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12th April 2024
Atogepant (brand name Aquipta), the first oral drug for chronic and episodic migraine prophylaxis where other treatments have failed should be available on the NHS, according to final draft guidance from NICE.
Up to 170,000 people could be eligible for atogepant, which is manufactured by AbbVie, under the recommendations.
This follows the approval of atogepant by the European Commission in August 2023 for chronic and episodic migraine prophylaxis in adults. The Scottish Medicines Consortium also accepted atogepant for restricted use in suitable patients in October 2023.
With this latest recommendation, it is expected that use of the drug, which works by blocking the calcitonin gene-related peptide receptor (CGRP), will be initially managed in secondary care, under a commercial agreement agreed with NICE.
But in the evidence provided to the appraisal process, drug manufacturer AbbVie noted there was potential for it to be monitored in primary care, and for follow-up appointments to be done by GPs.
Patient and professional organisations also told the committee that the availability of atogepant through GPs would improve access to treatment and reduce NHS costs.
The committee said that while atogepant would initially be prescribed and monitored in secondary care, ‘there would be interest in being able to use it in primary care’.
Under the recommendations outlined in the final draft guidance, the oral, once-daily atogepant will be an option for chronic and episodic migraine prophylaxis in adults who have had at least four migraine days per month.
To be eligible for the drug, patients must also have tried at least three previous preventive treatments.
Atogepant may be useful for those who cannot tolerate current fourth-line injectable treatments or who have contraindications to them, the guidance said.
The drug should be stopped after 12 weeks if the frequency of migraine attacks does not stop by at least 50% for episodic migraine and at least 30% for chronic migraine, NICE said.
It is also considered to be one of a range of suitable treatments and, after discussing the advantages and disadvantages of all the options, the least expensive should be used, NICE added.
Professor Peter Goadsby, honorary consultant neurologist, King’s College Hospital, said: ‘We know that people living with migraine may battle for years without an effective treatment to mitigate the daily struggles of living with this debilitating condition.
‘The decision by NICE should have a positive impact on patients who are eligible to receive atogepant as the treatment has been shown to reduce significantly the number of mean monthly migraine days in pivotal trials.
‘This welcome news increases the treatment options available that clinicians can offer to suitable patients, providing them with access to an additional preventive treatment that is now available on the NHS in England and Wales.‘
The NICE recommendation is supported by data from three pivotal Phase 3 clinical studies evaluating atogepant 60 mg once-daily in adults living with episodic (ADVANCE and ELEVATE) and chronic (PROGRESS) migraine.
In the three trials, the treatment met the primary endpoint of a change from baseline in mean monthly migraine days across 12 weeks versus placebo. Additionally, the treatments achieved significant reductions from baseline in several secondary efficacy endpoints compared to placebo: mean monthly headache days and mean monthly acute medication days, along with an additional achievement of ≥50% reduction in three-month average of monthly migraine days in the ELEVATE study.
Atogepant was also found to be generally well tolerated.
The most commonly reported adverse reactions in the ADVANCE and PROGRESS trials were nausea (7%), constipation (7%) and fatigue/somnolence (5%).
For the ELEVATE study, treatment-emergent adverse events were reported by 81 participants (52%) in the atogepant group (n=156). The most common (≥5%) were constipation (10%), Covid-19 (8%), nausea (7%), and nasopharyngitis (5%).
NICE director of medicines evaluation Helen Knight said: ‘[The] final draft guidance demonstrates our commitment to focusing on what matters most and getting the best care to people while ensuring value for the taxpayer.
‘Currently, the most effective options for people with chronic migraines who have already tried three preventative treatments are drugs that need to be injected.
‘The committee heard from patient experts that some people cannot have injectable treatments, for example because they have an allergy or phobia of needles. So, some people with chronic migraines would welcome an oral treatment. Atogepant also offers more choice for people with episodic migraine.’
Rob Music, chief executive of the Migraine Trust, added: ‘A migraine attack can be incredibly debilitating. Symptoms can include intense head pain, loss of or changes to senses and lack of ability to carry out day to day life.
‘It is positive to see even more therapies emerging for people with migraine after many still rely on treatments developed for other conditions. We now need to ensure access to the newer treatments is swift, so that migraine patients can benefit from them.‘
If there are no appeals, the final NICE guidance is expected to be published on 15 May 2024.
Last year, NICE recommended rimegepant as the first oral treatment for episodic migraine and acute migraine, in draft guidance published in June and September, respectively.
27th February 2023
In an appraisal consultation document from NICE, rimegepant is not being recommended within its marketing authorisation, for the acute treatment of migraine with or without aura in adults, or for the prevention of episodic migraine in adults, who experience at least 4 attacks per month.
Rimegepant belongs to a class of drugs referred to as ‘gepants’ which are calcitonin gene-related peptide receptor antagonists. Calcitonin gene-related peptide has been associated with sensitisation and pain generation but also plays a role in vasodilatation. In a recent phase 2/3 trial, oral rimegepant, when taken every other day, was found to be effective as a preventive treatment of migraine, with its tolerability similar to placebo.
It is proposed by the manufacturer that rimegepant is used for acute migraine treatment in patients who have failed to respond to two or more triptans. However, in its consultation document, while accepting that the drug is likely to reduce pain at 2 hours post-dose more than placebo, NICE added that the evidence submitted by the manufacturer, for patients who have not responded to two triptans, is uncertain and hence requires more evidence.
Moreover, while it also reduces monthly migraine days, NICE argued that there is an absence of comparative long-term evidence to support this view. As a result, the organisation believes that this clinical uncertainty affects the certainty of the cost-effectiveness estimate and which is likely to be above what NICE considers to be an acceptable use of NHS resources.
In response to the consultation, the Migraine trust has expressed concern, stating that ‘a significant proportion of those seeking help from The Migraine Trust have an inadequate response, or contraindication to the best current acute treatment triptans, or have medication overuse headache as a result of inadequate care and treatment of their migraine.’
The statement added that ‘we believe that Rimegepant is an important opportunity to help those who have medication overuse headache and prevent others from developing it.’ These concern arose following a 2019 survey of 1,800 migraine sufferers undertaken by the trust, which found that migraine treatments caused medication overuse headache in a third of respondents.
Chief executive of the migraine trust, Rob Music said that ‘we are very disappointed by this decision and urge those affected by migraine, and particularly those without an effective treatment for migraine and who have experienced medication overuse headache, to respond to NICE’s consultation and let it know how much this new treatment option [rimegepant] is needed.’
19th December 2022
The identification of enlarged perivascular spaces in the centrum semiovale in patients with migraine compared to healthy controls, is suggestive of a disruption in the glymphatic system according to the findings of a study using ultra-high-field 7T MRI and presented at the Radiological Society of North America conference 2022.
Migraine is a common headache-related condition that affects an estimated 12% of the population. With the development of magnetic resonance imaging, it has become clear that some migraine patients (both with and without aura) are at an increased risk for subclinical lesions in certain brain areas. Such lesions include white matter hyper-intensities (WMH), i.e., lesions that have infarction features but which do not cause any clinical symptoms or other stroke-related signs. In addition, cerebral micro-bleeds (CMBs) are another biomarker of small-vessel disease and which have been found to co-occur with infarcts more often in migraine than in control patients. Advances in imaging techniques by 7 Tesla MRI might improve the visualisation of smaller anatomical structures and allow detailed pathological findings with a high spatial resolution by reducing the voxel size related to the increased signal-to-noise (SNR) ratio.
In the present study, US researchers used the 7T MRI modality to study microvascular changes in the brain due to migraine, particularly in perivascular spaces and compared the findings with those seen in headache-free control patients. They enrolled participants with both chronic migraine (CM), episodic migraine without aura (EMWoA) and age matched healthy controls. Patients were excluded if they had overt cognitive impairment, a brain tumour, prior intracranial surgery, contraindications to MRI or if they suffered with claustrophobia. The team calculated enlarged perivascular volume spaces (EPVS) in the centrum semiovale (CSO) and basal ganglia (BG), WMH using the Fazekas scale, and CMB using the micro-bleed anatomical rating scale. In addition, they also collected clinical data such as disease duration and severity, symptoms at time of scan, presence of aura, and side of headache.
Enlarged perivascular spaces in migraine and control patients
A total of 10 CM, 10 EMWoA and 5 health control participants were included.
The results showed that the number of EPVS in the CSO, but not in the BG, was significantly higher with migraine compared to healthy controls (p = 0.04). However, while the frequency of WMH and CMB in migraine did not significantly differ from controls, among migraine patients, there was a significant correlation between EPVS quantity in CSO and deep WMH severity (p = 0.04).
The authors concluded that there were significant differences in the EPVS in migraine compared to controls and which might indicate be suggestive of glymphatic disruption, i.e., the system for clearance of waste materials from the central nervous system and which utilises perivascular channels. Nevertheless, whether such changes affect migraine development or result from migraine is unknown.
In a related press release, study co-author Wilson Xu, from Keck School of Medicine of the University of Southern California in Los Angeles, said ‘although we didn’t find any significant changes in the severity of white matter lesions in patients with and without migraine, these white matter lesions were significantly linked to the presence of enlarged perivascular spaces. He added how ‘this suggests that changes in perivascular spaces could lead to future development of more white matter lesions.’
Citation
Xu W et al. Migraine-Associated Vascular Changes on Structural 7T-MRI. RSNA 2022
27th October 2022
Messoud Ashina MD PhD DMsc is Professor of Neurology, Danish Headache Center and Department of Neurology, University of Copenhagen. He spoke to Hospital Healthcare Europe about his work into headache and migraine, some of the innovations in patient management and his hopes for the future for helping sufferers of this debilitating condition.
Messoud Ashina has been involved in headache research since 1995 and has completed a PhD in headache science focusing on tension-type headaches. Since 2006, Professor Ashina has been working on migraine and, in particular, experimental models of migraine.
His research at the Danish Headache Centre’s Human Migraine Research Unit focuses on experimental models of migraine in humans. This work involves provoking a migraine attack in patients and then trying to ascertain the specific biomarkers involved in induction with a view to developing drugs that can target these markers. In addition to his basic scientific research, Professor Ashina is also a lead investigator on clinical trials, yet still manages to practice as a neurologist seeing headache patients.
Professor Ashina described migraine as ‘quite a complicated neurological disease characterised by attacks, and which are paroxysmal in nature and self-limiting’. He explained how typically the disease first presents during the teenage years and then gradually evolves over the following decades but then gradually becomes less severe and less frequent with advancing age.
He sees migraine as a ‘fascinating disease to study’ because it is not just a headache but also associated with a sensitivity to light, sound, smell and nausea or vomiting. As a result, he felt that it was important for clinicians to recognise that migraine can be a debilitating disease. In many instances, during an attack, patients tend to either stay in bed or remain sat at home since the slightest movement ‘aggravates the pain’. Both the headache and sensitivities have contributed to the archetypal depiction of a migraine sufferer as someone who remains in a darkened room during their attack, for anywhere between two to three days.
Despite much research time and effort spent trying to understand the condition, Professor Ashina concedes that we are still very much in the dark as to why a migraine starts. He believes that the underlying cause most likely involves some form of complex communication between areas within and outside of the brain that which will ultimately ignite a migraine attack. Furthermore, because attacks naturally abate after a few days, either the same, or another communication pathway, transpires to somehow extinguish the migraine flame. Thus, exactly how a migraine starts and stops remain some of the biggest unanswered questions in migraine research.
Professor Ashina said there are only two subtypes of migraine: ‘migraine with aura and migraine without aura’, with the latter accounting for around two-thirds of all cases. Those who have migraines with aura experience symptoms that normally persist up until the development of the headache. He explained how patients often experience ‘transient neurological symptoms usually occurring before the headache starts and which are usually visual symptoms (known as fortification spectra) of different colours or sometimes black and white that move around the visual field’.
In terms of the clinical presentation, patients report both uni- and bilateral headaches and to consider a headache as a migraine, it requires the presence of at least two of four main pain characteristics: localisation; throbbing; intensity; and aggravation by physical activity. Professor Ashina described how where a patient had a ‘bilateral headache and with intense throbbing, this would fulfil two of the four criteria’ [for migraine]. In other words, although in the past, migraine was classically defined by hemicrania (one-sided headache), the definition has evolved to include a headache which ‘migrates’ to cover a larger area of the head. If patients display at least two of the four headache pain characteristics, if this occurs in conjunction with associated symptoms such as photo- or phonophobia or nausea/vomiting, it is possible to diagnose migraine.
Globally, Professor Ashina said a staggering one billion people suffer with migraine. However, a clearer estimate can be derived from considering either the annual or life-time prevalence of headaches. For instance, he defined the mean one-year prevalence of migraine as affecting ‘15% of the population’ and while the method of data collection in self-reported surveys can vary, these figures are generally very reproducible.
Migraines occur three-times more frequently in women but when considering the lifetime rather than one-year prevalence, the figure increases to around 25% of the population. Typically, he says, migraines begin during the teenage years and the incidence increases further over the next 30-40 years though interestingly, after the age of around 60, the incidence starts to decline.
While far less common in children, Professor Ashina mentioned that children as young as six can be affected. As he said, ‘if we look at the data around children, it’s quite high and in fact it’s about 8%’. Fortunately, migraine attacks in children are far less frequent than in adults and the duration of an attack is also shorter.
There is little doubt that migraines have a significant impact on quality of life. Professor Ashina discussed a recent paper published in the Lancet that examined the global impact of various disease on years lived with disability.
While migraine was the second most common condition after low back pain, a closer look at the data on years lived with disability among the women aged between 18 and 50 years revealed how migraine was the most common condition. Professor Ashina portrayed a typical chronic migraine sufferer as someone who experienced multiple attacks during the week.
Furthermore, another factor that no doubt contributed to the disability associated with migraine he said, was how some of these patients rarely had pain-free days between attacks. At the other end of the disease spectrum, patients were more fortunate, perhaps only enduring one or more attacks per month or even just a few per year.
The management of migraine therefore largely depends upon the number of attacks. For those with infrequent episodes, treatment is directed at stopping an acute attack whereas for those who suffer more frequent attacks, preventative therapy is designed to reduce the ‘number, frequency and intensity and, in some cases, the duration of attacks.’
While migraines clearly have a huge effect upon patient’s quality-of-life, there is also a significant economic impact. To illustrate this impact, Professor Ashina portrayed a patient who had two days of migraine every week. This, he said, amounts to 96 days every year and if the patient’s medication is ineffective and they decide to attend work, it is highly likely that their performance, and hence productivity, will be significantly impaired. Equally, if they stayed at home, there is still a major economic impact in personal terms, in lost productivity, and at a cost to their employer.
The economic burden also become apparent when considering treatment. Most patients will initially self-medicate with treatments purchased at a pharmacy and although these can help, for many, the medicines are ineffective, prompting a visit to the GP, and even then, some treatments will remain ineffective.
Professor Ashina deems it necessary for migraine patients be assessed holistically, which is impossible within the limited time available in a GP consultation. Consequently, patients are ultimately referred to a neurologist, yet he feels that neurology services are insufficiently resourced in relation to the volume of migraine sufferers requiring a more in-depth assessment.
Professor Ashina thinks that acute, over-the-counter migraine treatments are probably effective in many cases but admits that as a neurologist, he only sees those whose disease has not responded to both over the counter and prescription medicines. He considers that many migraine sufferers can manage their condition with non-steroidal anti-inflammatory drugs such as ibuprofen, aspirin, et cetera.
When these drugs fail to provide adequate relief, patients turn to the triptans, which are perceived as stronger medicines. Professor Ashina feels that this perception is incorrect as triptans are simply a class of drugs specifically designed to abort a migraine attack. But it is easy to understand a patient’s misconception when examining efficacy data, especially if assessed against the endpoint of two-hour pain freedom.
Using this scale, he said ‘the triptans are better than non-steroidal anti-inflammatory drugs – there’s no doubt about that’ and as a result, many patients report how ‘triptans have completely changed their lives’. While he welcomes the increased availability of triptans in countries where the medicines have OTC status, he also recognises a possible problem. As he says, ‘when patients start taking too many triptans, they develop medication overuse headache’.
A further problem with over-the-counter medicines is that combination products, particularly those which contain caffeine, can be what he described as ‘medicine overuse-inducing’. He generally advises patients to limit the weekly use of such medicines but in cases where patients feel that they need better treatments, it is better to consider prophylactic agents.
Professor Ashina says that globally, the most common prophylactic agents are beta-blockers but while effective, adherence problems do occur as some patients experience side-effects or are unable to tolerate the drugs.
Overall, he believes that beta-blockers can be just as effective as other prophylactic agents but are often limited by side-effects. Other prophylactic agents such as anti-hypertensives and anti-epileptics are also effective but less widely used. But, as with beta-blockers, adherence becomes an issue with anti-epileptics due to adverse effects. Professor Ashina also mentioned how Botox is an effective migraine prophylactic agent but is normally reserved for patients with chronic migraine who have failed to respond to other therapies.
Some of the latest migraine treatments to be introduced are directed against calcitonin gene-related peptide (CGRP). As Professor Ashina explained, ‘CGRP is widely distributed in migraine-specific structures such as the trigeminal nerve, cranial blood vessels and certain other parts of the brain’. While its physiological role is yet to be clarified, it is known that migraine attacks can be provoked after infusion of the molecule. Similarly, he said, ‘administration of an anti-CGRP agent can abort or prevent attacks.’.
The original CGRP agents were the gepants that specifically target the CGRP receptor. These oral treatments are used for acute attacks and serve as an alternative to triptans. While not as effective as triptans, Professor Ashina sees the gepants as a useful alternative to the triptans, especially for patients who are either triptan intolerant or for whom triptans are contra-indicated.
Nevertheless, overall he considers the gepants to be a third-line treatment option after triptans. Although most gepants are used for acute migraine, some can also be used as prophylactics. Professor Ashina sees this as an interesting concept, especially given that the triptans cannot be used as prophylactics because they induce medication-overuse headache.
Currently, there are four monoclonal antibody CGRP drugs, three of which target the CGRP molecule itself and one its receptor. These drugs are available either as intravenous or a subcutaneous formulation. Two are administered on a monthly basis and others are approved for use every 12 weeks or either monthly or quarterly.
Although the efficacy endpoint of these agents within clinical trials is normally measured in terms of a reduction in monthly migraine days, Professor Ashina prefers to translate this in clinical practice as the ‘proportion of patients who report at least a 50% reduction’ though as he says, ‘some patients even report a 75% reduction.’
While these newer agents significantly reduce the frequency of attacks, Professor Ashina cites a further benefit of the drugs in being able to reduce the intensity of attacks which therefore become more manageable for the patient. An added bonus in that patients can then use triptans and may even feel that the triptans are more effective because the attacks are less intense.
Professor Ashina feels that the introduction of CGRP agents is an important paradigm shift in the preventative management of migraine because these molecules have a highly specific target. Moreover, he feels that these drugs have elevated the status of migraine to one of a disease and not, as in the past, just a headache. He is excited to see how these treatments might change patients’ lives and says how as a physician, it is highly rewarding to see patients return to some semblance of normality that was not possible before therapy.
Despite the benefit for many patients, he also acknowledges that ‘about 40% or sometimes 50% of patients do not respond’ to these drugs hence the continued search for novel drug targets, which is an active area of his research.
Professor Ashina believes that the ultimate goal in migraine research is not to provide a cure – he thinks that this is highly unlikely – but to be able to control an attack so that ‘patients can return to an almost normal life’. While he thinks that current treatments have a level of good tolerability and are without serious adverse events, there will always be room for improvement.
He added that a further consideration is that while the trajectory of an individual’s migraines is unpredictable, there is a natural tendency to resolve with advancing age. Consequently, it is worth occasionally stopping preventative therapy to determine whether an individual’s migraines have spontaneously resolved. Due to this unpredictability, he described how in his own clinic they have introduced an 18-month stop rule to assess whether or not continued preventative therapy is required.
Professor Ashina is clearly very enthusiastic and motivated in his search for efficacious migraine treatments. One potential molecular target that he is currently working on, is pituitary adenylate cycles-activating peptide (PACAP) and he mentions how, just like CGRP, administration of PACAP provokes a migraine attack.
With two ongoing trials assessing monoclonal antibodies directed at PACAP, there is hope that, in the near future, many more migraine sufferers will achieve relief of their symptoms and be able to regain some semblance of normality in their lives.
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