Calcitonin Gene-related Peptide Antibodies Research Articles

Effect of calcitonin gene-related peptide (-receptor) antibodies in chronic cluster headache: Results from a retrospective case series support individual treatment attempts.

ObjectiveTo assess the efficacy of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor in chronic cluster headache (CCH) treatment under real world conditions.BackgroundCalcitonin gene-related peptide has an important pathophysiological role in cluster headache. Although the randomised controlled trial with the calcitonin gene-related peptide antibody galcanezumab was negative, chronic cluster headache patients with insufficient response to other preventive treatments have been receiving individual off-label treatment attempts with calcitonin gene-related peptide-(receptor) antibodies.MethodsData from 22 chronic cluster headache patients who received at least one dose of a calcitonin gene-related peptide(-receptor) antibody and recorded attack frequency in a headache diary were retrospectively collected at eight headache centres.ResultsThe number of previous preventive therapies was 6.5 ± 2.4 (mean ± standard deviation, range: 2–11). The average number of attacks per week was 23.3 ± 16.4 at baseline and significantly decreased by −9.2 ± 9.7 in the first month of treatment with a calcitonin gene-related peptide(-receptor) antibody (p < 0.001). Fifty-five percent of the patients were 50% responders and 36% were 75% responders with respect to attack frequency. Significant reduction of attack frequency started at week 1 (−6.8 ± 2.8 attacks, p < 0.01). Results were corroborated by significant decreases in weekly uses of acute headache medication (−9.8 ± 7.6, p < 0.001) and pain intensity during attacks (−1.2 ± 2.0, numerical rating scale (NRS) [0–10], p < 0.01) in the first month. In months 2 (n = 14) and 3 (n = 10), reduction of attack frequency from baseline was −8.0 ± 8.4 (p = 0.004) and −9.1 ± 10.0 (p = 0.024), respectively.ConclusionUnder real-world conditions, individual treatment with calcitonin gene-related peptide(-receptor) antibodies was effective in 55% of our chronic cluster headache patients. This finding supports individual off-label treatment attempts with calcitonin gene-related peptide-(receptor) antibodies in chronic cluster headache patients insufficiently responding to other therapies.

Two-Hour CGRP Infusion Causes Gastrointestinal Hyperactivity: Possible Relevance for CGRP Antibody Treatment.

The monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor are new antimigraine drugs from which many patients already benefit. Very few side effects have been reported from the antibody trials, including very few gastrointestinal (GI) side effects. The current data derive from a double-blind cross-over study of CGRP infusion for 2hours. We present the GI side effects of the infusion and raise the question if underreporting of GI symptoms in CGRP antibody trials has occurred. We also discuss why constipation may be more likely with CGRP receptor blockade than with CGRP neutralizing antibodies. Thirty healthy volunteers were recruited to receive a 2-hour infusion of CGRP 1.5µg/minutes on 2 different days. The participants were pretreated with sumatriptan tablets (2×50mg) 1day and with placebo the other day. During the infusion, the participants were asked about side effects including a detailed description about their GI symptoms. Clinical observations like flatulence, rumbling, and use of bedpan were also noted. After the infusion, the participants filled out a questionnaire about side effects at home until 12-hour after the infusion start. The study was conducted at the Danish Headache Center at Rigshospitalet Glostrup in the period February 2018 to July 2018. On both study days 93% (27/29 participants) experienced symptoms from the GI system during the infusion. Rumbling, stomach pain, nausea, diarrhea, and an urge to defecate were the most commonly experienced GI side effects. There was no difference in symptoms between placebo and sumatriptan pretreatment. We conclude that a 2-hour infusion of CGRP causes frequent and sometimes severe symptoms from the GI system. The symptoms are not antagonized by sumatriptan. More attention should be paid to constipation as a possible side effect of CGRP receptor antagonists.

Cervicogenic Headache Responsive To Galcanezumab In Patients With Comorbid Migraine: A Case Series. Running Head: CH And Migraine Responsive To CGRP Abs

Introduction Cervicogenic headache (CH) is a chronic headache that is referred to the head from the cervical spine that typically starts or worsens with neck movement. The pain typically presents posteriorly with anterior radiation. Nociceptive input from structures innervated by the upper three cervical spinal nerves can theoretically exacerbate primary headache disorders like migraine. We present three cases of CH related to C1-C2 joint arthropathy that significantly improved after treatment with calcitonin gene-related peptide (CGRP) antibodies initiated for chronic comorbid migraine. Case Descriptions We describe a case series of 3 patients with co-morbid CH and migraine that were treated with CGRP antibodies. All three patients had significant improvement in their migraines with C1-C2 joint injections and subsequently CGRP antibodies provided a greater than 50% benefit in each patient preventing the need for repeat injections. Conclusions The diagnosis of CH in patients is confirmed when treatment of the cervical spine lesion alleviates pain significantly. While CH itself has not been shown to be associated with elevated serum CGRP as has been demonstrated in migraine, animal models of osteoarthritis have shown reduction of hyperalgesia with galcanezumab. An upregulation in CGRP related to nociceptive input from degenerative changes in the cervical spine could lead to potentiation and sensitization which could potentially respond to systemic administration of CGRP antibodies. As a result, the presence of features suggestive of CH in patients with migraine may be a predictor of a positive response to CGRP antibodies. For patients with comorbid migraine and CH, CGRP antibodies could prevent the need for invasive injection treatments.

Calcitonin Gene-Related Peptide (CGRP) and Cluster Headache.

Cluster headache (CH) is a severe primary headache with a prevalence of 1/1000 individuals, and a predominance in men. Calcitonin gene-related peptide (CGRP) is a potent vasodilator, originating in trigeminal neurons and has a central role in CH pathophysiology. CGRP and the CGRP receptor complex have recently taken center stage as therapeutic targets for primary headaches, such as migraine. Multiple CGRP and CGRP receptor monoclonal antibodies, as well as small molecule antagonists (gepants) are on their way constituting a new frontier of migraine and possibly CH medication. During a CH attack, there is an activation of the trigeminal-autonomic reflex with the release of CGRP, and inversely if CGRP is administered to a CH patient in an active disease phase, it triggers an attack. Increased levels of CGRP have been found in ipsilateral jugular vein blood during the active phase of CH. This process is hypothesized to have a key role in the intense pain perception and in the associated distinctive vasodilation. So far, clinical tests of CGRP antibodies have been inconclusive in CH patients. This review summarizes the current state of knowledge on the role of CGRP in CH pathology, and as a target for future treatments.

What's New in the Treatment of Migraine?

Migraine is very common. In addition to affecting visual quality of life, migraine can be seen in the neuro-ophthalmology office with regularity. Treatment is critical to assist in the reduction of disability and symptoms. Knowing the evidence-based new treatments is important for every neuro-ophthalmologist. Using PubMed, and using the term migraine as it related to the terms treatment, evidence-based, calcitonin gene-related peptide (CGRP) inhibitor or antibody, electrical stimulation, vagal nerve stimulation, a literature review was performed. Aside from standard well-described and evidence-based therapies for the acute treatment and prevention of migraine, many new therapies have received FDA approval. In this review, we summarize the contribution of new classes of migraine-specific therapies: CGRP antibodies (erenumab, fremanezumab, galcanezumab, and eptinezumab) for prevention and inhibitors referred to as gepants (ubrogepant and rimegepant) for acute treatment. We also cover newer medications about to be approved, such as lasmitiditan. Devices, including the hand-held vagal nerve stimulator, supraorbital stimulation, transmagnetic stimulation, and remote electrical stimulation, are now approved by the FDA for treatment of migraine. Many new and exciting therapies exist for the treatment of migraine. Keeping up with this rapidly evolving field is important in reducing disability from the common disease of migraine.

Fremanezumab versus placebo for migraine prevention in patients with documented failure to up to four migraine preventive medication classes (FOCUS): a randomised, double-blind, placebo-controlled, phase 3b trial

Antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor have shown efficacy in the prevention of migraine attacks. We investigated the efficacy and tolerability of fremanezumab, a fully humanised CGRP antibody, in patients with migraine who had previously not responded to two to four classes of migraine preventive medications. The randomised, double-blind, placebo-controlled, parallel-group, phase 3b FOCUS trial was done at 104 sites (including hospitals, medical centres, research institutes, and group practice clinics) across Belgium, the Czech Republic, Denmark, Finland, France, Germany, Italy, the Netherlands, Poland, Spain, Sweden, Switzerland, the UK, and the USA. We enrolled participants aged 18-70 years with episodic or chronic migraine who had documented failure to two to four classes of migraine preventive medications in the past 10 years. Failure was defined as no clinically meaningful improvement after at least 3 months of therapy at a stable dose, as per the treating physician's judgment; discontinuation because of adverse events that made treatment intolerable; or treatment contraindicated or unsuitable for the preventive treatment of migraine for the patient. Participants were randomly assigned (1:1:1) by electronic interactive response technology to subcutaneously administered quarterly fremanezumab (month 1, 675 mg; months 2 and 3: placebo), monthly fremanezumab (month 1: 225 mg in episodic migraine and 675 mg in chronic migraine; months 2 and 3: 225 mg in both migraine subgroups), or matched monthly placebo for 12 weeks. The primary outcome was mean change from baseline in the monthly average number of migraine days during the 12-week treatment period. This trial is registered with ClinicalTrials.gov, number NCT03308968, and is now completed. Between Nov 10, 2017, and July 6, 2018, 838 participants with episodic (329 [39%]) or chronic (509 [61%]) migraine were randomly assigned to placebo (n=279), quarterly fremanezumab (n=276), or monthly fremanezumab (n=283). Reductions from baseline in monthly average migraine days over 12 weeks were greater versus placebo (least-squares mean [LSM] change -0·6 [SE 0·3]) with quarterly fremanezumab (LSM change -3·7 [0·3]; LSM difference vs placebo -3·1 [95% CI -3·8 to -2·4]; p<0·0001) and with monthly fremanezumab (LSM change -4·1 [0·34]; LSM difference vs placebo -3·5 [-4·2 to -2·8]; p<0·0001). Adverse events were similar for placebo and fremanezumab. Serious adverse events were reported in four (1%) of 277 participants with placebo, two (<1%) of 276 with quarterly fremanezumab, and four (1%) of 285 with monthly fremanezumab. Fremanezumab was effective and well tolerated in patients with difficult-to-treat migraine who had previously not responded to up to four classes of migraine preventive medications. Teva Pharmaceuticals.

Getting to the Heart of the Matter: Migraine, Triptans, DHE, Ditans, CGRP Antibodies, First/Second-Generation Gepants, and Cardiovascular Risk.

The science of migraine pathophysiology has advanced significantly since the 1930's. Imaging techniques, neurochemical analysis, clinical trials, and the clinical experience of providers treating migraine patients have not only sharpened our understanding of the disease, but have also led to the development of novel neural-based targets. Targeted therapies such as calcitonin gene-related peptide (CGRP) antibodies and "Second Generation" CGRP receptor antagonists (Gepants) have not only demonstrated efficacy, but have not resulted in any significant cardiovascular nor other serious adverse events. "First Generation" Gepants were associated with liver toxicity. Triptans and dihydroergotamine (DHE) are contraindicated in patients with hemiplegic and basilar migrainebased on theories of migraine pathophysiology from the 1930s. While our understanding of migraine has evolved substantially, perceived concerns of safety from almost a century ago continue to preclude their use in certain patient populations. While migraine aura was once thought to be primarily due to vasoconstriction, current evidence debunks this concept. For instance, hemiplegic migraine is the consequence of genetic mutations resulting in channelopathies without evidence of cerebral ischemia or infarction. Evidence of basilar artery constriction as postulated in basilar migraine is also lacking. This recognition has led the International Headache Society to rename basilar-type migraine to migraine with brainstem aura. The following discussion reviews current literature with respect to migraine as a neuronal disorder, as well as the published data on the safety of triptans, DHE, Ditans (a novel class of 5-HT1f receptor agonists), CGRP antibodies, and Gepants.

Targeting CGRP via receptor antagonism and antibody neutralisation in two distinct rodent models of migraine-like pain

Rodent disease models can play an indispensable role in drug development. Confirming that translationally-relevant disease mechanisms are engaged in such models is a crucial facet of this process. Accordingly, we have validated the role of calcitonin gene-related peptide signaling in a mouse model of glyceryl trinitrate-provoked migraine-like pain and a spontaneous rat model of migraine-like pain by assessing their pharmacological responsiveness to the small molecule calcitonin gene-related peptide receptor antagonist olcegepant, and the humanised monoclonal calcitonin gene-related peptide antibody ALD405. Cutaneous sensitivity to hind paw, and periorbital mechanical stimulation were used as surrogate markers of activation of relevant pain pathways in each respective model. Separate experiments were performed to identify the time-course of treatment response to olcegepant (1 mg/kg i.p.) and ALD405 (10 mg/kg i.p.). Olcegepant and ALD405 significantly alleviated cutaneous mechanical hypersensitivity in both models compared with corresponding control treatments (saline and IgG control antibody respectively). As expected, the duration of anti-nociceptive action obtained with ALD405 was considerably longer than that associated with olcegepant. Surprisingly, in the spontaneous rat model the onset of action of ALD405 occurred within just 4 hours after administration. The current data clearly show that calcitonin gene-related peptide-mediated signaling is critically involved in the manifestation of cutaneous hypersensitivity in distinct rodent models of migraine-like pain and emphasise their translational relevance. Moreover, the unexpected rapidity of onset observed for ALD405 supports i) a probable site of action outside the blood-brain barrier, and ii) a potential clinical utility of specific monoclonal calcitonin gene-related peptide antibodies in the abortive treatment of migraine.

CGRP antibodies for migraine prevention — new kids on the block

In the past few years, a number of new migraine treatments have emerged, including monoclonal antibodies against calcitonin gene-related peptide (CGRP) and the CGRP receptor. Now, a position statement from the American Headache Society offers guidance on the integration of these agents into clinical practice in the prevention of migraine.

Fremanezumab for the prevention of chronic and episodic migraine.

On September 15, 2018, the U.S. Food and Drug Administration (FDA) approved subcutaneous fremanezumab, a calcitonin gene-related peptide (CGRP) monoclonal antibody, for the treatment of episodic and chronic migraine in adults, with two recommended dosages: 225 mg monthly or 675 mg every 3 months. On March 28, 2019, the European Commission granted fremanezumab Marketing Authorization in the E.U. for the same indication. In this monograph we review data on the pharmacokinetics, metabolism and safety of fremanezumab as reported in the scientific literature from phase I to phase III studies. Fremanezumab demonstrated a very low incidence of adverse events. Primary and secondary endpoints in randomized, controlled trials on the efficacy of fremanezumab were achieved. Fremanezumab was demonstrated to be able to reduce the number of migraine days, headache hours and number of days with use of acute treatment agents. No data on drug-drug interactions with fremanezumab are available. However, it is worth mentioning that fremanezumab showed a very low incidence of development of adverse drug antibodies compared with other CGRP antibodies.

CGRP Antibodies as Prophylaxis in Migraine

Monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (CLR + RAMP1) offer considerable improvements over existing drugs in migraine prophylaxis and are the first designed to act on the trigeminal pain system. Erenumab is approved by the FDA and EMA and has reached the market since May 2018. Two antibodies, fremanezumab and galcanezumab, directed towards the CGRP ligand, were approved by the FDA in September 2018. To view this Bench to Bedside, open or download the PDF.

From LBR-101 to Fremanezumab for Migraine.

Calcitonin gene-related peptide (CGRP) is a neuropeptide of importance in migraine pathogenesis. Its central role in migraine was proven pharmacologically by the development of CGRP receptor antagonists. Monoclonal antibodies targeting CGRP or its receptor are effective in the preventive treatment of episodic and chronic migraine and are considered potential breakthroughs in their treatment. Fremanezumab (previously known as TEV-48125, LBR-101, or RN-307) is a humanized IgG2a monoclonal antibody that binds to CGRP. The development of this antibody validated the role of CGRP in chronic migraine and the drug has been recently approved in the US by the FDA, while it continues to be reviewed by other regulatory agencies. Herein we provide an in-depth review of its development. We start by summarizing its in vitro and in vivo pharmacology, and the phase I studies. We then review the late-stage clinical development, with a focus on its efficacy, safety, similarities, and uniqueness relative to other CGRP antibodies. We close by discussing lessons learned on the mechanisms of migraine and areas for future development and exploration.

Two novel agents for migraine prevention could be on the horizon

Two investigational monoclonal antibodies that target either the calcitonin gene-related peptide (CGRP) receptor or CGRP itself were effective for preventive treatment of migraines compared with placebo, according to results from two recent studies. Erenumab, a fully human monoclonal antibody that inhibits the CGRP receptor, was assessed in a Phase III trial involving 955 adult patients with episodic migraine. Patients with at least 4 but fewer than 15 migraine days per month and fewer than 15 headache days per month on average were randomized to either erenumab 70 mg (n = 317), erenumab 140 mg (n = 319), or placebo (n = 319) given as monthly S.C. injections for 6 months. At month 6, use of erenumab at either dose significantly reduced the mean number of migraine days per month compared with placebo (−3.2 d for 70 mg and −3.7 d for 140 mg vs. −1.8 d for placebo; P < 0.001 for both comparisons). Also, significantly more patients in the two active treatment groups had a 50% or greater reduction in mean number of migraine days per month and used less acute migraine-specific medication compared with those in the placebo group. Physical impairment scores and everyday activities scores were also significantly improved in the erenumab groups compared with placebo. The frequency of adverse events was similar across the three treatment groups (55.5%–63.0%). Fremanezumab, a humanized monoclonal antibody that targets CGRP itself, was assessed in a Phase III trial involving 1,130 adult patients with chronic migraine. Eligible patients included those with a headache of any duration or severity on 15 or more days per month and migraine on 8 or more days per month. Patients were randomized to a single quarterly S.C. dose of fremanezumab 675 mg (n = 376), monthly fremanezumab (675 mg at baseline and 225 mg at weeks 4 and 8, n = 379), or placebo (n = 375). After 12 weeks, use of fremanezumab resulted in a significant reduction in mean number of headache days per month compared with placebo (−4.3 d for quarterly fremanezumab and −4.6 d for monthly vs. −2.5 d for placebo; P < 0.001 for both comparisons). Also, significantly more patients in the active treatment arms had at least a 50% reduction in mean number of headache days per month compared with placebo. The frequency of adverse events was similar across the three treatment groups (64%–71%), and injection-site reactions occurred in approximately one-quarter to one-third of the patients. Efficacy of both novel agents was modest, but these agents worked rapidly, and some patients became completely headache free. Four different CGRP antibodies are currently in development (i.e., erenumab, eptinezumab, fremanezumab, and galcanezumab), and clinical data are needed to differentiate these agents and determine if their effects are sustained after discontinuation or if long-term treatment is needed. Data from two trials showed that novel investigational injectable agents are effective in reducing the frequency of episodic and chronic migraines. Patients with a history of migraines should speak to their health care provider about alternative treatment options that may be appropriate for them.

Recognizing the role of CGRP and CGRP receptors in migraine and its treatment

The brain and the sensory nervous system contain a rich supply of calcitonin gene-related peptide (CGRP) and CGRP receptor components. Clinical studies have demonstrated a correlation between CGRP release and acute migraine headache that led to the development of CGRP-specific drugs that either abort acute attacks of migraine (gepants) or are effective as prophylaxis (antibodies). However, there is still much discussion concerning the site of action of these drugs. Here we describe the most recent data related to CGRP in the trigeminal ganglion and its connections to the CNS, putative key regions involved in migraine pathophysiology. Gepants are small molecules that have limited ability to cross the blood-brain barrier (BBB), whereas CGRP antibodies are 1500 times larger molecules, and are virtually excluded from the brain, with a BBB permeability of < 0.1%. Thus we propose that the primary site of action for the antimigraine drugs is outside the CNS in areas not limited by the BBB. Therefore, it is reasonable to discuss the localization of CGRP and its receptor components in relation to the BBB. The trigeminovascular system, located outside the BBB, has a key role in migraine symptomatology, and it is likely targeted by the novel CGRP drugs that successfully terminate migraine headache.

Calcitonin gene-related peptide monoclonal antibodies for migraine prevention: comparisons across randomized controlled studies

The results of phase 2 randomized controlled trials for the prevention of episodic and chronic migraine demonstrating the efficacy and safety of four mAbs targeting the calcitonin gene-related peptide (CGRP) pathway [ALD403 (eptinezumab), AMG334 (erenumab), LY2951742 (galcanezumab) and TEV48125 (fremanezumab)] have been published recently, and phase 3 trials are in process. This development will change headache management fundamentally. We aim to summarize and compare the phase 2 data. The change from baseline in the number of migraine days at the end of treatment in high-frequency episodic migraine was -1 (at weeks 5-8), -1.1 (at weeks 9-12), -1.2 (at weeks 9-12) and -2.6 (at weeks 9-12) days for ALD403, AMG344, LY2951742 and TEV48125 (225 mg), respectively. Number needed to treats for responders and odds ratio for any adverse event were 4.7, 6.2, 4.0 and 4.0 and 1.09, 0.96, 1.07 and 1.05, respectively. All four CGRP antibodies display comparable efficacy that does not differ significantly from that of the currently available oral antimigraine drugs. However, their safety and tolerability profiles as well as low frequency of administration looks promising but remains to be verified in long-term and large-scale trials. Considerations related to pregnancy, risk for cardiovascular effects and cost are subject for further evaluation.

A human trigeminovascular biomarker for antimigraine drugs: A randomised, double-blind, placebo-controlled, crossover trial with sumatriptan.

Current antimigraine drugs are believed, besides their direct vasoconstrictive effect, to inhibit calcitonin gene-related peptide (CGRP) release from trigeminal nerve endings during migraine. Objective The objective of this report is to establish a biomarker for the CGRP-interfering effect of antimigraine drugs. Methods We quantified the effect of sumatriptan on the trigeminal nerve-mediated rise in forehead dermal blood flow (DBF), induced by capsaicin application (0.6 mg/ml) and electrical stimulation (0.2-1.0 mA), in a randomised, double-blind, placebo-controlled, crossover study in healthy male ( n = 11, age ± SD: 29 ± 8 years) and female ( n = 11, 32 ± 7 years) individuals. Results DBF responses to capsaicin were attenuated by sumatriptan (ΔDBF, mean ± SEM: 82 ± 18 AU, p = 0.0002), but not by placebo (ΔDBF: 21 ± 12 AU, p = 0.1026). Conclusion We demonstrated that sumatriptan inhibits increases in DBF, induced by the release of, most likely, CGRP. Thus, our model may be used as a biomarker to establish the trigeminovascular effects of (potential) antimigraine drugs, such as CGRP receptor antagonists or antibodies directed against CGRP or its receptor.

Prevention of stress- or nitric oxide donor-induced medication overuse headache by a calcitonin gene-related peptide antibody in rodents.

Objective The objective of this study was the determination of the role of calcitonin gene-related peptide (CGRP) in the induction of medication overuse headache (MOH)-related migraine in an injury-free preclinical model. Methods Rats were primed by a 7-day period of exposure to acute migraine therapies including sumatriptan and morphine. After an additional 14-day drug-free period, rats were exposed to putative migraine triggers including bright light stress (BLS) or nitric oxide (NO) donor in the presence or absence of TEV48125, a fully humanized CGRP antibody. Cutaneous allodynia (CA) was used as an outcome measure and CGRP blood and cerebrospinal fluid (CSF) levels were measured. Results BLS and NO donor challenge evoked delayed, long-lasting CA selectively in rats that were previously treated with sumatriptan or morphine. BLS produced a significant increase in CGRP in the plasma, but not CSF, in animals that were previously exposed to sumatriptan compared to saline controls. TEV48125 did not modify baseline tactile thresholds or produce behavioral side effects, but significantly inhibited both BLS- and NO donor-induced CA in animals that were previously primed with sumatriptan or morphine; an isotype control protein that does not bind CGRP had no effect. Interpretation These data suggest that acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and that anti-CGRP antibodies may be a useful clinical strategy for the treatment of MOH.

Translational Pharmacodynamics of Calcitonin Gene-Related Peptide Monoclonal Antibody LY2951742 in a Capsaicin-Induced Dermal Blood Flow Model

LY2951742, a monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being developed for migraine prevention and osteoarthritis pain. To support the clinical development of LY2951742, capsaicin-induced dermal blood flow (DBF) was used as a target engagement biomarker to assess CGRP activity in nonhuman primates and healthy volunteers. Inhibition of capsaicin-induced DBF in nonhuman primates, measured with laser Doppler imaging, was dose dependent and sustained for at least 29 days after a single intravenous injection of the CGRP antibody. This information was used to generate a pharmacokinetic/pharmacodynamic model, which correctly predicted inhibition of capsaicin-induced DBF in humans starting at a single subcutaneous 5-mg dose. As expected, the degree of inhibition in capsaicin-induced DBF increased with higher LY2951742 plasma concentrations. Utilization of this pharmacodynamic biomarker with pharmacokinetic data collected in phase I studies provided the dose-response relationship that assisted in dose selection for the phase II clinical development of LY2951742.

CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment.

Recently developed calcitonin gene-related peptide (CGRP) receptor antagonistic molecules have shown promising results in clinical trials for acute treatment of migraine attacks. Drugs from the gepant class of CGRP receptor antagonists are effective and do not cause vasoconstriction, one of the major limitations in the use of triptans. However their use had to be discontinued because of risk of liver toxicity after continuous exposure. As an alternative approach to block CGRP transmission, fully humanized monoclonal antibodies towards CGRP and the CGRP receptor have been developed for treatment of chronic migraine (attacks >15 days/month). Initial results from phase I and II clinical trials have revealed promising results with minimal side effects and significant relief from chronic migraine as compared with placebo. The effectiveness of these various molecules raises the question of where is the target site(s) for antimigraine action. The gepants are small molecules that can partially pass the blood-brain barrier (BBB) and therefore, might have effects in the CNS. However, antibodies are large molecules and have limited possibility to pass the BBB, thus effectively excluding them from having a major site of action within the CNS. It is suggested that the antimigraine site should reside in areas not limited by the BBB such as intra- and extracranial vessels, dural mast cells and the trigeminal system. In order to clarify this topic and surrounding questions, it is important to understand the localization of CGRP and the CGRP receptor components in these possible sites of migraine-related regions and their relation to the BBB.

TEV-48125: a review of a monoclonal CGRP antibody in development for the preventive treatment of migraine.

Calcitonin gene-related peptide (CGRP) is a 37-amino-acid neuropeptide whose involvement in migraine pathophysiology is well established. Originally migraine was believed to be a disease of the vasculature, but research has highlighted this to be a disease of the brain with CGRP playing an important role. While targeting CGRP using small molecule antagonists against the receptor has been effective, long-term use of these agents has not been possible due to safety concerns and/or formulation challenges. Recent advances in therapeutic antibodies have opened up new possibilities for treatment of migraine. TEV-48125 is one of four monoclonal antibodies targeting CGRP or its receptors, currently in development for the preventive treatment of migraine. This article discusses the in vitro and in vivo pharmacology of TEV-48125 as well as highlighting its safety profile through the six Phase 1 studies that have been conducted. Finally, the current state of development and future studies for TEV-48125 will be reviewed.