Neurology March 31, 2020

Efficacy and safety of eptinezumab in patients with chronic migraine: PROMISE-2

Richard B Lipton, Peter J Goadsby, Jeff Smith, Barbara A Schaeffler, David M Biondi, Joe Hirman, Susan Pederson, Brent Allan, Roger Cady

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Bottom Line

In patients with chronic migraine, intravenous eptinezumab rapidly and significantly reduced mean monthly migraine days compared to placebo over 12 weeks, demonstrating an acceptable safety profile.

Key Findings

1. Baseline mean monthly migraine days (MMDs) were approximately 16.1 across all groups.

2. Eptinezumab 100 mg significantly reduced MMDs by 7.7 days across weeks 1 to 12, compared with a 5.6-day reduction for placebo (p < 0.0001).

3. Eptinezumab 300 mg significantly reduced MMDs by 8.2 days across weeks 1 to 12, compared with the 5.6-day reduction for placebo (p < 0.0001).

4. Treatment-emergent adverse events (TEAEs) were comparable across the groups: 43.5% in the 100 mg arm, 52.0% in the 300 mg arm, and 46.7% in the placebo arm.

5. Nasopharyngitis was the only TEAE reported for >2% of eptinezumab-treated patients at an incidence >2% over placebo (9.4% in the 300 mg eptinezumab arm vs. 6.0% in the placebo arm).

Study Design

Design

RCT

Double-Blind

Sample

1,072

Patients

Duration

12 wk

Median

Setting

Multicenter

Population Adults 18-65 years old with chronic migraine (headaches on >=15 days/month for >=3 months, with >=8 days/month meeting criteria for migraine).

Intervention Intravenous eptinezumab 100 mg or 300 mg administered on day 0 and week 12.

Comparator Intravenous placebo administered on day 0 and week 12.

Outcome Change from baseline in mean monthly migraine days (MMDs) over weeks 1 to 12.

Study Limitations

• The 12-week primary efficacy endpoint period was relatively short for evaluating long-term durability of effect and safety, though long-term extension data was collected subsequently.

• The trial excluded patients with continuous unremitting headache (zero pain-free days).

• The trial excluded patients with recent cardiovascular or cerebrovascular disease, limiting safety generalizability in higher-risk populations.

• The study population lacked racial and ethnic diversity, as it was predominantly Caucasian.

Clinical Significance

The PROMISE-2 trial established intravenous eptinezumab as a highly effective, rapid-acting preventive therapy for chronic migraine. Because it is administered intravenously, it provides immediate peak plasma concentrations, offering a rapid onset of prevention that differentiates it pharmacokinetically from subcutaneously administered CGRP-targeting monoclonal antibodies. Significant reductions in migraine days were observed as early as the day after the first infusion, alongside a highly acceptable tolerability profile.

Historical Context

At the time of PROMISE-2's publication, several CGRP pathway-targeting monoclonal antibodies had recently revolutionized migraine prophylaxis. However, they were all formulated for subcutaneous injection, which can take several days to reach maximal concentration. Eptinezumab was developed as the first intravenous anti-CGRP monoclonal antibody, hypothesized to provide a faster onset of preventive benefit due to immediate 100% bioavailability. PROMISE-2 successfully demonstrated this rapid and sustained clinical utility in the chronic migraine population, directly supporting its FDA approval (as Vyepti) in early 2020.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the mechanism of action of eptinezumab, and how does its intravenous route of administration theoretically contribute to the rapid onset of action observed in the PROMISE-2 trial?

Key Response

Eptinezumab is a monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) ligand, blocking its attachment to the receptor. Unlike subcutaneous CGRP inhibitors that require days to weeks for peak absorption, the intravenous formulation provides 100% immediate bioavailability, explaining the significant reduction in migraine days as early as Day 1 after infusion.

Resident

When considering prophylactic therapy for a patient with chronic migraine, what specific clinical scenarios would make quarterly IV eptinezumab a preferred option over daily oral preventative medications or monthly subcutaneous CGRP monoclonal antibodies?

Key Response

Eptinezumab is ideal for patients with severe adherence issues to daily oral medications, those who are needle-phobic and unwilling to perform self-injections but accept clinical infusions, or those with severe, debilitating chronic migraine who require a very rapid onset of efficacy rather than waiting for the gradual titration or absorption of other therapies.

Fellow

The PROMISE-2 trial included a subset of patients with concurrent medication overuse headache (MOH). How does the presence of MOH typically complicate chronic migraine management, and what is the significance of eptinezumab's efficacy in this specific subpopulation?

Key Response

MOH traditionally renders standard oral prophylactic medications ineffective and historically required a challenging medication withdrawal/detox phase before preventives could work. The finding that CGRP monoclonal antibodies like eptinezumab are effective even in the setting of MOH, without mandating prior withdrawal of the overused acute medication, represents a major paradigm shift in treating refractory chronic migraine.

Attending

Considering the logistical requirements of an IV infusion center, how do we justify the health system costs and resource utilization of eptinezumab compared to self-administered subcutaneous CGRP inhibitors in clinical practice?

Key Response

The decision requires weighing the rapid clinical benefit and guaranteed medication compliance (since it is administered by a healthcare professional) against the high infrastructure costs, infusion chair time, and nursing resources. It necessitates careful patient selection, emphasizing value-based care by reserving IV therapy for patients who have failed SC therapies or require immediate intervention.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The PROMISE-2 trial evaluated efficacy over a 12-week primary endpoint utilizing a mixed-model repeated-measures (MMRM) analysis. What are the statistical advantages and potential biases of using MMRM in headache trials with high day-to-day variance, and how might missing data handling affect the robustness of the Day 1 onset claims?

Key Response

MMRM elegantly accounts for intra-subject correlation over time and handles missing-at-random data well without requiring strict imputation like Last Observation Carried Forward (LOCF). However, if early dropouts occur due to lack of immediate efficacy or adverse events (missing not at random), MMRM might overestimate the sustained treatment effect. Evaluating the exact missingness mechanism is crucial for validating early onset efficacy claims.

Journal Editor

Given the robust placebo response commonly seen in migraine prophylaxis trials, particularly with invasive delivery methods like IV infusions, did the PROMISE-2 study adequately blind the infusion process, and how might the expectancy effect of an IV therapy inflate both the placebo and treatment arm responses?

Key Response

IV therapies inherently generate higher placebo responses than oral pills due to the medicalization and ritual of an infusion. A critical reviewer must scrutinize the placebo subtraction margin, evaluate the specific protocols used to mask the infusion (e.g., volume, color, infusion time), and assess whether a high baseline placebo response obscures smaller, yet clinically meaningful, secondary efficacy endpoints.

Guideline Committee

Based on the PROMISE-2 results, should clinical practice guidelines (such as the American Headache Society consensus statement) elevate eptinezumab to a first-line therapy for chronic migraine, or should it remain restricted to patients who have failed prior standard oral therapies?

Key Response

While PROMISE-2 provides Level A evidence for eptinezumab's efficacy and safety, current AHS guidelines recommend CGRP mAbs generally after the failure of at least two traditional oral preventives (e.g., topiramate, amitriptyline) largely due to cost and access constraints. The committee must debate whether the rapid onset and high efficacy justify modifying the step-therapy algorithm to allow earlier access for severe chronic migraine cases.

Clinical Landscape

Noteworthy Related Trials

2017

HALO CM Trial

n = 1130 · NEJM

Tested

Fremanezumab quarterly or monthly SC

Population

Adults with chronic migraine

Comparator

Placebo

Endpoint

Change in baseline monthly headache days of moderate severity or greater

Key result: Fremanezumab as both a quarterly and monthly regimen resulted in a significantly lower frequency of headache days than placebo.

2018

REGAIN Trial

n = 1113 · Neurology

Tested

Galcanezumab 120mg or 240mg monthly SC

Population

Adults with chronic migraine

Comparator

Placebo

Endpoint

Mean change from baseline in monthly migraine headache days

Key result: Galcanezumab significantly reduced the number of monthly migraine headache days and was well tolerated over 3 months.

2019

PROMISE-1 Trial

n = 888 · Cephalalgia

Tested

Eptinezumab 30mg, 100mg, or 300mg IV

Population

Adults with episodic migraine

Comparator

Placebo

Endpoint

Change in monthly migraine days

Key result: Eptinezumab 100mg and 300mg significantly reduced mean monthly migraine days compared to placebo.

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