Targeting Calcitonin Gene-related Peptide Research Articles

Reversion from medication overuse with fremanezumab treatment in patients with inadequate response to multiple migraine preventive medication classes

Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), has demonstrated efficacy for migraine prevention in patients with documented inadequate response to 2–4 prior preventive medication classes in the phase 3b FOCUS study. The aim of this subgroup analysis was to evaluate reductions in acute medication use in patients treated with fremanezumab with baseline medication overuse (MO; any acute medication ≥15 days/month or triptans, ergots, or combination medications ≥10 days/month).

Fremanezumab improves quality of life in patients with higher- and lower-frequency chronic migraine

Patients with migraine may experience increased disease burden as migraine frequency increases. Fremanezumab, a fully-humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), has been shown to have significant effectiveness for migraine prevention. This pooled analysis assessed disability and quality-of-life (QoL) outcomes in patients with higher-frequency chronic migraine (HFCM; ≥19 monthly migraine days [MMDs]) or lower-frequency chronic migraine (LFCM; 15–18 MMDs) treated with fremanezumab from 2 double-blind phase 3 trials.

Fremanezumab improves quality of life in patients with high- and moderate-frequency episodic migraine

Patients with migraine may experience increasing disease burden as migraine frequency increases. This pooled analysis evaluated quality-of-life and disability outcomes with fremanezumab, a fully-humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), in patients with high-frequency episodic migraine (HFEM; 10–14 days/month) or moderate-frequency episodic migraine (MFEM; 4–9 days/month) from 2 double-blind phase 3 studies (HALO EM and FOCUS).

Switching medication within 12 months of initiating calcitonin gene-related peptide monoclonal antibodies versus other preventive treatments for migraine

Monoclonal antibodies targeting calcitonin gene-related peptide pathway (CGRP mAb) for migraine prevention are FDA-approved. This study assessed 12-month real-world switching patterns for patients initiating CGRP mAb versus other preventive migraine (non‑CGRP) treatments.

Efficacy and tolerability of fremanezumab for migraine preventive treatment in Korean patients with chronic or episodic migraine

Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), has demonstrated efficacy in patients with chronic and episodic migraine (CM and EM). Efficacy and tolerability of fremanezumab for migraine preventive treatment in Korean patients with CM and EM have been evaluated in two randomized, double-blind, placebo-controlled phase 2b/3 clinical studies and compared with data from pivotal phase 3 HALO CM and HALO EM studies.

Pooled analysis of safety and efficacy of fremanezumab in different racial and ethnic subgroups of patients with migraine

Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), has proven efficacy for migraine prevention in adults. These pooled analyses evaluated the safety and efficacy of fremanezumab in racial/ethnic subgroups.

Update on Treatment of Cluster Headache

Cluster headache (CH) is characterized by severe unilateral short-lasting headache attacks, accompanying ipsilateral cranial autonomic symptoms or the sense of restlessness and agitation, or both. CH is a highly disabling primary headache disorder but often not optimally treated. High-flow oxygen and parenteral triptans are the most effective treatment to treat an acute CH attack. Transitional treatments include systemic steroid therapy and sub-occipital steroid injection. For preventive therapy, verapamil and lithium are recommended as first-line treatments. Novel treatments have appeared, such as neuromodulation and medication targeting calcitonin gene-related peptide (CGRP) or its receptor. Galcanezumab, the only anti-CGRP receptor monoclonal antibody with proven efficacy for the preventive treatment of episodic CH, represents an important advance for pharmacological treatment of CH. Neuromodulation strategies, such as the non-invasive vagus nerve stimulation and the sphenopalatine ganglion stimulation, have been proven effective in reducing the intensity and frequency of attacks, and also to be safe and well tolerated.

The Potentials of Uncariae Ramulus Cum Uncis for the Treatment of Migraine: Targeting CGRP in the Trigeminovascular System.

Migraine is a common chronic neurovascular disease characterized by headaches. Calcitonin gene-related peptide (CGRP) signaling in the trigeminovascular system plays a critical role in the development of migraine. The monoclonal antibodies against CGRP and its receptor have been used clinically for the prevention of migraine; however, they may not be a cost-effective option for patients with low-frequency episodic migraine. Thus, it is quite valuable to search for an alternative strategy to downregulate CGRP signaling. Uncariae Ramulus Cum Uncis (UR) has a long-term history for the treatment of cardiovascular and central nervous systems disorders in China and Eastern Asia. Several clinical studies showed that famous herbal formulas comprising UR were able to improve headaches in migraineurs. In addition, increasing in vivo studies further indicated that migraine-related changes, such as CGRP increase, inflammation, nitric oxide increase, and spontaneous behavior problems could be reduced by UR extraction and its active constituents. In this review, we summarize the pathophysiological factors affecting abnormal CGRP release in the trigeminovascular system during a migraine, and for the first time, analyze the effects of UR on these factors and evaluate the potentials of UR for the treatment of migraine.

PEARL study protocol: a real-world study of fremanezumab effectiveness in patients with chronic or episodic migraine.

Fremanezumab is a humanized monoclonal antibody (IgG2Δa) that selectively targets calcitoningene-related peptide and isapproved in Europe for migraine prevention in adults with ≥4 migraine days/month. The Pan-European Real Life (PEARL) study is a 24-month, prospective, observational study of fremanezumab in chronicor episodic migraine. End points include proportion of patients with ≥50% reduction in monthly migraine daysduring 6months of treatment (primary); changes in monthly migraine days, disability scores and acute headache medication use; adherence and persistence; and effectiveness in patients switching from another calcitonin gene-related peptide pathway-targeting monoclonal antibody. PEARL is being conducted in approximately 100 centers in 11 European countries (estimated n =1100). PEARL will generate important real-world data on effectiveness of fremanezumab and treatment patterns in patients with chronic migraine or episodic migraine.

Effects of fremanezumab in patients with chronic migraine and comorbid depression: Subgroup analysis of the randomized HALO CM study.

ObjectiveTo evaluate the efficacy of fremanezumab in patients with chronic migraine (CM) and moderate to severe depression.BackgroundFremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene–related peptide, has been approved for the preventive treatment of migraine in adults. CM and depression are highly comorbid.MethodsThe 12‐week, Phase 3 HALO trial randomized patients with CM to fremanezumab quarterly (675 mg/placebo/placebo), fremanezumab monthly (675/225/225 mg), or placebo. Post hoc analyses evaluated the effects of fremanezumab in patients with moderate to severe depression (baseline 9‐item Patient Health Questionnaire sum score ≥10) on monthly number of headache days of at least moderate severity; monthly migraine days; Patient Global Impression of Change (PGIC); 6‐item Headache Impact Test (HIT‐6) scores; and depression.ResultsFor the 219/1121 (19.5%) patients with moderate to severe depression at baseline, fremanezumab was associated with a significant reduction in monthly number of headache days of at least moderate severity for active treatment versus placebo (least‐squares mean change ± standard error for quarterly dosing: −5.3 ± 0.77; for monthly dosing: −5.5 ± 0.72; and for placebo: −2.2 ± 0.81; both p < 0.001). More patients achieved a ≥50% reduction in headache days of at least moderate severity with fremanezumab (quarterly: 31/78 [39.7%]; monthly: 39/96 [40.6%]) than placebo (9/67 [13.4%]; both p < 0.001). Compared with placebo, fremanezumab improved PGIC and HIT‐6 scores.ConclusionsFremanezumab demonstrated efficacy in the preventive treatment of CM and reduced headache impact in patients with comorbid depression.

Soluble fms-like tyrosine kinase-1 and angiotensin2 target calcitonin gene-related peptide family peptides in maternal vascular smooth muscle cells in pregnancy†.

Peptide function was assessed by Cyclic adenosine monophosphate (cAMP) assays and wire myograph; mRNA expression by Polymerase chain reaction (PCR) and protein-protein interaction by proximity ligation assay and co-immunoprecipitation. All three peptides increased cAMP synthesis in the order of efficacy CALCB > ADM = ADM2 and vascular endothelial growth factor (VEGF) mRNA in OASMC (P < 0.05); sFLT-1 mediated decrease in cAMP synthesis (P < 0.05) is differentially rescued by all three CALCB family peptides in OASMC (P < 0.005); sFLT-1 decreased receptor activity-modifying protein (RAMP)1 and RAMP2 mRNA expression (P < 0.05); Ang2 decreased the expression of calcitonin-receptor-like receptor and RAMP1 mRNA and desensitized CALCB and ADM2 receptors in OASMC (P < 0.05); sFLT-1 increased RAMP1and Ang2 type 1 receptor (AT1R) interaction in OASMC which is inhibited in presence of all three peptides; and all three peptides relax OA in PE with enhanced ADM2 response (P < 0.05). sFLT-1 and Ang2 impair OASMC mediated functional responses of CALCB family peptides which can be inhibited by respective peptide treatment. The sensitivity of OA for CALCB, ADM, and ADM2-mediated relaxation is retained in PE.

Neuronal calcitonin gene-related peptide promotes prostate tumor growth in the bone microenvironment

Advanced stage of prostate cancer cells preferentially metastasizes to varying bones of prostate cancer patients, resulting in incurable disease with poor prognosis and limited therapeutical treatment options. Calcitonin gene-related peptide (CGRP), a neuropeptide produced by prostate gland, is known to play a pivotal role in facilitating tumor growth and metastasis of numerous human cancers. In this study, we aim to investigate the clinical relevance of CGRP in prostate cancer patients and the effects of CGRP and CGRP antagonists on prostate tumor growth in the mouse model. The prostate tumor-bearing mice were received either CGRP or CGRP antagonist treatment, and the tumor growth was monitored by quantification of luminescence intensities. We found that the CGRP+ nerve fiber density and serum CGRP levels were substantially upregulated in the bone or serum specimens from advanced prostate cancer patients as well as in prostate tumor-bearing mice. Administration of CGRP promoted, whereas treatment of CGRP antagonists inhibited prostate tumor growth in the femurs of mice. In addition, CGRP treatment activated extracellular signal-regulated kinases (ERKs)/ Signal transducer and activator of transcription 3 (STAT3) signaling in prostate cancer cells. Targeting CGRP may serve as a potential therapeutic strategy for advanced prostate cancer patients.

An Evidence-Based Review of Galcanezumab for the Treatment of Migraine.

Purpose of ReviewThis is a comprehensive review of the current literature on the usage of galcanezumab for migraine treatment. It reviews the biology, pathophysiology, epidemiology, diagnosis, and conventional treatment of migraines, then compares the literature available for galcanezumab with historical treatment options.Recent FindingsMigraine is a common headache disorder and constitutes a significant source of distress from both a personal and societal perspective. Conventional treatment includes abortive and preventive treatment. Treatment options are limited and may be only partially or minimally effective in some of the population. Recent evidence points to metabolic changes in the brain as possible causes of migraine, via reduced available energy or a spiking need for it, resulting in a relative insufficiency. This leads to trigeminocervical complex (TCC) activation and a headache episode, modulated by calcitonin gene-related peptide (CGRP). Galcanezumab (Emgality) is a monoclonal antibody targeting CGRP that is given in a monthly injection for the prevention of migraines. Its safety was previously shown in phase 1 and 2 trials, and recent phase 3 trials showed efficacy, with up to 50% reduction in monthly migraine days and improved functional capacity in migraineurs. Studies show that the drug is well tolerated and safe.SummaryMigraine headache is a common neurological syndrome that causes great pain and suffering. Treatment options today are limited. Galcanezumab does not prevent migraines, but it is effective in decreasing their frequency and length. It is also much better tolerated than the currently existing therapies. While it is unlikely to provide monotherapy for migraines, it is a novel therapy that may be added for cases of severe or frequent migraines.

The impact of fremanezumab on medication overuse in patients with chronic migraine: subgroup analysis of the HALO CM study

BackgroundWe evaluated the efficacy of fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, in patients with chronic migraine (CM) with and without medication overuse (MO).MethodsIn a 12-week, phase 3 trial, patients with CM were randomized to fremanezumab quarterly (675 mg/placebo/placebo), monthly (675 mg/225 mg/225 mg), or placebo. Post hoc analyses assessed the impact of fremanezumab in patients with and without MO (monthly use of acute headache medication ≥15 days, migraine-specific acute medication ≥10 days, or combination medication ≥10 days) on efficacy outcomes, including headache days of at least moderate severity (HDs), and six-item Headache Impact Test (HIT-6) and Migraine-Specific Quality of Life (MSQoL) questionnaire scores.ResultsOf 1130 patients enrolled, 587 (51.9%) had baseline MO. Fremanezumab reduced placebo-adjusted least-squares mean (95% confidence interval) monthly HDs (− 2.2 [− 3.1 to − 1.2] and − 2.7 [− 3.7 to − 1.8]; P < 0.0001) in patients with MO and without MO (quarterly − 1.4 [− 2.3 to − 0.5], P = 0.0026; monthly − 1.4 [− 2.3 to − 0.6], P = 0.0017). Significantly more fremanezumab-treated patients had ≥ 50% reduction in HDs versus placebo, regardless of baseline MO (with: quarterly 70/201 [34.8%], monthly 78/198 [39.4%] vs placebo 26/188 [13.8%]; without: quarterly 71/174 [40.8%], monthly 75/177 [42.4%] vs placebo 41/183 [22.4%]). Fremanezumab improved HIT-6 and MSQoL scores. Significantly more fremanezumab-treated patients reverted to no MO (quarterly 111/201 [55.2%], monthly 120/198 [60.6%]) versus placebo (87/188 [46.3%]).ConclusionsFremanezumab is effective for prevention of migraine in patients with CM, regardless of MO, and demonstrated a benefit over placebo in reducing MO.Trial registrationClinicalTrials.gov NCT02621931 (HALO CM), registered December 12, 2012.

Treatment and management of migraine in neurological ambulatory practice in Poland by indicating therapy with monoclonal anti-CGRP antibodies.

To analyse Polish neurologists' familiarity with the diagnostic criteria for migraine, and how their methods of management of migraine work in daily practice. Migraine is a common primary headache disease that causes substantial disability and reduces quality of life. Many migraine patients remain undiagnosed and deprived of treatment. Migraine treatment is problematic, and many patients discontinue preventive treatment, mainly because of a lack of efficacy or adverse effects. Antibodies targeting calcitonin gene-related peptide and its receptor seem to be effective and well-tolerated agents in migraine prevention. This study was conducted using a computer-assisted web interview conducted with 51 neurologists in Poland, who agreed to participate in the study during a phone call. The questionnaire mainly assessed methods of treatment of migraine patients and diagnostic criteria used in neurological practice. Only one neurologist listed all of the diagnostic criteria for migraine, and 80% of physicians in their practice used only a part of the migraine diagnostic criteria, usually the migraine without aura criteria. On average, each neurologist had 55 patients under continuous care, seeing roughly 18 patients per month. On average, neurologists estimated that 77% of all patients with migraine had episodic migraine, whereas the rest had the chronic form. Importantly, 40% of patients with chronic migraine received all available preventive treatments without a satisfactory effect. Neurologists could offer monoclonal antibodies that target the CGRP-pathway (i.e. anti-CGRP and anti-CGRP receptor monoclonal antibodies) for the prevention of chronic migraine to about one in three patients with a chronic form of the disease. Migraine is underdiagnosed and undertreated in Poland. Understanding of the diagnostic criteria for migraine among neurologists is insufficient. Most neurologists in Poland see patients in whom anti-CGRP/R-targeting treatment is indicated.

Fremanezumab: a disease-specific option for the preventive treatment of migraine, including difficult-to-treat migraine.

Fremanezumab is a fully humanized monoclonal antibody (IgG2Δa) that targets calcitonin gene-related peptide (CGRP), a key neuropeptide involved in the pathophysiology of migraine. Fremanezumab is approved for quarterly and monthly subcutaneous dosing for the preventive treatment of migraine in adults. The phase 3 clinical development program for fremanezumab aimed to evaluate the efficacy of this preventive treatment across different patient populations, including those with difficult-to-treat migraine. Two pivotal 12-week, phase 3, placebo-controlled studies investigated quarterly and monthly dosing of fremanezumab in participants with chronic migraine (HALO CM) and episodic migraine (HALO EM). The efficacy of fremanezumab was further explored in individuals with difficult-to-treat chronic or episodic migraine in the 12-week FOCUS study, which enrolled participants who had previously experienced an inadequate response to 2–4 pharmacological classes of migraine preventive medications. The long-term efficacy of fremanezumab was assessed in a 12-month long-term study (HALO LTS), which enrolled participants completing the 12-week HALO studies and new participants. Across these studies, treatment with fremanezumab dosed quarterly or monthly provided significant reductions in the frequency of migraine days, headache days of at least moderate severity, and migraine- and headache-related disability compared with placebo. Sustained improvements were seen with long-term fremanezumab treatment. Subgroup analyses of participants with difficult-to-treat migraine (those with comorbid depression, overuse of acute headache medications, and concomitant use of other migraine preventive medications) demonstrated the effectiveness of quarterly or monthly fremanezumab in these populations. Ongoing studies are further exploring the potential benefits of fremanezumab in difficult-to-treat migraine and other headache and pain disorders.

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.

Utilization of B12 for the treatment of chronic migraine.

Chronic migraine is a particular classification of a headache that is typically unilateral and pulsatile and lasts for at least 3 months. Owing to its high prevalence and detrimental impact on personal, social, and economic aspects of patient lives, much desire has gone into fully understanding the pathogenesis of migraine, and to search for therapeutic agents. In addition to current therapeutics such as triptans, ergotamine, and monoclonal antibodies targeting calcitonin gene-related peptide receptors, vitamin B12 has been investigated for its possible use as a prophylactic agent for migraines. Specifically, the observed effects of vitamin B12 on nitric oxide and homocysteine prompt further investigation of its underlying mechanisms in migraine pathophysiology. In this comprehensive review, we provide a brief overview of migraines and current therapies while focusing on the promising role of vitamin B12 as a possible treatment option for chronic migraine management.

Dual Therapy With Anti-CGRP Monoclonal Antibodies and Botulinum Toxin for Migraine Prevention: Is There a Rationale?

To narratively review the pathophysiological rationale of dual therapy with anti-calcitonin gene-related peptide monoclonal antibodies and botulinum toxin type A in treatment-resistant chronic migraine prevention. For the prevention of chronic migraine, several pharmacological therapies are available, including oral medications, botulinum toxin type A, and the newly approved monoclonal antibodies targeting calcitonin gene-related peptide or its receptor. However, monotherapy does not yield benefits in some affected individuals, which raises the question of whether dual therapy with monoclonal antibodies and botulinum toxin type A hold promise in patients with treatment-resistant chronic migraine. We searched MEDLINE for articles published from database inception to December 31st, 2019. Publications were largely selected from the past 10years but commonly referenced and highly regarded older publications were not excluded. Preclinical data suggest that anti-calcitonin gene-related peptide monoclonal antibodies and botulinum toxin type A have synergistic effects within the trigeminovascular system. Of note, findings indicate that fremanezumab - an antibody targeting the calcitonin gene-related peptide - mainly prevents the activation of Aδ-fibers, whereas botulinum toxin type A prevents the activation of C-fibers. There is currently only indirect preclinical evidence to support a rationale for dual therapy with anti-calcitonin gene-related peptide monoclonal antibodies and botulinum toxin type A for chronic migraine prevention. Rigorous studies evaluating clinical efficacy, safety, and cost-effectiveness are needed.

CGRP antagonists for decreasing migraine frequency: New options, long overdue.

The cornerstone of preventive migraine treatment has long been drugs developed for other diseases such as epilepsy, depression, and hypertension. But a new set of drugs is available for preventing migraine attacks: erenumab, galcanezumab, fremanezumab, and eptinezumab. These monoclonal antibodies target calcitonin gene-related peptide (CGRP) or its receptors, each a key molecule in the pathophysiology of migraine.