# Fremanezumab for Chronic Migraine: A New Preventive Treatment Option Explained

**Main finding:** In a large Phase 3 clinical trial involving 1,130 patients with chronic migraine, treatment with fremanezumab (a new type of injectable medication) significantly reduced the number of headache days per month compared to a placebo (inactive injection). Over a 12-week period, patients receiving monthly fremanezumab injections experienced an average reduction of 4.6 headache days per month, while patients receiving placebo experienced a reduction of only 2.5 days — a difference that was highly statistically significant (P<0.001). The medication was generally well-tolerated, though injection-site reactions such as pain and redness were common.

# Fremanezumab for Chronic Migraine: A New Preventive Treatment Option Explained

## Table of Contents

- Key Points
- Understanding Chronic Migraine: Why This Research Matters
- Fremanezumab: A New Approach to Preventing Migraine
- How the Study Was Conducted
- Who Participated in the Trial
- Key Findings: Did Fremanezumab Work?
- Safety and Side Effects
- What This Means for Patients
- Study Limitations: What the Trial Couldn't Prove
- Recommendations for Patients
- Frequently Asked Questions
- Source Information

## Key Points

- Fremanezumab reduced chronic migraine headache days by 4.3–4.6 per month versus 2.5 with placebo in a 12-week trial of 1,130 patients.
- 38%–41% of fremanezumab patients achieved at least a 50% reduction in headache days, compared to 18% on placebo.
- Fremanezumab worked within 4 weeks and also reduced acute headache medication use by 3.7–4.2 days per month.
- Injection-site reactions occurred in 47% of treated patients; most side effects were mild to moderate.
- This study lasted only 12 weeks, so long-term safety, effectiveness, and rare side effects require further research.

## Understanding Chronic Migraine: Why This Research Matters

Migraine is far more than just a bad headache. It is a complex neurological disorder characterized by recurrent attacks of throbbing or pulsating head pain that is at least moderate in severity. According to the background information in this study, migraine affects an estimated 15 to 18% of the global population, making it one of the most common neurological conditions in the world. It is also a leading cause of disability worldwide, meaning it prevents millions of people from working, attending school, and participating in daily life.

Chronic migraine is a particularly severe form of the condition. It occurs in approximately 2% of the population and is defined as experiencing at least 15 headache days per month for a period of at least 3 months. For people living with chronic migraine, the pain comes almost daily or near-daily, leading to significant functional impairment and a substantially lower quality of life compared to those with less frequent migraines.

Medical experts have long agreed that patients with chronic migraine should receive preventive treatment — therapy designed to reduce the frequency and severity of migraine attacks before they start. However, the study authors note that existing preventive treatments are often underused, poorly adhered to, associated with troublesome side effects, or simply ineffective for many patients. This gap in effective treatment options is exactly why researchers have been searching for new approaches.

## Fremanezumab: A New Approach to Preventing Migraine

Fremanezumab (also known by its research name TEV-48125) represents a fundamentally new class of migraine treatment. It is a humanized monoclonal antibody — a laboratory-designed protein that acts like a guided missile to target a specific substance in the body. In this case, fremanezumab targets and neutralizes a molecule called **calcitonin gene-related peptide (CGRP)**.

CGRP is a 37-amino acid neuropeptide (a small protein fragment) that plays a central role in the chain of events that triggers migraines. During a migraine attack, CGRP levels rise, causing blood vessels to dilate (widen) and inflammation to develop in the brain's protective membranes. Fremanezumab works by binding to both the alpha (α) and beta (β) forms of CGRP, essentially "mopping up" this pain-promoting molecule before it can trigger the migraine cascade.

Unlike some other treatments, fremanezumab targets the CGRP *ligand* itself, not the receptor. It offers flexible dosing and is administered as a subcutaneous (under-the-skin) injection, similar to how insulin is given for diabetes. Preceding this Phase 3 trial, a Phase 2 study in patients with chronic migraine had shown significant reductions in both migraine days and headache days compared to placebo, with no serious treatment-related side effects. Those promising results paved the way for this larger, more definitive investigation.

## How the Study Was Conducted

This was a randomized, double-blind, placebo-controlled, parallel-group Phase 3 trial — the gold standard design for testing whether a new medication truly works. "Randomized" means patients were assigned to treatment groups by chance; "double-blind" means that neither the patients nor the doctors and researchers knew who was receiving the real medication and who was receiving placebo, eliminating bias; and "placebo-controlled" means one group received an inactive injection for comparison.

The trial was conducted at **132 headache clinics across nine countries**, with patient recruitment taking place from March 2016 through January 2017. It was funded by Teva Pharmaceuticals, the manufacturer of fremanezumab, and was registered on ClinicalTrials.gov under the number NCT02621931. A strict ethical framework was followed, including compliance with the International Conference on Harmonisation Guidelines for Good Clinical Practice, the principles of the Declaration of Helsinki, and all relevant national and local regulations. All participants signed informed consent documents.

The trial design consisted of three phases: a screening visit, a 28-day preintervention (baseline observation) period, and a 12-week active intervention period, with a final evaluation at the end of week 12. During the 28-day baseline period, patients recorded detailed information about their headaches in a daily electronic diary using a device called the ERT DIARYpro platform on a Bluebird Pidion BM-170 handheld device. This diary captured data on headache occurrence, duration, pain severity, the presence of symptoms like nausea, vomiting, photophobia (light sensitivity), phonophobia (sound sensitivity), and any medications used.

### Dosing Regimens: Three Groups, Two Approaches

Patients were randomly assigned in a 1:1:1 ratio to one of three groups:

1.
**Fremanezumab Quarterly (every 3 months):** A single dose of 675 mg (given as three 225 mg/1.5 ml injections) at the start of the trial, followed by placebo injections at weeks 4 and 8.
1.
**Fremanezumab Monthly:** A 675 mg dose at baseline (also three 225 mg injections), followed by 225 mg injections at weeks 4 and 8.
1.
**Placebo:** Inactive injections given at baseline, week 4, and week 8.

All patients received three abdominal subcutaneous injections at baseline and one injection at weeks 4 and 8, so the experience of receiving the injections was identical across all groups. Randomization was performed electronically and was stratified according to sex, country, and whether the patient was already using a preventive migraine medication. Up to 30% of patients were allowed to continue taking a stable dose of one existing migraine-preventive medication (such as topiramate or a beta-blocker) if it had been started at least 2 months before the trial began.

### Key Eligibility Criteria

To participate, patients had to be between the ages of 18 and 70 years, have a history of migraine (diagnosed according to the International Classification of Headache Disorders, 3rd edition beta version, or ICHD-3 beta) for at least 12 months, and meet the criteria for chronic migraine during the 28-day baseline period — defined as headache of any duration or severity on at least 15 days per month and migraine on at least 8 days per month.

Key exclusion criteria included:

- Use of onabotulinumtoxinA (Botox) for migraine during the 4 months before screening
- Use of migraine interventions or devices (such as nerve blocks or transcranial magnetic stimulation) during the 2 months before screening
- Use of opioid or barbiturate medications on more than 4 days during the preintervention period
- A documented lack of response to adequate trials of at least two of four categories of preventive medications

### How Effectiveness Was Measured

The **primary endpoint** of the trial was the mean change from baseline in the average number of headache days per month over the 12-week period after the first dose. A "headache day" was carefully defined as a calendar day in which:

- Headache pain lasted at least 4 consecutive hours and had a peak severity of at least moderate level, **or**

- The patient used acute migraine-specific medication (triptans or ergots) to treat a headache of any severity or duration

Secondary endpoints included changes in the number of migraine days per month, the percentage of patients achieving at least a 50% reduction in headache days, changes in the use of acute headache medications, and changes in the six-item Headache Impact Test (HIT-6) — a validated questionnaire measuring headache-related disability, with scores ranging from 36 to 78 (higher scores indicating greater disability).

Statistical analyses were conducted on a "modified intention-to-treat" population, meaning all randomly assigned patients who received at least one dose and had at least 10 days of post-baseline efficacy data. The researchers planned to enroll 1,020 participants to provide 90% statistical power to detect a difference of 1.7±6.3 headache days per month between groups, assuming a 15% discontinuation rate.

## Who Participated in the Trial

A total of **1,130 patients** were enrolled and randomly assigned to the three groups: 376 to the fremanezumab quarterly group, 379 to the fremanezumab monthly group, and 375 to the placebo group. The baseline characteristics of the patients were highly similar across all three groups, confirming that randomization worked well.

Key baseline characteristics of the participants included:

-
**Age:** Average age was approximately 41 years (42.0±12.4 quarterly, 40.6±12.0 monthly, 41.4±12.0 placebo)
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**Sex:** The majority were women — 88% (331 patients) in the quarterly group, 87% (330) in the monthly group, and 88% (330) in the placebo group
-
**Body-mass index:** Approximately 26.5 in all groups
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**Disease duration:** On average, patients had been living with migraine for about 20 years (19.7±12.8, 20.1±12.0, 19.9±12.9 years respectively)
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**Current medication use:** About 20-22% were using a preventive medication, and 95% were using acute headache medications as needed
-
**Previous treatments:** 28-31% had previously used topiramate; 13-18% had previously used onabotulinumtoxinA
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**Headache days:** The mean number of headache days (as defined in the trial) per month during baseline was 13.2 in the quarterly group, 12.8 in the monthly group, and 13.3 in the placebo group
-
**Migraine days:** Patients experienced an average of 16.2, 16.0, and 16.4 migraine days per month, respectively
-
**Overall headache burden:** Days with headache of any severity and duration averaged about 20 days per month (20.4, 20.3, and 20.3 days, respectively)
-
**Acute medication use:** Patients used acute headache medications on approximately 13 days per month and migraine-specific acute medications on approximately 11 days per month
-
**Disability score:** Baseline HIT-6 scores were elevated in all groups (64.3, 64.6, and 64.1), indicating a severe impact on daily life

Of the 1,130 patients randomly assigned, **1,034 patients (92%) completed the trial**: 349 (93%) in the quarterly group, 343 (91%) in the monthly group, and 342 (91%) in the placebo group. This high completion rate strengthens confidence in the results.

## Key Findings: Did Fremanezumab Work?

### Primary Endpoint: Reduction in Headache Days

The trial met its primary endpoint with clear results. After 12 weeks of treatment, the **least-squares mean reduction** (the average change, statistically adjusted for factors like sex, country, and baseline preventive medication use) in monthly headache days was:

-
**Fremanezumab quarterly:** -4.3±0.3 days per month
-
**Fremanezumab monthly:** -4.6±0.3 days per month
-
**Placebo:** -2.5±0.3 days per month

Both fremanezumab groups showed significantly greater reductions than placebo, with a difference versus placebo of 1.8 and 2.1 days, respectively. The statistical significance was **P<0.001** for both comparisons, meaning there is less than a 0.1% probability that these results occurred by chance.

In practical terms, during the 12-week treatment period, patients receiving placebo experienced an average of 10.4±6.4 headache days per month, compared to 8.5±6.3 days for those on quarterly fremanezumab and 8.0±6.3 days for those on monthly fremanezumab. This translates to roughly two fewer headache days per month over and above the placebo effect — a meaningful improvement for people living with daily or near-daily pain.

### Secondary Endpoints: Consistent Benefits Across the Board

**Reduction in migraine days.** The fremanezumab groups achieved greater reductions in monthly migraine days: -4.9±0.4 days for quarterly dosing and -5.0±0.4 days for monthly dosing, compared to -3.2±0.4 days for placebo. Both differences were statistically significant (P<0.001).

**"50% Responder" rates.** This is a key measure used in migraine research — the proportion of patients whose headache frequency is cut by at least half. The results were striking:

- 38% of patients in the quarterly group (141 out of 375) achieved at least a 50% reduction
- 41% of patients in the monthly group (153 out of 375) achieved at least a 50% reduction
- Only 18% of patients in the placebo group (67 out of 371) achieved this benchmark

Both differences were statistically significant at P<0.001. In other words, patients receiving fremanezumab were more than twice as likely to experience a dramatic improvement in their headache frequency compared to those receiving placebo.

**Reduced need for acute headache medication.** Patients in the fremanezumab groups also reduced their use of rescue medications. The mean reduction in days per month using any acute headache medication was:

- -3.7±0.3 days for quarterly fremanezumab
- -4.2±0.3 days for monthly fremanezumab
- -1.9±0.3 days for placebo

Both differences versus placebo were significant at P<0.001. This means patients treated with fremanezumab relied less on pain-relieving medications, which is good news because overuse of acute medications can itself lead to medication-overuse headache.

**Rapid onset of effect.** The benefits appeared quickly. In the first 4 weeks after the initial dose, headache days were reduced by -4.4±0.3 days (quarterly) and -4.5±0.3 days (monthly) compared to -2.1±0.3 days for placebo — again, P<0.001 for both. Patients did not have to wait months to see improvement.

**Benefits in patients not using other preventives.** The researchers also analyzed the subgroup of patients who were not receiving any concomitant preventive migraine medication (79% of the quarterly group, 77% of the monthly group, and 79% of the placebo group). This was important to isolate fremanezumab's pure effect. The reductions in headache days were -4.6±0.3 days (quarterly), -4.8±0.3 days (monthly), and -2.6±0.3 days (placebo), with both active-treatment differences versus placebo reaching P<0.001.

**Improved quality of life (HIT-6 scores).** Headache-related disability decreased significantly more with active treatment. HIT-6 scores dropped by:

- -6.4±0.5 points with quarterly fremanezumab
- -6.8±0.4 points with monthly fremanezumab
- -4.5±0.5 points with placebo

Both differences were statistically significant at P<0.001. A reduction of 6-7 points on the HIT-6 scale represents a clinically meaningful improvement in how migraines affect daily functioning. Importantly, fremanezumab also reduced headache days during the 12-week period when evaluated at all measurement time points, indicating a sustained benefit over the entire dosing interval.

## Safety and Side Effects

Adverse events were reported in a substantial proportion of patients in all three groups, which is typical for studies involving injectable medications:

- 64% of patients receiving placebo experienced at least one adverse event
- 70% of patients receiving quarterly fremanezumab (P=0.06 compared to placebo)
- 71% of patients receiving monthly fremanezumab (P=0.03 compared to placebo)

Notably, the vast majority of events were mild to moderate in severity — 95 to 96% across all three groups. The difference between the fremanezumab and placebo groups was driven largely by reactions at the injection site, which were the most commonly reported adverse events.

### Injection-Site Reactions

Injection-site reactions occurred in:

- 40% of patients receiving placebo
- 47% of patients receiving quarterly fremanezumab (P=0.08 versus placebo)
- 47% of patients receiving monthly fremanezumab (P=0.03 versus placebo)

These reactions included redness (erythema), swelling (induration), bruising (ecchymosis), and pain at the injection site. The severity of these reactions did not differ significantly among the three groups. The most common specific adverse event was **injection-site pain**, which occurred in 30% of the quarterly group, 26% of the monthly group, and 28% of the placebo group.

A total of 20 patients discontinued the trial due to adverse events: 1% in the quarterly group, 2% in the monthly group, and 2% in the placebo group. This low and even distribution of discontinuation rates suggests that fremanezumab was generally well tolerated.

### Liver Function and Other Safety Monitoring

Abnormalities of hepatic (liver) function occurred in 5 patients in each fremanezumab group (approximately 1%) and in 3 patients in the placebo group (less than 1%). The clinical significance of these laboratory abnormalities was not fully characterized in this 12-week trial.

Safety monitoring was comprehensive. The researchers checked vital signs (blood pressure, pulse, body temperature, respiratory rate), performed physical examinations, conducted 12-lead electrocardiography (heart monitoring), and ran clinical laboratory tests including blood chemistry, hematology, coagulation, and urinalysis. They also systematically assessed local injection-site reactions both immediately and 1 hour after each injection, tracked suicidal ideation and behavior using the electronic Columbia-Suicide Severity Rating Scale, and tested blood samples for antibodies against the medication (anti-drug antibodies, which could potentially reduce the drug's effectiveness or cause side effects). Injection-site pain was the most common adverse event across all groups, and overall, the side-effect profile was considered acceptable and consistent with previous studies of this class of medication.

## What This Means for Patients

These findings represent a meaningful advance in the preventive treatment of chronic migraine. For patients who have struggled with daily or near-daily headaches, and who may have failed to obtain relief from existing oral preventive medications, fremanezumab offers a new mechanism of action that directly targets a core molecule in the migraine pathway.

The clinical benefits are substantial. Nearly twice as many patients achieved at least a 50% reduction in headache days with fremanezumab compared to placebo (38-41% versus 18%). This is not just statistically significant — it is a level of improvement that can change a patient's day-to-day life, restoring the ability to work, care for family, and participate in social activities.

The rapid onset of benefit is also important. Patients responded within the first month of treatment, and improvements were maintained throughout the 12-week study period. The fact that benefits occurred even in patients who were not on other preventive medications confirms that fremanezumab works on its own, though it can also be added to an existing regimen.

The reduction in acute medication use (3.7-4.2 fewer days per month) is particularly relevant from a kidney, liver, and brain health perspective. Overuse of acute pain medications can actually worsen the migraine cycle, so breaking this cycle with an effective preventive is valuable.

Finally, the convenience of the dosing schedules should not be overlooked. The option of receiving an injection either monthly or quarterly provides flexibility for patients, many of whom struggle with having to remember to take daily oral preventive medications. The quarterly regimen was similarly effective to the monthly regimen, which could be very attractive for convenience.

## Study Limitations: What the Trial Couldn't Prove

It is important to contextualize these findings with the limitations of the trial, which the authors candidly acknowledge.

**The trial was only 12 weeks long.** This is a relatively short time frame for a chronic condition like migraine. The study could demonstrate that fremanezumab works in the short term, but the **long-term durability, safety, and tolerability of fremanezumab require further study**. Questions remain about whether the benefits continue beyond 3 months, whether patients develop resistance over time, and whether any rare long-term side effects emerge.

**A significant placebo effect was observed.** Patients in the placebo group also experienced an average reduction of 2.5 headache days per month. This is not unexpected in pain studies, but it underscores that the true drug-specific effect, while clearly significant, is somewhat smaller than the raw reduction — the difference versus placebo was 1.8 to 2.1 headache days per month.

**Injection-site reactions were common.** While not severe for most patients, the fact that roughly half of fremanezumab-treated patients experienced injection-site reactions is an important consideration. Patients who are needle-averse may find this challenging.

**The trial excluded certain complex patients.** Notably, patients who had injected onabotulinumtoxinA in the 4 months before screening, those using opioid or barbiturate medications on more than 4 days during the baseline period, and those who had not responded to two of four preventive medication categories were excluded. Therefore, results may not fully generalize to the most treatment-refractory migraine population or those with significant medication overuse.

**Industry funding.** The trial was funded by Teva Pharmaceuticals, the developer of fremanezumab. While the authors vouched for the conduct of the trial and the accuracy and completeness of the data, and the trial was registered on ClinicalTrials.gov, patients should be aware that industry-sponsored trials can have inherent biases in design and reporting. The majority of patients were women (87-88%), which is consistent with the epidemiology of migraine but means results in men are less thoroughly characterized.

**Clinical significance of liver function tests.** Although hepatic function abnormalities occurred in only about 1% of treated patients, the clinical meaning of these lab findings is not fully explained in this 12-week study, and longer-term surveillance would be necessary to understand whether these represent a meaningful safety signal.

## Recommendations for Patients

For patients living with chronic migraine, this research provides important new information to discuss with their healthcare provider. Here is what patients might consider:

1.
**Ask about CGRP-targeting therapies.** Fremanezumab is part of a new class of "anti-CGRP" medications that have fundamentally changed migraine prevention. Many of these agents have now been approved by regulatory agencies around the world. Discuss with your neurologist or headache specialist whether this medication class may be appropriate for you.
1.
**Know your migraine days.** Keeping a headache diary — like the electronic diary used in this trial — can help you and your doctor accurately document your headache frequency, triggers, medication use, and response to treatment. The trial's careful definitions (at least 4 hours of pain, moderate severity, or the use of triptan/ergot medications) can serve as a useful model for tracking your own migraines.
1.
**Set realistic expectations.** The average reduction in headache days was about 4.3 to 4.6 days per month with fremanezumab, versus 2.5 days with placebo, and 38-41% of patients achieved a 50% or greater reduction. This means that while many patients benefit substantially, not every patient becomes headache-free — and more than half of patients in the trial did not achieve the 50% benchmark.
1.
**Discuss dosing frequency with your doctor.** Both monthly (225 mg) and quarterly (675 mg every 3 months) regimens were effective in this trial. If you prefer fewer injections, quarterly dosing may be an appealing option worth discussing.
1.
**Plan for injection-site reactions.** About 47% of treated patients experienced injection-site reactions such as pain, redness, or swelling. Ask your provider about techniques to minimize discomfort, such as allowing the syringe to reach room temperature, using ice before injection, or rotating injection sites.
1.
**Do not stop your current medications without guidance.** The trial allowed patients to continue a stable dose of existing preventive medications, suggesting fremanezumab can be used as an add-on therapy. Never change your migraine treatment plan without consulting your healthcare provider.
1.
**Remember that long-term data are still accumulating.** This study only evaluated 12 weeks of treatment. As longer-term follow-up studies are published, they will provide important additional information about the durability of benefits, safety over years of use, and the proper place of this medication in the treatment algorithm.

## Frequently Asked Questions

### What is chronic migraine and how is it different from regular migraine?

Chronic migraine is a severe form of migraine affecting about 2% of people. It means having at least 15 headache days per month for at least 3 months, with migraine features on at least 8 of those days. It causes daily or near-daily pain and significant impairment in work, school, and daily life.

### How well did fremanezumab work for chronic migraine in this trial?

In a 12-week study of 1,130 patients, fremanezumab reduced monthly headache days by about 4.3 to 4.6 days, compared to 2.5 days with placebo. About 38% to 41% of treated patients had at least a 50% reduction in headache days, versus 18% with placebo. Benefits appeared within the first month.

### What side effects did patients experience with fremanezumab?

The most common side effects were injection-site reactions, such as pain, redness, swelling, and bruising. These occurred in about 47% of treated patients, compared to 40% with placebo. Most side effects were mild to moderate. About 1% to 2% of patients stopped treatment due to side effects.

### Who was eligible to participate in this trial?

Participants were adults aged 18 to 70 with chronic migraine, defined as at least 15 headache days and 8 migraine days per month. They had migraine for at least 12 months. Exclusion criteria included recent Botox use, opioid overuse, or lack of response to two prior preventive medications.

### What are the limitations of this study on fremanezumab?

The trial lasted only 12 weeks, so long-term safety and durability are not yet known. A significant placebo effect occurred, and the true drug-specific reduction was 1.8 to 2.1 headache days per month. Injection-site reactions were common. The study excluded some complex patients, so results may not apply to everyone.

## Source Information

**Original article title:** Fremanezumab for the Preventive Treatment of Chronic Migraine

**Authors:** Stephen D. Silberstein, M.D., David W. Dodick, M.D., Marcelo E. Bigal, M.D., Ph.D., Paul P. Yeung, M.D., M.P.H., Peter J. Goadsby, M.D., Ph.D., Tricia Blankenbiller, M.A., Melissa Grozinski-Wolff, B.S., Ronghua Yang, Ph.D., Yuju Ma, M.S., and Ernesto Aycardi, M.D.

**Journal:** The New England Journal of Medicine (N Engl J Med 2017;377:2113-22)

**Publication date:** November 30, 2017

**DOI:** 10.1056/NEJMoa1709038

**Trial registration:** ClinicalTrials.gov number, NCT02621931

**Funding source:** Teva Pharmaceuticals, which also provided the trial medication and performed the data analysis.

**Institutional affiliations:** Thomas Jefferson University (Jefferson Headache Center), Philadelphia; Teva Pharmaceuticals, Frazer, PA; Mayo Clinic Arizona, Phoenix; and King's College London, London.

*This patient-friendly article is based on peer-reviewed research published in a leading medical journal. It has been written to help patients and the general public understand the study's findings without needing a medical degree. The original scientific article contains additional tables, statistical details, and supplementary materials that may be accessed through the New England Journal of Medicine.*


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