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PROMISE-2

Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-2

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Year of Publication: 2020

Authors: Richard B. Lipton, Peter J. Goadsby, Jeff Smith, ..., Roger Cady

Journal: Neurology

Citation: Neurology. 2020;94:e1365-e1377. doi:10.1212/WNL.0000000000009169

Link: https://pubmed.ncbi.nlm.nih.gov/32209650/

PDF: https://pmc.ncbi.nlm.nih.gov/articles/PM...Y2019981969.pdf

Clinical Question

Does intravenous eptinezumab, a humanized anti-CGRP monoclonal antibody, demonstrate efficacy and safety in the preventive treatment of chronic migraine compared to placebo?

Study Overview

Objective

Eptinezumab - To evaluate the efficacy and safety of intravenous eptinezumab in the preventive treatment of chronic migraine (CM).

Study Summary

Eptinezumab significantly reduced monthly migraine days (MMDs) compared to placebo.
Effect was observed as early as Day 1 post-infusion.
Well tolerated with a favorable safety profile.

Intervention

Phase 3, randomized, double-blind, placebo-controlled, parallel-group study. 1,121 adults with chronic migraine were randomized (1,072 treated and included in the safety/full analysis populations) to receive IV eptinezumab 100 mg, 300 mg, or placebo at Day 0 and Week 12. Primary endpoint: change in MMDs over Weeks 1–12.

Patients per Arm

100 mg: 356; 300 mg: 350; Placebo: 366

Bottom Line

In patients with chronic migraine, intravenous eptinezumab 100 mg and 300 mg demonstrated significant reduction in monthly migraine days from the day after IV administration through week 12, was well tolerated, and had an acceptable safety profile with preventive effects observed as early as day 1 after administration

        Major Points
        First phase 3 trial evaluating IV eptinezumab (anti-CGRP mAb) for chronic migraine prevention
Both doses achieved primary endpoint: significant reduction in MMDs over weeks 1-12 (100 mg: -7.7 days, 300 mg: -8.2 days vs placebo -5.6 days, p<0.0001)
Rapid onset of action: preventive effect observed on day 1 after first IV administration with >50% reduction in migraine incidence
Day 1 migraine prevalence: 28.6% (100 mg) and 27.8% (300 mg) vs 42.3% (placebo), p<0.0001 for both doses
High responder rates: ≥75% responder rate at weeks 1-12 was 26.7% (100 mg) and 33.1% (300 mg) vs 15.0% (placebo)
≥50% responder rate weeks 1-12: 57.6% (100 mg) and 61.4% (300 mg) vs 39.3% (placebo), p<0.0001
Significant reduction in acute medication use: 100 mg -3.3 days, 300 mg -3.5 days vs placebo -1.9 days (p<0.0001 for 300 mg)
Significant improvement in HIT-6 scores at week 12: 300 mg -2.9 difference from placebo (p<0.0001)
Well-tolerated safety profile: TEAEs similar across groups (100 mg 43.5%, 300 mg 52.0%, placebo 46.7%)
93.6% of patients completed study through week 12; 95.5% of 100 mg and 96.6% of 300 mg patients received both doses

      

Design

Study Type: Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study

Randomization: 1

Blinding: Double-blind; patients, investigators, clinicians, and all research personnel remained blinded throughout study; assignment concealed; investigational product administered by blinded investigator

Enrollment Period: November 30, 2016 to April 20, 2018

Follow-up Duration: 32 weeks total (28-day screening, dosing on day 0 and week 12, eDiary through week 24, safety follow-up visit at week 32); primary efficacy period through week 12

Centers: 128

Countries: United States, Spain, Ukraine, Russian Federation, United Kingdom, Republic of Georgia, Hungary, Italy, Slovakia, Germany, Czech Republic, Denmark, Belgium

Sample Size: 1072

Analysis: Full analysis set (FAS) and safety analysis set (SAF) included all randomized patients receiving ≥1 dose; patients analyzed by randomized treatment in FAS, by actual treatment received in SAF; serial procedure for multiplicity using Holm procedure within endpoint groups; ANCOVA model for primary endpoint with treatment and stratification factors; Cochran-Mantel-Haenszel tests for responder endpoints; stratification by MMD (≤17 vs >17) and prior preventive use (yes vs no); power 90% for 350 patients per group assuming treatment effect ≥1 day and SD ≤4 days; SAS version 9.2 or higher used for analyses

Inclusion Criteria

Adults 18-65 years of age (inclusive)
Diagnosis of migraine at or before 50 years of age
History of chronic migraine for ≥12 months before screening per ICHD-3 criteria
Completed headache eDiary on ≥24 of 28 days during screening period before randomization
Experienced ≥15 to ≤26 headache days during 28-day screening period
Experienced ≥8 migraine days during 28-day screening period
If using prescription or over-the-counter acute or preventive migraine medication: medications prescribed/recommended by healthcare professional
If using preventive migraine medication: stable for ≥3 months before screening
If using hormonal therapy (contraceptive, hormone replacement): stable and ongoing ≥3 months before screening
If using barbiturates or prescription opioids: ≤4 days/month, stable for ≥2 months before screening, maintained through week 24
Patients with CM and medication-overuse headache eligible except for overuse of barbiturates or opioids

Exclusion Criteria

Confounding pain disorder or clinically significant pain syndromes
Uncontrolled or untreated psychiatric conditions
Acute or active temporomandibular disorders
History or diagnosis of headache/migraine disorders not meeting ICHD-3 beta Section 1.3 criteria for CM
Present or previous malignancies (except squamous/basal cell carcinoma with excision for cure or breast/cervical cancer ≥10 years since diagnosis without recurrence)
Any active, progressive, or unstable cardiovascular, neurologic, or autoimmune disorder
Newly diagnosed or uncontrolled hypertension (mild primary hypertension well controlled for ≥6 months allowed)
History or evidence of substance abuse or dependence
Clinically significant abnormal ECG findings
Concurrent medical condition or laboratory abnormality during screening or before day 0 dosing
Body mass index ≥39 kg/m²
Recent or planned surgery requiring general anesthesia within 8 weeks before screening or during study
Experimental/unregistered therapy within 30 days or 5 plasma half-lives before screening
Prohibited devices, neuromodulation, neurostimulation, or injectable therapy within 2 months before screening or during screening
Botulinum toxin (any type) for migraine or cosmetic reasons within 4 months before screening or during screening
Monoamine oxidase inhibitors, ketamine, methylergonovine, or nimesulide within 3 months before screening or during screening
Any monoclonal antibody treatment within 6 months of screening
Prior eptinezumab or any monoclonal antibody targeting CGRP pathway
Women who were pregnant, breastfeeding, or planning pregnancy during study
Participating in any other clinical study
Positive for HIV, hepatitis B surface antigen, or hepatitis C

Baseline Characteristics

Eptinezumab 100 mg:

Sample size: 356
Age (years): 41.0 ± 11.7
Female (%): 86.2
White (%): 93.3
Hispanic or Latino (%): 9.3
Weight (kg): 73.3 ± 15.6
Height (cm): 166.2 ± 8.2
BMI (kg/m²): 26.4 ± 5.0
Age at migraine diagnosis (years): 22.8 ± 10.6
Duration of migraine diagnosis (years): 18.3 ± 12.2
Duration of CM (years): 11.6 ± 11.7
Headache days/month: 20.4 ± 3.1
Migraine days/month: 16.1 ± 4.6
Medication-overuse headache diagnosis (%): 39.0
Triptan use ≥33% of days (%): 34.8
Opioid or barbiturate use at any time (%): 12.9

Eptinezumab 300 mg:

Sample size: 350
Age (years): 41.0 ± 10.4
Female (%): 89.7
White (%): 92.0
Hispanic or Latino (%): 5.1
Weight (kg): 72.7 ± 15.3
Height (cm): 166.1 ± 7.9
BMI (kg/m²): 26.2 ± 5.0
Age at migraine diagnosis (years): 22.0 ± 9.3
Duration of migraine diagnosis (years): 19.0 ± 11.5
Duration of CM (years): 12.4 ± 11.2
Headache days/month: 20.4 ± 3.2
Migraine days/month: 16.1 ± 4.8
Medication-overuse headache diagnosis (%): 42.0
Triptan use ≥33% of days (%): 35.7
Opioid or barbiturate use at any time (%): 11.1

Placebo:

Sample size: 366
Age (years): 39.6 ± 11.3
Female (%): 88.8
White (%): 87.7
Hispanic or Latino (%): 9.6
Weight (kg): 74.8 ± 16.2
Height (cm): 166.3 ± 7.9
BMI (kg/m²): 27.0 ± 5.6
Age at migraine diagnosis (years): 22.6 ± 10.0
Duration of migraine diagnosis (years): 17.0 ± 11.6
Duration of CM (years): 11.6 ± 10.9
Headache days/month: 20.6 ± 2.99
Migraine days/month: 16.2 ± 4.6
Medication-overuse headache diagnosis (%): 39.6
Triptan use ≥33% of days (%): 31.7
Opioid or barbiturate use at any time (%): 13.1

Arms

Field	Eptinezumab 100 mg IV	Eptinezumab 300 mg IV	Control
Intervention	Eptinezumab 100 mg IV administered over 30 minutes (plus additional 15 minutes if required per protocol) on day 0 and week 12; reconstituted in total volume of 100 mL 0.9% saline; supplied as single-use, preservative-free solution shipped frozen on dry ice in tamper-proof 2-mL type I glass vials; patients monitored for ≥2 hours after treatment	Eptinezumab 300 mg IV administered over 30 minutes (plus additional 15 minutes if required per protocol) on day 0 and week 12; reconstituted in total volume of 100 mL 0.9% saline; supplied as single-use, preservative-free solution shipped frozen on dry ice in tamper-proof glass vials; patients monitored for ≥2 hours after treatment	Matching placebo IV administered over 30 minutes (plus additional 15 minutes if required per protocol) on day 0 and week 12; reconstituted in total volume of 100 mL 0.9% saline; supplied in identical vials to active drug; patients monitored for ≥2 hours after treatment
Duration	24 weeks (with dosing on day 0 and week 12)	24 weeks (with dosing on day 0 and week 12)	24 weeks (with dosing on day 0 and week 12)

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Change from baseline in mean monthly migraine days (MMDs) over weeks 1 to 12, assessed with electronic diary (eDiary) data; migraine day defined using ICHD-3 criteria (lasted ≥4 hours or 30 min-4 hours relieved by acute medication; ≥2 pain features: unilateral, pulsating, moderate/severe intensity, aggravation by physical activity; ≥1 associated symptom: nausea/vomiting or photophobia and phonophobia)	Primary	Mean -5.6 days (from 16.2 to 10.5 days)	100 mg: Mean -7.7 days (from 16.1 to 8.5 days); 300 mg: Mean -8.2 days (from 16.1 to 7.9 days)		100 mg: <0.0001; 300 mg: <0.0001
≥75% migraine responder rate over weeks 1-4	Secondary	57/366 (15.6%)	100 mg: 110/356 (30.9%); 300 mg: 129/350 (36.9%)	100 mg: OR 2.4 (95% CI 1.7-3.5), difference 15.3% (9.3-21.4); 300 mg: OR 3.2 (95% CI 2.2-4.6), difference 21.3% (15.0-27.6)	<0.0001 for both doses
≥75% migraine responder rate over weeks 1-12	Secondary	55/366 (15.0%)	100 mg: 95/356 (26.7%); 300 mg: 116/350 (33.1%)	100 mg: OR 2.0 (95% CI 1.4-3.0), difference 11.7% (5.8-17.5); 300 mg: OR 2.8 (95% CI 1.9-4.0), difference 18.1% (12.0-24.3)	100 mg: 0.0001; 300 mg: <0.0001
≥50% migraine responder rate over weeks 1-12	Secondary	144/366 (39.3%)	100 mg: 205/356 (57.6%); 300 mg: 215/350 (61.4%)	100 mg: OR 2.1 (95% CI 1.6-2.8), difference 18.2% (11.1-25.4); 300 mg: OR 2.4 (95% CI 1.8-3.3), difference 22.1% (14.9-29.2)	<0.0001 for both doses
Percentage of patients with migraine on day 1 after dosing	Secondary	42.3%	100 mg: 28.6%; 300 mg: 27.8%		<0.0001 for both doses vs placebo
Change from baseline in average daily percentage of patients with migraine over weeks 1-4	Secondary	Mean -18.8% (from 58% baseline)	100 mg: Mean -27.1%; 300 mg: Mean -29.8%	100 mg: difference -8.3% (-11.5 to -5.0); 300 mg: difference -11.0% (-14.2 to -7.8)	<0.0001 for both doses
Change in HIT-6 total score from baseline to week 12	Secondary	Mean -4.5 (from 64.8 to 60.5)	100 mg: Mean -6.2 (from 65.0 to 58.8); 300 mg: Mean -7.3 (from 65.1 to 57.6)	100 mg: difference -1.7 (-2.8 to -0.7); 300 mg: difference -2.9 (-3.9 to -1.8)	100 mg: 0.0010 (nominally significant); 300 mg: <0.0001
Change in acute migraine medication use days from baseline to weeks 1-12	Secondary	Mean change -1.9 days (actual weeks 1-12 mean 4.3 days)	100 mg: Mean change -3.3 days (actual weeks 1-12 mean 3.3 days); 300 mg: Mean change -3.5 days (actual weeks 1-12 mean 3.2 days)	100 mg: difference -1.2 (-1.7 to -0.6); 300 mg: difference -1.4 (-1.9 to -0.9)	100 mg: <0.0001 (not formally tested); 300 mg: <0.0001
Change in mean headache days over weeks 1-12	Secondary	Mean -6.4 days (from 20.6 to 14.1 days)	100 mg: Mean -8.2 days (from 20.4 to 12.2 days); 300 mg: Mean -8.8 days (from 20.4 to 11.7 days)	100 mg: difference -1.7 (-2.6 to -0.9); 300 mg: difference -2.3 (-3.2 to -1.4)	Not specified for this exploratory endpoint
HIT-6 scores in severe range at week 12	Secondary	60.1% at week 12 (from 87.4% at baseline)	100 mg: 51.4% at week 12 (from 89.6% at baseline); 300 mg: 42.9% at week 12 (from 88.6% at baseline)
Any treatment-emergent AE	Adverse	171/366 (46.7%)	100 mg: 155/356 (43.5%); 300 mg: 182/350 (52.0%)
Study drug-related TEAEs	Adverse	29/366 (7.9%)	Combined eptinezumab groups: 93/706 (13.2%); no 100 mg- or 300 mg-specific value reported
Nasopharyngitis	Adverse	22/366 (6.0%)	100 mg: 19/356 (5.3%); 300 mg: 33/350 (9.4%)	Only TEAE reported >2% in eptinezumab-treated patients at incidence >2% over placebo
Upper respiratory tract infection	Adverse	20/366 (5.5%)	100 mg: 15/356 (4.2%); 300 mg: 19/350 (5.4%)
Sinusitis	Adverse	15/366 (4.1%)	100 mg: 7/356 (2.0%); 300 mg: 9/350 (2.6%)
Migraine	Adverse	16/366 (4.4%)	100 mg: 6/356 (1.7%); 300 mg: 8/350 (2.3%)
Urinary tract infection	Adverse	6/366 (1.6%)	100 mg: 8/356 (2.2%); 300 mg: 12/350 (3.4%)
Nausea	Adverse	7/366 (1.9%)	100 mg: 6/356 (1.7%); 300 mg: 12/350 (3.4%)	Study drug-related: 100 mg + 300 mg: 11 (1.6%), placebo: 1 (<1%)
Fatigue	Adverse	7/366 (1.9%)	100 mg: 8/356 (2.2%); 300 mg: 6/350 (1.7%)	Study drug-related: 100 mg + 300 mg: 13 (1.8%), placebo: 3 (<1%)
Serious adverse events	Adverse	3/366 (<1%)	100 mg + 300 mg: 7/706 (<1%)	Most frequent: nervous system disorders, injury/poisoning/procedural complications, psychiatric disorders
Study drug-related serious AE	Adverse	0	1 patient (300 mg): worsening migrainous visual phenomena, 126 days after second dose, lasted 4 days
Life-threatening serious AEs	Adverse	0	0
Deaths	Adverse	0	0
TEAEs leading to study drug withdrawal	Adverse	2/366 (<1%)	100 mg: 3/356 (<1%); 300 mg: 8/350 (2.3%)	Total: 13/1072 (1.2%)
Hypersensitivity leading to withdrawal	Adverse	0	300 mg: 6/350 (1.7%); all mild-moderate, treatment-day events, resolved same day or within 2 days	3 after first dose, 3 after second dose
Seizure (SAE)	Adverse	0	1 patient (300 mg): required hospitalization, assessed as not study drug-related, resolved same day
AEs of special interest	Adverse	Occurred in <1% of total group	Occurred in <1% of total group	Included: Columbia-Suicide Severity Rating Scale-associated AEs, cardiovascular AEs, hepatic AEs, hypersensitivity and anaphylaxis AEs
Anti-drug antibodies (ADAs) at week 24	Adverse	Not applicable	100 mg: 56/326 (17.2%); 300 mg: 56/329 (17.0%); declined by week 32	No clear dose-response trend; did not affect efficacy or safety
ADAs with neutralizing potential (NAbs)	Adverse	Not applicable	100 mg: 26 patients; 300 mg: 19 patients; 24/112 (21.4%) of ADA-positive patients at week 24 were NAb-positive	No impact on efficacy or safety

Subgroup Analysis

Post hoc analysis in patients with no barbiturate or opioid use at any time showed similar MMD reduction compared to placebo (100 mg -2.3 [-3.2 to -1.4], p<0.0001; 300 mg -2.8 [-3.7 to -1.9], p<0.0001)

Criticisms

High placebo response rate (5.6-day reduction) attributed to novelty of treatment, IV administration, multiple active treatment arms increasing expectations, high percentage of preventive-naïve patients, and intensive patient contact with migraine experts
Excluded patients with significant cardiovascular disease or clinically significant concurrent medical conditions, limiting generalizability to these populations
Excluded patients with >26 headache days during screening period, limiting applicability to most severe CM patients
Excluded patients with history of significant opioid (≥5 d/mo) or barbiturate use, limiting applicability to regions with high opioid prescribing patterns
Single ethnicity dominance: 91.0% White, 8.0% Hispanic/Latino, limiting generalizability to other ethnic groups
Industry-sponsored trial (H. Lundbeck A/S) with multiple authors as employees or with financial relationships
Relatively short follow-up for primary endpoint (12 weeks) though study continued to 32 weeks
No direct comparison to other approved preventive treatments for CM (e.g., onabotulinumtoxinA, other CGRP mAbs)
40.2% of patients had medication-overuse headache at baseline; results may differ in non-MOH CM population
Serial testing procedure controlled for multiplicity but some secondary endpoints (e.g., 100 mg HIT-6) nominally significant but not formally tested
Formation of ADAs observed (peak 17% at week 24) though no impact on efficacy or safety demonstrated; long-term immunogenicity unknown
IV administration requires healthcare setting and monitoring, less convenient than subcutaneous or oral preventives

Funding

H. Lundbeck A/S (Copenhagen, Denmark)

Based on: PROMISE-2 (Neurology, 2020)