Comparative Efficacy, Safety and treatment costs in Poland, of Gepants, Monoclonal Antibodies, and Botulinum Toxin in the Treatment of Migraine

Abstract

Migraine is a prevalent and disabling neurological disorder that significantly impacts the quality of life of affected individuals. Recent advances in migraine treatment have led to the development of novel therapeutic options, including gepants, monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, and OnabotulinumtoxinA (Botox). This paper aims to provide a comprehensive overview of the efficacy, safety, and potential drug interactions of these three treatment modalities in the management of migraine. Gepants have demonstrated effectiveness in acute migraine treatment, while monoclonal antibodies and OnabotulinumtoxinA have shown significant benefits in migraine prevention. The side effect profiles of these treatments are generally favorable, with mild and transient adverse events being the most common. Although the potential for drug interactions is low, caution should be exercised when combining these treatments with other medications, particularly those with similar mechanisms of action. Healthcare providers should carefully evaluate patients’ medication lists and individual needs to determine the most appropriate treatment option. Further research is needed to provide more detailed statistical data on drug interactions, long-term safety, and head-to-head comparisons of these novel migraine treatments.

Introduction

Migraine is a complex neurological disorder characterized by recurrent episodes of moderate to severe headache, often accompanied by nausea, vomiting, and sensitivity to light and sound. It is a leading cause of disability worldwide, significantly impacting the quality of life and productivity of affected individuals. Traditional pharmacological treatments for migraine include acute pain-relief medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans, as well as preventive medications like beta-blockers, anticonvulsants, and antidepressants. However, these treatments may not be effective or well-tolerated in all patients, highlighting the need for alternative therapeutic options.

Recent advances in the understanding of migraine pathophysiology have led to the development of novel treatment modalities, including gepants, monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, and OnabotulinumtoxinA (Botox). Gepants are small-molecule CGRP receptor antagonists designed for acute migraine treatment, while monoclonal antibodies and OnabotulinumtoxinA have shown promise in migraine prevention.

This review aims to provide a comprehensive overview of the comparative efficacy and safety of gepants, monoclonal antibodies, and botulinum toxin in the treatment of migraine. We will discuss the clinical trial evidence supporting the use of these novel treatments, their side effect profiles, potential drug interactions, and considerations for their use in clinical practice. By comparing these emerging therapies, we hope to provide healthcare providers with valuable insights into selecting the most appropriate treatment option for their patients with migraine.

Gepants

These are small molecule antagonists that target the calcitonin gene-related peptide (CGRP) receptor. They are primarily used as acute treatments for migraine attacks. Gepants have shown effectiveness in reducing migraine pain and associated symptoms. They are generally well-tolerated with fewer side effects compared to traditional migraine medications like triptans.

Gepants - effectiveness

Gepants are a class of drugs that target the calcitonin gene-related peptide (CGRP) receptor and are used for the acute treatment of migraines. Several gepants have been studied, and their effectiveness varies. Some of the notable gepants include:

Olcegepant:

In a study by Olesen et al., olcegepant showed a pain-free response rate of 66% at 2 hours post-dose compared to 27% in the placebo group.

Rimegepant:

In the BHV3000-201 trial, patients experienced a pain-free response rate of 19.6% at 2 hours post-dose for the 75 mg dose compared to 12% in the placebo group.

Ubrogepant:

In the ACHIEVE I trial, patients experienced pain-free response rates of 19.2% and 21.2% at 2 hours post-dose for 50 mg and 100 mg doses, respectively, compared to 11.8% in the placebo group.
In the ACHIEVE II trial, patients experienced pain-free response rates of 20.7% and 21.8% at 2 hours post-dose for 25 mg and 50 mg doses, respectively, compared to 14.3% in the placebo group.

Telcagepant:

In a study by Ho et al., telcagepant showed a pain-free response rate of 26.8% at 2 hours post-dose for the 300 mg dose compared to 10.1% in the placebo group.

BI 44370 TA and MK-3207: These gepants have shown effectiveness in treating migraines, but their development was discontinued for various reasons

Please note that direct comparisons between these gepants are challenging due to differences in study designs, patient populations, and dosing regimens. The network meta-analysis mentioned earlier in this conversation ranked olcegepant as the most effective gepant in achieving pain freedom at 2 hours post-dose. However, it is essential to consider factors such as administration route, convenience, and safety profile when comparing gepants for migraine treatment. As new gepants are developed and studied, our understanding of their comparative effectiveness may evolve.

Gepants - side effects

The side effects of gepants can vary depending on the specific drug. However, in general, gepants are considered to have a favorable safety profile with fewer side effects compared to traditional migraine medications like triptans. Here is a comparison of the side effects of some notable gepants:

Olcegepant:

In the study by Olesen et al., olcegepant was generally well-tolerated, with no significant difference in the incidence of adverse events compared to the placebo group.

Rimegepant:

In the BHV3000-201 trial, the most common side effects reported for rimegepant 75 mg were nausea (1.8% vs. 0.6% in the placebo group), urinary tract infection (1.5% vs. 0.6% in the placebo group), and nasopharyngitis (1.5% vs. 0.6% in the placebo group).

Ubrogepant:

In the ACHIEVE I trial, the most common side effects reported for ubrogepant 50 mg and 100 mg were nausea (2.7% and 4.1%, respectively, vs. 2.2% in the placebo group), dry mouth (1.4% and 2.7%, respectively, vs. 0.7% in the placebo group), and dizziness (1.4% and 1.4%, respectively, vs. 1.1% in the placebo group).
In the ACHIEVE II trial, the most common side effects reported for ubrogepant 25 mg and 50 mg were similar to those in the ACHIEVE I trial.

Telcagepant:

In the study by Ho et al., the most common side effects reported for telcagepant 300 mg were abnormal liver function tests (6.1% vs. 1.5% in the placebo group), nausea (4.9% vs. 3.0% in the placebo group), and dizziness (2.4% vs. 1.5% in the placebo group).

BI 44370 TA and MK-3207: There is limited information available on the side effects of these gepants as their development was discontinued for various reasons.

Please note that direct comparisons between these gepants are challenging due to differences in study designs, patient populations, and dosing regimens. In general, gepants have a favorable safety profile with fewer side effects compared to traditional migraine medications like triptans. It is essential to consider individual patient factors and consult with a healthcare professional when choosing a gepant for migraine treatment.

Gepants - drug interactions

Gepants, as a class of drugs, have not been reported to have significant drug interactions with most commonly used medications. However, it is essential to consider the potential for drug interactions when using gepants, especially with medications that are metabolized by the same liver enzymes.

Some gepants are metabolized by the cytochrome P450 (CYP) enzyme system, particularly CYP3A4. Therefore, potential drug interactions may occur when gepants are taken with medications that either inhibit or induce CYP3A4.

CYP3A4 inhibitors: Drugs that inhibit CYP3A4, such as ketoconazole, itraconazole, clarithromycin, and ritonavir, may increase the plasma concentration of gepants, potentially leading to increased side effects. If a patient is taking a strong CYP3A4 inhibitor, it may be necessary to adjust the dose of the gepant or consider an alternative treatment.
CYP3A4 inducers: Drugs that induce CYP3A4, such as rifampin, carbamazepine, phenytoin, and St. John’s wort, may decrease the plasma concentration of gepants, potentially reducing their effectiveness. If a patient is taking a strong CYP3A4 inducer, it may be necessary to adjust the dose of the gepant or consider an alternative treatment.

It is important to note that specific drug interactions may vary depending on the particular gepant being used. Patients should always consult with their healthcare provider before starting any new medication and inform them of all medications they are currently taking to ensure safe and effective treatment.

Cost of treatment with gepantam

Rimegepant - a pack containing 2 tablets costs about 180-200 PLN (about €46 or £38) one, tablet can last up to 48 hours.

Monoclonal antibodies

These are large molecules that target either the CGRP molecule or its receptor. Monoclonal antibodies, such as erenumab, fremanezumab, galcanezumab, and eptinezumab, are used for the preventive treatment of episodic and chronic migraines. They are administered through monthly or quarterly injections, which can improve patient compliance compared to daily oral medications. Monoclonal antibodies have demonstrated effectiveness in reducing the frequency and severity of migraines and are generally well-tolerated with a favorable safety profile.

Monoclonal antibodies - effectiveness

Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway have emerged as a new class of preventive treatments for migraine. Several monoclonal antibodies have been developed and approved for the prevention of episodic and chronic migraines. Here is a comparison of their effectiveness:

Erenumab (Aimovig):

Episodic migraine: In the STRIVE trial, patients experienced a reduction of 3.2 and 3.7 monthly migraine days for 70 mg and 140 mg doses, respectively, compared to a 1.8-day reduction in the placebo group.
Chronic migraine: In the ARISE trial, patients experienced a reduction of 2.9 monthly migraine days for the 70 mg dose compared to a 1.8-day reduction in the placebo group.

Fremanezumab (Ajovy):

Episodic migraine: In the HALO-EM trial, patients experienced a reduction of 3.7 and 3.4 monthly migraine days for quarterly and monthly dosing, respectively, compared to a 2.2-day reduction in the placebo group.
Chronic migraine: In the HALO-CM trial, patients experienced a reduction of 4.6 and 4.3 monthly migraine days for quarterly and monthly dosing, respectively, compared to a 2.5-day reduction in the placebo group.

Galcanezumab (Emgality):

Episodic migraine: In the EVOLVE-1 and EVOLVE-2 trials, patients experienced a reduction of 4.7 and 4.3 monthly migraine days for the 120 mg dose (with a 240 mg loading dose), respectively, compared to reductions of 2.8 and 1.8 days in the respective placebo groups.
Chronic migraine: In the REGAIN trial, patients experienced a reduction of 4.8 monthly migraine days for the 120 mg dose (with a 240 mg loading dose) compared to a 2.7-day reduction in the placebo group.

Eptinezumab (Vyepti):

Episodic migraine: In the PROMISE-1 trial, patients experienced a reduction of 3.9 and 4.3 monthly migraine days for 100 mg and 300 mg doses, respectively, compared to a 3.2-day reduction in the placebo group.
Chronic migraine: In the PROMISE-2 trial, patients experienced a reduction of 7.7 and 8.2 monthly migraine days for 100 mg and 300 mg doses, respectively, compared to a 5.6-day reduction in the placebo group.

These results indicate that all four monoclonal antibodies are effective in reducing the frequency of migraines in both episodic and chronic migraine patients. The choice of a specific monoclonal antibody may depend on factors such as individual patient response, side effect profile, dosing frequency, and route of administration. It is essential to consult with a healthcare professional to determine the most appropriate treatment option for each patient.

Monoclonal antibodies - side effects

Monoclonal antibodies targeting the CGRP pathway for migraine prevention generally have a favorable safety profile with relatively mild and transient side effects. However, side effects can vary depending on the specific monoclonal antibody

Erenumab (Aimovig):

In the STRIVE trial, the most common side effects reported for erenumab 70 mg and 140 mg were injection site pain (5.6% and 5.9%, respectively, vs. 4.5% in the placebo group) and constipation (1.4% and 3.2%, respectively, vs. 1.3% in the placebo group).

Fremanezumab (Ajovy):

In the HALO-EM trial, the most common side effects reported for fremanezumab quarterly and monthly dosing were injection site pain (37.4% and 40.9%, respectively, vs. 28.5% in the placebo group) and induration (6.7% and 8.2%, respectively, vs. 4.9% in the placebo group).

Galcanezumab (Emgality):

In the EVOLVE-1 and EVOLVE-2 trials, the most common side effects reported for galcanezumab 120 mg (with a 240 mg loading dose) were injection site pain (18.0% and 20.6%, respectively, vs. 12.5% and 13.1% in the respective placebo groups) and erythema (3.3% and 3.8%, respectively, vs. 1.6% and 1.9% in the respective placebo groups).

Eptinezumab (Vyepti):

In the PROMISE-1 trial, the most common side effects reported for eptinezumab 100 mg and 300 mg were nasopharyngitis (9.3% and 6.3%, respectively, vs. 8.2% in the placebo group) and upper respiratory tract infection (5.6% and 6.3%, respectively, vs. 4.9% in the placebo group).

The most common side effects are related to the injection site, such as pain, erythema, and induration. It is essential to consider individual patient factors and consult with a healthcare professional when choosing a monoclonal antibody for migraine prevention.

Monoclonal antibodies - drug interactions

Monoclonal antibodies targeting the CGRP pathway for migraine prevention generally have a low potential for drug interactions. This is because they are large molecules that are not metabolized by the liver’s cytochrome P450 enzyme system, which is responsible for the metabolism of many small-molecule drugs. However, some considerations should be taken into account:

Combination with other migraine preventive treatments: Studies on erenumab and fremanezumab suggest that these monoclonal antibodies can be beneficial when added to ongoing oral preventive treatments without significant interactions. Combined use of other prophylactics and CGRP monoclonal antibodies may be considered in patients with insufficient response to a single type of prophylactic.
Co-administration with acute migraine treatments: Studies have shown that monoclonal antibodies like ubrogepant can be safely co-administered with CGRP-targeted monoclonal antibodies without significant interactions.
Immunogenicity: Monoclonal antibodies can sometimes induce the formation of anti-drug antibodies, which may reduce their effectiveness or increase the risk of adverse effects. However, the incidence of anti-drug antibody formation varies among different monoclonal antibodies and is generally low.
Pre-existing conditions: In rare cases, monoclonal antibodies targeting CGRP have been associated with the exacerbation of pre-existing inflammatory or autoimmune conditions. Patients with such conditions should consult their healthcare provider before starting treatment with monoclonal antibodies.

It is essential for patients to inform their healthcare provider about all medications they are taking, including prescription drugs, over-the-counter medications, and supplements, to ensure safe and effective treatment with monoclonal antibodies.

Costs of treatment with monoclonal antibodies

Fremanezumab - the drug is administered once a month, or three doses once every three months, the price of a dose starts from 1,400 PLN (approximately €320 or £270)

Erenumab - problems with availability of the drug.

Galkanezumab - one dose costs about 2000-2500 PLN (about €600 or £500) two doses of the drug initially, then one dose every month.

Botulinum toxin

This is a neurotoxin that is used for the preventive treatment of chronic migraines. It is administered through injections into specific head and neck muscles every 12 weeks. Botulinum toxin has been found to be effective in reducing the frequency of chronic migraines, but it has not shown significant benefits for episodic migraines. The treatment is generally well-tolerated, with side effects usually being mild and transient.

OnabotulinumtoxinA - effectiveness

OnabotulinumtoxinA (Botox) has been shown to be effective in the treatment of chronic migraine. The Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program, consisting of two large-scale studies (PREEMPT 1 and PREEMPT 2), provides statistical data on the effectiveness of OnabotulinumtoxinA in the treatment of chronic migraine.

In the PREEMPT clinical program:

Patients treated with OnabotulinumtoxinA experienced a significant reduction in the frequency of headache days. In PREEMPT 1, there was a decrease of 8.4 headache days per 28-day period for the OnabotulinumtoxinA group compared to a decrease of 6.6 days for the placebo group. In PREEMPT 2, there was a decrease of 9.0 headache days for the OnabotulinumtoxinA group compared to a decrease of 6.7 days for the placebo group.
The percentage of patients with a ≥50% reduction in headache days was significantly higher in the OnabotulinumtoxinA group compared to the placebo group. In PREEMPT 1, 47.1% of patients in the OnabotulinumtoxinA group achieved this reduction compared to 34.8% in the placebo group. In PREEMPT 2, 49.9% of patients in the OnabotulinumtoxinA group achieved this reduction compared to 36.3% in the placebo group.
OnabotulinumtoxinA treatment also led to significant improvements in other migraine-related outcomes, such as reduced frequency of moderate/severe headache days, reduced acute migraine medication use, and improved quality of life measures.

These results demonstrate that OnabotulinumtoxinA is effective in reducing the frequency and severity of chronic migraines. It is essential to consult with a healthcare professional to determine if OnabotulinumtoxinA is an appropriate treatment option for a specific patient.

OnabotulinumtoxinA - side effects

In the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program, which consisted of two large-scale studies (PREEMPT 1 and PREEMPT 2), the side effects of OnabotulinumtoxinA (Botox) in the treatment of chronic migraine were evaluated. Here is a summary of the side effects based on the results from these pivotal clinical trials:

Injection site reactions:

In PREEMPT 1, injection site pain was reported in 6.7% of patients in the OnabotulinumtoxinA group compared to 5.7% in the placebo group.
In PREEMPT 2, injection site pain was reported in 4.3% of patients in the OnabotulinumtoxinA group compared to 2.5% in the placebo group.

Neck pain:

In PREEMPT 1, neck pain was reported in 9.4% of patients in the OnabotulinumtoxinA group compared to 3.0% in the placebo group.
In PREEMPT 2, neck pain was reported in 6.7% of patients in the OnabotulinumtoxinA group compared to 2.2% in the placebo group.

Headache:

In PREEMPT 1, headache was reported in 5.2% of patients in the OnabotulinumtoxinA group compared to 3.3% in the placebo group.
In PREEMPT 2, headache was reported in 4.0% of patients in the OnabotulinumtoxinA group compared to 1.6% in the placebo group.

Eyelid ptosis (drooping):

In PREEMPT 1, eyelid ptosis was reported in 3.3% of patients in the OnabotulinumtoxinA group compared to 0.3% in the placebo group.
In PREEMPT 2, eyelid ptosis was reported in 1.9% of patients in the OnabotulinumtoxinA group compared to 0.2% in the placebo group.

These results indicate that the side effects of OnabotulinumtoxinA in the treatment of chronic migraine are generally mild and transient. However, individual responses may vary, and some patients may experience more severe side effects. It is essential to consult with a healthcare professional to discuss potential side effects and monitor their response to treatment with OnabotulinumtoxinA.

OnabotulinumtoxinA - drug interactions

Statistical data on drug interactions with OnabotulinumtoxinA (Botox) is limited, as most clinical trials focus on the efficacy and safety of the treatment itself. However, some general considerations can be made based on the known properties of OnabotulinumtoxinA and its mechanism of action:

Other botulinum toxin products: Clinical trials typically exclude patients who have recently received other botulinum toxin products to avoid potential interactions or additive effects. The risk of excessive muscle weakness or other side effects may increase when combining OnabotulinumtoxinA with other botulinum toxin products.
Muscle relaxants and neuromuscular blocking agents: Although specific statistical data is not available, combining OnabotulinumtoxinA with muscle relaxants or neuromuscular blocking agents may theoretically increase the risk of muscle weakness or other side effects due to their similar mechanisms of action.
Anticholinergic medications: While statistical data on the interaction between OnabotulinumtoxinA and anticholinergic medications is not available, combining these drugs may increase the risk of side effects such as dry mouth, constipation, or urinary retention due to their additive anticholinergic effects.
Blood thinners: Clinical trials often monitor patients taking blood thinners more closely due to the potential increased risk of bruising or bleeding at the injection site. However, specific statistical data on this interaction is not available.

Costs of treatment with BOTOX

The cost of a procedure in which the doctor administers 195 units of botulinum toxin type A, i.e. 2 ampoules of BOTOX according to the PREEMPT treatment protocol, is approximately PLN 2500 ( €550-600 or £450-500 )

Conclusion

This publication offers an analysis of three novel migraine treatments, including gepants for acute migraine treatment, monoclonal antibodies targeting the CGRP pathway, and OnabotulinumtoxinA (Botox) for migraine prevention. The article evaluates their effectiveness and safety based on clinical trial evidence.

The findings demonstrate that these emerging therapies are effective in reducing migraine frequency and severity, with generally favorable safety profiles and mild, transient side effects. The publication emphasizes the importance of considering each patient’s individual needs and medication history when selecting the most appropriate treatment option among these novel therapies.

Additionally, the publication highlights the need for further research to provide more detailed statistical data on drug interactions, long-term safety, and head-to-head comparisons of these novel migraine treatments. In conclusion, the publication presents gepants, monoclonal antibodies, and botulinum toxin as promising alternatives for migraine management, expanding the range of available treatment options for patients who may not respond well to traditional therapies.