CGRP-targeted medication in chronic migraine - systematic review.

BACKGROUND: Chronic migraine is a highly debilitating condition that is often difficult to manage, particularly in the presence of medication overuse headache. Drugs targeting the calcitonin gene-related peptide (CGRP), or its receptor have shown promising results in treating this disorder. METHODS: We searched Pubmed and Embase to identify randomized clinical trials and real-world studies reporting on the use of medication targeting the calcitonin gene-related peptide in patients with chronic migraine. RESULTS: A total of 270 records were identified. Nineteen studies qualified for the qualitative analysis. Most studies reported on monoclonal antibodies targeting CGRP (anti-CGRP mAbs), that overall prove to be effective in decreasing monthly migraine days by half in about 27.6-61.4% of the patients. Conversion from chronic to episodic migraine was seen in 40.88% of the cases, and 29-88% of the patients stopped medication overuse. Obesity seems to be the main negative predictor of response to anti-CGRP mAbs. There is no evidence to suggest the superiority of one anti-CGRP mAb. Despite the lack of strong evidence, the combination of anti-CGRP medication with onabotulinumtoxinA in chronic migraine is likely to bring benefits for resistant cases. Atogepant is the first gepant to demonstrate a significant decrease in monthly migraine days compared to placebo in a recent trial. Further, anti-CGRP mAb and gepants have a good safety profile. CONCLUSION: There is strong evidence from randomized trials and real-world data to suggest that drugs targeting CGRP are a safe and effective treatment for chronic migraine.

Developments in targeting calcitonin gene-related peptide.

INTRODUCTION: Calcitonin Gene-Related Peptide (CGRP)-targeted therapy has revolutionized migraine treatment since its first approval in 2018. CGRP-targeted therapy includes monoclonal antibodies (mAbs) and gepants, which modulate trigeminal nociceptive and inflammatory responses, alleviating pain sensitization involved in migraine pathogenesis. CGRP-targeted therapy is effective not only for migraine but also for other chronic headache disorders that share the CGRP pathway. AREAS COVERED: The authors review the latest developments and evidence for CGRP-targeted therapy for episodic migraine and chronic migraine. In addition, the authors discuss the emerging evidence on response prediction, menstrual migraine, vestibular migraine, idiopathic intracranial hypertension, post-traumatic headache, and the relationship between selected migraine comorbidities and CGRP. EXPERT OPINION: Since the launch of CGRP-targeted therapy, many practical issues have been raised. Generally, it's safe to combine CGRP-targeted mAbs and gepants; this is an excellent option for patients with partial response. When considering stopping CGRP-targeted therapy, although a disease-modifying effect is likely, the optimal time for discontinuation remains unknown. Finally, beyond migraine, CGRP-targeted therapy may be used for other chronic pain disorders and psychological comorbidities.

A multicenter, open-label long-term safety study of rimegepant for the acute treatment of migraine.

BACKGROUND: The present study evaluated the long-term safety and tolerability of rimegepant, an orally administered small molecule calcitonin gene-related peptide receptor antagonist, in people with migraine. METHODS: This multicenter, long-term, open-label safety study included adults (≥18 years) with ≥1 year history of migraine who were sequentially enrolled into three groups: participants in the first two groups had either 2-8 or 9-14 moderate to severe migraine attacks per month by history and treated as needed (pro re nata [PRN]) with one rimegepant 75 mg oral tablet up to once per calendar day for 52 weeks (PRN 2-8 and PRN 9-14); a third group, included to collect safety data during higher-frequency dosing, had 4-14 moderate to severe migraine attacks per month by history and who took one rimegepant tablet every other day as scheduled dosing plus PRN dosing of one rimegepant tablet for migraine attacks of any severity on nonscheduled dosing days for 12 weeks (every other day (EOD) + PRN). RESULTS: Overall, 1800 participants self-administered rimegepant (PRN 2-8: n = 1033; PRN 9-14: n = 481; EOD + PRN: n = 286). The most common on-treatment adverse events (AEs) were upper respiratory tract infection (8.8%), nasopharyngitis (6.8%) and sinusitis (5.1%). Most AEs were mild or moderate and considered unrelated to rimegepant. Serious AEs considered possibly (n = 1) or unlikely (n = 9) related to rimegepant were reported in ten (0.6%) participants. No signal of drug-induced liver injury because of rimegepant was identified. CONCLUSIONS: Rimegepant 75 mg up to once per day as EOD + PRN for 12 weeks or PRN for up to 52 weeks was safe and well tolerated. No signal of hepatotoxicity, potential drug abuse, or medication-overuse headache was identified.Trial registration: Clinicaltrials.gov: NCT03266588.

Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: An American Headache Society position statement update.

OBJECTIVE: To provide a position statement update from The American Headache Society specifically regarding therapies targeting calcitonin gene-related peptide (CGRP) for the prevention of migraine. BACKGROUND: All migraine preventive therapies previously considered to be first-line treatments were developed for other indications and adopted later for migraine. Adherence to these therapies is often poor due to issues with efficacy and tolerability. Multiple new migraine-specific therapies have been developed based on a broad foundation of pre-clinical and clinical evidence showing that CGRP plays a key role in the pathogenesis of migraine. These CGRP-targeting therapies have had a transformational impact on the management of migraine but are still not widely considered to be first-line approaches. METHODS: Evidence regarding migraine preventive therapies including primary and secondary endpoints from randomized placebo-controlled clinical trials, post hoc analyses and open-label extensions of these trials, and prospective and retrospective observational studies were collected from a variety of sources including PubMed, Google Scholar, and ClinicalTrials.gov. The results and conclusions based upon these results were reviewed and discussed by the Board of Directors of The American Headache Society to confirm consistency with clinical experience and to achieve consensus. RESULTS: The evidence for the efficacy, tolerability, and safety of CGRP-targeting migraine preventive therapies (the monoclonal antibodies: erenumab, fremanezumab, galcanezumab, and eptinezumab, and the gepants: rimegepant and atogepant) is substantial, and vastly exceeds that for any other preventive treatment approach. The evidence remains consistent across different individual CGRP-targeting treatments and is corroborated by extensive "real-world" clinical experience. The data indicates that the efficacy and tolerability of CGRP-targeting therapies are equal to or greater than those of previous first-line therapies and that serious adverse events associated with CGRP-targeting therapies are rare. CONCLUSION: The CGRP-targeting therapies should be considered as a first-line approach for migraine prevention along with previous first-line treatments without a requirement for prior failure of other classes of migraine preventive treatment.

Evaluation of the effect of Exercise Trainings and CGRP receptor antagonist (BIBN 4096) on mitochondrial dynamic in the hippocampus of male Wistar rats.

BACKGROUND: Exercise training showed beneficial effects on brain. The purpose of the present study is to evaluate the effect of six weeks of high-intensity interval training (HIIT) and Endurance training (ET) with calcitonin gene-related peptide (CGRP) receptor antagonist on the expression of genes involved in mitochondrial dynamics and apoptosis in hippocampal tissue of male Wistar rats. METHODS: In this study, forty-two healthymale Wistar rats (8-week) were randomly divided into 6 groups (n = 7) as follow; 1) Control; 2) HIIT which performed 6 weeks of HIIT; 3) ET which performed 6 weeks of endurance training; 4) CGRPi received 10 mg/kg CGRP receptor antagonist every day at the last 2 weeks; 5) CGRPi-HIIT performed HIIT and received CGRP receptor antagonist; 6) CGRPi-ET performed ET and received CGRP receptor antagonist. Real-time PCR (2-ΔΔCT) and western blotting were employedto measure the expression of genes and protein, respectively. RESULTS: HIIT and ET significantly increased Bcl-2, Pgc-1α, Sirt3, and Nrf-1 gene expression in the hippocampal tissue (p < 0.05, p < 0.01, p < 0.01, and p < 0.001, respectively). ET-CGRPi and HIIT-CGRPi significantly increased Sirt3, Pgc-1α, and Nrf-1 gene expression compared to the control group (p < 0.05, p < 0.01, and p < 0.05, respectively). CONCLUSION: ET and HIIT-induced physiological alterations in the hippocampus. In fact, this modulation showed protective properties in the hippocampusvia up regulation of Bcl-2, Pgc-1α, Nrf-1, and Sirt3 gene expression. CGRPi did not cause gene or protein changes harmful to mitochondrial dynamic balance and apoptosis in the hippocampus of rats.

Evaluation of outcomes of calcitonin gene-related peptide (CGRP)-targeting therapies for acute and preventive migraine treatment based on patient sex.

BACKGROUND: Women show increased prevalence and severity of migraine compared to men. Whether small molecule calcitonin gene-related peptide receptor (CGRP-R) antagonists (i.e., gepants) and monoclonal antibodies targeting either the CGRP-R or the CGRP peptide might show sexually dimorphic outcomes for acute and preventive therapy has not been established. METHODS: We conducted a subpopulation analysis of available published data from FDA reviews to evaluate potential sex differences in the response rates of ubrogepant, rimegepant and zavegepant for acute migraine therapy. Available data from FDA reviews of erenumab, fremanezumab, galcanezumab and eptinezumab, approved CGRP-R and CGRP monoclonal antibodies and of atogepant were examined for prevention outcomes based on patient sex. Preventive outcomes were analyzed separately for patients with episodic migraine and chronic migraine. RESULTS: In women, the three approved gepants produced statistically significant drug effects regardless of dose tested on the FDA mandated co-primary endpoints, the proportion of patients achieving two-hour pain-freedom and the proportion of patients free of their most bothersome symptom at two hours post-dose. In women, the average placebo-subtracted two-hour pain-freedom proportion was 9.5% (CI: 7.4 to 11.6) and the average numbers needed to treat was 11. The free from most bothersome symptom at two hours outcomes were also significant in women. The gepant drugs did not reach statistically significant effects on the two-hour pain-freedom endpoint in the men, with an average drug effect of 2.8% (CI: -2.5 to 8.2) and an average number needed to treat of 36. For freedom from most bothersome symptom at two hours post-dose endpoint, differences were not significant in male patients. The treatment effect in each of the gepant studies was always numerically greater in women than in men. In evaluation of prevention outcomes with the antibodies or atogepant using the change from the specified primary endpoint (e.g., monthly migraine days), the observed treatment effect for episodic migraine patients almost always favored drug over placebo in both women and men. For chronic migraine patients the treatment effects of antibodies were similar in men and women and always favored the drug treated group.Conclusion/Interpretation: Small molecule CGRP-R antagonists are effective in acute migraine therapy in women but available data do not demonstrate effectiveness in men. CGRP-targeting therapies are effective for migraine prevention in both male and female episodic migraine patients but possible sex differences remain uncertain. In male and female chronic migraine patients, CGRP/CGRP-R antibodies were similarly effective. The data highlight possible differential effects of CGRP targeted therapies in different patient populations and the need for increased understanding of CGRP neurobiology in men and women.

Blood pressure elevation in erenumab-treated patients with migraine: A retrospective real-world experience.

BACKGROUND: Erenumab is a monoclonal antibody that targets the calcitonin gene-related peptide (CGRP) receptor and is approved for the preventative treatment of migraine in adults. CGRP is involved in the regulation of vasomotor tone under physiologic and pathologic conditions, including hypertension. While there has not been evidence of hypertension in preclinical models or clinical trials, post-marketing data suggest erenumab may be associated with hypertension. This led to a warning in the United States Food and Drug Administration prescribing information for erenumab. OBJECTIVE: To determine the frequency of worsening blood pressure (BP) after initiation of erenumab in patients with migraine and how this is associated with hypertension. METHODS: This is an observational retrospective cohort study evaluating patients at a tertiary headache or neurology department. Systolic and diastolic BPs were compared between the initial visit prior to initiation of erenumab, and follow-up visit while on erenumab. Worsening BP was defined as moving from a lower stage to a higher stage of BP, as defined by the American Heart Association. Serious adverse vascular events were also recorded. RESULTS: A total of 335 patients were included in the final analysis (mean [SD] age of 45.7 [14.40] years, 83.9% [281/335] female). At baseline, 20.9% (70/335) of patients had a prior diagnosis of hypertension. The median (interquartile range) time to follow-up appointment from initial appointment was 20.5 (13.3-35.3) weeks. The mean (SD) BP at baseline was systolic 124.7 (15) mmHg and diastolic 77 (11) mmHg, and at follow-up was systolic 124.0 (15) mmHg and diastolic 77.8 (9) mmHg. Overall, 23.3% (78/335) of all patients had worsening BP, whereas 13/225 (3.9%) patients had improvement in their BP. Patients with atrial fibrillation were more likely to develop worsening BP (odds ratio, 4.9, 95% confidence interval 1.12-21.4; p = 0.035). There was no association between worsening BP and pre-existing hypertension, sex, body mass index, or age. One patient had non-ST elevation myocardial infarction attributed to a hypertensive emergency while on erenumab. CONCLUSION: We found that 23.3% of patients initiated on erenumab may have developed worsening BP, suggesting the need for BP monitoring in patients initiated on erenumab.

Bioequivalence of rimegepant, a small molecule CGRP receptor antagonist, administered as an oral tablet, a sublingual orally disintegrating tablet, and a supralingual orally disintegrating tablet: two phase 1 randomized studies in healthy adults.

BACKGROUND: Rimegepant is an orally administered small molecule calcitonin gene-related peptide receptor antagonist indicated for the acute and preventive treatment of migraine. METHODS: Two single-center, phase 1, open-label, randomized bioequivalence studies were conducted in healthy adult non-smokers, aged 18-55 years. One study compared the rate and extent of absorption of the marketed formulation of rimegepant 75 mg orally disintegrating tablet (ODT) administered sublingually with rimegepant 75 mg oral tablet, an earlier development formulation; the second compared the rate and extent of absorption of 75 mg rimegepant ODT administered supralingually with rimegepant oral tablet. RESULTS: The ln-transformed geometric mean ratios for the area under the curve (AUC) from time 0 to the last available concentration time point (time t) (AUC0-t), AUC from time 0 to infinity (AUC0-inf), and maximum observed concentration (Cmax) of sublingual rimegepant ODT vs. rimegepant tablet were 97, 97, and 105%, respectively, and the 90% confidence intervals (CIs) were all within the predefined range (80-125%) for bioequivalence. The ln-transformed geometric mean ratios for the AUC0-t and AUC0-inf of supralingual rimegepant ODT vs. rimegepant tablet were 98%, the 90% CIs were within the predefined range (80-125%), and the geometric mean ratio for Cmax was 103% with the 95% upper confidence bound for the scaled average bioequivalence criterion of -0.0575 (within-participant coefficient of variation for the reference for Cmax > 30%) for bioequivalence. CONCLUSIONS: Rimegepant 75 mg ODT, administered sublingually or supralingually, and rimegepant 75 mg oral tablet were bioequivalent.

Update on gepants for the treatment of chronic migraine.

Chronic migraine (CM) is a profoundly debilitating condition that has detrimental clinical and social outcomes. Over the past two decades, novel small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists, known as gepants, and CGRP monoclonal antibodies (mAbs) have been developed, ushering in a new era of migraine-specific treatment. In this review, we discuss the literature investigating the role of gepants for the treatment of CM. Numerous completed and ongoing clinical studies have conclusively demonstrated the safety, tolerability, and efficacy of several gepants for the acute treatment of migraine. However, preventive trials involving gepants have focused on patients with episodic migraine, with atogepant being the only gepant approved for CM prevention by the US Food and Drug Administration at the time of writing. Although some preliminary positive results have been reported, further research is still required to achieve additional advancements in the future. In summary, the effectiveness of gepants for treating individuals with CM are highly expected. This review highlights the development and current progress of gepants for the treatment of CM, focusing both on their role as acute abortive agents and preventive measures and on their concomitant use with other antimigraine medications, such as CGRP mAbs or triptans.

CGRP monoclonal antibodies and CGRP receptor antagonists (Gepants) in migraine prevention.

Migraine is a prevalent and disabling neurological disease. Its preventive treatment for decades has been rather limited due to the absence of disease-specific therapies with limited efficacy and tolerability. The advances made in migraine research have led to the discovery of the calcitonin gene-related peptide (CGRP) and its role in migraine pathophysiology. CGRP is a neuropeptide that acts as potent vasodilator and is involved in pain processing. Increased levels of plasma CGRP have been observed during migraine attacks as well as interictally when comparing patients with migraine and healthy controls. In the last years, two classes of drugs antagonizing CGRP have therefore been developed as the first migraine-specific preventive treatments: anti-CGRP monoclonal antibodies (mAbs) and gepants. Four mAbs have been approved: erenumab, galcanezumab, fremanezumab, and eptinezumab. Gepants are small molecules that antagonize the CGRP receptor; currently only rimegepant and atogepant have been approved for migraine prevention. These new drugs have demonstrated efficacy and safety in clinical trials for both episodic and chronic migraine, and results from their real-world experience are being increasingly reported in literature. In this review, we provide an overview of anti-CGRP drugs and their placement in migraine prevention.

Potential treatment targets for migraine: emerging options and future prospects.

Migraine is a leading cause of disability worldwide. Despite the recent approval of several calcitonin gene-related peptide-targeted therapies, many people with migraine do not achieve satisfactory headache improvement with currently available therapies and there continues to be an unmet need for effective and tolerable migraine-specific treatments. Exploring additional targets that have compelling evidence for their involvement in modulating migraine pathways is therefore imperative. Potential new therapies for migraine include pathways involved in nociception, regulation of homoeostasis, modulation of vasodilation, and reward circuits. Animal and human studies show that these targets are expressed in regions of the CNS and peripheral nervous system that are involved in pain processing, indicating that these targets might be regarded as promising for the discovery of new migraine therapies. Future studies will require assessment of whether targets are suitable for therapeutic modulation, including assessment of specificity, affinity, solubility, stability, efficacy, and safety.

CGRP receptor antagonists (gepants).

Small molecule calcitonin gene-related peptide (CGRP) receptor antagonists are commonly referred to as gepants. The first generation of gepants provided the first line of evidence of CGRP-mediated antimigraine medication in 2004-2011. However, further development was halted due to either lack of oral availability or concerns of hepatotoxicity. More than 15 years later, the first second generation of gepants, ubrogepant and rimegepant, are now approved for the acute treatment of migraine with or without aura. Furthermore, a novel and promising third-generation gepant, zavegepant, has recently been approved as well. In this chapter, we review the evidence supporting the effectiveness, safety, and tolerability of gepants for the acute treatment of migraine. Furthermore, we discuss the potential limitations and future directions of this class of migraine-specific medication.

CGRP Antagonism and Ketogenic Diet in the Treatment of Migraine.

The study of migraine is based on the complexity of the pathology, both at the pathophysiological and epidemiological levels. Although it affects more than a billion people worldwide, it is often underestimated and underreported by patients. Migraine must not be confused with a simple headache; it is a serious and disabling disease that causes considerable limitations in the daily life of afflicted people, including social, work, and emotional effects. Therefore, it causes a daily state of suffering and discomfort. It is important to point out that this pathology not only has a decisive impact on the quality of life of those who suffer from it but also on their families and, more generally, on society as a whole. The clinical picture of migraine is complex, with debilitating unilateral or bilateral head pain, and is often associated with characteristic symptoms such as nausea, vomiting, photophobia, and phonophobia. Hormonal, environmental, psychological, dietary, or other factors can trigger it. The present review focuses on the analysis of the physiopathological and pharmacological aspects of migraine, up to the correct dietary approach, with specific nutritional interventions aimed at modulating the symptoms. Based on the symptoms that the patient experiences, targeted and specific therapy is chosen to reduce the frequency and severity of migraine attacks. Specifically, the role of calcitonin gene-related peptide (CGRP) in the pathogenesis of migraine is analyzed, along with the drugs that effectively target the corresponding receptor. Particularly, CGRP receptor antagonists (gepants) are very effective drugs in the treatment of migraine, given their high diffusion in the brain. Moreover, following a ketogenic diet for only one or two months has been demonstrated to reduce migraine attacks. In this review, we highlight the diverse facets of migraine, from its physiopathological and pharmacological aspects to prevention and therapy.

Effect of chronic intermittent hypoxia on ocular and intraoral mechanical allodynia mediated via the calcitonin gene-related peptide in a rat.

STUDY OBJECTIVES: Obstructive sleep apnea, a significant hypoxic condition, may exacerbate several orofacial pain conditions. The study aims to define the involvement of calcitonin gene-related peptide (CGRP) in peripheral and central sensitization and in evoking orofacial mechanical allodynia under chronic intermittent hypoxia (CIH). METHODS: Male rats were exposed to CIH. Orofacial mechanical allodynia was assessed using the eyeblink test and the two-bottle preference drinking test. The CGRP-immunoreactive neurons in the trigeminal ganglion (TG), CGRP-positive primary afferents projecting to laminae I-II of the trigeminal spinal subnucleus caudalis (Vc), and neural responses in the second-order neurons of the Vc were determined by immunohistochemistry. CGRP receptor antagonist was administrated in the TG. RESULTS: CIH-induced ocular and intraoral mechanical allodynia. CGRP-immunoreactive neurons and activated satellite glial cells (SGCs) were significantly increased in the TG and the number of cFos-immunoreactive cells in laminae I-II of the Vc were significantly higher in CIH rats compared to normoxic rats. Local administration of the CGRP receptor antagonist in the TG of CIH rats attenuated orofacial mechanical allodynia; the number of CGRP-immunoreactive neurons and activated SGCs in the TG, and the density of CGRP-positive primary afferent terminals and the number of cFos-immunoreactive cells in laminae I-II of the Vc were significantly lower compared to vehicle-administrated CIH rats. CONCLUSIONS: An increase in CGRP in the TG induced by CIH, as well as orofacial mechanical allodynia and central sensitization of second-order neurons in the Vc, supported the notion that CGRP plays a critical role in CIH-induced orofacial mechanical allodynia.

A Drug-Drug Interaction Study to Evaluate the Impact of Rimegepant on OCT2- and MATE1-Mediated Transport of Metformin in Healthy Participants.

Rimegepant is a calcitonin gene-related peptide receptor antagonist approved for migraine treatment. This phase 1, open-label, single-center, fixed-sequence study evaluated the effect of rimegepant on the pharmacokinetics (PK) of metformin. Twenty-eight healthy participants received metformin 500 mg twice daily from Days 1 to 4 and Days 7 to 10, and once daily on Days 5 and 11. Rimegepant, 75 mg tablet, was administered once daily from Days 9 to 12. At pre-specified time points, plasma metformin concentration, serum glucose levels, and safety and tolerability were evaluated. A 16% increase in the area under the plasma metformin concentration-time curve (AUC) for 1 dosing interval (AUC0-τ,ss), a statistically insignificant increase in maximum and minimum steady-state metformin concentration (Cmax,ss and Cmin,ss), and a decrease in metformin renal clearance were observed on Day 11 following metformin-rimegepant coadministration compared with metformin alone; however, the changes were not clinically relevant. Additionally, coadministration of rimegepant with metformin did not induce clinically meaningful change in the maximum observed glucose concentration (Gmax) or AUCgluc compared with metformin alone. Overall, rimegepant and metformin coadministration did not result in clinically relevant changes in metformin PK, renal clearance, or the antihyperglycemic effects of metformin. Rimegepant is considered safe for use with metformin.

Nueva era terapéutica para el ataque de migraña con los recientemente aprobados anticuerpos monoclonales, ditanes y gepantes / New therapeutic era for migraine attacks with recently approved monoclonal antibodies, ditans and gepants

El tratamiento de los ataques de migraña se aconseja en todos los pacientes, utilizando antiinflamatorios no esteroideos cuando el dolor es leve y triptanes cuando la intensidad del dolor es moderada-grave. Sin embargo, la efectividad de estos fármacos es modesta, un porcentaje elevado de pacientes presenta efectos secundarios y los triptanes están contraindicados en las personas con antecedentes de ictus, cardiopatía isquémica o hipertensión mal controlada. Por tanto, es imprescindible disponer de nuevas alternativas terapéuticas. En los últimos años han ido apareciendo nuevos fármacos para los ataques de migraña, entre los que destacan los ditanes (lasmiditán) y los gepantes (ubrogepant y rimegepant). Por otro lado, el eptinezumab, que ha sido aprobado para el tratamiento preventivo de la migraña en adultos, se ha utilizado también para los ataques de migraña. En este manuscrito se revisan los resultados de eficacia y seguridad de los nuevos fármacos para los ataques de migraña que se comercializarán próximamente. (AU)

Treatment of migraine attacks is advised in all patients, using non-steroidal anti-inflammatory drugs when the pain is mild and triptans when the pain intensity is moderate-severe. However, the effectiveness of these drugs is moderate, a high percentage of patients have side effects, and triptans are contraindicated in people with a history of stroke, ischaemic heart disease or poorly controlled hypertension. Hence, there is an urgent need for new therapeutic alternatives. In recent years, new drugs for migraine attacks have become available, most notably ditans (lasmiditan) and gepants (ubrogepant and rimegepant). Furthermore, eptinezumab, which has been approved for the preventive treatment of migraine in adults, has also been used for migraine attacks. This manuscript reviews the efficacy and safety results of the new drugs for migraines that will soon be on the market. (AU)

[New therapeutic era for migraine attacks with recently approved monoclonal antibodies, ditans and gepants]. / Nueva era terapéutica para el ataque de migraña con los recientemente aprobados anticuerpos monoclonales, ditanes y gepantes.

Treatment of migraine attacks is advised in all patients, using non-steroidal anti-inflammatory drugs when the pain is mild and triptans when the pain intensity is moderate-severe. However, the effectiveness of these drugs is moderate, a high percentage of patients have side effects, and triptans are contraindicated in people with a history of stroke, ischaemic heart disease or poorly controlled hypertension. Hence, there is an urgent need for new therapeutic alternatives. In recent years, new drugs for migraine attacks have become available, most notably ditans (lasmiditan) and gepants (ubrogepant and rimegepant). Furthermore, eptinezumab, which has been approved for the preventive treatment of migraine in adults, has also been used for migraine attacks. This manuscript reviews the efficacy and safety results of the new drugs for migraines that will soon be on the market.

TITLE: Nueva era terapéutica para el ataque de migraña con los recientemente aprobados anticuerpos monoclonales, ditanes y gepantes.El tratamiento de los ataques de migraña se aconseja en todos los pacientes, utilizando antiinflamatorios no esteroideos cuando el dolor es leve y triptanes cuando la intensidad del dolor es moderada-grave. Sin embargo, la efectividad de estos fármacos es modesta, un porcentaje elevado de pacientes presenta efectos secundarios y los triptanes están contraindicados en las personas con antecedentes de ictus, cardiopatía isquémica o hipertensión mal controlada. Por tanto, es imprescindible disponer de nuevas alternativas terapéuticas. En los últimos años han ido apareciendo nuevos fármacos para los ataques de migraña, entre los que destacan los ditanes (lasmiditán) y los gepantes (ubrogepant y rimegepant). Por otro lado, el eptinezumab, que ha sido aprobado para el tratamiento preventivo de la migraña en adultos, se ha utilizado también para los ataques de migraña. En este manuscrito se revisan los resultados de eficacia y seguridad de los nuevos fármacos para los ataques de migraña que se comercializarán próximamente.

Pharmacologic characterization of atogepant: A potent and selective calcitonin gene-related peptide receptor antagonist.

BACKGROUND: The trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) is identified as an essential element in migraine pathogenesis. METHODS: In vitro and in vivo studies evaluated pharmacologic properties of the CGRP receptor antagonist atogepant. Radioligand binding using 125I-CGRP and cyclic adenosine monophosphate (cAMP) accumulation assays were conducted in human embryonic kidney 293 cells to assess affinity, functional potency and selectivity. Atogepant in vivo potency was assessed in the rat nitroglycerine model of facial allodynia and primate capsaicin-induced dermal vasodilation (CIDV) pharmacodynamic model. Cerebrospinal fluid/brain penetration and behavioral effects of chronic dosing and upon withdrawal were evaluated in rats. RESULTS: Atogepant exhibited high human CGRP receptor-binding affinity and potently inhibited human α-CGRP-stimulated cAMP responses. Atogepant exhibited significant affinity for the amylin1 receptor but lacked appreciable affinities for adrenomedullin, calcitonin and other known neurotransmitter receptor targets. Atogepant dose-dependently inhibited facial allodynia in the rat nitroglycerine model and produced significant CIDV inhibition in primates. Brain penetration and behavioral/physical signs during chronic dosing and abrupt withdrawal were minimal in rats. CONCLUSIONS: Atogepant is a competitive antagonist with high affinity, potency and selectivity for the human CGRP receptor. Atogepant demonstrated a potent, concentration-dependent exposure/efficacy relationship between atogepant plasma concentrations and inhibition of CGRP-dependent effects.

Pharmacotherapies for Migraine and Translating Evidence From Bench to Bedside.

Migraine is a ubiquitous neurologic disorder that afflicts more than 1 billion people worldwide. Recommended therapeutic strategies include the use of acute and, if needed, preventive medications. During the past 2 decades, tremendous progress has been made in better understanding the molecular mechanisms underlying migraine pathogenesis, which in turn has resulted in the advent of novel medications targeting signaling molecule calcitonin gene-related peptide or its receptor. Here, we provide an update on the rational use of pharmacotherapies for migraine to facilitate more informed clinical decision-making. We then discuss the scientific discoveries that led to the advent of new medications targeting calcitonin gene-related peptide signaling. Last, we conclude with recent advances that are being made to identify novel drug targets for migraine.

Unmet Needs in the Acute Treatment of Migraine.

Migraine represents the most common neurologic disorder, ranking second among the world's causes of disability [expressed as years lived with disability (YLDs)]. Patients often do not receive the best therapy because of safety issues, tolerance, and prescription accessibility. General practitioners are not always educated about the disease, and specialists are few and often difficult to reach. Therapies are limited and have many side effects that can impede the prescription. Prophylactic therapy is recommended in case of four or more headaches a month, eight or more headache days a month, debilitating headaches, and medication-overuse headaches. The available therapeutic options are in constant development. The classic one consists of non-specific drugs: ß-blockers, tricyclics, antiepileptics, and botulinum toxin. Monoclonal antibodies targeting the calcitonin gene receptor (CGRP) peptide or its receptor are the only ones specifically designed to treat migraine. Their efficiency and convenient safety profile have been demonstrated in a number of trials versus both placebo and classic therapies. The treatment of acute migraine attack consists of medications designed to affect the painful symptoms. For over 30 years, the cornerstones of treatment in clinical practice have continued to be represented by triptans and non-steroidal anti-inflammatory drugs (NSAIDs), with the well-know related adverse effects. Opioids are used inappropriately and overprescribed. Polytherapy is strongly not recommended but is still a common practice because treatment is not optimized and thus not efficient. Great promise comes from gepants, also targeting CGRP, and ditans, 5-HT1F receptor agonists. They seem to outweigh the risk of medication overuse headache because of their efficacy and rapid onset and have no cardiovascular contraindications. Nonetheless, these points remain to be confirmed. Although therapies have been implemented in the last years, significant unmet treatment needs remain a reality in patients' lives. This commentary aims to identify the most important unmet needs in the acute treatment of migraine, analyzing the current status of available therapies and their limits. We also analyzed some of the prophylactic therapies available, especially focusing on anti-CGRP monoclonal antibodies, to better understand the importance of setting a therapeutic strategy that includes the two modes, both acute and prophylactic, to reach the best result. We hope that having an overview of the shortcomings will help to provide constructive ideas for improvement.