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Atogepant (Qulipta): CADTH Reimbursement Review: Therapeutic area: Migraine, prevention [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2023 Aug.
Migraine Canada is a national federally registered charity, founded in late fall of 2018, with a mission to provide support and education as well as raise awareness about the impact of migraines. We advocate for optimal care for those living with migraines and support research to find a cure. With the help of dedicated physicians and contributors, Migraine Canada delivers evidence based, up-to-date disease and treatment information to Canadian living with migraine, including patients and caregivers, as well as healthcare professionals. We educate patients, caregivers, and healthcare professionals by researching, developing, and sharing electronic and print materials containing the most current migraine information. We drive awareness and education through our website, social media channels and forums. We have a growing community of over 2,000 individuals subscribing to our email list. We provide patient support through participation in regional on-line support groups, with more than 3,000 members on our Facebook page.
Migraine Quebec is a provincial non-profit patient organization founded in 2014 whose mission is to provide support and information to people with the disease, as well as to educate the public about the repercussions of migraine. We advocate for optimal care for migraine sufferers and support research to find cures to improve the quality of life of patients with this chronic disease. We educate patients, caregivers and healthcare professionals by researching, developing and sharing electronic and print documents containing the most recent data on migraine. We promote awareness and education through our website, social media, workshops and forums. We help patients by offering regional on-line support groups, with more than 5,000 members on our Facebook page) for the province of Quebec).
Both organizations have a broader reach by interacting with several other on-line Canadian and International groups and leverage traditional and social media channels to empower patients to share stories and experiences to advocate for the supports needed to live full and active lives while coping with migraines.
Website (English): www.migrainecanada.org
Website (French): www.migrainequebec.com
The information provided in this submission was collected through a Quality-of-Life online survey that was launched by Migraine Canada in late fall of 2021. It was promoted across Canada in both French and English through Migraine Canada’s digital and social media channels with promotion support by Migraine Quebec. In total, 1,165 Canadian adults with migraine and their caregivers responded to the online survey. Of our total respondents, 19% live with low frequency migraine, 28% live with 8-14 days / month with migraine and 52% live with chronic migraine 15 or more days. The spectrum of representation was national with the majority (68%) participating between the age of 30-59.
Migraine Canada launched a second national online survey in mid-January 2022 to gather additional insights to support our submission and seek input from patients with experience on atogepant. It was promoted across Canada through Migraine Canada’s digital and social media channels with promotion support by Migraine Quebec. In total, 300 Canadian with migraine responded to the survey. Of our total respondents, 15% live with low frequency migraine, 26% live with 8-14 days / month with migraine and 59% live with chronic migraine 15 or more days. The spectrum of representation was national with the majority (74%) participating between the age of 30-59
Migraine Canada also received direct input from 8 patients (2 Canadian / 6 American) who have experience taking atogepant that has been integrated into the submission.
Migraines are not just headaches but a neurological disease. Migraine impacts 1 billion people worldwide, or about 1 in 7 people. Migraine is most common between the ages of 25 and 55 but it can impact people of all ages including children (10%) but it affects three-times as many women as men (8%).
Migraines are classified according to their monthly frequency. Episodic Migraine is defined as impacting less than 15 days per month and 12% of adults living with migraine fall into this group; Chronic Migraine impacts more than 15 days per month and 2% of the adult migraine populations. Migraines often present with severe, throbbing, recurring pain, usually on one side of the head (or both sides or no pain at all). Nausea, vomiting, dizziness, extreme sensitivity to sound, light, touch, and smell, and tingling or numbness in the extremities or face are also common symptoms. About 25% of migraine sufferers also have a visual disturbance called an aura, which usually lasts less than an hour. Attacks usually last between 4 and 72 hours.
Migraine is usually categorized according to accompanying symptoms (aura, vestibular, hemiplegic) but also according to monthly frequency of attacks. Episodic migraine refers to attacks occurring 14 days or less and is now further separated in low-frequency (1-6 days) and high frequency (7-14 days). Chronic migraine is diagnosed when patients have 15 or more headache days per month. Chronic migraine is associated with increased disability and co-morbidities. It is also associated with medication overuse headache (MOH), a complication of frequent use of acute treatments that induce even more frequent and intractable headaches. The estimated prevalence of MOH varies according to countries but is usually between 0.5% and 2% of the global population (GBD 2015). Medication overuse feeds the headache cycle and patients are trapped in a vicious cycle, unable to get adequate pain relief.
There are two main states of life for a migraine patient: the active attack (ictal state) and in-between attacks (interictal state). During the attack itself, symptoms may prevent the person’s ability to accomplish their tasks, work and interact with others. The pain is at least moderate and often severe, throbbing, and diffuse. The nausea and vomiting are obviously disruptive and may prevent oral medications efficiency. The sensory hypersensitivity forces many patients to isolate themselves in a dark room and stop all activities. Auras are neurological deficits that can accompany migraines (including loss of vision, speech, and sensation, even muscle strength) which can last for hours. Some migraines are also accompanied with dizziness, vertigo, and loss of balance. People generally experience reduced cognition during a migraine, with slowed thinking, lack of focus, and difficulty reading and speaking. This typically disrupts most activities involving a computer or interacting with other people. A controlled migraine attack managed with effective treatment can be brief, but uncontrolled attacks may last multiple days in a row.
Migraine patients’ quality of life is considerably negatively impacted. Participants in the quality-of-life survey indicated all aspects of their life is impacted and range from regularly needing to change or cancel plans or avoid interacting with people altogether (67%).
Percentage Avoiding Interactions With People.
When asked, over the last month, how often was it difficult to keep a daily routine or schedule, over 52% had difficulty. 39% of patients were unable to do usual household chores. Many people reported that although their migraine was excruciating, they learn to push through it because they have no other choice.
Percentage Having Difficulty With Daily Routine or Schedule.
Approximately 30% did not have concentration affected while 29% noted they sometimes had trouble (6-10 days) and 68% were regularly unable to do activities that required concentration.
The majority (73%) of survey respondents indicated they live in fear of the next attack and have difficulty planning ahead. Only 9% they didn’t worry about their next attack.
A significant number of people (55%) experience feeling lack control of their life because of migraine ranging from always (25-30 days/month) to often (11-15 days/month).
Percentage Feeling Lack of Control.
Only 46% of patients reported to work full time and 11% are able to work part-time. For many who indicated they work part time, they are also on CPP disability. Over 20% are on short- or long-term disability or retired early due to their condition (migraine). There were many people (3%) who shared they were unemployed and not able to have any support through disability programs.
For the patients who are on short-term or long-term disability, 81% reported it was due to their migraines and 66% have been on disability more than 18 months.
Percentage on Disability.
The graph below illustrates the impact migraine has on people’s work / career.
Impact of Migraine on Career.
Patient Testimonials
“It sucks. I'm in too much pain and missed so much work that I lost my job of 25 years. But not disabled enough for LTD or disability pension. Since I was the primary income earner it was a HUGE impact on our family-not just paycheques but also medical, dental, pension-all those sorts of things that all come with a long-term job. And the impact it has on my sense of self and self-worth.”
“My colleagues don’t understand. When I have a migraine, I suffer in silence and can’t wait for the day to be done.”
“I feel guilty when I call in sick and then show up a couple days later looking fine. People don’t understand what a migraine is.”
“I’ve asked for accommodations and been denied. I had to get a doctor’s note to be somewhat believed.”
Issues with sleep is significant ranging from 7% having no issues with sleep to 38% always or regularly have sleep disrupted due to their migraine.
Sleep disruption reported by patients caused by migraine over the past month was significant for respondents. Close to 20% reported 16-30 days as always or very often disrupted, followed by 19% who reported 11-15 days of disrupted sleep.
Patients rated their quality of sleep as very poor (17%), often disrupted (37%) and sometimes disrupted (30%). Only 16% rated their sleep as “good”. When as specifically if migraine impacts sleep, 84% of patients attribute their migraine as having a negative impact.
Impact of Migraine on Sleep.
When asked if migraine has led to the development of depression and anxiety, 39% reported that migraine has caused the individual to be depressed and/or anxious (moderate to severe) requiring counselling and/or medication. Approximately 48% said migraine has caused them to become depressed and/or anxious but not to the point counselling or medication was required. Only 13% reported migraine has had no significant impact.
Impact of Migraine on Mental Health.
The secondary survey had similar responses. For 88%, their migraine led to depression and anxiety. About 45% reported that migraine has caused the individual to be depressed and/or anxious (moderate to severe) requiring counselling and/or medication and 43% said migraine has caused them to become depressed and/or anxious but not to the point counselling or medication was required. Only 4% reported migraine has had no significant impact mental health.
When asked how often individuals felt they were a burden on others, only 14% responded with never and 21% rarely (2-5 days). The majority felt they were a burden (31% 16-30 days/month) and 35% between 6-15 days/month.
Migraine and Burden on Others.
Respondents reported (39%) that they always or very often feel a lack of control over their life because of migraine. Only 9% did not feel migraine impacts control over their life.
When asked, over the last month, how often did the participants partner have to take over the parenting activities, only 30% had no impact. 60% had some degree of impact (10% noted their partner had to take over between 12-30 days/month.
Over the last month, although the patients reported to rarely or never (56%) miss a family activity, 23% missed activities 6-10 days/month and 14% between 11-15 days/month.
Approximately 37% of respondents agreed they would be a better parent if they didn’t have migraine and only 7% feel their migraine has no influence on parenting.
Because of their migraine 50% worry about their family’s financial stability.
The majority of people (54%) indicated migraine has a negative impact on their relationship with their partners. Only 15% disagreed with the statement.
Impact of Migraine on Partner.
Patient Testimonials
“I’ve had chronic migraine for about 10 years. It has impacted every aspect of my life. I’m not able to earn a consistent income, I’m not able to look after my kids or my home in any regular way and more often than not, I have to cancel plans with my spouse, family and friends because of my migraines. It’s very isolating and discouraging, and there have been times when I’ve felt like it’s just not worth living like this.”
“I’m not a mother or a wife anymore. I am a shell. I take up space in my home but don’t contribute. This is not a life.”
“My children see a much more angry, frustrated mom because of migraine. They also experience more anxiety and fear not knowing if I will be able to do things with them or seeing me violently throwing up or going to emerge. The on my kids is huge.”
“I cannot be there for my family because I’m not physically or emotional available for them, even if I try my hardest. I know my family loves me but just being unavailable to do my job as a mom and wife. I also become a huge burden as they to adapt their needs to accommodate mine, not to mention the INCREDIBLY big expense just to have me able a little bit more functional. I feel I’m watching life go by without being able to participate in it. Like a by-stander. This is no way to live, specifically if we are not supported or recognized as disable, or even worse, dismissed.”
“My ex-husband was not able to understand the level of pain that I had and was not able to understand the limitations that it gave me some days. It put a huge strain on our relationship and it probably was a part of the demise of the marriage along with other issues.”
"With how bad my migraines have become, I am not the partner or parent that I once was. A lot of my day is spent in the bedroom. My husband must pick up the slack on my bad days after he has worked really hard all day. It is hard to explain to my family that even with meds and some treatments, none of it is a long-term fix. I try to push thru a lot but feel like I am letting them down a lot. I feel like emotionally I am wrecked. I am so tired of pain.”
When asked, at this point in time, if the care patients have received so far has led to an improvement in quality of life, 25% report no improvement and 49% has a mild improvement. Only 24% has experienced a marked improvement.
We also learned that in the past 6 months 57% of people did not fill their prescription due to cost and lack of coverage.
Over 78% of respondents have taken a prescriptions medication to prevent migraines. Close to 53% reported they were not satisfied with the current preventative medication treatment available that they have access to.
Close to 45% of people have not found an effective and tolerated way to control the majority of their migraine attacks. When asked how satisfied patients are with the current preventative prescriptions that are available in Canada, 53% are not satisfied. Only 21% reported they were satisfied with the options available.
Patient Testimonials on Satisfaction of Current Medications
“Helps reduce frequency but has side effects.”
“I have only tried one CGRP. It worked better in the beginning; it seems to be growing less effective. I am also disturbed that what I have tried to report as side effects are discounted by my neurologist. And although I answered "yes" to the previous question (have you found an effective and tolerated way to control the majority of your migraines - the answer is not really. I used to get more than 20 per month, now I usually get about half that BUT - they seem to be increasing in frequency.”
“I have a prescription that helps prevent one type of migraine symptoms…. haven’t found anything that prevents the migraines which feel like an axe is in my head.”
“CGRP has reduced me from 19.6/month on average to 10-12.”
“I'm not completely dissatisfied. The med I'm on lowers the severity but I'm still living with daily constant headaches/migraine”.
“I still have migraine symptoms daily but the intensity of the symptoms are markedly less severe than without my medication protocol”.
“I’ve tried everything. Nothing has worked for me. I feel at times its hopeful and this is my death sentence and punishment. I would like to try some of the newer products”.
Overall, the patients who responded indicated they have tried the following treatments, when given the option to choose all that apply.
Preventives to Relieve Migraines.
For respondents who have had experience on new treatments (CGRP’s) many have had notable improvements in ability to work. Close to 10% were able to work 20 or more days per month and 20% were able to work 10-19 more days per month.
Additional Number of Working Days After Taking CGRP mAb.
Over 85% of respondents believe there would be a need for a new oral daily preventative medication.
Need for New Oral Daily Preventive Medication.
In the secondary survey, close to 62% of patients have tried 5 or more preventative treatments, followed by 21% who have tied 3 or 4.
When asked if patients had found an effective and tolerated way to control their migraines, 45% they have not.
Most respondents (73%) believe there is a need for additional new treatment options in Canada. And 19% were unsure. For those who answered, “it depends”, there were several comments specific to side effects and efficacy.
Patient Testimonials Who Answered “It depends”
“There is always need for new medications and more medications. They wear off and people need to know there are more to try.”
“I have tried almost everything. My doctor doesn’t know what else do to. Yes, more medication is needed if they have less side effects and work.”
“We need more medication. We also need to be able to get them. The new ones are expensive, and I can’t afford to pay, and I don’t have private insurance. I hear from many people they work really well.”
“Only if they are safe and have fewer side effects.”
“I agree Canadians need to have more options but with less side effects.”
Percent With Effective Ways to Control Migraine Attacks.
When asked if people have found a preventative providing >50% improvement in frequency and/or intensity of migraines with NO significant side effects, close to 30% have found a treatment.
Patient Testimonials on Currently Available Treatments
“The side effects are horrible.”
“They made symptoms more manageable, but I still struggle with side effects.”
“CGRP’s have changed my life for the better.”
“CGRP has reduced my migraine from 20 times/month to 8 times/month.”
“It has recently stopped working and I’ve tried all the others, but I don’t have private insurance and can’t access new medications.”
“I have been on three and after 11-14 months, they all stop working. So far, the one I am now on is starting to work. I pray it continues.”
When asked about side effects experienced from the current preventative medication for migraine, 66% responded side effects lead to discontinuation of the prescribed medication and close to 25% had side effects but tolerated them.
Canadians diagnosed with migraine expect to have access to new innovative medicines that address gaps in the current treatment options, names medications that will address their condition and improve quality of life. Many of the therapies currently available are not effective and have intolerable side effects.
In both surveys, the three outcomes that would be most valuable to patients when trying a preventative were:
Most Valuable Preventive Treatment Outcomes.
Patient Testimonials from patients who answered the questions asking how daily and quality of life for patients, caregivers and families be different if the new treatment provide desired improvements.
“Being able to live life again…being able to care for yourself without help…being able to care for others in your instead of the one being cared for.”
“It would allow patients to have better quality of life. It wouldn’t come down to whether or not the patient has a specialist, or even a doctor (in BC especially). It would help people riddled with pain to return to work and family life without feeling stressed if they could afford treatment or not.”
“Decrease symptoms and increase quality of life for patients which will create less demand on caregivers.”
“Having a normal life with normal activities would make a huge different. Not just on pain but also on social and intimate relationships. And more efficiency at work.”
“No more 4-hour car to go to Botox every 10 weeks that cause big migraine and family dispute.”
“It would be a major life change in every way.”
“I’d be able to take part in my life again and be with those I love.”
“I would feel like a good mom, a good spouse and feel less depressed because I can’t take it anymore.”
“For me, being able to get back to work would be a great outcome. Migraine has made me leave a job I loved and created financial strain on our family.”
“If my migraines were reduced in frequency and / or severity, I would be able to engage in social and physical activities. I would also be able to drive again (due to my migraines, I have not driven in a few years).”
“I would be able to work and contribute financially to the family. I would also be able to take part in more of family life. Years have passed without me able to do so.”
“To be able to access, easily access, treatments that can rapidly help reduce migraine can open up while new worlds for migraine patients. There’s nothing more dehumanizing than waiting in an ER room waiting for someone to believe you are in as much pain as you are, and to have to literally beg for relief through the tears.”
“People could live without life-altering pain. They and their family members could live life regularly like regular people, making plans and enjoying their days without the threat of a migraine looking over them. They could be more productive in terms of work and social contributions.”
When asked about what trade-offs are considered when choosing a therapy, people responded with:
“Tolerable side effects for reduction in frequency and pain would be more than welcome.”
“Some side effects that aren’t harmful but are better than the migraine.”
“I’m desperate for anything to work.”
“I would pay anything and give nearly anything to have them stop or be reduced more.”
“Cost and effectiveness.”
“Lower intensity migraines, taking meds every day.”
“I will take some mild side effects as long as the intense pain from my migraine is gone.”
“Benefits need to outweigh the negatives – I’m using Botox. I don’t like the aesthetics or costs (I’m broke) but I’m not vomiting daily at work.”
“If it improves pain management, length of time between migraines etc. it’s worth it even if minor side effects of it allows more normal levels of activity in daily life.”
“Convenience (how many pills/injections) side effects (short term vs long term).”
“Everything.”
“I’m willing to accept non-life-threatening side effects as long as they do not impair my ability to physically and mentally function more than migraines currently do.”
“Honestly, I’ve tried all the preventatives out there except Botox because I can’t afford it. None of them work. I will take ANYTHING to make the pain stop…I don’t care what the tradeoffs are.”
“Anything at this point.”
“At this time in my life, I don’t really have any, I just keep trying different treatments and pray one will work real soon.”
“I am willing to try ANYTHING if there’s a real chance that the number and intensity of my migraine is lessened. But I can’t stay on a therapy when it makes my non-migraine life intolerable.”
There was a total of 8 people who have had experience on atogepant. Two were Canadian and 6 were from the US.
Overall, the majority (6 of 8) experienced improvement in the frequency and/or intensity of their migraine.
There were only three comments about the benefits and disadvantages:
“I had my first 6-day migraine streak for the first time in years in December.”
“Helped by slightly reducing frequency and severity.”
“Even though the benefits are constant right now (not improving more after 4 months of use), the overall improvement has been significant, going from 17 migraines per month to around 4-5.”
When asked about side effects, 66% report they did experience some side effect which were either slight and/or improved/stopped after some time.
Because there have not been new medications to treat migraine in decades, with the exception of Botox, new and innovative treatments like atogepant are welcome to the patient and clinician community. New options that are safe, tolerable and effective bring hope to Canadians and their loved ones living with this disease.
Not applicable.
Migraine affects children, women, and men worldwide. It is a life altering and debilitating condition characterized by severe, often “pounding”, head pain, nausea and/or vomiting and sensory hypersensitivity. In the case of aura, neurological deficits occur. Dizziness, vertigo and cognitive difficulties and neck pain are frequently associated with migraine attacks. Migraine significantly impacts quality of life, mental health, relationships, social interactions, and workplace productivity.
For some Canadian patients’ current therapies are sufficient in managing their condition, however for many others, current therapies are ineffective or poorly tolerated leaving patients suffering and without hope. Struggling with 8, 14, or even 28 days of migraine per month is not living and significantly impacts quality of life. Although people will not die from migraine, it steals life away, one day in the dark room at a time. The stigma associated with migraine (it’s all in your head) makes this suffering worse. People with migraine need access to effective treatments to get back to living life and be productive.
There is currently no cure for migraine, but years of research have led to the development of the CGRP antibody and Gepant classes, specific migraine preventatives. For the first time, preventative treatments based on the biological understanding of migraine mechanisms are now available. For many Canadians living with chronic migraine, new innovative medications like atogepant have been life changing, giving back days of normal function. Atogepant is the first Gepant to receive an NOC in Canada; making it the first Gepant option for patients and clinicians.
It is important Canadians and clinicians have options. Canadians living with migraine are desperate to find a treatment that may improve their quality of life. Until a cure is found, patients are looking for improved outcomes. Many are desperate to have any degree of normalcy returned to their lives. New treatment options may allow patients the ability to return to work, interact with their family and friends and feel like they are contributing to society.
Patient Testimonials
When asked about the need for new medications in Canada, shared the following comments:
“Migraine is very debilitating and it is being a big limitation in my life (sometimes I am afraid I will not be bel to finish my Ph.D studies. I would request please to make novel and medications for migraine available with public coverage and promote they are covered by all insurers.”
“Need more availability of choices in Canada without have to wait years for approval.”
“It is completely cruel and unacceptable that some of the leading treatment for migraine disease like Botox and CGRP’s are NOT covered on provincial programs. Migraine disease is debilitating and yet there’s potential new medications could work but they are only available to the privileged.”
“This is an incredibly misunderstood, stigmatized disability. I feel like I spend just as much energy defending and 'proving' the fact that I'm truly ill as I do cope with the symptoms. It impacts my every single day. My career, family, finances, (lifespan I'm sure), and quality of life have all been drastically affected. I have spent tens of thousands of dollars out of pocket on medications and treatments when I've been between drug plans DUE TO migraine affecting my ability to work, or limits and maximums on drug and benefits plans. My passion head given me a lot of patience and compassion for others, but you don't see a lot of that back, even from medical professionals unfortunately. I hate feeling like a criminal who has to answer 20 questions correctly every time I pick up a T3 prescription (to manage pain for the really bad ones) - I know pharmacists have to be careful but my doctor and I have a good relationship and she would not prescribe them otherwise. I have no idea what 'normal' life would be like.”
“It is VERY difficult to access critical mental health care services. Near impossible to receive government disability payments. No idea where to go to get advice on managing work. I was forced out because I didn't know my rights or what to ask for in order to get the short-term disability that I deserved. Access to new medications is awful. be it waiting on Health Canada approvals, or negotiations for provincial formularies or insurance.”
“It’s heartbreaking to see the lack of knowledge and compassion that we encounter, we have to beg and push for more treatments and medication to helps us, we are continuously being looked at like attention seeking, depressive/anxious patients, drug seeking addicts. We are not taken seriously, and it takes many months or years for a diagnosis, acute treatment at home or preventatives. We are not recognized as people who are suffering from a complex and debilitation condition, but instead we get the acknowledgment of suffering migraines/chronic migraines but not the compassion and support we need. It’s hard to find a specialist and they are spread so thin that it’s really hard if not impossible to make an appointment between follow ups and the latter ones are a few minutes long if you consider that it’s at the same time as your being injected with Botox that happens every 3 or more months. Not being able to work and not have any help to offset the amount of money that goes out of the family budget to pay out of pocket needed for accommodations, treatment and prevention of migraines is very high, not only for meds but also for accommodations needed (noise canceling earphones, special glasses that tend to be many) lifestyle changes, multidisciplinary approach (physio, ENT, Ophthalmologist, personal trainer for exercising with this disability, psychologist, massage therapist, diet, etc.).”
“Migraines have huge impacts in our lives, as I mentioned above, but also it impedes our cognitive function, emotion and physical, plus impacts everyone’s mental and physical health around us.”
“I constantly worry about how I’m going to get through this and how will we get through without bringing in an income and hemorrhaging money because right my big disability that is not recognized as such. I’m treated like a healthy person when I most certainly am not.”
“I feel I have reached a plateau as does my healthcare team, my insurance and work. They have deemed me fully disabled, and I am resigned to that outcome after almost 2 plus years of continuous 5-7 pain. I have a high pain tolerance and that is only thing I think that allows me to function.”
“I am learning new ways of living after being active, outgoing, and going to the gym 5-6 days a week 2-3 hours a day. Life is going to be what I make it and I am not saying it’s rosy, but I will try my best to NOT sink into my manic depression disorder.”
“Anything you can do to help us or anyone else coming home who has migraines would be amazing. It is an utterly lonely, debilitating and soul sucking disease. It takes away everything and is extremely hard to navigate and make people understand. It is not just a headache and if I just had a headache, I’d be happy with that.”
To learn more about migraine, please refer to our Quality-of-Life survey report that will be posted in April on our website (www.migrainecanada.org)
To maintain the objectivity and credibility of the CADTH reimbursement review process, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This Patient Group Conflict of Interest Declaration is required for participation. Declarations made do not negate or preclude the use of the patient group input. CADTH may contact your group with further questions, as needed.
Did you receive help from outside your patient group to complete this submission? If yes, please detail the help and who provided it.
This submission was summarized and written solely by the staff at Migraine Canada and reviewed by Migraine Quebec, free from consultation, advice, influence or financial support from any outside individual, group, or company.
Did you receive help from outside your patient group to collect or analyze data used in this submission? If yes, please detail the help and who provided it.
Migraine Canada worked with a third party to create the on-line Quality of Life survey. Analysis was completed internally.
Migraine Canada independently developed and analyzed the second survey circulated for feedback on atogepant.
List any companies or organizations that have provided your group with financial payment over the past 2 years AND who may have direct or indirect interest in the drug under review.
Financial Disclosures for Migraine Canada.
Financial Disclosures for Migraine Quebec.
The Women’s Health Coalition of Alberta Society (WHC) is committed to creating a movement that empowers people to speak openly, learn and engage with purpose to address barriers, gaps, policies, and unconscious bias, that impact women’s menstrual, reproductive, and sexual health. We are enabling advocacy, awareness, and education in gynecological, uro-gynecological, menstrual, uterine, and reproductive health, through all the ages and stages of a woman’s life.
The WHC is pleased to support Migraine Canada’s recommendations for access and reimbursement of atogepant as a therapeutic option for preventive treatment of episodic migraine.
The WHC is highly committed to ensuring that women have access to the right treatment and support at the right time, for improved health outcomes. An oral calcitonin gene-related peptide (CGRP) option for the treatment of episodic migraine offers significant treatment plan advantages that will be better tolerated and easier to adhere to.
Women’s health matters and migraines affect women more often than men (80%). Severe and debilitating migraines are often associated with hormonal imbalances, perimenopause, and menopause – affecting as many as 25% of women. WHC members and stakeholders have reported that episodic menstrual and hormonal migraine attacks can be severe, causing pain, nausea, anxiety, and depression, and prompt absences from work, and opting out of family activities.
Women in their 40’s, dealing with perimenopause, may be at increased risk of disease progression, more frequent attacks, and progression to chronic migraines. Conditions are complicated further by increased family and professional demands. Enhanced options for preventive treatment of migraines is significant to managing health and quality of life for women of all ages.
Recommendation of atogepant will not only improve treatment options, choice, and access for women dealing with hormonal migraine symptoms, it may raise clinician awareness of the importance of treating menstrual, perimenopause and menopausal conditions.
Thank you for taking the lead on advancing options for treatment and choice in the treatment of migraines. If you would like to address this further, please contact me at moc.liamg@CHWnemraC.
Sincerely,
Carmen Wyton, Chair/President
March 10, 2023
The Women’s Health Coalition of Alberta has not received any assistance in preparing this letter of support and has not collected or analyzed data using sources outside of the organization.
Financial Disclosures for The Women’s Health Coalition of Alberta Society.
The Canadian Headache Society (CHS) is a scientific society of health care professionals dedicated to Headache Medicine. The CHS was created in 1988. Our goals include research, education of residents and physicians, and promotion of better care for patients suffering from headache disorders. https://headachesociety.ca/
The information is gathered from published clinical evidence and expert opinions from Headache specialists in Canada and internationally.
Therapies available for migraine management include the following.
Acute Treatments recommended: NSAIDs, acetaminophen, triptans, dihydroergotamine, neuroleptics
Acute treatments: the guidelines on the acute therapy for migraine are published. The goal of acute therapy is a return to function as quickly as possible and with no or minimal side effects. Triptans are specific to migraine. Access to triptans does vary from one province to the other, with some provinces requiring an Exceptional Access Program. In some patients with frequent attacks, the regular use of acute treatments can lead to medication-overuse headache, a complication of migraine. This is relevant to the discussion of preventive therapy. Some patients do use opioids and cannabinoids to relieve migraine attacks. Both have been linked to a risk of chronification and deterioration of migraine, in addition to other well-known health risks.
Acute treatments, used but non recommended: opioids, cannabinoids
The use of opioids and cannabinoids is still present despite recommendations to avoid them or keep them as last resort. Patients might not respond to, or have contraindications to, other therapies.
The Canadian Headache Society guidelines were published in 2010 and are therefore outdated. An update based on a systematic literature review is ongoing and the publication is planned for 2023. Options for migraine prevention available in 2022 include:
In Canada, for cost-effectiveness reasons, patients suffering from episodic migraine or chronic migraine are required to try non-specific therapies prior to onabotulinumtoxinA and CGRP antibodies. Access to onabotulinumtoxinA and CGRP antibodies varies significantly between provinces depending on public coverage policies. For example, onabotulinumtoxinA is accessible through a Patient of Exception form in Quebec, publicly covered in Ontario and Alberta, and not covered in British Columbia. Fremanezumab is now covered publicly in Alberta, Saskatchewan and Quebec. Erenumab did not reach an agreement with PcPA and therefore is not likely to be covered publicly. Galcanezumab and eptinezumab are under assessment. Criteria for coverage also vary from one province to the other even for the same product.
Atogepant became the second FDA-approved oral gepants for migraine prevention, gaining approval on September 28, 2021 in the USA. Atogepant is also the first oral drug to be exclusively developed for the preventive treatment of episodic migraine. According to the FDA label, the recommended dose is 10mg, 30mg, or 60mg once per day.
Atogepant is a calcitonin gene-related peptide receptor antagonist (CGRP). The role of CGRP in migraine pathophysiology has been well demonstrated over 30 years and lead to the attribution of the Brain Prize to key researchers in 2021. It is fair to say that CGRP blockade for migraine is a breakthrough in neurology. https://www.theguardian.com/science/2021/mar/04/scientists-discovered-migraine-mechanism-win-brain-prize
The treatment goals of atogepant include the following:
Some of the currently available treatments:
Which patients have the greatest unmet need for an intervention such as the drug under review?
How would the drug under review fit into the current treatment paradigm?
Please indicate whether or not it would be appropriate to recommend that patients try other treatments before initiating treatment with the drug under review. Please provide a rationale from your perspective.
From a purely medical perspective, looking at studies of similar methodology and also acknowledging the lack of head-to-head trials, atogepant could be a first line medication as it compares favorably to other oral preventives for effectiveness, tolerability and mode of administration. The fact that it is a migraine-specific medication, targeting a scientifically demonstrated pathophysiology, is also a strong element for patients who want to treat the cause of their disease. The opinion of neurologists specialized in headache medicine is quite clear on this.
Unfortunately, access to treatments is also strongly influenced by their cost. In a public health care system, cost-effectiveness is key. Therefore, if the cost of atogepant is significantly higher than the cost of other oral preventives, it would probably be pushed farther along the therapeutic path. Failure of other oral preventives could be required. Would it be 2, or 3 as we see for onabotulinumToxinA and CGRP antibodies?
The question remains: how many patients would find an effective and tolerated option through these trials? Our experience suggests that many patients are left without relief and discouraged by side effects after many oral trials.
Would there be harm to patients submitted to drugs with a higher risk of side effects? Weight gain is harmful to health and is commonly seen with tricyclic. It is not easily reversible. Tricyclics have been associated with an increased risk of dementia. Is it reasonable to ask a young patient to take it for years in the presence of an alternative? Cognitive issues are common with topiramate, often causing significant distress and disability to patients. Many patients with migraine are young women with low baseline pressure. Many have a tendency to vagal syncope. How reasonable is it to ask them to try a beta blocker or candesartan? The same reasoning goes for young patients who exercise, a very favorable element of a healthy life. A limitation in exercise capacity is a well-known side effect of beta-blockers. And older options such as valproate, flunarizine and pizotifen carry even higher risks of adverse events such as weight gain and depression, not to mention long term risks of parkinsonism and tremor. Many headache specialists now prescribe these only as a last resort.
Therefore, awaiting the systematic literature review of our society, atogepant could be seen as a first line treatment from a medical perspective. Only financial arguments would justify a second-line place and the requirement of other oral preventives.
How would this drug affect the sequencing of therapies for the target condition?
At present time, there is no scientifically supported way to predict the response to a treatment in a migraine patient, and this applies both to acute and preventive medications. Therefore, the choice of preventives is usually based on contraindication and selection of the «less harmful» adverse events profile. Strategies for selection can be found in the guidelines. For example, a patient with a normal weight with insomnia and low blood pressure might favor a tricyclic, but an overweight patient with hypertension might be a better candidate for a beta-blocker or candesartan.
As the number of options increases, medical and financial factors complexify the decisions, and add significantly to the paperwork that headache specialists have to fill.
Therefore, a lot depends on the proposed cost for atogepant.
If the cost allows its use as a first line therapy, then other preventives could be used in different sequences based on each patient’s comorbidity profile and preferences, just as we do at present time in practice.
If it leads to the requirement of previous failures, then it could be used only after 2 or 3 other preventives. Evidence and experience suggest that some patients may respond to CGRP blockade with antibodies event after failing 4 to 11 other preventives. Whether this applies to atogepant or not remains to be demonstrated by future studies in refractory populations and real-world evidence.
It seems very unlikely that atogepant will be priced higher than CGRP antibodies. Therefore, if it comes after cheaper oral preventives, it could probably be used prior to CGRP antibodies, once again for financial reasons. From a medical perspective, effectiveness and tolerability are similar across RCTS for episodic migraine for CGRP antibodies and atogepant.
Since onabotulinumtoxinA is only approved for chronic migraine and atogepant for episodic migraine (for now, as future RCTs may change this), the algorithm for atogepant would be separate from the one for chronic migraine.
As a separate note, the dichotomial approach between episodic and chronic migraine is also under scrutiny as it does not represent the continuum of attack frequency in migraine. The future may allow a more precise approach with two arbitrarily defined categories.
Which patients would be best suited for treatment with the drug under review?
Currently, there is no specific markers to suggest patients would respond to the medication under review.
The need for treatment increases with the attack frequency and severity (see the list of goals for migraine prevention). Still, the need for prevention and the importance of the migraine burden are underestimated by health care providers. For example, some providers might think that only chronic migraine is worth treatment. It is true, and supported by evidence, that the burden of chronic migraine is higher than the one of episodic migraine.
Still, the burden of episodic migraine is also worth of intervention. For example, In the world of epilepsy, the goal is to be seizure-free. The fact that a person is expected to be happy with 6 to 8 migraine attacks per month is only determined by centuries of lowering expectations due to ineffective or poorly tolerated treatments. Expectations for migraine treatment are now revisited in the light of specific therapies and it is quite interesting to observe this shift in paradigm where the term «migraine freedom» is starting to be used.
What is an «acceptable» migraine state is therefore under discussion and research is now demonstrating the burden associated with «high frequency episodic migraine» usually defined as 8 or more days of migraine per month. From a cost-effectiveness perspective, we must remind that 80% of people with migraine have less than 6 migraine days per month. Of course, the frequency is not the only parameter to take into account, since severity and response to acute medications are also key to the return to function.
Regarding the stage of disease, migraine is not considered to be a degenerative disease. The majority of patients with migraine do not progress over time and will remain in the «low frequency episodic» migraine category. Still, a subset of patients will «chronify», or increase their frequency past the arbitrarily defined 15 days /month bar. Intervention before chronification is a therapeutic goal. Factors for chronification have been described. A high baseline frequency is a key factor for chronification. Even if there are no studies to demonstrate in long term cohorts that a successful preventive therapy can prevent chronification, it would be scientifically rational to think so. Experience in the clinic suggests that patients who are successfully treated with a preventive function better on all parameters. Indeed, we often see patients who, due to a neglect of their migraine treatment or limited access to care, have progressed to a severe state and endured significant distress, loss of quality of life, personal life difficulties and even disability. Any physician treating migraine patient’s wishes to prevent this painful scenario.
Therefore, any migraine preventive should be available to patients who present a «high frequency episodic migraine» or a lower frequency but with severe attacks impacting function.
How would patients best suited for treatment with the drug under review be identified?
The diagnosis of migraine is clinical. There are no specific laboratory testing or diagnostic tools. Imaging is indicated uniquely in presence of red flags or an abnormal neurological examination. The condition is not challenging to diagnose in routine neurology clinical practice.
Evidence suggests underdiagnosis in primary care practice. The absence of a readily available and reliable biomarker imposes on primary care providers a longer questionnaire which is difficult with the limited time they have. Primary care providers receive very limited education on migraine diagnosis and treatment compared to other chronic diseases. Quite often, patients and providers will focus on symptoms or triggers leading to a misdiagnosis («sinus headache», «neck headache», «hormonal headache»).
Migraine is quantified with a headache diary, an essential tool that is underused in primary care because time is limited to perform these initial steps of therapeutic education.
There is currently no evidence that migraine has a pre-symptomatic stage. It does frequently start at a young age and fluctuates over a lifetime depending on very numerous factors. Treatment must be adjusted depending on the current state of the patient, always including the three axes of lifestyle adjustment, acute therapy, prevention of medication overuse and appropriate preventive therapy. Early therapeutic education and patient empowerment is key to avoid learned helplessness.
Which patients would be least suitable for treatment with the drug under review?
Pregnancy: There is insufficient data on the developmental risk associated with the use of atogepant in pregnant women. CGRP does play a role in pregnancy, and therefore drugs blocking CGRP could be harmful. Still, the shorter half-life of atogepant (5-7h) would be an advantage compared to the long half-life of antibodies (27-31 days) in the case of a woman planning a pregnancy.
Lactation: There is insufficient data on the presence of atogepant in breastmilk, the effects of atogepant on breastfed infants, and the effects of atogepant on milk production. In lactating rats, oral dosing with atogepant resulted in twice the amount of atogepant in milk than in maternal plasma.
Pediatrics: Safety and effectiveness in pediatric patients has not been established.
Geriatrics: Population pharmacokinetic modeling suggests no clinically significant pharmacokinetic differences between elderly and younger subjects. Clinical studies of atogepant contained an insufficient number of patients aged 65 years and over to determine if they respond differently than younger patients. In general, caution should be exercised in dose selection for an elderly patient, typically starting with the lowest dosage in the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Renal Impairment: The renal route of elimination plays a minor role in the clearance of atogepant. In patients with severe renal impairment (CLcr 15-29 mL/min), and in patients with end-stage renal disease (ESRD) (CLcr <15 mL/min), the recommended dosage of atogepant is 10mg once daily. For patients with ESRD undergoing intermittent dialysis, atogepant should preferably be taken after dialysis. No dose adjustment is recommended for patients with mild or moderate renal impairment.
Hepatic Impairment: No dose adjustment of atogepant is recommended for patients with mild or moderate hepatic impairment. Avoid use of atogepant in patients with severe hepatic impairment.
CYP3A4 Inhibitors: Coadministration of atogepant with itraconazole, a strong CYP3A4 inhibitor, resulted in a significant increase in exposure of atogepant in healthy subjects. The recommended dosage of atogepant with concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) is 10mg once daily. No dosage adjustment of atogepant is needed with concomitant use of moderate or weak CYP3A4 inhibitors.
CYP3A4 Inducers: Coadministration of atogepant with steady state rifampin, a strong CYP3A4 inducer, resulted in a significant decrease in exposure of atogepant in healthy subjects. Concomitant administration of atogepant with moderate inducers of CYP3A4 can also result in decreased exposure of atogepant. The recommended dosage of atogepant with concomitant use of strong or moderate CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort, efavirenz, etravirine) is 30mg or 60mg once daily. No dosage adjustment of atogepant is needed with concomitant use of weak CYP3A4 inducers.
OATP Inhibitors: Coadministration of atogepant with single dose rifampin, an OATP inhibitor, resulted in a significant increase in exposure of atogepant in healthy subjects. The recommended dosage of atogepant with concomitant use of OATP inhibitors (e.g., cyclosporine) is 10 mg or 30 mg once daily.
Is it possible to identify those patients who are most likely to exhibit a response to treatment with the drug under review?
There are no specific identifying factors to determine patients who are most likely to exhibit a response to treatment.
What outcomes are used to determine whether a patient is responding to treatment in clinical practice?
Health care providers will usually evaluate the response based on the stated goals of decreasing attack frequency and severity improving function and quality of life and decreasing distress and comorbidities. The level of detail will vary based on the experience of the clinician and available time in the clinic.
The methodology of migraine preventive trials has evolved over time in parallel with the clinical assessment of patients. Most headache specialists are now aware of the typical research outcomes and evaluate their patients with a similar approach. Questionnaires, scales and other PROs are used in research. Their use and utility in clinical practice varies, but they are now frequently asked by the insurance companies.
The evaluation of patients with migraine in primary care varies greatly. Some physicians will roughly ask if a patient is «doing better, approximately how much% ». Others will ask for frequencies. Few will use a diary. Even fewer will evaluate the impact of migraine work, sleep and mood.
Still, with episodic migraine patients, the identification of responders (50%) and super-responders (75%) can be relatively easy compared to the complex clinical pictures of patients with chronic migraine. A basic headache diary should be sufficient to ensure a reliable monitoring of outcomes.
What would be considered a clinically meaningful response to treatment?
The usual key parameter for a response in episodic migraine is a 50% in monthly migraine days (frequency), usually evaluated with a headache diary.
Other clinically meaningful responses supported by evidence to atogepant include the following:
Clinically meaningful responses not yet demonstrated by evidence include the following:
The challenge from a clinical perspective is to find a time-effective way to document this and acknowledge what a significant response is for a particular patient. A «quick’n easy» option is good, but not always sufficient.
The key example, as seen with CGRP antibodies, is the patients who does not reach a 50% improvement in frequency but does see a significant improvement in severity with a functional gain (for example, less presenteeism). The insurance decides not to cover, and the patient is desperate.
We hope that both frequency and severity (as both contribute to quality of life and ability to function) will be considered in the evaluation of response, as this is what we do in clinical practice. The MIDAS or HIT-6 score could be used to monitor benefit and determine whether to continue or alter preventive therapies.
How often should treatment response be assessed?
Oral preventive therapies can take 3 months at therapeutic dosages to see benefits. Therefore, monitoring at 3-month intervals is recommended when the treatment is initiated. Then, once a patient is stable, yearly visits could be sufficient.
What factors should be considered when deciding to discontinue treatment?
The following factors should be considered when deciding to discontinue treatment:
We would like to underline that a therapeutic success (for example a decrease in migraine frequency) should not be seen as a reason to discontinue treatment. This quite absurd reasoning has been seen with other therapies for migraine. We always wondered if any doctor would stop an anti-epileptic if seizures are controlled, or an anti-hypertensive if blood pressure is now within normal limits. A patient who responds to atogepant should be allowed to stay on treatment.
What settings are appropriate for treatment with the drug under review?
Physicians treating migraine patients usually work in outpatient clinics (academic or community).
For non-oncology drugs, is a specialist required to diagnose, treat, and monitor patients who might receive the drug under review?
Atogepant can be prescribed by primary care providers. Atogepant prescription should not be restricted to neurologists or specialists. It is indeed well tolerated and safe compared to many other drugs prescribed in primary care.
We would like to emphasize that:
To maintain the objectivity and credibility of the CADTH drug review programs, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This conflict of interest declaration is required for participation. Declarations made do not negate or preclude the use of the clinician group input. CADTH may contact your group with further questions, as needed. Please refer to the Procedures for CADTH Drug Reimbursement Reviews (section 6.3) for further details.
Did you receive help from outside your clinician group to complete this submission?
No.
Did you receive help from outside your clinician group to collect or analyze any information used in this submission?
No.
List any companies or organizations that have provided your group with financial payment over the past two years AND who may have direct or indirect interest in the drug under review. Please note that this is required for each clinician who contributed to the input — please add more tables as needed (copy and paste). It is preferred for all declarations to be included in a single document.
Name: Tasjeel Ansari, MD, FRCPC, DABPN
Position: Headache Neurologist
Date: 09/03/2022
COI Declaration for Canadian Headache Society — Clinician 1.
Name: Lik Hang Tommy Chan, MBBS, FRCPC, DABPN
Position: Headache Neurologist
Date: 12/03/2022
COI Declaration for Canadian Headache Society — Clinician 2.
Name: Danny Adel Monsour, MD, FRCPC
Position: Headache Neurologist
Date: 14/03/2022
COI Declaration for Canadian Headache Society — Clinician 3.
Name: Elizabeth Leroux, MD, FRCPC
Position: Headache Neurologist, President - Canadian Headache Society
Date: 16/03/2022
COI Declaration for Canadian Headache Society — Clinician 4.
Name: William Kingston, MD, FRCPC, FAHS
Position: Headache Neurologist, Board member – Canadian Headache Society
Date: 16-03-2022
COI Declaration for Canadian Headache Society — Clinician 5.
Copyright © 2023 - Canadian Agency for Drugs and Technologies in Health. Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND).
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