this would be outside of rimegepant's licence.

The company's clinical evidence for rimegepant for preventative treatment came from BHV3000‑305 (n=741), a phase 2/3, double-blind randomised controlled trial. This evaluated rimegepant in adults aged 18 years and over, with at least a 1‑year history of migraine with or without aura. It only included people with 4 to 8 moderate-to-severe migraine attacks per month that last, on average, 4 hours to 72 hours if left untreated. Rimegepant (75 mg administered orally as a tablet on alternate days) was compared with placebo over 12 weeks. The primary outcome was the change in mean MMDs in the last 4 weeks of the trial treatment phase. A key secondary outcome, which was used to inform response in the economic model at 12 weeks, was a reduction of at least 50% from baseline in mean number of moderate-to-severe MMDs in the last 4 weeks of the trial treatment phase.

The company presented results from the trial definition (the proportion with at least a 50% reduction in mean number of moderate-to-severe MMDs compared with baseline MMDs in the last 4 weeks of the trial). It also presented results using the definition from the trials for rimegepant's comparators (see section 3.3; the proportion with a reduction in mean MMDs by at least 50% [any severity] compared with baseline during the whole 12‑week treatment period). In both definitions, rimegepant was more effective at reducing MMDs than placebo. Adverse events were considered mild to moderate by both the company and ERG, with low rates of severe or serious events. For this reason, they were not included in the economic model. The committee concluded that rimegepant was more effective at reducing MMDs than placebo.

There was no direct evidence comparing rimegepant with erenumab, fremanezumab and galcanezumab. So, the company did a network meta-analysis (NMA) using data from separate clinical trials of rimegepant, erenumab, galcanezumab and fremanezumab. After technical engagement, the company and the ERG agreed on an NMA including 14 studies. A random effects NMA adjusted for baseline risk was determined to be the most suitable model to use, given that there were limitations in the evidence (see section 3.7). The outcomes of the model were similar to those in the trial. The results of the NMA numerically favoured erenumab, fremanezumab and galcanezumab in both outcomes (the results are academic in confidence and cannot be reported here) (see section 3.4). The committee concluded that rimegepant is likely to be similar to or less effective than erenumab, fremanezumab and galcanezumab at reducing MMDs.

The ERG explained that the NMA was uncertain. This was because of the limitations of BHV3000‑305 (see section 3.8) and the comparability of the trials included. The ERG explained that the trials in the indirect treatment comparison had different populations, different methods to handle missing data, and different treatment stopping histories. Also, some studies included people with chronic migraines, which is not in rimegepant's licence for preventative treatment. The company acknowledged that there was a lack of direct clinical trial evidence comparing rimegepant with erenumab, fremanezumab and galcanezumab. The ERG accepted that the company had attempted to reduce the uncertainty and that the outstanding limitations were unresolvable. The Association of British Neurologists and British Association for the Study of Headache commented that direct comparisons between trials cannot be made because of differences in study design and placebo response. In response to consultation, NICE received comments saying that not enough evidence had been collected, and further trials are needed directly comparing rimegepant with erenumab, fremanezumab and galcanezumab. The committee acknowledged that BHV3000‑305 excluded the most relevant patient population, which limited the NMA and its applicability to this appraisal. The committee concluded that the NMA limitations were unresolvable, largely because of the issues with BHV3000‑305, but that the NMA was suitable for decision making.

The company proposed a narrower population than the licence for rimegepant for preventing migraine (see section 3.3). The clinical evidence presented by the company did not reflect this population. Eleven out of 14 studies included in the NMA excluded people with a history of no response to prior treatment. Also, BHV3000‑305 excluded people with no response to at least 2 preventative treatments. A key concern from a clinical expert, which was also noted in comments from the Association of British Neurologists and the British Association for the Study of Headache, was that a history of no response to prior treatments indicates that the migraine could be treatment resistant. The company stated that this issue was unresolvable. This is because no data was collected to assess how no response to prior treatment affects rimegepant's efficacy. The company presented evidence from comparator trials suggesting that the rimegepant results may be conservative in a population with refractory migraine (the results are academic in confidence and cannot be reported here). The ERG did not agree with this conclusion, stating that the evidence was uncertain and did not show a substantial difference between refractory or non-refractory migraine. Clinical advice to the ERG suggested that refractory migraine could be more difficult to treat, with a higher risk of treatment not working. The committee concluded that the clinical evidence from the NMA was not aligned with the company's positioning for rimegepant, which is after 3 preventative treatments. The committee took this uncertainty into account in its decision making.

For preventing migraine, the company modelled the assessment period of