Introduction

Migraine is a common neurological disorder characterized by recurrent, mostly unilateral, moderate-to-severe throbbing headaches, often accompanied by nausea, vomiting, photophobia, and phonophobia,1 and has become one of the major public health problems worldwide. Migraine causes the second highest number of life years lost due to disability among all human diseases and the highest number of disability-adjusted life years among females aged 15–49 years, with a very negative impact on patients, their families, and society. About 1.04 billion people worldwide suffer from migraine.2 In China, the annual prevalence of migraine is 9%, and the yearly cost of treatment for migraine sufferers exceeds $299.4 billion.3,4 The annual cost of treating migraineurs diagnosed with migraine exceeds 299.4 billion dollars.

Drugs previously used in the acute treatment of migraine include non-migraine-specific therapeutic drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) and other analgesics, in addition to migraine-specific therapeutic drugs such as the Triptans class.5,6 However, about 1/3 of patients have an inadequate response to treatment with Triptans, and 20% or more of migraine patients have contraindications to the use of Triptans due to co-morbid cardiovascular disease that precludes the use of such medications. In addition, there are few patients with medication-overuse headache (MOH) due to the unregulated use of NSAIDS and Triptans.7–9 Calcitonin gene-related peptide (CGRP) is a novel therapeutic target for the treatment of migraine, for which therapeutic options are increasingly being updated. CGRP and its receptors are widely distributed in the trigeminal vascular and central nervous systems, and play an important role in the pathogenesis of migraine. Novel drugs targeting CGRP have been a hot research topic in recent years, and have been recommended by national and international migraine guidelines for acute and/or prophylactic treatment of migraine.

Rapid health technology assessment (rHTA) as an evidence synthesis methodology can provide evidence support to decision makers by rapidly assessing the efficacy, safety, and economy of drugs through simplified health technology assessment methods and processes. Many health authorities and hospitals in the world have applied rHTA in the decision-making of drug access and payment.10,11 To scientifically evaluate the clinical value of the comprehensive attributes of CGRP-targeted therapy drugs, a comprehensive literature-based clinical evaluation of CGRP-targeted therapy drugs was conducted using the drug evaluation method modified by expert discussion in the Rapid Guide for Drug Evaluation and Selection in Chinese Medical Institutions (Second Edition) (hereinafter referred to as the Selection Guidelines)12 to provide reference and a basis for the rational use of drugs in clinics as well as the provision of individualized treatment protocols for different patients. To provide a reference and basis for rational clinical use of drugs and individualized treatment plans for different patients.

Materials and MethodsEvaluation Basis

Based on the “Selection guide” published in 2023, and applying the Mini-health technology assessment (Mini-HTA) combined with the system of objectified judgment analysis(SOJA) to evaluate 8 CGRP-targeted therapy drugs. The evaluation dimensions and weights were determined by the guideline guidance group and the expert group through the Delphi method. The pharmaceutical properties, effectiveness, safety, economy and other properties of CGRP-targeted therapies were evaluated.

Evaluation of Drugs

New migraine-specific preventive therapies targeting the CGRP pathway have been recently introduced. These novel treatments are injectable monoclonal antibodies targeting the CGRP ligand (fremanezumab, galcanezumab, eptinezumab) or its receptor (erenumab), and the orally administrated small molecule CGRP receptor antagonists, the so called gepants (ubrogepant, atogepant, rimegepant and zavegepant). The final drugs included in the evaluation and drug information are shown in Table 1.

Table 1 CGRP-Targeted Therapies Drugs Information

Relevant Evidence Retrieval and Evaluation Contents

Based on drug labels, drug registration information, some government websites (eg, American Food and Drug Administration (FDA) provide safety information. We searched English databases PubMed, Embase, and Cochrane Library, as well as Chinese databases Chinese Biomedical Sciences (CBM) and China National Knowledge Infrastructure (CNKI). The goal is to score the 8 CGRP-targeted therapy drugs on five dimensions, the total score is 100 points, including an assessment of their pharmacologic properties (28 points), efficacy (27 points), safety (25 points), economy (10 points), and other attributes (10 points).

Analysis and Evaluation

Based on evidence-based data and the relevant elements and weighting in the “Drug Selection Guidelines” quantification record form for drug evaluation and selection in medical institutions, adjustments were made according to the characteristics of CGRP-targeted therapies. Ultimately, a quantitative evaluation record form was developed, which includes scoring across five dimensions based on specific project indicators. The evaluation was conducted independently by two clinical pharmacists. When there was a significant discrepancy between their scores in any dimension (greater than 3 points), a third expert from the relevant field was invited to discuss and make a final determination. This process aimed to minimize subjective error and reduce bias. The comprehensive score system recommends strong support for scores above 70 points; for scores between 60 and 70, depending on the availability of alternative treatments, the recommendation is either weak or negative. Scores below 60 are advised as non-recommendations.

ResultsPharmacological Properties (28 Points)Pharmacological Effects

8 CGRP-targeted therapy drugs with definite clinical efficacy, precise mechanism of action, and innovative mechanism of action or target point of action, all scored 5 points.

In vivo Processes

At the same time, pharmacokinetic parameters are complete, scored 5 points.

Pharmacy and Method of Use

8 CGRP-targeted therapies drugs main ingredients and auxiliary materials are clear, scored 2 points; Specifications and packaging are suitable for clinical and dose adjustment, scored 2 points.

Dosage forms: among them, erenumab, fremanezumab and galcanezumab are subcutaneous injections, scored 1.5 points; eptinezumab is the intravenous injection, scored 1 point. Ubrogepant, rimegepant and atogepant are oral tablets, scored 2 points. Zavegepant is a nasal spray,scored 2 points.

The dose administered: in addition to zavegepant, which uses a fixed dose each time, scored 2 points, the other 7 kinds need to adjust the dose according to the course of treatment and the degree of disease, scored 1.5 points.

The eight CGRP-targeted therapies all have a dosing frequency of ≤1 time per day, though there are significant differences in actual dosing intervals. To enhance the evaluation and make the scoring more meaningful, we adjusted the scoring criteria based on the real-world dosing frequency of these drugs. Eptinezumab, which is administered once every three months, scored 2 points. Erenumab, fremanezumab, and galcanezumab, which are administered monthly, scored 1.5 points. Ubrogepant, rimegepant, and zavegepant require multiple doses per month, and dosing frequency should be confirmed with a physician. Therapies administered more than once per month are scored 1 point. Atogepant, which is taken once daily, scored 0.5 points.

Ease of use: patients treated with erenumab, fremanezumab, galcanezumab need to be trained by a healthcare provider, scored 1.5 points. Patients treated with eptinezumab need to be administered by medical personnel,scored 1 point. The rest of the drugs can be self administered, scored 2 points.

Storage Conditions

Erenumab, fremanezumab, galcanezumab, eptinezumab need to be stored in refrigerated storage,scored 1 point; ubrogepant, rimegepant, atogepant, zavegepant need to be stored in the shade, scored 2 points.

Expiry Date

The expiry date of rimegepant is 48 months, and the expiry date of erenumab is 36 months, scored 1.5 points; Other drugs have 24 months, scored 1 point.

The results of the pharmaceutical properties scoring are presented in Table 2.

Table 2 Pharmaceutical Properties Score Results

Efficacy (27 Points)Indications

All 8 CGRP-targeted therapy drugs have been approved for the treatment of migraines. Among them, erenumab, fremanezumab, galcanezumab, eptinezumab and atogepant are used for the preventive treatment of migraines. Ubrogepant and zavegepant are specifically indicated for the acute treatment of migraine attacks. Rimegepant is currently the only drug approved for both the acute treatment and preventive therapy of migraines, and it has gradually become the first-choice drug in clinical practice, scored 5 points. Erenumab, fremanezumab, galcanezumab, eptinezumab, ubrogepant and atogepant are considered secondary recommendations in clinical practice,scored 3 points. Zavegepant, as a newly marketed drug with limited research on its safety and efficacy, is less frequently used in clinical practice, and given the availability of multiple alternatives, scored 1 point.

Guideline Recommendations

Erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant, atogepant were recommended in several guidelines. All highest recommendation grade was IA, and they scored a guideline recommendation score of 12. The highest recommendation grade of ubrogepant was IIA, scored 9 points. Zavegepant did not have a high recommendation grade due to its late introduction to the market,scored 2 points.

Domestic and international guidelines or consensus recommendations are shown in Table 3.

Table 3 Recommendations From National and International Guidelines/Consensus

Clinical Efficacy

The trial endpoint is mean monthly migraine days. Responder rates have emerged as an important secondary efficacy endpoint that indicates the magnitude of efficacy in individual patients. Other key secondary endpoints of the trials include reduced acute medication use and multiple patient-reported outcomes.

A prospective randomized head-to-head study of galcanezumab and rimegepant showed that both were effective, safe, and well tolerated. Galcanezumab was not superior to rimegepant for the primary endpoint.19 In another head-to-head experiment comparing the effectiveness of atogepant and rimegepant, oral atogepant once daily demonstrated a significantly greater reduction.20,21 A study of erenumab vs topiramate found that adherence to erenumab was significantly better than adherence to topiramate (primary endpoint), and found as a secondary endpoint that the efficacy of erenumab was statistically superior to that of topiramate.22 Multiple meta-analyses have been performed to evaluate the CGRP-targeting migraine preventive therapies.23–28 All confirm their efficacy, and some also confirm their safety and tolerability.

Overall, on the primary outcome endpoint erenumab, fremanezumab, galcanezumab, eptinezumab, ubrogepant, rimegepant, atogepant and zavegepant scored 5, 4, 5, 4, 4,6,5, and 4, respectively. At the secondary outcome endpoint, the scores for erenumab, fremanezumab, galcanezumab, eptinezumab, ubrogepant, rimegepant, atogepant and zavegepant were 3, 3, 3, 3, 4, 4.4 and 2, respectively.

The efficacy score results are shown in Table 4.

Table 4 Efficacy Score Results

Safety (25 Points)Adverse Events

The severity of adverse events was graded according to the “Common Terminology Criteria for Adverse Events”.29 Erenumab: most adverse drug reactions (ADRs) were mild or moderate. The most common ADRs were injection site reactions and constipation, with an incidence of 1% to <10%, scored 2 points. Fremanezumab: the most common ADR was injection site reactions (1%), scored 3 points.Galcanezumab (120 mg): the ADRs included injection site pain (10.1%), injection site reactions (9.9%), dizziness (0.7%), constipation (1.0%), itching (0.7%), and hives (0.3%). Most reactions were mild or moderate in severity, with an average incidence of 1% to <10%,scored 2 points. Eptinezumab: the most common ADRs were nasopharyngitis and allergic reactions, with an incidence of 1% to <10%, scored 2 points.Ubrogepant: common ADRs included nausea (2%), somnolence (2%), and dry mouth (2%), with an incidence of 1% to <10%, scored 2 points. Rimegepant: the most common ADR was nausea (1.2%), with most reactions being mild to moderate, scored 2 points.Atogepant: common ADRs included constipation (6%), nausea (5%), decreased appetite (1%), and fatigue/somnolence (4%), with an average incidence of 1% to <10%, scored 2 points.Zavegepant: common ADRs included taste disorders (18%), nausea (4%), nasal discomfort (3%), and vomiting (2%), with an average incidence of 1% to <10% scored 2 points.

Both rimegepant and zavegepant had rare severe allergic reactions, with an incidence of less than 1%, scored 3 points. All other therapies had no severe ADRs or an incidence of less than 0.01%, scored 5 points.

Special Populations

All 8 CGRP-targeted therapy drugs were not suitable for children.For elderly, erenumab, galcanezumab, ubrogepant, atogepant and zavegepant should be used with caution, scored 0.5 points. Fremanezumab, eptinezumab and rimegepant did not determine whether they responded differently from younger subjects, scored 0 points. All 8 CGRP-targeted therapy drugs should be avoided during pregnancy, with each receiving a score of 0 points. For breastfeeding women, it is recommended to consult a physician and use the medications with caution, each receiving a score of 0.5 points. Patients with liver impairment can take erenumab, fremanezumab, galcanezumab, eptinezumab and ubrogepant, with each receiving a score of 3 points. However, patients with severe liver impairment should avoid using rimegepant, atogepant and zavegepant, scored 2 points.Patients with renal impairment can use all eight CGRP-targeted therapies, with each receiving a score of 3 points.

Drug Interactions

Erenumab, fremanezumab, galcanezumab and eptinezumab are not metabolized by cytochrome P450 enzymes, so taking them with other drugs does not affect absorption efficiency, and they each receive a score of 3 points. Atogepant requires a dose adjustment when administered concomitantly with CYP3A4 inhibitors, scored 2 points. Ubrogepant should be avoided when taken concomitantly with strong CYP3A4 inhibitors, scored 1 point. Rimegepant should be avoided when taken concomitantly with strong CYP3A4 inhibitors, strong CYP3A4 inducers, and moderately potent CYP3A4 inducers, scored 1 point. Zavegepant should be avoided when taken concomitantly with inhibit OATP1B3 or NTCP transporters,scored 1 point.

Other

All adverse reactions of the drugs included in the study were reversible and scored 1 point. The instructions for all drugs have no special medication warning, and all scored 1 point. Fremanezumab and eptinezumab have not undergone carcinogenicity or teratogenicity studies, scored 0 points. Erenumab, galcanezumab, ubrogepant and atogepant have no known carcinogenicity but may cause harm to the fetus, scored 0.5 points. Rimegepant and zavegepant show no evidence of carcinogenicity or teratogenicity, scored 1 point.

The safety score results are shown in Table 5.

Table 5 Safety Score Results

Economy (27 Points)

The specifications, dosages, and prices of all 8 CGRP-targeted therapy drugs were sourced from the US FDA Drugs Database, Pharmacy Checker, PharmStore, and GoodRx websites.

All information counted as of September 20, 2024. 8 CGRP-targeted therapy drugs do not have the same generic name. The drug with the lowest average daily treatment cost of the same kind of drug is scored 7 points, and the evaluation drug score = the lowest average daily treatment cost/the average daily treatment cost of the evaluated drug * 7. Among the 8 CGRP-targeted therapies drugs, the drug with the lowest average daily treatment cost is rimegepant, with an average daily cost of 69.11 yuan; the corresponding scores were calculated according to the evaluation method, and the score of the erenumab, fremanezumab, galcanezumab, eptinezumab, ubrogepant, rimegepant, atogepant, and zavegepant were scored as5.78, 6.22, 5.34, 6.19, 5.57, 10, 4.93, and 4.44 respectively. See Tables 6 and 7 for details. See Tables 6 and 7 for details.

Table 6 Basic Economy Information

Table 7 Economy Score Results

Other Attributes (10 Points)National Health Insurance and National Essential Drug Characteristics

All 8 CGRP-targeted therapies drugs are not included in the National Health Insurance and National Essential Drug Catalog.

National Centralized Drug Procurement and Original Research Drugs

All 8 CGRP-targeted therapy drugs are originator drugs, all scored 1 point. In addition, none of the CGRP-targeted therapies drugs are national centralized drug procurement drugs, scoring 0 points.

Status of producers

Table 1 shows the manufacturer of all 8 CGRP-targeted therapies drugs. The manufacturers of erenumab, rimegepant, atogepant and zavegepant are among the top 50 pharmaceutical companies in terms of global sales and are ranked 4th, 1st, 2nd, and 7th, respectively (2023 rankings). Fremanezumab, galcanezumab and ubrogepant are among the top 50 pharmaceutical companies in terms of global sales and are ranked 21 st,24th, and 13th.Eptinezumab is not on the list of the top 100 pharmaceutical industry in China and the World’s top 50 pharmaceutical companies.

Global Utilization

Erenumab, galcanezumab, rimegepant are available in China, USA, Europe, Japan.

Fremanezumab, eptinezumab are available in the United States, Europe, and Japan. They are used regularly in some parts of China. Fremanezumab is used in hospitals within the Guangdong-Hong Kong-Macao Greater Bay Area under the “Hong Kong and Macao Drug and Device Access” policy. Eptinezumab is utilized at Hainan Ruijin Hospital under the “Pioneer Pilot” policy. Ubrogepant, atogepant, zavegepant are not available in China.

The other attributes’ score results are shown in Table 8.

Table 8 Other Attribute Score Results

Discussion

CGRP analogs are currently used clinically as an important option for migraine treatment, but their clinical efficacy and drug costs vary widely.16,30,31 According to the “Selection Guidelines”, the clinical comprehensive evaluation of CGRP-targeted therapy drugs marketed globally is carried out from five dimensions, which evaluates the core attributes of drugs (pharmacological properties, safety, efficacy and economy), policy attributes (inclusion in the National Health Insurance, inclusion in the National Essential Drugs), and the basic attributes of drugs (storage conditions, the expiration date of the drugs, use, status of the manufacturing enterprises, etc.) to evaluate the comprehensive clinical value of CGRP-targeted therapy drugs can effectively measure the difference in clinical utility between different drugs, and provide a reference basis for the selection of drugs by medical institutions and the rational selection of clinical drugs.

As shown in Table 9, the drugs included in this study in descending order of final quantitative scores were: rimegepant, erenumab, fremanezumab, atogepant, galcanezumab, eptinezumab, ubrogepant and zavegepant. Final scores were 84.5, 75.78, 74.02, 73.93, 72.64, 71.69, 70.37, 56.44. Among them, rimegepant, erenumab, fremanezumab, atogepant, galcanezumab, eptinezumab, and ubrogepant scored higher than 70 and made strong recommendations for the treatment of migraine in clinical use. Other drugs (zavegepant) scored between 60 ~ 70, which is a weak recommendation, and medical institutions can choose according to the actual situation.

Table 9 Final Total Score Results

According to the evaluation results, rimegepant has the best overall evaluation results. Rimegepant is a second-generation gepant drug. Rimegepant has been marketed in China, the United States, Europe, Japan and other countries, and is currently the only drug approved for dual indications of acute phase treatment and prophylactic treatment of migraine. The drug dosage form is orally disintegrating tablets, which has the advantages of easy to take, fast onset of action.Rimegepant also has high bioavailability, and provides migraine sufferers with a more convenient and novel choice. Erenumab, galcanezumab and fremanezumab are monoclonal antibodies.The monoclonal antibodies have a higher binding specificity and longer half-life than the gepant, so the safety is higher. They are administered by subcutaneous injection, and the frequency of administration is ≤1 ·d−1, which will greatly improve the compliance of migraine patients.Atogepant is an oral tablet, indicative for the preventive treatment of episodic migraine in adults. Its clinical effectiveness is better. The course of administration is long, the dose needs to be adjusted according to the condition, and it is expensive.

Eptinezumab is an intravenous monoclonal antibody that requires specialized administration by a health care provider. Ubrogepant had lower efficacy and safety scores. The lowest scoring zavegepant is the only nasal spray that specifically treats migraine, has limited clinical data, and is recommended less frequently by guidelines.Side effects of the currently marketed CGRP antagonists are all relatively rare, with common side effects including injection site reactions, constipation, mild joint pain, nausea, fatigue, and nasal irritation (nasal preparations).

In recent years, with the increasing research on the mechanism of migraine occurrence, the role of CGRP in the trigeminal vascular system in the pathogenesis of migraine has attracted much attention and has become a new target for migraine treatment and prevention.32–34 Compared to the current mainstay of migraine treatment, the CGRP drug is well tolerated and opens up new possibilities with an additional option for patients who cannot tolerate triptan or who have not had an effect with other preventive medications.There are two types of CGRP-targeted therapy drugs: monoclonal antibodies and small molecule antagonists (gepants). These drugs are available as injections, nasal sprays, oral medications and so on.

Clinical trials on the safety and efficacy of CGRP-targeted therapy drugs are currently underway. Some clinical trials are developing indications for different CGRP-targeted therapy drugs for different types of migraine attacks, and the safety of the dosage of CGRP-targeted therapy drugs needs to be verified in subsequent clinical trials, as well as pediatric data, carcinogenicity, etc. The extent to which CGRP controls neurotransmission associated with migraine and its independence from other neurotransmitters remains to be examined.35 At this stage, CGRP-targeted therapy drugs are expensive and long-term use requires a certain degree of affordability.This study also has some limitations: (1) The clinical trial data referenced for the evaluation are small, and further real-world based clinical synthesis is still needed. (2) As each drug is marketed differently, some drug attributes, such as economics, cannot be compared under the same conditions. (3) CGRP-targeted therapy drugs are listed late in China, with a short clinical use time, and there are many deficiencies in indications, guideline recommendations, and health insurance reimbursement, etc. There is an urgent need for further dynamic evaluations of CGRP-targeted therapy drugs on the basis of new evidence-based bases, new health insurance policies, and pricing information.

Conclusion

Rimegepant, erenumab, fremanezumab, atogepant, galcanezumab, eptinezumab, ubrogepant can be entered into the medication list of medical institutions as strongly recommended drugs. The evaluation results can provide a reference for medical institutions to select CGRP-targeted therapies drugs.

Acknowledgment

We would like to thank all of the author that participated in the present study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was supported by the National Key Specialty Construction Project (Clinical Pharmacy) and the High-level Clinical Key Specialty of Guangdong Province, and the funders were the central finance subsidy fund for the improvement of medical services and guarantee capacity, code Z155080000004; the Guangzhou Minsheng Science and Technology Research Program Project, code 201803010096.

Disclosure

The authors report no conflicts of interest in this work.

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