Neurology MARCH 31, 2020

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

Richard B. Lipton, Peter J. Goadsby, Jeff Smith, et al.

Bottom Line

In this phase 3 trial, intravenous eptinezumab (100 mg and 300 mg) demonstrated superior efficacy to placebo in reducing monthly migraine days in patients with chronic migraine.

Key Findings

1. The primary endpoint was met: patients treated with 100 mg and 300 mg of eptinezumab experienced mean reductions in monthly migraine days of 7.7 and 8.2 days, respectively, over weeks 1 to 12, compared to 5.6 days for the placebo group (p < 0.0001 for both doses).

2. Eptinezumab provided a rapid onset of preventive effect, with efficacy observed on the first day after intravenous administration.

3. The 50% and 75% migraine responder rates (the proportion of patients achieving at least a 50% or 75% reduction in monthly migraine days) were significantly higher in both eptinezumab groups compared to placebo during the first 12 weeks.

4. The safety profile was favorable and consistent across groups, with nasopharyngitis being the only treatment-emergent adverse event reported by >2% of eptinezumab-treated patients at an incidence greater than placebo (9.4% in the 300 mg arm vs 6.0% in the placebo arm).

Study Design

Design

RCT

Double-Blind

Sample

1,072

Patients

Duration

32 wk

Median

Setting

Multicenter, International

Population Adults with chronic migraine (defined as headache on ≥15 days/month, with ≥8 days fulfilling criteria for migraine)

Intervention Intravenous eptinezumab (100 mg or 300 mg) administered at day 0 and week 12

Comparator Intravenous placebo administered at day 0 and week 12

Outcome Change from baseline in mean monthly migraine days over weeks 1 to 12

Study Limitations

• The study design utilized a relatively short primary efficacy assessment period of 12 weeks, though data were collected through 24 weeks.

• Patients with severe comorbidities or prior failure of multiple migraine preventive medications were not specifically characterized in the main primary efficacy analysis.

• The study was conducted in a controlled clinical trial environment, which may not fully capture real-world adherence and long-term safety profile.

Clinical Significance

Eptinezumab represents the first intravenous anti-CGRP monoclonal antibody for migraine prevention. Its ability to produce rapid onset of efficacy is a critical clinical differentiator, offering a treatment option for patients who require immediate or robust migraine prophylaxis in a setting where adherence to daily oral medications is challenging.

Historical Context

The approval of CGRP-targeted therapies revolutionized migraine management. PROMISE-2 was one of the pivotal trials that supported the FDA approval of eptinezumab in early 2020, establishing it as a key alternative in the therapeutic armamentarium of anti-CGRP monoclonal antibodies, distinguishing itself via its unique intravenous delivery mechanism compared to subcutaneous alternatives.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the biological role of Calcitonin Gene-Related Peptide (CGRP) in the trigeminovascular system, and how does eptinezumab's mechanism of action interfere with this pathway?

Key Response

CGRP is a potent neuropeptide and vasodilator released from trigeminal nerve endings that mediates neurogenic inflammation and pain transmission during a migraine. Eptinezumab is a humanized monoclonal antibody that binds directly to the CGRP ligand (rather than the receptor), preventing it from interacting with its receptors and thereby inhibiting the activation of the trigeminovascular system.

Resident

In the context of the PROMISE-2 trial results, which clinical criteria are required to diagnose 'chronic migraine' as opposed to 'episodic migraine,' and what is a primary clinical advantage of IV eptinezumab over traditional oral prophylactic medications?

Key Response

Chronic migraine is defined as 15 or more headache days per month for more than 3 months, of which at least 8 days meet migraine criteria. A major clinical advantage of IV eptinezumab highlighted by the trial is its 100% bioavailability and rapid achievement of peak plasma concentration, leading to efficacy that can be observed as early as the first day after infusion, whereas oral agents often require weeks of titration.

Fellow

PROMISE-2 included a significant cohort of patients with concurrent Medication Overuse Headache (MOH). How do the efficacy results for this subgroup challenge traditional management strategies for refractory chronic migraine?

Key Response

Traditionally, patients with MOH were often required to undergo a 'washout' or detoxification from acute medications before starting prophylaxis. PROMISE-2 demonstrated that eptinezumab was effective in reducing monthly migraine days even in patients actively overusing acute medications, suggesting that CGRP-targeted therapies can be initiated successfully without necessitating a prior detoxification period.

Attending

Given the 'day 1' efficacy and 12-week dosing interval demonstrated in PROMISE-2, where does eptinezumab fit into the treatment algorithm for a patient who has failed multiple subcutaneous CGRP inhibitors and suffers from severe functional impairment?

Key Response

Eptinezumab's IV administration ensures total compliance for 3 months and provides the fastest onset of action among preventives. For patients failing subcutaneous options (erenumab, fremanezumab, galcanezumab), the different binding profile (ligand vs. receptor) and the higher peak concentration of IV delivery may overcome prior resistance or 'wearing-off' effects noted toward the end of subcutaneous dosing cycles.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The PROMISE-2 trial observed a substantial placebo response (a reduction of approximately 4.6 monthly migraine days). How does the intravenous route of administration potentially amplify the 'expectancy effect' in pain trials, and what statistical methods can be employed to disentangle this from the pharmacological effect?

Key Response

More invasive delivery routes (IV > SC > Oral) are associated with higher placebo responses in migraine trials due to increased patient expectation. To address this, researchers can use responder rate analyses (e.g., 50%, 75%, 100% reduction) which often show a wider separation between drug and placebo than mean changes, or utilize covariate adjustment for baseline severity and prior treatment failure to refine the treatment effect estimate.

Journal Editor

As a reviewer, what concerns would you raise regarding the generalizability of the PROMISE-2 results considering the trial's exclusion of patients with significant cardiovascular disease or those who had failed more than two classes of prior preventives?

Key Response

While the trial shows high internal validity, excluding 'super-refractory' patients (those failing >2 classes) may overstate the drug's efficacy in the most difficult-to-treat real-world populations. Furthermore, because CGRP is a vasodilator with potentially protective roles in ischemic events, the exclusion of cardiovascular-risk patients leaves a gap in safety data for older populations or those with comorbidities.

Guideline Committee

Based on the Level A evidence provided by PROMISE-2, how should eptinezumab be positioned relative to OnabotulinumtoxinA in updated clinical practice guidelines for chronic migraine?

Key Response

Current AHS/AAN guidelines place CGRP mAbs and Botox as evidence-based options for CM. PROMISE-2 establishes eptinezumab as having comparable efficacy to the PREEMPT Botox trials but with a faster onset of action and less frequent administration (quarterly). Guidelines should now reflect that eptinezumab is a first-line monoclonal antibody option for CM, particularly when rapid reduction in disease burden is the primary clinical goal.

Clinical Landscape

Noteworthy Related Trials

2010

PREEMPT 1 Trial

n = 678 · Cephalalgia

Tested

OnabotulinumtoxinA

Population

Adults with chronic migraine

Comparator

Placebo

Endpoint

Change in frequency of headache episodes

Key result: OnabotulinumtoxinA showed significant reduction in headache frequency compared to placebo in chronic migraine patients.

2017

REGAIN Trial

n = 1,130 · Lancet Neurol

Tested

Galcanezumab

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 compared to placebo over a 3-month period.

2017

HALO-CM Trial

n = 1,113 · JAMA

Tested

Fremanezumab

Population

Adults with chronic migraine

Comparator

Placebo

Endpoint

Mean change from baseline in average number of headache days per month

Key result: Monthly and quarterly dosing of fremanezumab significantly reduced monthly migraine days compared to placebo.

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