Fremanezumab for preventing migraine: <scp>NICE</scp> guidance

The National Institute for Health and Care Excellence (NICE) published, on 3 June 2020, a Technology appraisal guidance (TAG) for the use of fremanezumab for preventing migraine.1 Migraine is a common disabling primary headache disorder2, 3 affecting 10% of men and 22% of women.4 The prevalence of migraine climbs to a peak at 40 years of age and then declines in both sexes.5, 6 It is ranked as seventh highest cause of disability globally7 responsible for 2.9% of all years of life lost to disability.7 In a meta-analysis published in 2018, globally, migraine is the second highest cause of years lived with disability and is the primary cause of disability in adults under the age of 50 years.8 Migraine without aura can be summarised as a high impact, episodic headache associated with symptoms and features (see Table 1). The headache typically lasts 4 to 72 hours and patients are symptom free between each bout of migraine.2, 3 Positive visual symptoms: - small bright dots/stars, zigzag or jagged lines, flashes of bright light, flickering light, white spots, colored dots/spots of light, curved or circular lines, ‘bean-like’ forms like a crescent or C-shaped round forms - 67% of visual aura patients report at least one positive phenomenon B: One or more of one of the following fully reversible aura symptoms 1. Visual 2. Sensory 3. Speech and/or language 4. Motor 5. Brainstem 6. Retinal Negative visual symptoms: - scotoma, black spots, small black dots, hemianopia, tunnel vision, anopia - 38% of visual aura patients report at least one negative phenomenon C: Headache has >2 of the following characteristics a. Unilateral location b. Pulsating quality c. Moderate or severe pain intensity d. Aggravation by or causing avoidance of routine physical activity (eg walking, climbing stairs) C: At least 3 of the following 6 characteristics 1. At least one aura symptom spreads gradually over ≥5 minutes 2. Two or more aura symptoms occur in succession 3. Each individual aura symptom lasts 5–60 minutes 4. At least one aura symptom is unilateral 5. At least one aura symptom is positive 6. The aura is accompanied, or followed within 60 minutes by headache Disturbances of visual perception (DVP): - blurred/foggy vision, ‘like looking through heat waves or water’ - deformed images (alteration of the shape of objects) - visual snow, fractured vision, oscillopsia, corona phenomena - alteration of the perception of distance (things look close or far away) - 45% of visual aura patients report at least one DVP D: During headache >1 of the following a. Nausea and/or vomiting b. Photophobia and phonophobia Patients with typical migraine aura experience fully reversible visual, sensory or motor symptoms developing over several minutes and resolving within the hour. Those symptoms can be described as positive or negative phenomena (see Table 1).2, 3 Chronic migraine (CM) is defined by the International Headache Society (IHS) as a headache occurring on 15 days or more each month, with at least 8 headache days having features of migraine (see Table 2).2 CM affects approximately 2% of the population11 with a reduced quality of life (QOL)12 and increased risk of anxiety, depression, chronic pain and use of health care resource.11 C: On ≥8 days/month for >3 months, fulfilling any of the following 1. Criteria C and for 1.1 Migraine without aura 2. Criteria B and C for 1.2 Migraine with aura 3. Believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative The IHS also state that approximately 50% of patients diagnosed with chronic migraine revert to episodic migraine when all acute treatments are stopped.2 In phase 2 and 3 trials of fremanezumab the comparisons were made between high frequency episodic migraine (HFEM) and CM, where HFEM was defined as:16 • having headache for 8 or more days each month for at least 3 months • having 8 to 14 headache days of migraine or probable migraine - relieved by ergot or a triptan • could take one standard migraine preventative for at least 2 months before study onset • could take acute migraine medication for no more than 14 days per month - with a maximum of 4 days of opioid or barbiturate use. Early studies demonstrated the link between migraine and calcitonin gene-related peptide (CGRP),15 with much debate as to the use of CGRP blockers in the acute treatment of migraine.15 CGRP receptors are found in the central and peripheral nervous systems, most importantly in the trigeminovascular pathways.15 Humans have two isoforms – -αCGRP and -βCGRP – with β-CGRP most common in the primary spinal afferents, and β-CGRP most common in the enteric nervous system. The CGRP receptor has three subunits – receptor activity-modifying protein 1 (RAMP1), calcitonin-like receptor (CLR) and receptor component protein (RCP).15 Gepants were the first class of drugs to act as a CGRP receptor antagonist. The first was olcegepant, which was effective but had low oral bioavailability.15 Following the proof of concept study with olcegepant five other gepants were studied, including telcagepant, ubrogepant , rimegepant, BI 44370 TA and MK-3207. Further development was suspended following the development of liver toxicity on repeat exposure. Anti-CGRP monoclonal antibodies (mAbs) target the CGRP ligand or its canonical receptor.16 They have a high specificity and are degraded and cleared within the reticuloendothelial system with no involvement of the liver or kidney.16 Drug interactions are minimal, they do not cross the blood brain barrier in significant amounts but do require parenteral administration. mAbs have a long half-life of between three to six weeks allowing administration either monthly or quarterly.16 mAbs have the potential to produce neutralising antibodies and the possibility of hypersensitivity at the injection site. Anti-CGRP mAbs (a-CGRP mAbs) have been engineered to minimise this response and injection site reactions have been extensively studied.16 There are four a-CGRP mAbs for the preventive treatment of migraine and three have been approved by the FDA to date – erenumab, fremanezumab and galcanezumab (see Table 3) They have different IgG subtypes, methods of administration, bioavailability, cell line and presence of murine proteins.16 The most important difference is that three target the CGRP ligand and the fourth targets the canonical CGRP receptor. All have been demonstrated to be effective, well tolerated and safe in phase II and III trials. Mammalian (Chinese hamster ovary) Mammalian (Chinese hamster ovary) Mammalian (Chinese hamster ovary) Fremanezumab is a fully humanised IgG2a monoclonal antibody that potently and selectively binds to the CGRP ligand. Fremanezumab can be administered subcutaneously. The monthly dose is 225mg and the quarterly dose is 675mg. Fremanezumab was studied in two phase 3 trials (HALO) for the preventive treatment of episodic and chronic migraine.16 mAbs targeting CGRP are unlikely to need dose titration, with a speed of onset within days and a long half-life allowing a monthly or quarterly dosing regimen. The tolerability profile is similar to placebo with a lack of serious adverse events, likely to enhance patient use and long-term outcomes, with better concordance and compliance. The current evidence shows that patients with medication overuse headache (MOH) given mAbs experience significant reduction in acute medication use, in the absence of active management of the MOH. A series of phase 2 and 3 clinical trials17-19 have demonstrated that fremanezumab quarterly and fremanezumab monthly is well tolerated and shows a sustained improvement in monthly migraine days, headache days and headache-related disability for up to 12 months in patients with migraine. Another study20 showed fremanezumab was associated with improvement in migraine-specific quality of life, overall health status, patients’ global impression of change with treatment and productivity when compared with placebo. Adverse event (AE) assessment included injection site monitoring, laboratory testing, checking vital signs, 12-lead ECGs, physical examination and a mental health assessment using the Columbia-Suicide Severity Rating Scale (C-SSRS), which is electronic.19 AEs were reported in 84–89% of patients in all treatment groups, the most common being injection site reactions, the most likely reason for patients to stop treatment. AEs leading to stopping the treatment occurred in 3% to 5% of patients, with serious AE events affecting 5–7% of patients across all treatment groups.19 NICE accepted the high impact and level of disability associated with migraine, with chronic migraine having an adverse effect on physical and mental wellbeing and ability to work.1 NICE recognised that in episodic migraine a 50% reduction in migraine frequency is clinically meaningful, whereas in chronic migraine a 30% reduction is meaningful.1 Expert opinion recommended that a failed response to three oral preventive drugs was a reasonable threshold for consideration of fremanezumab, as the trial of further oral agents is unlikely to be effective and may be associated with significant side-effects.1 This mirrors the guidance for the use of botulinum toxin type A (Botox).21 NICE accepted that not all patients are able to use, respond to or have access to Botox.21 NICE recognised that: • HFEM is not a clinical subgroup recognised internationally • The FOCUS trial provides the most clinically relevant clinical evidence - But does not reflect the patients eligible in clinical practice • The differences between doses across the trials does not affect applicability of the results • Fremanezumab is clinically effective compared with placebo for episodic and chronic migraine • The long-term comparative effectiveness is unknown • There are no comparative trials with Botox • All cause discontinuation rates were higher than expected - Which may affect cost-effectiveness No conflicts of interest were declared. Dr Fontebasso is a member of the British Association for the Study of Headache, International Headache Society and American Headache Society.