Indication: Indicated for the prevention of migraine in adults who have had at least 4 migraine days per month.
Sponsor: Lundbeck Canada Inc.
Final recommendation: Reimburse with conditions
Summary
What Is the CADTH Reimbursement Recommendation for Vyepti?
CADTH recommends that Vyepti be reimbursed by public drug plans for the prevention of episodic migraine (EM) or chronic migraine (CM) in adults who have had at least 4 migraine days per month if certain conditions are met.
Which Patients Are Eligible for Coverage?
Vyepti should only be covered to treat patients who have tried at least 2 other types of oral treatments for the prevention of migraine. When it is first prescribed, the drug plans must receive documented confirmation of the patient’s monthly number of headache and migraine days to demonstrate treatment is working.
What Are the Conditions for Reimbursement?
Vyepti should only be reimbursed for patients being cared for by a physician with experience managing those with migraine headaches. To continue treatment with Vyepti, the physician must provide proof that treatment with Vyepti reduced the average number of migraine days per month by at least 50% since starting Vyepti, and that the reduction in the frequency of migraines is maintained. Vyepti will only be reimbursed for 6 months at a time and if the total treatment cost of Vyepti does not exceed the total cost of the lowest-cost reimbursed anti-calcitonin gene-related peptide (CGRP) comparator.
Why Did CADTH Make This Recommendation?
Evidence from 3 clinical trials demonstrated that Vyepti reduced the frequency of migraines based on the number of migraine days per month and the proportion of patients with a 50% or 75% reduction in migraine days per month. The trials also included evidence that Vyepti reduced symptoms of migraine and is well-tolerated.
Based on CADTH’s assessment of the health economic evidence, Vyepti does not represent good value to the health care system at the public list price and there is not enough evidence to justify a greater cost for Vyepti compared with relevant anti-CGRP comparators.
Based on public list prices, Vyepti is estimated to cost the public drug plans approximately $12 million over the next 3 years.
Additional Information
What Is Migraine?
Migraine is a neurological disease characterized by recurrent episodes of pulsating headache pain that can be accompanied by sensitivity to light or sound, nausea, vomiting, numbness, and auras. It affects 1 person in 10 in Canada, and women are more affected than men.
Unmet Needs for Patients With Migraine
Many patients have trouble finding effective treatments that reduce migraine frequency and need to try several medications before realizing benefit. Furthermore, conventional migraine-prevention treatments are associated with unwanted side effects.
How Much Does Vyepti Cost?
Treatment with Vyepti is expected to have an annual cost of $7,240 to $21,720 per patient for the 100 mg or 300 mg dose, respectively, where the 300 mg dose is assumed to be priced linearly.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that eptinezumab be reimbursed for the prevention of migraine in adults who have had at least 4 migraine days per month only if the conditions listed in Table 1 are met.
Three multicentre, double-blind, randomized controlled trials (RCTs) (DELIVER, PROMISE-1, and PROMISE-2) demonstrated that treatment with eptinezumab 100 mg and 300 mg given by IV every 12 weeks for 24 to 48 weeks resulted in added clinical benefit compared to placebo for patients with EM or CM. Of the 3 included trials, DELIVER was the only trial that exclusively enrolled patients with a history of at least 2 prior prophylactic treatments. The DELIVER trial demonstrated that treatment with eptinezumab was associated with statistically significant and clinically meaningful reduction in migraine frequency relative to placebo based on the change from baseline in the number of monthly migraine days (MMDs) from weeks 1 to 12 (100 mg = by 2.7 days; 95% confidence interval [CI], –3.4 to –2.0; P < 0.0001; and 300 mg = by 3.2 days; 95% CI, –3.9 to –2.5; P < 0.0001). The results of the DELIVER trial also demonstrated a benefit for treatment with eptinezumab 100 mg and eptinezumab 300 mg relative to placebo based on the key secondary outcomes, such as a 50% and 75% reduction in MMDs from baseline to weeks 1 to 12, a change from baseline in MMDs from baseline to weeks 13 to 24, and a change from baseline in Headache Impact Test (HIT-6) scores. Patients identified a need for a preventive treatment that reduces the frequency of headaches and migraines, reduces symptoms of migraine, is well-tolerated, and improves quality of life, some of which may be met with eptinezumab.
At the sponsor-submitted price for eptinezumab 100 mg and publicly listed prices for comparators, eptinezumab was more costly than other anti-CGRP therapies used as a preventive treatment for migraine in adults. There was insufficient evidence to support a clinical benefit with eptinezumab versus relevant anti-CGRP comparators; as such, the total treatment cost of eptinezumab should not exceed the total treatment cost of the lowest-cost reimbursed anti-CGRP comparator.
Table 1: Reimbursement Conditions and Reasons
Reimbursement condition | Reason | Implementation guidance |
|---|---|---|
Initiation | ||
1. The patient has a confirmed diagnosis of EM or CM according to the International Headache Society criteria, defined as: 1.1. EM: migraine headaches on at least 4 days per month and less than 15 headache days per month for more than 3 months. 1.2. CM: headaches for at least 15 days per month for more than 3 months of which at least 8 days per month are with migraine. | The DELIVER trial included a mixed population of patients with EM or CM. The PROMISE-1 and PROMISE-2 trials enrolled patients with EM and CM, respectively. All 3 RCTs provided evidence that eptinezumab is superior to placebo in reducing the mean MMDs in patients with EM and CM. | — |
2. The patient has experienced an inadequate response, intolerance, or contraindication to at least 2 oral prophylactic migraine medications. | The DELIVER trial included adults with EM or CM who had documented inadequate response to at least 2 classes of prior preventive treatment. | Inadequate response to oral prophylactic therapies is defined as less than a 30% reduction in frequency of headache days to an adequate dose and duration of at least 2 prophylactic medications, which must be of a different class. At least 1 of the 2 prophylactic medications previously used must have been discontinued because of lack of therapeutic effectiveness. Oral prophylactic therapies to be considered include:
A list of previously tried oral prophylactic medications, including doses, duration, and reasons for discontinuance, should be provided by the requesting physician. There is no evidence to support the combination of eptinezumab with onabotulinumtoxin A; therefore, these drugs should not be used together. |
3. The physician must provide the number of headache and migraine days per month at the time of initial request for reimbursement. | Refer to initiation condition 1 and renewal condition 5. | — |
4. The maximum duration of initial authorization is 6 months. | Authorization of funding for 6 months provides flexibility to accommodate the practical challenges of assessing clinical response after 3 months of treatment. The 6-month-long maximum duration of authorization is also consistent with the duration recommended for other migraine prophylactic medications reviewed previously by CDEC. | — |
Renewal | ||
5. The physician must provide proof of beneficial clinical effect when requesting continuation of reimbursement, defined as a reduction of at least 50% in the average number of migraine days per month at the time of first renewal compared with baseline. At subsequent renewals the physician must provide proof that the initial 50% reduction in the average number of migraine days per month has been maintained. | A 50% reduction in the number of monthly MMDs was a predefined secondary end point in each of the included RCTs. | Some jurisdictions may want to include a reduction of at least 30% in the number of headache days per month and an improvement of at least 5 points in the HIT-6 score, compared with baseline, as an alternative criterion for renewal of reimbursement. Jurisdictions that choose to include this criterion should also request that the physician provide the score obtained on the HIT-6 at the time of the initial request for reimbursement. |
6. The maximum duration of subsequent authorizations following the initial authorization is 6 months. | See initiation criterion 4. | — |
Prescribing | ||
7. The patient should be under the care of a physician who has appropriate experience in the management of patients with migraine headaches | Accurate diagnosis of migraine is important to ensure that eptinezumab is prescribed to the appropriate patients. In addition, several migraine prophylaxis treatment options must be considered when selecting the most appropriate therapy for patients who are refractory to 1 or more first-line options. | — |
Pricing | ||
8. Eptinezumab should be negotiated so that the total cost does not exceed the cost of treatment with the least costly anti-CGRP reimbursed for the preventive treatment of EM or CM in adults. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| As such, there is insufficient evidence to justify a cost premium for eptinezumab over the least-expensive anti-CGRP reimbursed for the preventive treatment of EM or CM in adults. | — |
CDEC = Canadian Drug Expert Committee; CGRP = calcitonin gene-related peptide; CM = chronic migraine; EM = episodic migraine; HIT-6 = Headache Impact Test; MMDs = monthly migraine days; RCT = randomized controlled trial.
Migraine is a common and debilitating neurological disease that may lead to poor quality of life, social isolation, and an inability to participate in daily activities. CDEC discussed patient and clinician input that current prophylactic medications do not benefit everyone with migraine and have adverse effects that may make them difficult to tolerate, leading to poor adherence and non-achievement of desired outcomes.
CDEC discussed the unmet therapeutic need in treatment-refractory EM and CM and noted that eptinezumab may provide an additional treatment option for patients.
Comparative evidence was limited to indirect treatment comparisons of eptinezumab against other medications used to prevent migraine. The results of the network meta-analysis (NMA) submitted by the sponsor |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| were inconclusive due to methodological limitations with the analysis. Also, the indirect comparison did not assess safety. As such, it is uncertain that eptinezumab would address needs that are not currently addressed through other prophylactic treatments for migraine.
Long-term efficacy and safety cannot be established based on the results of the 24-week DELIVER and PROMISE-2 trials, and the 48-week PROMISE-1 trial, in which patients received 2 infusions or 4 infusions of eptinezumab, respectively. The PREVAIL trial assessed the longer-term (up to 104 weeks) safety and patient-reported outcomes; however, methodological issues with the PREVAIL trial, including the absence of a comparator arm, create uncertainty regarding the long-term safety of eptinezumab.
Improvement in quality of life and a reduction in adverse events (AEs) were identified as outcomes of importance to patients. Although health-related quality of life (HRQoL) instruments were included in the clinical trials, none of the statistical testing procedures were controlled for multiplicity, which limits any conclusions that can be drawn regarding this important outcome. Regarding AEs, no comparative safety evidence (direct or indirect) for eptinezumab and other CGRP inhibitors or onabotulinumtoxin A was identified.
CDEC noted that the lack of evidence regarding the combination use of eptinezumab with onabotulinumtoxin A and other medications used for the prevention of migraine is an important gap in the evidence. CDEC also discussed that in clinical practice, patients on migraine prophylaxis treatments frequently discontinue or switch treatments due to lack of efficacy or tolerability, which is not supported by the evidence for eptinezumab.
CDEC noted the difference in the method of administration between eptinezumab (IV injection) and other CGRP inhibitors (subcutaneous injection). The use of IV infusion may be associated with increases in health care resource utilization (e.g., infusion time, nursing time). Given the insufficient evidence to support a difference in comparative efficacy between treatments, it may be necessary for the drug price of eptinezumab to be lower than the drug price of the least costly CGRP inhibitor to account for these differences in total treatment cost.
CDEC noted that the sponsor’s pharmacoeconomic submission priced a 300 mg dose based on 3 vials of the 100 mg dose, as a 300 mg dose was not yet available. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Should a 300 mg dose not be made available, or should a different price be introduced for a 300 mg dose, the price should be negotiated such that the total treatment cost with the 300 mg dose does not exceed the total treatment cost of the least costly CGRP inhibitor.
Migraine is a complex neurological disorder whose precise cause is not completely understood. Patients with migraine report migraine attacks that are characterized by severe headache (e.g., throbbing, diffuse pain), accompanied by other symptoms such as nausea and vomiting, dizziness, sensory hypersensitivity, and tingling or numbness in the extremities and/or face. Migraines can occur with or without aura, and the aura is characterized by a wide range of primarily neurological symptoms that can affect vision, speech, sensations, muscle strength, and cognitive function. All of these symptoms can impair quality of life. Based on a study published in 2011, in Canada, at least 2.6 million adult females and almost 1 million adult males have migraine, although this may be an underestimation as not everyone who has migraine seeks medical help and therefore do not have an official diagnosis. Approximately three-fourths of patients experiencing migraine report impaired function, and one-third require bedrest during a migraine attack.
There are 2 approaches to treating migraine: management of acute attacks and prophylaxis, the latter of which is typically only considered for those with more frequent migraines (i.e., ≥ 4 migraine days per month). Topiramate is an oral anticonvulsant that is indicated in adults for the prophylaxis of migraine headache. Onabotulinumtoxin A has a Health Canada indication for CM prophylaxis and was previously reviewed by CADTH. The CGRP inhibitors (erenumab, fremanezumab, galcanezumab, and eptinezumab) have been approved by Health Canada for the prevention of migraine. Many other therapies used for migraine prophylaxis are used off-label, as they lack an official indication for this purpose from Health Canada. Broadly speaking, the main categories are antidepressant, anti-convulsant, and cardiovascular drugs. While these are well-established drugs, they all have various tolerability issues for patients, and this is important given that they are to be used on a chronic basis in migraine prophylaxis.
Eptinezumab has been approved by Health Canada for the prevention of migraine in adults who have at least 4 migraine days per month. Eptinezumab is a CGRP-binding antibody. It is available as a 100 mg/mL solution for IV infusion and the dosage recommended in the product monograph is 100 mg administered by IV infusion every 12 weeks. Some patients may benefit from a dosage of 300 mg administered by IV infusion every 12 weeks.
To make its recommendation, the committee considered the following information:
a systematic review of 3 double-blind RCTs in adult patients with either EM, CM, frequent EM, or frequent CM
patients perspectives gathered by 2 patient groups, Migraine Canada and Migraine Quebec
input from the public drug plans that participate in the CADTH review process
input from 1 clinical specialist with expertise diagnosing and treating patients with migraine
a review of the pharmacoeconomic model and report submitted by the sponsor.
Note that no clinician group input was received for this review.
The information in this section is a summary of input provided by the patient groups that responded to CADTH’s call for patient input and from 1 clinical expert consulted by CADTH for the purpose of this review.
Patient input was provided as a joint submission by 2 groups, Migraine Canada and Migraine Quebec, for the review of eptinezumab, and data were collected via 2 online surveys, as well as through direct input from patients who have experience with eptinezumab who reside in the US.
Patients report migraine as impacting their quality of life, sleep, mental health, social relationships, and day-to-day functioning at work and school. Patients indicated that improving quality of life and decreasing the frequency and the intensity of headaches and symptoms other than pain are key outcomes of interest.
According to the surveys conducted in 2021 and 2022, 30% and 24% of respondents reported having found a preventive treatment that provided a greater than 50% improvement in the frequency and intensity of their migraines with no significant side effects. According to the 2021 survey, 66% of respondents reported discontinuing their preventive medication due to side effects. Additionally, 57% of respondents in the 2021 survey indicated that they had not filled their prescription in the past 6 months due to lack of coverage.
The clinical expert consulted by CADTH on this review identified the following as unmet needs: patients who have a delayed response with migraine prevention treatment, patients whose migraines are refractory to current treatment options, lack of therapies that reverse the course of the disease, and bioavailability (i.e., lack of an IV formulation).
With respect to place in therapy, the clinical expert indicated that eptinezumab would complement onabotulinumtoxin A, and that eptinezumab would ideally be used in the first-line setting along with other CGRP monoclonal antibodies (mAbs); however, they also noted that in real-world use eptinezumab is likely to be used as a later treatment due to cost and insurance coverage requirements.
The clinical expert noted that the patients most likely to benefit from eptinezumab are those with EM or CM. The patients most in need of an intervention such as eptinezumab are those who have difficulty self-administering subcutaneous injections, those with chronic daily headache, and those with medication overuse headache.
According to the clinical expert, a clinically meaningful response could include a reduction in monthly headache days (MHDs) and MMDs and a 50% responder (i.e., a 50% reduction in MMDs). The clinical expert also indicated that patient-reported outcomes should also be taken into account, as well as a reduction in use of acute medications for migraine.
Indications for discontinuing treatment, according to the clinical expert, would include lack of response after a 6-month trial, intolerable side effects, allergy and/or anaphylaxis, patient preference, or switching to another CGRP mAb due to inconvenience with IV administration.
No clinician group input was received for the review of eptinezumab.
Table 2: Responses to Questions From the Drug Programs
Implementation issues | Response |
|---|---|
Relevant comparators | |
In the pivotal studies for eptinezumab, the comparator was placebo, while other therapies for the prevention of migraine may have been appropriate comparators. | Comment from the drug programs to inform CDEC deliberations. |
Considerations for initiation of therapy | |
The sponsor reimbursement request is for patients who have experienced an inadequate response, intolerance, or contraindication to at least 2 oral prophylactic migraine medications (per the CDEC initiation criteria for fremanezumab and galcanezumab). The sponsor also indicated that there is growing evidence that a patient not appropriately responding to one anti-CGRP antibody may respond better to another one. Should prior treatment with another preventive therapy, including other anti-CGRP antibodies, be considered when determining eligibility for the reimbursement of eptinezumab? | The clinical expert noted that some patients may respond to alternative CGRPs despite failure to a previous CGRP and that it is not possible to identify who those patients are in advance. The clinical expert believed that ideally, eptinezumab would be used in the first-line setting, along with other CGRP mAbs; however, due to limitations such as cost and coverage, reimbursement will likely only be considered after a trial or 2 oral prophylaxis treatments. CDEC indicated that if reimbursement is to be recommended, it should be consistent with how jurisdictions currently fund CGRP mAbs. Additionally, it was noted that the DELIVER trial excluded patients who had previously used anti-CGRP antibodies. |
The CDEC initiation criteria for fremanezumab and galcanezumab are as follows: 1. The patient has a confirmed diagnosis of EM or CM according to the International Headache Society criteria, defined as: 1.1. EM: migraine headaches on at least 4 days per month and less than 15 headache days per month for more than 3 months. 1.2. CM: headaches for at least 15 days per month for more than 3 months of which at least 8 days per month are with migraine. 2. The patient has experienced an inadequate response, intolerance, or contraindication to at least 2 oral prophylactic migraine medications. 3. The physician must provide the number of headache and migraine days per month at the time of initial request for reimbursement. 4. The maximum duration of initial authorization is 6 months. Should the initiation criteria for eptinezumab be aligned with those of fremanezumab and galcanezumab? | The clinical expert agreed with all the initiation criteria described for fremanezumab and galcanezumab, with the exception of the maximum duration of initial authorization. The clinical expert noted that 6 months is not enough time to adequately evaluate response, given that eptinezumab is administered every 3 months. The clinical expert believed that up to 1 year for initial authorization would be more clinically appropriate. CDEC indicated that if reimbursement is to be recommended, it should be consistent with how jurisdictions currently fund CGRP mAbs. |
Considerations for continuation or renewal of therapy | |
The CDEC renewal criteria for fremanezumab and galcanezumab are as follows: 1. The physician must provide proof of beneficial clinical effect when requesting continuation of reimbursement, defined as a reduction of at least 50% in the average number of migraine days per month at the time of first renewal compared with baseline. At subsequent renewals the physician must provide proof that the initial 50% reduction in the average number of migraine days per month has been maintained. 2. The maximum duration of subsequent authorizations following the initial authorization is 6 months. Should the renewal criteria for eptinezumab be aligned with those of fremanezumab and galcanezumab? | The clinical expert indicated that if the 50% reduction criterion was not fulfilled, the specialist should be given the opportunity to provide a rationale for continued use given that not every patient will achieve a 50% reduction. The clinical expert suggested using a 30% reduction and a reduction of 5 points in HIT-6 score for eligibility for renewal. CDEC indicated that if reimbursement is to be recommended, it should be consistent with how jurisdictions currently fund CGRP mAbs. |
Considerations for prescribing of therapy | |
The recommended dose of eptinezumab is 100 mg administered by IV infusion every 12 weeks. Some patients may benefit from a dosage of 300 mg administered by IV infusion every 12 weeks. The need for dose escalation should be assessed within 12 weeks after initiation of the treatment. Are there any cases in which a patient should receive the 300 mg dose immediately without first trialling the 100 mg dose? Specifically, would immediate reimbursement of the 300 mg dose be a valid option in certain cases? | The clinical expert stated that there is a lack of data on switching between doses and therefore uncertainty exists on this issue. The clinical expert believed this would depend on the cost of the drug. If eptinezumab 300 mg is 3 times the cost of eptinezumab 100 mg, if a patient fails at least 2 doses of 100 mg then at least 2 doses of 300 mg will be tried next. If eptinezumab 300 mg is the same or a similar cost to eptinezumab 100 mg, the clinical expert suggested offering 300 mg to patients who are refractory at the first visit, depending on patient characteristics. CDEC was in agreement with the response from the clinical expert consulted by CADTH. Further, CDEC noted that the |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |
Eptinezumab is administered via IV infusion by a health care professional and requires the availability of infusion clinics and trained health care professionals. | Comment from the drug programs to inform CDEC deliberations. |
The CADTH recommendations for galcanezumab and fremanezumab state that given that there is no evidence for combination usage of the respective therapies with onabotulinumtoxin A, they should not be used together. Is there any evidence to support the combination usage of eptinezumab with onabotulinumtoxin A, compared with the previous drugs and onabotulinumtoxin A? | The clinical expert noted that there are no data for eptinezumab combined with onabotulinumtoxin A, but noted that there are data for onabotulinumtoxin A combined with other monoclonal antibodies. Based on this, the clinical expert suggested that eptinezumab could be used with onabotulinumtoxin A. CDEC agreed that no evidence was identified that supported the use of eptinezumab in combination with onabotulinumtoxin A. |
System and economic issues | |
Currently, a 300 mg SKU for eptinezumab is not available and is still under development. In economic components of the submission, the 300 mg dose is costed linearly with the 100 mg dose given that the only way to obtain a 300 mg dose is by purchasing three 100 mg/mL vials. Compared with eptinezumab 300 mg, eptinezumab 100 mg was found to be less costly and less effective. Following the review of eptinezumab by CADTH, Lundbeck Canada Inc. plans to address the 300 mg dose cost with the pCPA and to provide participating drug plans ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| | Comment from the drug programs to inform CDEC deliberations. |
CDEC = Canadian Drug Expert Committee; CGRP = calcitonin gene-related peptide; CM = chronic migraine; EM = episodic migraine; HIT-6 = Headache Impact Test; mAb = monoclonal antibody; pCPA = pan-Canadian Pharmaceutical Alliance; SKU = stock-keeping unit.
There were 3 pivotal, sponsor-funded, multicentre, double-blind RCTs included in this review, each comparing 2 different doses of eptinezumab, 100 mg and 300 mg every 12 weeks, to placebo. In the DELIVER trial, 892 patients with either EM or CM, in the PROMISE-1 trial, 674 patients with frequent EM, and in the PROMISE-2 trial, 1,050 patients with CM were randomized at a ratio of 1:1:1 to each of the eptinezumab 100 mg, eptinezumab 300 mg, or placebo groups. In each study, patients received 2 doses of eptinezumab or placebo, 1 at baseline and 1 at week 12. The primary outcome in each of the 3 studies was the change from baseline to weeks 1 to 12 in MMDs. Key secondary outcomes, all controlled for multiplicity, included the number of patients achieving at least a 75% or at least a 50% reduction in MMDs, the number of patients with a migraine 1 day after dosing, migraine prevalence on days 1 to 28 post-dose, change from baseline in HIT-6 scores, and acute medication usage.
In the DELIVER trial, the mean age of patients was approximately 44 years, while in the PROMISE studies the mean age of patients was approximately 40 years. In all studies, the majority of patients were female (approximately 90% in the DELIVER trial, 84% in the PROMISE-1 trial, and 88% in the PROMISE-2 trial) and White (96% in the DELIVER trial, 84% in the PROMISE-1 trial, and 91% in the PROMISE-2 trial). In the DELIVER trial, 60% of patients had EM, | || had 14 or fewer MHDs, 62% had 2 prior migraine prophylaxis failures (31% with 3 prior failures and 7% with 4 prior failures), and 12% had a diagnosis of medication overuse headache. In the PROMISE-1 trial, 36% had more than 9 MMDs, and in the PROMISE-2 trial, 45% had 17 MMDs or more.
For weeks 1 to 12 of the DELIVER trial, MMDs were estimated to be reduced among patients on eptinezumab compared to those on placebo by 2.7 days for the 100 mg dose (95% CI, −3.4 to −2.0; P < 0.0001) and by 3.2 days for the 300 mg dose (95% CI, −3.9 to −2.5; P < 0.0001). For weeks 13 to 24, MMDs were estimated to be reduced among patients on eptinezumab compared to those on placebo by 3.0 days for the 100 mg dose (95% CI, −3.8 to −2.2; P < 0.0001) and by 3.7 days for the 300 mg dose (95% CI, −4.5 to −3.0; P < 0.0001). These comparisons were statistically significant based on the prespecified sequence of testing. Sensitivity analyses of the primary outcome were consistent with that of the primary analysis. For weeks 1 to 12 of the PROMISE-1 trial, MMDs were estimated to be reduced among patients on eptinezumab by 0.7 days for the 100 mg dose (95% CI, −1.3 to −0.1; P = 0.0182) and by 1.1 days for the 300 mg dose (95% CI, −1.7 to −0.5; P < 0.0001). These comparisons were statistically significant based on the prespecified sequence of testing. Results of the sensitivity analyses were consistent with that of the primary analysis. For weeks 13 to 24, MMDs were estimated to be reduced among patients on eptinezumab by ||||||| on the 100 mg dose (|||||||||||||||) and by ||||||| on the 300 mg dose (|||||||||||||||). These comparisons fell outside of the multiple testing procedure (MTP); therefore, no P values are reported here. In the PROMISE-2 trial, for weeks 1 to 12, MMDs were estimated to be reduced among patients on eptinezumab by 2.0 days for the 100 mg dose (95% CI, −2.9 to −1.2; P = < 0.0001) and by 2.6 days for the 300 mg dose (95% CI, −3.4 to −1.7; P < 0.0001). These comparisons were statistically significant based on the prespecified sequence of testing. For weeks 13 to 24, MMDs were estimated to be reduced among patients on eptinezumab by 2.0 days for the 100 mg dose (95% CI, −2.9 to −1.0) and by 2.7 days for the 300 mg dose (95% CI, −3.6 to −1.7). These comparisons fell outside of the MTP; therefore, no P values are reported here. Results of the sensitivity analysis were consistent with that of the primary analysis. No formal prespecified subgroup analyses of the primary outcome were performed for the PROMISE-1 and PROMISE-2 trials. In DELIVER, prespecified subgroup analyses of the primary outcome were conducted with no control for multiplicity. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
In the DELIVER trial, the proportion of patients achieving a 50% or greater reduction in MMDs at weeks 1 to 12 was 42% in the eptinezumab 100 mg group, 50% in the eptinezumab 300 mg group, and 13% with placebo, with an odds ratio in the eptinezumab 100 mg group of 4.91 (95% CI, 3.29 to 7.47; P < 0.0001) and in the eptinezumab 300 mg group of 6.58 (95% CI, 4.41 to 10.01; P < 0.0001). These comparisons were statistically significant based on the prespecified sequence of testing. Proportion of patients achieving a 50% or greater reduction in MMDs at weeks 1 to 12 was also reported in the PROMISE-1 trial, with a mean difference in proportions between eptinezumab 100 mg and placebo of 12.4% (95% CI, 3.2, 21.5) and between eptinezumab 300 mg and placebo of 18.9% (95% CI, 9.8 to 28.0; P = 0.0001). The comparison between eptinezumab 300 mg and placebo was statistically significant based on the prespecified sequence of testing; however, the P value for the comparison between eptinezumab 100 mg and placebo will not be reported here due to early failure of the hierarchy. The proportion of patients achieving a 50% or greater reduction in MMDs at weeks 1 to 12 was also reported in the PROMISE 2 trial with a difference in proportions between eptinezumab 100 mg and placebo of 18.2% (95% CI, 11.1 to 25.4; P < 0.0001) and between eptinezumab 300 mg and placebo of 22.1% (95% CI, 14.9 to 29.2; P < 0.0001). These comparisons were statistically significant based on the prespecified sequence of testing.
In the DELIVER trial, the proportion of patients achieving a 75% or greater reduction in MMDs at weeks 1 to 12 was 16% in the eptinezumab 100 mg group, 19% in the eptinezumab 300 mg group, and 2% with placebo, for an odds ratio in the eptinezumab 100 mg group of 9.19 (95% CI, 4.16 to 24.35; P < 0.0001) and in the eptinezumab 300 mg group of 11.43 (95% CI, 5.22 to 30.15; P < 0.0001). These comparisons were statistically significant based on the prespecified sequence of testing. The proportion of patients achieving a 75% or greater reduction in MMDs in weeks 1 to 4 was also reported in PROMISE-1, with a difference in proportions between eptinezumab 100 mg and placebo of 10.5% (95% CI, 2.4 to 18.6; P = 0.0112) and between eptinezumab 300 mg and placebo of 11.3% (95% CI, 3.2 to 19.3; P = 0.0066), both in favour of eptinezumab. These comparisons were statistically significant based on the prespecified sequence of testing. From weeks 1 to 12 in the PROMISE-1 trial, the difference in proportions between eptinezumab 100 mg and placebo was 6.0% (95% CI, −1.4 to 13.3; P = 0.1126) and between eptinezumab 300 mg and placebo was 13.5% (95% CI, 5.8 to 21.2; P = 0.0007). The comparison between eptinezumab 300 mg and placebo was statistically significant based on the prespecified sequence of testing; however, the comparison between eptinezumab 100 mg and placebo was not statistically significant, and this is where the hierarchy failed in the PROMISE-1 trial. The proportion of patients achieving a 75% or greater reduction in MMDs at weeks 1 to 4 was also reported in the PROMISE-2 trial, with a difference in proportions between eptinezumab 100 mg and placebo of 15.3% (95% CI, 9.3 to 21.4) and between eptinezumab 300 mg and placebo of 21.3% (95% CI, 15.0 to 27.6; P < 0.0001). These comparisons were statistically significant based on the prespecified sequence of testing. From weeks 1 to 12, the difference between eptinezumab 100 mg and placebo was 11.7% (95% CI, 5.8 to 17.5; P < 0.0001) and between eptinezumab 300 mg and placebo was 18.1% (95% CI, 12.0 to 24.3; P < 0.0001). These comparisons were statistically significant based on the prespecified sequence of testing.
In the DELIVER trial, the proportion of patients achieving a 100% or greater reduction in MMDs (100% responders) was also reported for weeks 1 to 12 as 5.9% for eptinezumab 100 mg versus 7.7% for eptinezumab 300 mg versus 1.1% for placebo. The number of 100% responders were also reported for weeks 1 to 4 as 9% for eptinezumab 100 mg, 15% for eptinezumab 300 mg, and 6% for placebo in the PROMISE-1 trial, and 8% versus 13% versus 3%, respectively, in the PROMISE-2 trial. The number of 100% responders were reported, with 13% for eptinezumab 100 mg, 16% for eptinezumab 300 mg, and 10% for placebo in weeks 9 to 12 of the PROMISE-1 trial, and 11%, 17%, and 6%, respectively, in the PROMISE-2 trial.
The proportion of patients who had a migraine the first day after dosing was a secondary outcome of the DELIVER trial. From a baseline of ||||| of patients with migraine, on the first day after dosing 27.2% had a migraine in the eptinezumab 100 mg group, while from a baseline of |||||, 24.4% had a migraine the day after dosing in the eptinezumab 300 mg group, and in placebo, from a baseline of |||||, 43.7% had a migraine the first day after dosing. The proportion of patients with a migraine the first day after dosing was a key secondary outcome of the PROMISE trials. In PROMISE-1, from a baseline of 31.0% with migraine, 14.8% of patients had a migraine the day after dosing in the eptinezumab 100 mg group, and from a baseline of 30.8% with migraine, 13.9% had a migraine the day after dosing in the eptinezumab 300 mg group, and in the placebo group, from a baseline of 29.8% with migraine, 22.5% had a migraine the day after dosing. The P values reported by the sponsor were tested after failure of the statistical hierarchy and will not be reported here. In the PROMISE-2 report, from a baseline of 57.5% of patients with migraine, 28.6% had a migraine the day after dosing in the eptinezumab 100 mg group, from a baseline of 57.4% with migraine, 27.8% had migraine the day after dosing in the eptinezumab 300 mg group, and with placebo, from a baseline of 58.0% with migraine, 42.3% had a migraine the day after dosing. The differences between eptinezumab 100 mg and placebo (P < 0.0001) and eptinezumab 300 mg and placebo (P < 0.0001) were statistically significant based on the prespecified sequence of testing.
In the DELIVER trial, the MHD mean ± SE change from baseline to weeks 1 to 12 for eptinezumab 100 mg was −4.6 ± 0.37 (from a baseline of 14.5 ± 5.6), for eptinezumab 300 mg it was −5.1 ± 0.37 (from a baseline mean ± SD of 14.4 ± 5.5), and for placebo it was −2.1 ± 0.38 (from a baseline mean ± SD of 14.5 ± 5.8). The change from baseline in MHD was not part of the MTP; therefore, P values were not reported. In the PROMISE-1 trial, the difference in the mean change from baseline to weeks 1 to 12 in MHD versus placebo for eptinezumab 100 mg was ||||||||||||||||||||| from a baseline mean ± SD of 10.0 ± 3.0, and eptinezumab 300 mg was ||||||||||||||||||||| from a baseline mean ± SD of 10.1 ± 3.1. The change from baseline in MHD was not part of the MTP; therefore, P values were not reported. In the PROMISE-2 trial, the difference in the mean change from baseline to weeks 1 to 12 in MHD versus placebo for eptinezumab 100 mg was −1.7 (95% CI, −2.6 to −0.9) from a baseline mean ± SD of 20.4 ± 3.1 and for eptinezumab 300 mg was −2.3 (95% CI, −3.2 to −1.4) from a baseline mean ± SD of 20.4 ± 3.2. The change from baseline in MHD was not part of the MTP; therefore, P values were not reported.
In weeks 1 to 12 of the DELIVER trials, monthly days using migraine medications was estimated to be reduced by 2.5 days among patients on eptinezumab compared to those on placebo (from a mean ± SD baseline of 11.2 ± 5.5 days) for the 100 mg dose (95% CI, −3.2 to −1.9) and by 3.0 days (from a mean ± SD baseline of 11.0 ± 5.3 days) for the 300 mg dose (95% CI, −3.6 to −2.4). For weeks 13 to 24 in the DELIVER trial, monthly days using migraine medications was estimated to be reduced 2.9 days among patients on eptinezumab compared to those on placebo by for the 100 mg dose (95% CI, −3.6 to −2.2) and by 3.5 days for the 300 mg dose (95% CI, −4.2 to −2.8). These comparisons were not part of the MTP; therefore, P values are not reported here. For weeks 1 to 12 in the PROMISE-1 trial, monthly days using migraine medications was estimated to be reduced by 0.5 days among patients on eptinezumab compared to those on placebo (from a mean ± SD baseline of 1.5 ± 2.6 days) for the 100 mg dose (95% CI, −0.7 to −0.3) and by 0.4 days (from a mean ± SD baseline of 1.6 ± 2.7 days) for the 300 mg dose (95% CI, −0.6 to −0.2). No P values are reported here because this outcome was not part of the MTP. For weeks 1 to 12 in the PROMISE-2 trial, monthly days using migraine medications was estimated to be reduced by 1.2 days among patients on eptinezumab compared to those on placebo (from a mean ± SD baseline of 6.6 ± 6.9 days) for the 100 mg dose (95% CI, −1.7 to −0.7) and by 1.4 days (from a mean ± SD baseline of 6.7 ± 6.5 days) for the 300 mg dose (95% CI, −1.9 to −0.9; P < 0.0001). No P value is reported here for the 100 mg dose in the PROMISE-2 trial because testing was not part of the MTP.
Patient Global Impression of Change (PGIC) scores were reported in the DELIVER trial, and the difference at week 24 versus placebo was |||||||||||||||||||| in the eptinezumab 100 mg group and |||||||||||||||||||| in the eptinezumab 300 mg group. PGIC was not part of the MTP; therefore, P values are not reported here. Improvement in PGIC scores was reported as a binary outcome in the PROMISE-2 trial, with the percentage of patients who were “very much improved” for eptinezumab 100 mg versus eptinezumab 300 mg versus placebo of |||||||||||||, and “much improved” |||||||||||||, respectively. This outcome was not assessed in the PROMISE-1 trial.
In the DELIVER trial, the change from baseline to week 24 in the 5-Level EQ-5D visual analogue scale (EQ-5D-5L VAS) score was estimated to be improved by 4.7 points among patients on eptinezumab compared to those on placebo (from a baseline mean ± SD of 75.9 ± ||||) for the 100 mg dose (95% CI, 1.8 to 7.7) and by 8.0 points (from a baseline mean ± SD of 74.5 ± ||||) for the 300 mg dose (95% CI, 5.1 to 10.8). In the PROMISE-1 trial, the EQ-5D-5L VAS mean (SD) change from baseline to week 24 for eptinezumab 100 mg was ||||||||| and eptinezumab 300 mg was ||||||||| and for placebo was |||||||||. In the PROMISE-2 trial, the EQ-5D-5L VAS mean (SD) change from baseline to week 32 for eptinezumab 100 mg was ||||||||| and eptinezumab 300 mg was ||||||||| and for placebo was |||||||||. Positive changes indicate improvement on this scale.
In the DELIVER trial, for the Migraine-Specific Quality of Life Questionnaire (MSQ), the change from baseline to week 24 in the role function restrictive domain was estimated to be improved by 15.1 points among patients on eptinezumab compared to those on placebo (from a baseline mean ± SD of 35.7 ± ||||) for the 100 mg dose (95% CI, 11.7 to 18.5) and by 15.0 points (from a baseline mean ± SD of 35.7 ± ||||) with the 300 mg dose (95% CI, 11.6 to 18.4). For the MSQ role function preventive domain, the mean change from baseline to week 24 was estimated to be improved by 12.6 points among patients on eptinezumab compared to those on placebo (from a mean ± SD baseline of 50.2 ± ||||) for the 100 mg dose (95% CI, 9.4 to 15.8) and by 13.2 points (from a mean ± SD baseline of 51.0 ± ||||) for the 300 mg dose (95% CI, 10.1 to 16.4). For MSQ emotional function domain, the change from baseline to week 24 was estimated to be improved by 14.1 points among patients on eptinezumab compared to those on placebo (from a mean ± SD baseline of 50.3 ± ||||) for the 100 mg dose (95% CI, 10.5 to 17.7) and by 14.1 points (from a mean ± SD baseline of 48.6 ± ||||) for the 300 mg dose (95% CI, 10.6 to 17.7).
In the DELIVER trial, the mean (SE) change from baseline to week 12 in the HIT-6 score was estimated to be decreased (improved) by −3.8 points among patients on eptinezumab compared to those on placebo (from a mean ± SD baseline of 66.6 ± 4.7) for the 100 mg dose (95% CI, −5.0 to −2.5; P < 0.0001) and by −5.4 points (from a mean ± SD baseline of 66.5 ± 4.4) for the 300 mg dose (95% CI, −6.7 to −4.2; P < 0.0001). In the PROMISE-2 trial, the mean (SE) change from baseline to week 12 in the HIT-6 score was estimated to be decreased (improved) by −1.7 points among patients on eptinezumab compared to those on placebo (from a mean ± SD baseline of 65.0 ± 4.9) for the 100 mg dose (95% CI, −2.8 to −0.7; P < 0.0001) and by −2.9 points (from a mean ± SD baseline of 65.1 ± 5.0) for the 300 mg dose (95% CI, −3.9 to −1.8; P < 0.0001).
In the DELIVER trial, Most Bothersome Symptom (MBS) scores were also reported under symptoms, and the mean (SE) scores at week 24 were estimated to be decreased (improved) among patients on eptinezumab compared to those on placebo by ||||||||||||||||||||||||||| for eptinezumab 100 mg and by ||||||||||||||||||||||||||| for eptinezumab 300 mg. In the PROMISE-2 trial, MBS scores at week 32 were reported as very much improved for ||||||||||||| in the eptinezumab 100 mg, eptinezumab 300 mg, and placebo groups and much improved for |||||||||||||, respectively. HIT-6 and the MBS scores were not assessed in the PROMISE-1 trial.
In the DELIVER trial, for health care resource utilization, the number of patients with no visit to a family physician for eptinezumab 100 mg versus eptinezumab 300 mg versus placebo was |||||||||||||||||||||; those who had no visit to a specialist was |||||||||||||||||||||; and those with no emergency department visits due to migraine was ||||||||||||||||||||| respectively. There were few hospitalizations due to migraine |||| of patients in each group and similar numbers were seen for overnight hospital stays due to migraine.
In the DELIVER trial, the mean (SD) change from baseline to week 24 in absenteeism score on the Work Productivity and Activity Impairment Questionnaire was estimated to be decreased (improved) among patients on eptinezumab compared to those on placebo by −4.5 points (from a mean ± SD baseline of 11.4 ± ||||) for the 100 mg dose (95% CI, −7.8 to −1.1) and by −4.7 points (from a mean ± SD baseline of 12.0 ± ||||) for the 300 mg dose (95% CI, −8.0 to −1.5). Outcomes related to the loss of workdays were not assessed in the PROMISE-1 and PROMISE-2 trials.
There were no deaths in any of the studies.
In the DELIVER trial, AEs were reported by 43%, 41%, and 40% of patients; in the PROMISE-1 trial, by 63%, 58%, and 60% of patients; and in the PROMISE-2 trial by 44%, 52%, and 47% of patients who were randomized to the eptinezumab 100 mg, eptinezumab 300 mg, and placebo groups, respectively.
Serious AEs occurred in 2%, 2%, and 1% of patients in the DELIVER trial; 2%, 1%, and 3% of patients in the PROMISE-1 trial; and less than 1%, 1%, and less than 1% of patients in the PROMISE-2 trial who were randomized to eptinezumab 100 mg, eptinezumab 300 mg, and placebo, respectively. There were no serious AEs that occurred in more than 1 patient.
In the DELIVER trial, treatment stoppages due to an AE occurred in 0.3% of patients in the eptinezumab 100 mg and placebo groups and 2% of patients in the eptinezumab 300 mg group. In the PROMISE-1 trial, 3% of patients in the eptinezumab 100 mg and placebo groups, and 2% in the eptinezumab 300 mg group, stopped treatment due to an AE. In the PROMISE-2 trial there were less than 1% who stopped treatment due to an AE in the eptinezumab 100 mg and placebo groups, and 2% of patients in the eptinezumab 300 mg group.
Notable harms identified by the review team included anaphylaxis or hypersensitivity reactions, antibody formation, cardiovascular events, suicidality, alopecia, and fatigue. The most common notable harms in the DELIVER trial were hypersensitivity and/or anaphylaxis, which occurred in 2% of patients in each of the eptinezumab 100 mg and placebo groups, and 3% of patients in the eptinezumab 300 mg group, and cardio or cerebrovascular disorders, which occurred in 3% of patients in the eptinezumab 100 mg and placebo groups, and 1% of patients in the eptinezumab 300 mg group. All other notable harms occurred in 1% of patients or less, and in the PROMISE-1 and PROMISE-2 trials, notable harms occurred in 1% of patients or less.
Issues related to internal validity included a large number of withdrawals in the PROMISE-1 trial (> 20% across groups) that may have impacted the efficacy and harms results, most notably by changing the mix of baseline characteristics in the study population. According to the sponsor, 94% of patients remained in the study at the time of the 12-week assessment for the primary end point and a number of key secondary outcomes; however, this large number of withdrawals may have impacted the results after week 12, particularly those for harms, and particularly if the patients who already discontinued the study would have been more or less likely to experience harm from continued use of eptinezumab. None of the HRQoL hypothesis testing procedures were controlled for multiplicity in any of the included studies; therefore, any conclusions that can be drawn from these important outcomes are limited as the lack of control for multiple statistical comparisons increases the risk of type I error.
With respect to external validity, none of the included studies featured an active comparator; therefore, any comparisons to other drugs for migraine prophylaxis are indirect and the limitations of these analyses are outlined in the following section. In 2 of the 3 included studies, patients only received 2 doses of eptinezumab, for a total double-blind observation period of 24 weeks. This is not of sufficient duration to adequately assess the durability of response to eptinezumab as well as the long-term harms. Although a longer-term study, PREVAIL, is available, it did not include a control group, which limits any conclusions that can be drawn regarding long-term efficacy or harms.
The sponsor submitted an unpublished NMA that was informed by a systematic literature review to identify all existing RCTs for the treatment of migraine. The NMA aimed to compare eptinezumab with key comparators (erenumab, fremanezumab, galcanezumab, and onabotulinumtoxin A) for the prevention of EM or CM in adults who have experienced an inadequate response, intolerance, or contraindication to at least 2 oral prophylactic migraine medications.
A feasibility assessment was conducted by the manufacturer to assess the suitability of an NMA for the comparison of the identified studies with the DELIVER trial. A total of 11 studies were included in the Bayesian NMA, which evaluated the comparative impact of eptinezumab, key CGRP mAbs, and placebo on efficacy and HRQoL in patients with EM and CM. The characteristics of the trials that reported on anti-CGRPs and onabotulinumtoxin A in EM and CM were assessed for heterogeneity of study characteristics and baseline characteristics. Given the differences in treatment by migraine type, separate analyses were conducted for EM and CM.
The NMA was conducted in a Bayesian framework using fixed-effect models as base-case analyses due to the limited number of studies per comparison. No closed loops were formed in the networks; therefore, it was not possible to assess consistency between the direct and indirect evidence.
The primary analysis of the NMA consisted of comparisons between eptinezumab and anti-CGRPs for EM and CM separately. The outcomes included in the NMA were 50% migraine response rate (MRR), change from baseline in MMDs at 12 weeks, change from baseline in MMDs at 12 weeks with acute medication use, change from baseline in MSQ v2.1 domains (role function restrictive, emotional function, and role function preventive) at 12 weeks, 75% MRR, and change from baseline in HIT-6 score at 12 weeks.
Two secondary analyses were conducted: the first consisted of comparisons with onabotulinumtoxin A for the end points of change from baseline in MMDs and 50% MRR using data from 24 weeks for onabotulinumtoxin A and 12 weeks for eptinezumab due to limited data availability. The other secondary analysis consisted of comparisons with anti-CGRPs, adjusting for the route of administration for change from baseline in MMDs at week 12 given that eptinezumab is the only treatment administered by IV, and may demonstrate greater placebo effects.
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Harms were not evaluated in the sponsor-submitted NMA.
Given the common comparator of placebo in migraine RCTs, the sponsor conducted a Bayesian NMA, which was considered appropriate. The NMA was informed by an adequately conducted systematic literature review that included planned searches of multiple databases, conference proceedings, clinical trial registries, and regulatory and health technology assessment agency websites, which was recently updated to mid-2021.
The CADTH team and the clinical expert consulted by CADTH believed that the methods for the inclusion of studies in the NMA by the sponsor were reasonable but additional sources of heterogeneity were noted, yet not explored in the sponsor’s feasibility analyses, including differences in dosing schedules and time of assessment. Concurrent with the feasibility assessment, the sponsor identified the following potential treatment effect modifiers based on the results of subgroup analyses from the included trials: medication overuse headaches (for patients with CM only), baseline severity (i.e., EM versus CM and baseline MMDs), and number of prior treatment failures. Given the lack of comparability of patients with EM and CM due to differences in migraine frequency and severity, all analyses were separately conducted based on the diagnosis of EM or CM, as well as only including patients with 2 or more prior treatment failures.
Outcomes included in the NMA were relevant to the treatment of both EM and CM in Canada. Outcomes focused on reductions from baseline in migraine frequency (50% and 75% MRR and change from baseline in MMDs [with use of acute medication]) and HRQoL (MSQ v2.1 domains and HIT-6 score). No outcomes related to safety were evaluated; thus, the comparative safety of eptinezumab and other CGRP mAbs remains unknown.
The NMA was conducted within a Bayesian framework using fixed effects for all efficacy outcomes. Generation of model statistics (i.e., deviance information criterion) for model selection were performed, though the results were not reported. Also, based on the lack of available data, only arm-level data were used for comparisons. Given the absolute outcome measures examined in the analyses, this was considered appropriate; however, arm-based models do not preserve randomization, hence comparative estimates are at a greater risk of bias in relative treatment effects.
While some NMAs suggested that eptinezumab is favoured when compared with erenumab and galcanezumab for certain outcomes (i.e., 50% MRR and change from baseline in MMDs) it is worth noting that the results are produced using fixed-effect models, and it is uncertain if the fixed-effect model is the appropriate model to use in these comparisons due to lack of reporting of Deviance Information Criterion. As a result, superiority of eptinezumab compared with erenumab and galcanezumab cannot be concluded. Moreover, in all fixed-effects analyses, results were associated with wide 95% credible intervals, with most estimates crossing the threshold of no effect, resulting in notable imprecision in the results. Results for random-effects analyses for the 2 main outcomes were generally associated with even wider 95% credible intervals.
One open-label, phase III study, PREVAIL, was summarized to provide additional information on the long-term safety and efficacy of repeated quarterly administered IV infusions of eptinezumab in patients with CM for the preventive treatment of CM.
The open-label, phase III study, PREVAIL, was conducted to evaluate the long-term safety of up to 8 IV infusions of eptinezumab 300 mg administered at 12-week intervals in 128 adult patients with CM for up to 84 weeks of treatment. The secondary objective was to evaluate the efficacy of eptinezumab by assessing its impact on patient-reported outcomes. The inclusion and exclusion criteria were generally consistent with the pivotal PROMISE-2 clinical trial. Patients were eligible to enrol into the PREVAIL trial if they were diagnosed with migraine at 50 years or younger and had a history of CM for 1 or more year before screening. The duration of the study was 106 weeks, which included a 2-week screening period, 48-week primary treatment period, 36-week secondary treatment period, and 20-week follow-up period. In each treatment period, patients received 4 IV infusions of eptinezumab every 12 weeks; only patients who received all 4 infusions in the primary treatment period were permitted to enter the secondary treatment period. Patients were evaluated at day 0; weeks 2, 4, 8, and 12; and every 12 weeks thereafter. Patients who failed to receive all 4 infusions of eptinezumab in the primary treatment period or did not provide consent for participation in the secondary treatment period were followed-up at weeks 48 and 56.
The mean age of patients in the PREVAIL trial was 41.5 years (SD = 11.33). The majority of patients were female (85.2%) and White (95.3%). The mean duration of migraine diagnosis at baseline was 21.2 years (SD = 11.65). The patient-reported mean number of headache days, migraine days, and migraine attacks per 28-day period in the 3 months before screening was 20.3 days (SD = 3.68), 14.1 days (SD = 4.25), and 10.5 days (SD = 4.29), respectively.
A total of 128 patients were enrolled in the PREVAIL trial and all patients received at least 1 dose of eptinezumab (i.e., the safety population). A total of 22 patients (17.2%) prematurely discontinued the study with the most common reason being withdrawal by patient in (18 patients;14.1%). Overall, 100 patients (78.1%) completed the study (week 104). A total of 86 patients (67.2%) received a total of 8 doses of the study drug. The concomitant use of at least 1 acute and 1 prophylactic treatment for headaches was reported in 127 patients (99.2%) and 46 patients (35.9%), respectively.
For EQ-5D-5L VAS, the mean scores at baseline and week 48 were ||||||||||||| and |||||||||||||, respectively, demonstrating improvement (n = 114).
For HIT-6, the mean total score at baseline and week 101 to 104 were 65.2 (SD = 4.76) and 56.1 (SD = 9.07), respectively, demonstrating improvement (n = 96).
At baseline, the MBS reported were sensitivity to light in 31 patients (24.2%), nausea in 14 patients (10.9%), sensitivity to sound in 10 patients (7.8%), pain with activity in 10 patients (7.8%), mental cloudiness in 4 patients (3.1%), vomiting in 2 patients (1.6%), mood changes in 2 patients (1.6%), and other symptom in 55 patients (43.0%). Most patients reported “very much improved” (35.7%) or “much improved” (39.3%) at week 48 relative to baseline (n = 112). “No change” was reported by 11 patients (9.8%). No patients reported “minimally worse,” “much worse,” or “very much worse” at week 48 relative to baseline.
For the PGIC, most patients reported “very much improved” (49.0%) or “much improved” (34.4%) at week 104 relative to baseline (n = 96). “No change” was reported by 5 patients (5.2%). No patients reported “minimally worse,” “much worse,” or “very much worse” at week 104 relative to baseline.
A total of 91 patients (71.1%) reported at least 1 treatment-emergent AE (TEAE), with the most common event being nasopharyngitis in 18 patients (14.1%). A total of 5 (3.9%) patients reported at least 1 serious TEAE; no single event was reported in more than 1 patient (< 1%). A total of 8 patients (6.3%) reported any TEAE that led to study drug withdrawal, of which 3 patients (2.3%) reported study drug withdrawal due to hypersensitivity. No other single event was reported in more than 1 patient (1%). No deaths were reported for the duration of the study. For notable TEAEs, hypersensitivity was reported in 5 patients (3.9%), hypertension was reported in 2 patients (1.6%), and anaphylactic reaction, hypotension, and deep vein thrombosis were reported in 1 patient (< 1%) each.
In the absence of an active comparator or placebo group, interpretation of the safety and efficacy results from the open-label study, PREVAIL, is limited. This interpretation may be further limited by the missing data in patient-reported outcomes at week 104, and only 86 patients (67.2%) received a total of all 8 doses of eptinezumab. The open-label study design can bias the reporting of end points, particularly in any subjective measures included in the efficacy and safety parameters due to the unblinding of the study drug during the treatment period; however, the direction and magnitude of the bias is uncertain. Of note, 28 patients (21.9%) had participated in a prior clinical trial of eptinezumab. These patients were eligible to enrol if they had not experienced any clinically significant AEs related to the study drug during the previous study as determined by the investigator. Consequently, these patients may be more tolerant to eptinezumab, and their inclusion may result in lower AE rates than would be expected in a nonselected population.
The baseline characteristics in patients with CM in the PREVAIL study were generally consistent with the baseline characteristics in the PROMISE-2 study, which also included patients with CM. The clinical expert consulted by CADTH for this review estimated that at least 80% of patients who present with migraines in clinical practice are female; 109 patients (85.2%) were female in the PREVAIL trial. Only eptinezumab 300 mg was evaluated in the PREVAIL trial; therefore, the generalizability of the safety and efficacy results in the open-label study to eptinezumab 100 mg is limited.
Table 3: Cost and Cost-Effectiveness
Component | Description |
|---|---|
Type of economic evaluation | Cost-utility analysis 12-week decision tree followed by Markov model |
Target population | Deviation from the Health Canada indication: Adult patients who have at least 4 migraine days per month and have failed 2 or more prior preventive treatments, in 2 populations:
|
Treatments | Eptinezumab 100 mg Eptinezumab 300 mg |
Dose regimen | 100 mg or 300 mg every 12 weeks |
Submitted price | Eptinezumab, 100 mg/mL solution vial: $1,665.00 per single-use vial |
Treatment cost | Annual cost of $7,240 to $21,720 for the 100 mg or 300 mg dose, assumes linear pricing for the 300 mg dose |
Comparators | Fremanezumab 225 mg Fremanezumab 675 mg Galcanezumab 120 mg |
Perspective | Canadian publicly funded health care payer |
Outcomes | QALYs, LYs |
Time horizon | 5.1 years (66 cycles, including the initial 12-week decision tree) |
Key data source | Clinical efficacy of eptinezumab: DELIVER, a phase III, double-blind, placebo-controlled trial with a 48-week dose-blinded extension. Comparative clinical efficacy data were derived from a sponsor-submitted NMA to inform the odds of achieving a ≥ 50% reduction in MMDs over weeks 1 to 12. |
Key limitations |
|
CADTH reanalysis results |
|
CM = chronic migraine; CGRP = calcitonin gene-related peptides; EM = episodic migraine; LY = life-year; MMDs = monthly migraine days; NMA = network meta-analysis; QALY = quality-adjusted life-year; vs. = versus.
CADTH identified the following key limitations with the sponsor’s budget impact analysis: the market share of onabotulinumtoxin A may be underestimated, which was explored in a scenario analysis. Results of the sponsor’s base case suggest that the reimbursement of eptinezumab for the prevention of migraine in adults who have had at least 4 migraine days per month and have experienced inadequate response, intolerance, or contraindication to at least 2 oral prophylactic migraine medications is associated with an incremental cost of $961,199 in year 1, $4,169,910 in year 2, and $7,061,793 in year 3. Therefore, the cumulative incremental budget impact over 3 years is expected to be $12,192,901. CADTH’s scenario analyses suggest that the impact of reimbursing eptinezumab is highly sensitive to the eptinezumab drug cost. In a scenario analysis that assumed flat pricing for both the 100 mg and 300 mg doses of eptinezumab that was no greater than the lowest-cost reimbursed anti-CGRP comparator, the estimated incremental 3-year budget impact was −$237,734. The budget impact of reimbursing eptinezumab for the full Health Canada population remains unknown.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Mr. Morris Joseph, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed.
Meeting date: October 27, 2022
Regrets: One expert committee member did not attend.
Conflicts of interest: None
ISSN: 2563-6596
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