Headache Medicine 2020, 11(3):72-76 ISSN 2178-7468, e-ISSN 2763-6178

ASAA

DOI: 10.48208/HeadacheMed.2020.20

Headache Medicine

Original

A framework for decision making of migraine treatment with anti-

CGRP monoclonal antibodies: a guide for real-world practice and

public policies

Reinilza Nunes da Gama Thaiza Agostini Córdoba de Lima Iron Dangoni Filho

Mario Fernando Prieto Peres

Hospital Israelita Albert Einstein, Neurology, São Paulo, São Paulo, Brazil

Abstract

Anti-CGRP monoclonal antibodies have been developed for migraine preventive treatment. There is

evidence of good efcacy and safety of these medications; however, cost is a factor that interferes with

the choice of treatment. This paper proposes a framework in order to better assist the decision-making

processes on the use of these drugs in developing countries without coverage of health care costs for

migraine. The framework was built after reviewing phase II and III studies on episodic and chronic mi-

graine treatment with erenumab, galcanezumab and fremanezumab.

Mario Fernando Prieto Peres

mariop3r3s@gmail.com

Edited by

Marcelo Moraes Valença

Received: August19, 2020

Accepted: September 14, 2020

Keywords:

Migraine Disorders

Calcitonin Gene-Related Peptide

Algorithms

Antibodies

Monoclonal

Public Health

ASAA

Gama RN, Lima TAC, Dangoni Filho I, Peres MFP

A framework for decision making of migraine treatment with anti-CGRP monoclonal antibodies: a guide for real-world practice and public policies

Introduction

igraine is a common and debilitating disorder, which

affects a signicant proportion of the population world-

wide.

1,2

Abortive and preventive treatment strategies are often

combined using pharmacological and nonpharmacological

methods. The most commonly used medication categories

are: antidepressants, beta blockers and anticonvulsants.

3,4

The

poor quality of life of these patients interferes in their function-

al status. There are losses in work performance, school, family,

relationships, in addition to affecting daily concentration,

generating fatigue and mood alterations. These medications

lead on average to a 50% frequency reduction in 50% of

patients, and their use are limited due to side effects or con-

traindications.

Four monoclonal antibodies (mAbs) have

been developed: one targeting the calcitonin gene-related

peptide receptor (erenumab) and three targeting the calci-

tonin gene-related peptide (eptinezumab, fremanezumab,

and galcanezumab).

Erenumab, galcanezumab, fremanezumab and eptinezum-

ab have yielded positive results concerning episodic and

chronic migraine prevention.

7,8

The new drugs have already

been approved in the United States and other countries

worldwide. Erenumab was approved in May, 2018 in the

US, in August, 2018 in Europe, while galcanezumab and

fremanezumab were approved in September, 2018 in the

US, and in November, 2018 in Europe. Eptinezumab was

approved in February, 2020?

Headache care lacks universal coverage even in developed

countries.

From the estimated 1 billion migraine sufferers across the

globe, at least half do not have full coverage even of essential

health services.10 About 100 million people worldwide have

been pushed into extreme poverty because they have to pay

for health care.

Migraine treatment and health care policies

should be planed according to patients’ access.

Although studies on phase II and III clinical trials have re-

vealed a protocol or a way of prescribing migraine by ad-

ministering subcutaneously injections every month for 3 to 6

months, there is scarce information regarding when to stop

medication, dosing strategies, management involving refracto-

ry patients or non-responsive patients, and other issues yet to

be examined.

Administration and use of new monoclonals

are expected to vary according to the environment, physicians

experience, patient’s responses, and nancial aspects. Head-

ache related health care policies are not available worldwide,

and patient access is still a matter of intense debate. Medical

systems across the globe have country specic regulations for

patient access, reimbursement and price policies.

Therefore,

CGRP monoclonal antibodies protocols should consider not

only the pre-xed protocols studied in clinical trials, but should

be customized for the real-world practice, individualized ac-

cording to the medical system.

In order to account for socio-economic factors, a decision

tree algorithm for migraine preventive treatment with mAbs

should be generated. In this paper we suggest a framework

for improving the decision making process in real life and

for public policies.

Methods

This is an opinion article in which the authors propose a frame-

work for improving the decision making in choosing steps

for the management of preventive treatment of migraine with

monoclonal antibodies. This could be a ground for gathering

opinions and collecting data towards cost-benet analysis,

aiding decisions in the context of limited nancial resources.

The framework was built after reviewing phase II and III studies

on episodic and chronic migraine treatment with erenumab,

galcanezumab and fremanezumab.

Information regarding dosage, timing, half-life and administra-

tion protocol were reviewed. Eptinezumab data were excluded

due to its approval in limited countries.

The authors created an algorithm that summarizes strategies

for the treatment of migraine with anti-CGRP monoclonal

antibodies.

Evaluating the response pattern according to the percentage

of reduction in pain days, three categories were considered:

Group 1: Poor response, less than 25% reduction;

Group 2: Partial response, reduction between 25% and 75%;

Group 3: Good response, more than 75% reduction.

The framework was set in order to facilitate the opinion on

the following questions:

1. When should treatment be offered?

2. How long to maintain treatment in cases of good response?

4. How long to maintain treatment until no response is

established?

5. In cases of partial response, what steps can be taken in

order to increase efcacy?

ASAA

Gama RN, Lima TAC, Dangoni Filho I, Peres MFP

A framework for decision making of migraine treatment with anti-CGRP monoclonal antibodies: a guide for real-world practice and public policies

After analyzing data, we modeled an algorithm so a frame-

work could be the basis for clinical migraine prevention

decision-making in different health care scenarios.

Results

We propose an algorithm to clarify the phases in migraine

management through anti-CGRP monoclonal antibodies.

The decision tree is intended to support the clinical practice

and was developed according patient’s response. We tried

to generate an approach that is based on efcacy data but

also could be taken different economic scenarios into account.

Erenumab, galcanezumab and fremanezumab half-life is

around 25-30 days, regarding subcutaneous injections perfo-

med in the abdomen, thigh, or upper arm. The recommended

dose are: erenumab, 70 mg or 140 mg monthly; fremanezu-

mab 225 mg monthly or 675 mg every three months; and

galcanezumab 120 mg monthly. Framanezumab can be also

administered quarterly. Galcanezumab can be started with

a loading dose of 240 mg (Table 1).

Treatment with monoclonal antibodies should be offered to

what kind of patients? Should only to those who have failed

two classes of preventive treatment: antidepressant, anticon-

vulsant or beta-blocker? Once the treatment with monoclo-

nal antibodies is decided, following the protocol studied is

the obvious indication, therefore galcanemuzab would be

administered with a loading dose (240 mg). But what if the

medication cost is dose dependent? Should starting with 120

mg be cost effective?

The next step is to measure the clinical response and classify

the patient in the three groups. For group 3, in which the

patient presents substantial improvement in the rst month,

we suggest repeating the dose as soon as reducing the

effectiveness for less than 50%.

For group 2, in partial response, should the same dose be

repeated within a month? For group 1, with no response,

twice the dose of erenumab and the same dose of galca-

nezumab and fremanezumab should be prescribed? In the

following month, patients must be reclassied, according to

the response rate. Patients who remain in group 1 would be

advised not to continue treatment, within a context in which

nancial resources are limited? How much more time should

we insist in the trial? In this group, patients should be reas-

sessed in an attempt to conrm the diagnosis and identify

other factors that contribute to pain refractoriness, such as

mood disorders, sleep, postural errors, physical inactivity or

exposure to triggering factors.

For groups 2 and 3, the optimal or partial response is an

opportunity to optimize non-pharmacological treatment me-

asures and the pharmacological treatment kept for how

long? At least six months for chronic migraine? Three to six

in episodic migraine (Figure 1).

Discussion

Data from available clinical trials indicate that erenumab,

fremanezumab and galcanezumab are safe and effective for

the prevention of episodic chronic migraine.

Monoclonal antibodies present a good tolerability prole,

low incidence of side effects and easy application, which

may lead to patients who prefer such prophylaxis. The high

cost, however, does not allow their use as rst choice option

in most cases.

Regarding the question about when should treatment be

offered, most studies of prophylactic use of monoclonal

antibodies have as exclusion criteria patients that have failed

with two or more prophylactic medication. However, an

analysis in the subgroup of chronic migraine with erenumab

showed effectiveness of the medication, even in patients that

failed the previous prophylactic treatments, showing that

such medications can be considered in case of refractory

migraine.

In our opinion, to achieve a cost effective

treatment for migraine, we should rst try a preventive

treatment with low cost medication.

The loading dose is propose to galcanezumab, but in

the context of limited resources, after analyzing clinical

outcomes, one may have to evaluate the cost benet of 120

mg and 240 mg doses of galcanezumab.

Tabl e 1. Characteristics of approved anti-CGRP drugs

Generic name Commercial name Study phase Regulatory status Doses studied Half-life Administration protocol Mechanism of action

Erenumab Pasurta Phase 3 Approved 70mg/ 140mg 28 days SC/monthly CGRP receptor

Galcanezumab Emgality Phase 3 Approved 120mg/ 240mg 25-30 days SC/monthly CGRP

Fremanezumab Ajovy Phase 3 Approved 225mg/ 675mg 31-39 days SC/monthly or quarterly CGRP

ASAA

Gama RN, Lima TAC, Dangoni Filho I, Peres MFP

A framework for decision making of migraine treatment with anti-CGRP monoclonal antibodies: a guide for real-world practice and public policies

Regarding the time to determine the response, in the clinical

trials, the duration of the treatment varied from 3 months

to 1 year. There were reports of persisting benets during

the whole period. Studies with galcanezumab (EVOLVE-1,

EVOLVE-2 and REGAIN study) have shown satisfactory

responses of patients in continuous treatment.

16-18

These

patients responded in a modest way in the rst dose

application and have reached better responses in the

following months.

In another open clinical trial

that

veried the satisfaction of participants with the use of

galcanezumab, it was shown an enhancement in the

positive response in the visits of rst, sixth and twelfth month.

Although the studies concluded the main outcome for longer

periods, improvement can start to be observed as early as

the rst week; therefore, we consider that by the end of the

rst month it is possible to classify patients in group 1, 2

or 3.

Future directions

Ideally, this framework should be eld tested, and clinical

trials be done. The opinion of general practitioners, family

physicians, policy makers, neurologists, headache specialists

in several countries should besought and studied.

Divergence or controversy is expected as for what steps of

the algorithm should be followed. This is, however, only the

rst steps in clarifying this issue.

Conclusion

The framework is intended to provide an easier approach for

a better decision making in real life and regulatory affairs.

Author’s contributions: the authors contributed equally in data col-

lection, writing and editing.

Financing: No

Conflict of interests: No

Reinilza Nunes da Gama

https://orcid.org/0000-0003-3101-2277

Figure 1. Framework for improvement of decision making in migraine prophylaxis through anti-CGRP monoclonal antibodies.

ASAA

Gama RN, Lima TAC, Dangoni Filho I, Peres MFP

A framework for decision making of migraine treatment with anti-CGRP monoclonal antibodies: a guide for real-world practice and public policies

Thaiza Agostini Córdoba de Lima

https://orcid.org/0000-0001-6694-5259

Iron Dangoni Filho

https://orcid.org/0000-0003-2822-4033

Mario Fernando Prieto Peres

https://orcid.org/0000-0002-0068-1905

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S182563ORIGINAL ARTICLE