Targeting Calcitonin Gene-related Peptide Research Articles

Cardiovascular Safety of Anti-CGRP Monoclonal Antibodies in Older Adults or Adults With Disability With Migraine

Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) or its receptor (anti-CGRP mAbs) offer effective migraine-specific preventive treatment. However, concerns exist about their potential cardiovascular risks due to CGRP blockade. To compare the incidence of cardiovascular disease (CVD) between Medicare beneficiaries with migraine who initiated anti-CGRP-mAbs vs onabotulinumtoxinA in the US. This retrospective, sequential cohort study was conducted among a nationally representative population-based sample of Medicare claims from May 2018 through December 2020. Data analysis was performed from August to December 2023. This study included fee-for-service Medicare beneficiaries aged 18 years or older with migraine who initiated either anti-CGRP mAbs or onabotulinumtoxinA. Beneficiaries who had a history of myocardial infarction (MI), stroke, cluster headache, malignant cancer, or hospice service within a 1-year baseline period prior to treatment initiation were excluded. To minimize channeling bias from new drug introductions and time-related bias due to the COVID-19 pandemic, 5 cohorts were established, representing sequential 6-month calendar intervals based on the initial prescription or date of index anti-CGRP mAbs or onabotulinumtoxinA use. Anti-CGRP mAbs vs onabotulinumtoxinA. The primary outcome was time to first MI or stroke. Secondary outcomes included hypertensive crisis, peripheral revascularization, and Raynaud phenomenon. The inverse probability of treatment-weighted Cox proportional hazards models were used to compare outcomes between the 2 treatment groups. Among 266 848 eligible patients with migraine, 5153 patients initiated anti-CGRP mAbs (mean [SD] age, 57.8 [14.0] years; 4308 female patients [83.6%]) and 4000 patients initiated onabotulinumtoxinA (mean [SD] age, 61.9 [13.7] years; 3353 female patients [83.8%]). Use of anti-CGRP mAbs was not associated with an increased risk of composite CVD events (adjusted hazard ratio [aHR], 0.88; 95% CI, 0.44-1.77), hypertensive crisis (aHR, 0.46; 95% CI, 0.14-1.55), peripheral revascularization (aHR, 1.50; 95% CI, 0.48-4.73), or Raynaud phenomenon (aHR, 0.75; 95% CI, 0.45-1.24) compared with onabotulinumtoxinA. Subgroup analyses by age group and presence of established non-MI or stroke CVD showed similar findings. In this cohort study, despite initial concerns regarding the cardiovascular effects of CGRP blockade, anti-CGRP mAbs were not associated with an increased risk of CVD compared with onabotulinumtoxinA among adult Medicare beneficiaries with migraine, who were predominantly older adults or individuals with disability. Future studies with longer follow-up periods and in other populations are needed to confirm these findings.

Effectiveness of switching strategies in CGRP monoclonal antibody therapy for migraine: A retrospective cohort study.

To evaluate the effectiveness of first switching between monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) or its receptor in the treatment of migraine. Although mAbs targeting CGRP or its receptor have emerged as a leading treatment for migraine prevention, a proportion of patients do not respond. While switching between these antibodies is a common clinical practice in such cases, the effectiveness remains a subject of study. We conducted a retrospective cohort study at a tertiary headache center, analyzing data from clinical records of patients treated with anti-CGRP mAbs from January 2020 to March 2024. Baseline was defined as the monthly headache days (MHDs) in the 3 months prior to the start of the second mAb. The primary endpoint was the change in MHDs at month 3 and month 6 following the switch. Additionally, we evaluated response rates in both periods. Subgroup analyses were conducted based on changes in mechanism of action. Finally, we assessed the influence of the number of doses of the first mAb and the inter-treatment interval. Out of 1244 initially identified patients, 185 were included in the month-3 analysis and 123 in the month-6 evaluation. The median MHDs decreased from 27.0 (interquartile range [IQR] 16.1, 30.0; range 5.0, 30.7) at baseline to 21.0 (IQR 10.0, 30.0; range 0.0, 30.0; p < 0.001) at month 3, and to 20.0 (IQR 10.0, 30.0; range 0.0, 31.0; p < 0.001) at month 6. Subgroup analyses revealed no significant differences in MHDs between maintaining the same target or changing it (baseline: 28.0 [IQR 16.2, 30.0; range 5.0, 31.0] vs. 27.0 [IQR 6.0, 31.0; range 6.0, 31.0]; month 3: 23.0 [IQR 10.0, 30.0; range 0.0, 31.0] vs. 19.0 [IQR 11.0, 30.0; range 1.0, 31.0], p = 0.144; month 6: 24.0 [IQR 11.0, 30.0; range 0.0, 31.0] vs. 17.0 [IQR 10.0, 30.0; range 3.0, 31.0], p = 0.170). There was no association between a ≥50% reduction in MHDs and the number of previous doses of the first mAb (odds ratio [OR] 1.0; 95% confidence interval [CI] 1.0, 1.1; p = 0.189) or the inter-treatment interval (OR 1.0; 95% CI 0.9, 1.1; p = 0.914). Switching between anti-CGRP mAbs resulted in a reduction in MHDs, with no significant differences based on the mechanism of action. Factors such as the number of doses of the first mAb and the inter-treatment interval did not appear to predict a ≥50% reduction in MHDs at month 3. Our findings support the viability of switching as an effective treatment option for patients with migraine who do not respond to initial mAb therapy.

Crowdsourcing Adverse Events Associated With Monoclonal Antibodies Targeting Calcitonin Gene-Related Peptide Signaling for Migraine Prevention: Natural Language Processing Analysis of Social Media.

Clinical trials demonstrate the efficacy and tolerability of medications targeting calcitonin gene-related peptide (CGRP) signaling for migraine prevention. However, these trials may not accurately reflect the real-world experiences of more diverse and heterogeneous patient populations, who often have higher disease burden and more comorbidities. Therefore, postmarketing safety surveillance is warranted. Regulatory organizations encourage marketing authorization holders to screen digital media for suspected adverse reactions, applying the same requirements as for spontaneous reports. Real-world data from social media platforms constitute a potential venue to capture diverse patient experiences and help detect treatment-related adverse events. However, while social media holds promise for this purpose, its use in pharmacovigilance is still in its early stages. Computational linguistics, which involves the automatic manipulation and quantitative analysis of oral or written language, offers a potential method for exploring this content. This study aims to characterize adverse events related to monoclonal antibodies targeting CGRP signaling on Reddit, a large online social media forum, by using computational linguistics. We examined differences in word frequencies from medication-related posts on the Reddit subforum r/Migraine over a 10-year period (2010-2020) using computational linguistics. The study had 2 phases: a validation phase and an application phase. In the validation phase, we compared posts about propranolol and topiramate, as well as posts about each medication against randomly selected posts, to identify known and expected adverse events. In the application phase, we analyzed posts discussing 2 monoclonal antibodies targeting CGRP signaling-erenumab and fremanezumab-to identify potential adverse events for these medications. From 22,467 Reddit r/Migraine posts, we extracted 402 (2%) propranolol posts, 1423 (6.33%) topiramate posts, 468 (2.08%) erenumab posts, and 73 (0.32%) fremanezumab posts. Comparing topiramate against propranolol identified several expected adverse events, for example, "appetite," "weight," "taste," "foggy," "forgetful," and "dizziness." Comparing erenumab against a random selection of terms identified "constipation" as a recurring keyword. Comparing erenumab against fremanezumab identified "constipation," "depression," "vomiting," and "muscle" as keywords. No adverse events were identified for fremanezumab. The validation phase of our study accurately identified common adverse events for oral migraine preventive medications. For example, typical adverse events such as "appetite" and "dizziness" were mentioned in posts about topiramate. When we applied this methodology to monoclonal antibodies targeting CGRP or its receptor-fremanezumab and erenumab, respectively-we found no definite adverse events for fremanezumab. However, notable flagged words for erenumab included "constipation," "depression," and "vomiting." In conclusion, computational linguistics applied to social media may help identify potential adverse events for novel therapeutics. While social media data show promise for pharmacovigilance, further work is needed to improve its reliability and usability.

Case series on monoclonal antibodies targeting calcitonin gene-related peptide in migraine patients during pregnancy: Enhancing safety data.

Monoclonal antibodies targeting calcitonin gene-related peptide (CGRP-mAbs) are approved for adult migraine prevention but pose safety concerns in pregnancy. We assess the safety of CGRP-mAbs in the periconceptional period through a case series and literature review. Six migraine-diagnosed women received CGRP-mAbs; treatment ceased upon pregnancy. We collected data and conducted safety assessments. To provide a comprehensive context, we performed a literature review. The series includes three erenumab, two fremanezumab and one galcanezumab case. A fremanezumab recipient experienced miscarriage; severe perinatal asphyxia linked to dystocia occurred with erenumab (140 mg). Database reviews revealed 63 spontaneous abortions, eight premature births, and seven birth defects among 286 World Health Organization and 65 European Medicines Agency cases. These rates align with untreated population rates. CGRP-mAbs use in the periconceptional period does not lead to clinically significant increase in pregnancy-related pathology or adverse effects on newborns within our case series and the literature reviewed.

Exploring Erenumab's Efficacy and Safety for Migraine Prevention in Real-World Settings: A Systematic Review.

Migraine causes debilitating headaches and significantly impacts quality of life. Effective migraine-specific treatments have been lacking until the advent of monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) receptors, which have expanded therapy options for migraine treatment. This study explores the short- and long-term efficacy and safety of erenumab in migraine treatment. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 criteria guided this systematic review. Five databases - PubMed, PubMed Central, Google Scholar, ScienceDirect, and Sage Journal - were searched for published, freely accessible, full-text articles in English from the past five years. Eligible patients included those with episodic or chronic migraines who received erenumab intervention. From an initial search yielding 680 relevant studies, 12 prospective observational cohort studies were selected after assessing the risk of bias through the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. All included studies demonstrated a significant reduction in monthly migraine days (MMDs) by the end of the treatment period, with mild adverse effects observed. No significant short-term or long-term safety concerns were identified.

The TRPA1 Ion Channel Mediates Oxidative Stress-Related Migraine Pathogenesis.

Although the introduction of drugs targeting calcitonin gene-related peptide (CGRP) revolutionized migraine treatment, still a substantial proportion of migraine patients do not respond satisfactorily to such a treatment, and new therapeutic targets are needed. Therefore, molecular studies on migraine pathogenesis are justified. Oxidative stress is implicated in migraine pathogenesis, as many migraine triggers are related to the production of reactive oxygen and nitrogen species (RONS). Migraine has been proposed as a superior mechanism of the brain to face oxidative stress resulting from energetic imbalance. However, the precise mechanism behind the link between migraine and oxidative stress is not known. Nociceptive primary afferent nerve fiber endings express ion channel receptors that change harmful stimuli into electric pain signals. Transient receptor potential cation channel subfamily A member 1 (TRPA1) is an ion channel that can be activated by oxidative stress products and stimulate the release of CGRP from nerve endings. It is a transmembrane protein with ankyrin repeats and conserved cysteines in its N-terminus embedded in the cytosol. TRPA1 may be a central element of the signaling pathway from oxidative stress and NO production to CGRP release, which may play a critical role in headache induction. In this narrative review, we present information on the role of oxidative stress in migraine pathogenesis and provide arguments that TRPA1 may be "a missing link" between oxidative stress and migraine and therefore a druggable target in this disease.

Anti‑CGRP monoclonal antibodies in resistant migraine: preliminary real-world effectiveness and clinical predictors of response at twoyears.

Monoclonal antibodies targeting calcitonin gene-related peptide (anti-CGRP mAbs) have shown clinical effectiveness and safety in randomized clinical studies. However, long-term studies in clinical practice remain limited. To assess the long-term effectiveness, clinical predictors and safety of three anti-CGRP mAbs (erenumab, galcanezumab, fremanezumab) in resistant migraine patients. A single-center retrospective study was conducted from December 2019 to June 2023 involving 120 resistant migraine patients who received at least a month of anti-CGRP mAbs treatment. Patients completed a headache diary that included monthly acute medication intake (MAM), monthly migraine days (MMD), adverse events as well as completed Patient-Reported Outcome questionnaires (MIDAS [Migraine Disability Assessment] and Headache Impact Test 6 [HIT-6]). The number of patients achieving a ≥ 50% reduction in monthly migraine days was determined and classified as ≥ 50% responders, and baseline parameters and logistic regression between responders and non-responders were analyzed to identify potential predictors of response. Adverse events were registered in every follow-up. Treatment with anti-CGRP mAbs led to reductions in MIDAS, HIT-6, MMD and MAM from baseline to 6-24months. At 6-12months, responders (61% and 57%, respectively) exhibited lower baseline MMD and MAM. Medication overuse was associated with non-responders from 6 to 24months and it was identified as a negative predictor of treatment effectiveness (OR 0.23, 95% CI 0.07-0.74; p = 0.014). Anti-CGRP mAbs prove effectiveness and safety over a 24-month period in a RM population. Patients with no medication overuse and lower basal MMDs and MAM may respond better to anti-CGRP mAbs.

Pituitary cyclase-activating polypeptide targeted treatmentsfor the treatment of primary headache disorders.

Migraine is a complex and disabling neurological disorder. Recent years have witnessed the development and emergence of novel treatments for the condition, namely those targeting calcitonin gene-related peptide (CGRP). However, there remains a substantial need for further treatments for those unresponsive to current therapies. Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) as a possible therapeutic strategy in the primary headache disorders has gained interest over recent years. This review will summarize what we know about PACAP to date: its expression, receptors, roles in migraine and cluster headache biology, insights gained from preclinical and clinical models of migraine, and therapeutic scope. PACAP shares homology with vasoactive intestinal polypeptide (VIP) and is one of several vasoactive neuropeptides along with CGRP and VIP, which has been implicated in migraine neurobiology. PACAP is widely expressed in areas of interest in migraine pathophysiology, such as the thalamus, trigeminal nucleus caudalis, and sphenopalatine ganglion. Preclinical evidence suggests a role for PACAP in trigeminovascular sensitization, while clinical evidence shows ictal release of PACAP in migraine and intravenous infusion of PACAP triggering attacks in susceptible individuals. PACAP leads to dural vasodilatation and secondary central phenomena via its binding to different G-protein-coupled receptors, and intracellular downstream effects through cyclic adenosine monophosphate (cAMP) and phosphokinase C (PKC). Targeting PACAP as a therapeutic strategy in headache has been explored using monoclonal antibodies developed against PACAP and against the PAC1 receptor, with initial positive results. Future clinical trials hold considerable promise for a new therapeutic approach using PACAP-targeted therapies in both migraine and cluster headache.

A Risk-Difference Meta-Analysis for the Prophylactic Treatments of Chronic Migraine.

Chronic migraine (CM) imposes significant personal, societal, and financial burdens, historically lacking specific prophylactic treatments. Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) represent a novel, mechanism-based, and migraine-specific prophylactic approach. Four mAbs, namely, erenumab, fremanezumab, galcanezumab, and eptinezumab, have been marketed, although head-to-head trials with standard anti-migraine treatments are absent. This study aimed to compare the efficacy and safety of anti-CGRP mAbs with standard anti-migraine treatments using a cross-trial indirect model of the absolute risk difference (ARD) of a 50% responder rate, in order to express the final results in terms of the number needed to treat (NNT) and number needed to harm (NNH). Phase 3 and 2b randomized controlled trials (RCTs) for CM prophylaxis were searched in the MEDLINE and CENTRAL databases with specific inclusion and exclusion criteria. The ARD between groups for the percentage of trial participants who reported a 50% reduction in monthly migraine days and the differences in the number of adverse events (AEs), serious adverse events (SAEs), and participants who withdrew from each RCT were calculated, and subsequently, the NNT and NNH were calculated for each one of the outcome measures. In total, eight RCTs were considered eligible. A similar efficacy and safety have been demonstrated among CGRP mAbs and all standard CM treatments. The results of the ARD for the total number of studies concerning efficacy, total adverse events, serious adverse events, and dropout from the RCTs ranged from -0.688 (95% confidence interval (CI): -0.821-(-0.513)) to -0.018 (95% CI: -0.044-(0.007)), from 0.032 (95% CI: -0.041, 0.104) to -0.380 (95% CI: -0.589, -0.126), from -0.025 (95% CI: -0.046, -0.006) to 0.014 (95% CI: -0.015, 0.42), from 0.048 (95% CI: -0.112, 0.014) to 0.232 (95% CI: -0.016, 0.458) correspondingly. All anti-CGRP mAbs showed a roughly equal statistically significant ARD and similar NNTs, ranging from 5 to 8, while the ARD of onbotulinum toxin A (oBTA) was not significant with an NNT 56. The two studies of topiramate showed contradictory results, the one significant while the other not, with NNTs 2 and 22, respectively. All four anti-CGRP mAbs showed an invariably high efficacy among their studies, in terms of the ARD and its derivative measure of NNT, in contrast to oBTA, while in topiramate, the results are contradictory between the two studies.

Real-world effectiveness and safety of erenumab for the treatment of migraine: A systematic review and meta-analysis

BackgroundMigraine is a common and disabling primary headache disorder. Several drugs targeting calcitonin gene-related peptide (CGRP), such as erenumab (an anti-CGRP receptor mAb), have been developed recently. However, the real-world effects of erenumab are not well understood. ObjectiveTo assess the clinical effectiveness and safety of erenumab for reducing migraine intensity and frequency in the real world. MethodsA systematic search of PubMed, Scopus, Web of Science and the Cochrane Library was conducted from inception to December 2023. Studies estimating the real-world effect of erenumab on monthly migraine days (MMD), monthly headache days (MHD), headache impact test (HIT-6), number of days in medication (NDM), acute monthly intake (AMI), pain intensity (PI) and safety outcomes were included. Meta-analyses of proportions or mean differences were performed. ResultsFifty-three studies were included. At 3-months, the effect was −7.18 days for MMD, −6.89 days for MHD, −6.97 for HIT-6, -6.22 days for NDM, −15.75 for AMI, and −1.71 for PI. Generally, the effect at 6- and 12-months increased slightly and gradually. The MMD/MHD response rates revealed that approximately one-third of patients exhibited a response greater than 30%, while one-sixth demonstrated a response exceeding 50%. Additionally, 3–4% of patients achieved a response rate of 100%. Adverse event rates were 0.34 and 0.43 at 6- and 12-months, respectively. ConclusionThis study provides strong evidence of the effectiveness and safety of erenumab in the real world; to our knowledge, this is the first real-world meta-analysis specific to erenumab. Erenumab represents a solid therapeutic option for physicians.

A real-world prospective observational study of eptinezumab in Asian patients with migraine.

To evaluate the real-world effectiveness of eptinezumab for migraine prevention in Asian patients. Eptinezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP), a potent vasodilator with an important role in migraine pathophysiology. Although there is robust clinical evidence from pivotal Phase 3 placebo-controlled trials of the efficacy of eptinezumab for migraine prevention, there are limited data on the real-world effectiveness of eptinezumab in Asian patient cohorts. This was a non-interventional, prospective, multisite cohort study of adults with migraine (International Classification of Headache Disorders, 3rd edition criteria) in Singapore who were prescribed eptinezumab (100 mg at baseline and Month 3, administered intravenously) and were followed until Month 6. The primary endpoint was change from baseline in monthly migraine days (MMDs) at Month 3 and Month 6. Secondary endpoints were ≥30% and ≥50% responder rates, and change from baseline in the Headache Impact Test-6 (HIT-6), Migraine Disability Assessment (MIDAS), Migraine-Specific Quality of Life (MSQ), patient-identified most bothersome symptom (PI-MBS), acute medication use at Month 3 and Month 6, and safety. Enrolled patients (completed = 29/30) had on average 3.4 (SD 2.9) previous preventive treatments; 29/30 of the patients had trialed at least one previous preventive treatment without benefit. Most had previously trialed oral preventives (87%, 26/30) and anti-CGRP (70%, 21/30). Relative to baseline, mean MMDs decreased by 4.3 days (95% CI 2.1-6.4; p < 0.001) at Month 3 and 4.9 days (95% CI 2.1-7.7; p < 0.001) at Month 6. At Month 3 and Month 6, 14/30 (47%) and 15/29 (52%) of the patients were ≥30% responders, and 6/30 (20%) and 8/29 (28%) patients were ≥50% responders, respectively. The number of patients with severe life impairment based on the HIT-6 score (total score 60-78) decreased from 24/30 (80%) at baseline to 19/30 (63%) at Month 3 and 19/29 (66%) at Month 6. The mean MIDAS score decreased by 24.6 points (95% CI 2.82-46.38; p = 0.028) at Month 6, and the mean MSQ score increased by 12.2 points (95% CI 5.18-19.20; p = 0.001) at Month 3 and 13.6 points (95% CI 4.58-22.66; p = 0.004) at Month 6. Most patients reported improvement in the PI-MBS at Month 3 (73%, 22/30) and Month 6 (55%, 16/29). Acute medication use for headache relief decreased by 3.3 days/month (95% CI 1.0-5.6; p = 0.007) at Month 3 and 4.7 days/month (95% CI 1.7-7.7; p = 0.003) at Month 6. Treatment-emergent adverse events (TEAEs) were reported in 16/30 (54%) patients, mostly mild/moderate in severity. No serious TEAEs led to treatment discontinuation. Quarterly eptinezumab administration was effective and well-tolerated in Asian patients with chronic migraine.

Effectiveness and tolerability of eptinezumab in treating patients with migraine resistant to conventional preventive medications and CGRP (receptor) antibodies: a multicentre retrospective real-world analysis from Germany.

Eptinezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP mAb) and is used for migraine prophylaxis. Efficacy data are mainly from clinical trials, real-world data are hardly available yet. Reimbursement policy in Germany leads to eptinezumab mainly being used in patients having failed pre-treatment with other CGRP mAb. To date, it is unclear whether eptinezumab is efficacious and well tolerated in this population and how the treatment response differs from patients who are naive to CGRP mAbs. We analysed clinical routine data of 79 patients (episodic migraine (EM): n = 19; chronic migraine (CM): n = 60) from four different centres in Germany. All patients were treated with eptinezumab (100mg). Differences in monthly headache (MHD), migraine (MMD) and acute medication days (AMD) after three months were analysed. The correlation of response with the number of CGRP mAb failures was evaluated. Significance level has been corrected (alpha = 0.017). After three months MHD, MMD and AMD were significantly reduced. In EM, the median reduction for MHD was 4.0 days (IQR: -6.5 to -1.0; p = 0.001), for MMD 3.0 days (IQR: -5.5 to -1.5; p < 0.001) and for AMD 2.0 days (IQR: -5.0 to -0.5; p = 0.006). In CM, median reduction of MHD was 4 days (IQR: -8.0 to 0.0; p < 0.001), 3.0 days (IQR: -6.0 to-1.0; p < 0.001) for MMD and 1.0 day (IQR: -5.0 to 0.0; p < 0.001) for AMD. All patients were resistant to conventional preventive therapies and most to CGRP mAbs. Fourteen patients had never received a CGRP mAb and 65 patients had received at least one mAb without sufficient effectiveness and/or intolerability (one: n = 20, two: n = 28, three: n = 17). There was a significant association between the number of prior therapies and the 30% MHD responder rate (none: 78.6%, one: 45.0%, two: 32.1%, three: 23.5%, p = 0.010). Regarding tolerability, 10.4% (8/77) reported mild side effects. The effectiveness of eptinezumab is significantly reduced in patients who have not previously responded to other CGRP mAbs. However, limitations such as the retrospective nature of the analysis, the small sample size and the short treatment period with only the lower dose of eptinezumab must be considered when interpreting the results.

MicroRNA profiling in women with migraine: effects of CGRP-targeting treatment

BackgroundMigraine lacks biomarkers that can trace the biological pathways of the disease and predict the effectiveness of treatments. Monoclonal antibodies targeting calcitonin gene-related peptide pathway – including erenumab – offer the opportunity of investigating potential migraine biomarkers due to their specific mechanism of action in preventing both episodic (EM) and chronic (CM) migraine. Our study aims at evaluating the expression levels of circulating microRNAs (miRNAs) according to migraine type, before and after treatment with erenumab and based on treatment response, in order to identify miRNAs with potential role as epigenetic biomarkers.MethodsThe study included women aged 25–50 years with EM or CM treated with erenumab according to clinical indications. MiRNAs expression levels were assessed before (baseline) and after a 16-week treatment with erenumab, 140 mg every four weeks (post-treatment). An extensive miRNAs profiling was performed by qRT-PCR in small, pooled groups of ≤ 8 women each, classified according to migraine frequency (EM and CM) and the degree of response to erenumab. The expression levels of selected miRNAs were also validated using single miRNA assays in each woman with EM and CM.ResultsDuring the study, 36 women with migraine (19 with EM and 17 with CM) out of 40 who were initially screened, performed the assessment of miRNA expression at baseline and post-treatment, Erenumab treatment significantly improved migraine burden in both EM and CM. MiRNA profiling revealed differential expression levels of a wide set of miRNAs (hsa-let-7d-3p, hsa-miR-106b-3p, hsa-miR-122-5p, hsa-miR-143-3p, hsa-miR-144-3p, hsa-miR-16-5p, hsa-miR-181a-5p, hsa-miR-221-3p, hsa-miR-25-3p, hsa-miR-29b-2-5p, hsa-miR-326, miR-363-3p, hsa-miR-424-5p, hsa-miR-485-3p, hsa-miR-532-5p, hsa-miR-543, hsa-miR-629-5p, hsa-miR-660-5p, hsa-miR-92a-3p) depending on treatment response. Among them, single miRNA assays confirmed the progressive decrease of hsa-miR-143-3p expression levels in relation to increasing response to erenumab in women with EM (7 with low, 6 with medium, and 6 with high response; p = 0.02). Additionally, single assays showed higher hsa-miR-34a-5p and hsa-miR-382-5p expression levels at baseline in women with CM compared with those with EM (p = 0.0002 and p = 0.0007, respectively), as well as their expression level decrease in women with CM from baseline to follow-up (p = 0.04 and p = 0.02, respectively).ConclusionsOur study suggests that targeting the CGRP pathway in migraine changes the expression levels of certain miRNAs. These miRNA levels are linked to the levels of response to CGRP receptor blockage. Future research challenges include assigning specific functions to the modulated miRNAs to unravel pathways modulated by the disease and the treatment.Trial registrationThe study was registered in clinicaltrials.gov with code NCT04659226 and in the Novartis database with code CAMG334AIT05T.

Meningeal lymphatic CGRP signaling governs pain via cerebrospinal fluid efflux and neuroinflammation in migraine models.

Recently developed antimigraine therapeutics targeting calcitonin gene-related peptide (CGRP) signaling are effective, though their sites of activity remain elusive. Notably, the lymphatic vasculature is responsive to CGRP signaling, but whether meningeal lymphatic vessels (MLVs) contribute to migraine pathophysiology is unknown. Mice with lymphatic vasculature deficient in the CGRP receptor (CalcrliLEC mice) treated with nitroglycerin-mediated (NTG-mediated) chronic migraine exhibit reduced pain and light avoidance compared with NTG-treated littermate controls. Gene expression profiles of lymphatic endothelial cells (LECs) isolated from the meninges of Rpl22HA/+;Lyve1Cre RiboTag mice treated with NTG revealed increased MLV-immune interactions compared with cells from untreated mice. Interestingly, the relative abundance of mucosal vascular addressin cell adhesion molecule 1-interacting (MAdCAM1-interacting) CD4+ T cells was increased in the deep cervical lymph nodes of NTG-treated control mice but not in NTG-treated CalcrliLEC mice. Treatment of cultured hLECs with CGRP peptide in vitro induced vascular endothelial-cadherin (VE-cadherin) rearrangement and reduced functional permeability. Likewise, intra cisterna magna injection of CGRP caused rearrangement of VE-cadherin, decreased MLV uptake of cerebrospinal fluid (CSF), and impaired CSF drainage in control mice but not in CalcrliLEC mice. Collectively, these findings reveal a previously unrecognized role for lymphatics in chronic migraine, whereby CGRP signaling primes MLV-immune interactions and reduces CSF efflux.

New Daily Persistent Headache.

This article describes the clinical features, etiology, differential diagnosis, management, and prognosis of new daily persistent headache. New daily persistent headache has attracted renewed attention as it may arise in the setting of a COVID-19 infection. Spontaneous intracranial hypotension, particularly from CSF-venous fistulas, remains an important secondary headache disorder to consider before diagnosing new daily persistent headache. Symptomatic treatment for new daily persistent headache may include acute and preventive therapies used for migraine and tension-type headache, such as triptans, oral preventive agents, onabotulinumtoxinA, and agents that target calcitonin gene-related peptide. New daily persistent headache is a daily headache syndrome that starts acutely and can only be diagnosed after 3 months have elapsed and other secondary and primary headache diagnoses have been excluded. The clinical manifestations largely resemble either chronic migraine or chronic tension-type headache. The underlying cause is unknown, but it is plausible that multiple etiologies exist and that it is not a single disease entity. The prognosis is variable but often poor, and the treatment approach is largely extrapolated from the management of chronic migraine and chronic tension-type headache.

Elevated plasma levels of calcitonin gene-related peptide in individuals with rosacea: A cross-sectional case-control study.

Understanding the role of calcitonin gene-related peptide (CGRP) in the pathogenesis of rosacea might provide new therapeutic avenues for individuals with this disease. To compare plasma levels of CGRP between individuals with rosacea and healthy controls. In this cross-sectional case-control study conducted in Copenhagen, Denmark, we collected blood samples from the antecubital vein from adults with rosacea and from healthy controls. We enrolled 123 individuals with rosacea and 68 healthy controls. After adjusting for age and sex, plasma levels of CGRP were significantly higher in individuals with rosacea (mean, 95% confidence interval: 140.21 pmol/L, 128.50-151.92 pmol/L), compared with controls (110.77 pmol/L, 99.91-120.14 pmol/L, p = 0.002). Plasma levels of CGRP were not affected by age, sex, BMI, concomitant migraine, rosacea sub- or phenotype, concomitant disease or current treatment. Participants were not age-, sex- and BMI-matched. Elevated plasma levels of CGRP in individuals with rosacea suggest a role of CGRP in the pathogenesis of rosacea. Targeting CGRP signalling might hold therapeutic promise in people affected by this disease. NCT03872050.

Real-world Impact of Fremanezumab on Migraine-Related Health Care Resource Utilization in Patients with Comorbidities, Acute Medication Overuse, and/or Unsatisfactory Prior Migraine Preventive Response.

Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide, is indicated for preventive treatment of migraine in adults. Real-world evidence assessing the effect of fremanezumab on migraine-related medication use, health care resource utilization (HCRU), and costs in patient populations with comorbidities, acute medication overuse (AMO), and/or unsatisfactory prior migraine preventive response (UPMPR) is needed. Data for this US, retrospective claims analysis were obtained from the Merative® MarketScan® Commercial and supplemental databases. Eligible adults with migraine initiated fremanezumab between 1 September 2018 and 30 June 2019 (date of earliest fremanezumab claim is the index date), had≥ 12months of continuous enrollment prior to initiation (preindex period) and ≥ 6months of data following initiation (postindex period; variable follow-up after 6months), and had certain preindex migraine comorbidities (depression, anxiety, and cardiovascular disease), potential AMO, or UPMPR. Changes in migraine-related concomitant acute and preventive medication use, HCRU, and costs were assessed pre- versus postindex. In total, 3193 patients met the eligibility criteria. From pre- to postindex, mean (SD) per patient per month (PPPM) number of migraine-related acute medication and preventive medication claims (excluding fremanezumab), respectively, decreased from 0.97 (0.90) to 0.86 (0.87) (P < 0.001) and 0.94 (0.74) to 0.81 (0.75) (P < 0.001). Migraine-related outpatient and neurologist office visits, emergency department visits, and other outpatient services PPPM decreased pre- versus postindex (P < 0.001 for all), resulting in a reduction in mean (SD) total health care costs PPPM from US$541 (US$858) to US$490 (US$974) (P = 0.003). Patients showed high adherence and persistence rates, with mean (SD) proportion of days covered of 0.71 (0.29), medication possession ratio of 0.74 (0.31), and persistence duration of 160.3 (33.2) days 6months postindex. Patients with certain migraine comorbidities, potential AMO, and/or UPMPR in a real-world setting had reduced migraine-related medication use, HCRU, and costs following initiation of fremanezumab. Graphical abstract available for this article.

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

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. 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. 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. 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. 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.

Eptinezumab for the preventive treatment of episodic and chronic migraine: a narrative review.

Eptinezumab, a monoclonal antibody that targets calcitonin gene-related peptide (CGRP), was recently approved in Europe for the prophylactic treatment of migraine in adults who have at least four migraine days a month. Eptinezumab is administered by intravenous infusion every 12 weeks. During recent months, a considerable amount of evidence from eptinezumab trials has been published. The aim of this review is to describe the existing evidence on the tolerability, safety and efficacy of eptinezumab in patients with migraine. Data from randomized (PROMISE-1, PROMISE-2, RELIEF and DELIVER) and open-label (PREVAIL) phase 3 clinical trials have demonstrated the favorable effect of eptinezumab in migraine symptoms from first day of treatment. These studies showed that eptinezumab results in an overall reduction in mean monthly migraine days (MMDs), increases in the ≥50% and ≥ 75% migraine responder rates (MRRs) and improvements in patient-reported outcome measures in both patients with episodic migraine (EM) and with chronic migraine (CM), including patients who failed previous preventive treatments. The RELIEF trial also showed that eptinezumab, within 2 h of administration, reduced headache pain, migraine-associated symptoms and acute medication use when administered during a migraine attack. Eptinezumab benefits manifested as early as day 1 after dosing and with the subsequent doses lasted up to at least 2 years. Treatment-emergent adverse events reported by ≥2% of patients included upper respiratory tract infection and fatigue. Current evidence demonstrates that eptinezumab has a potent, fast-acting, sustained migraine preventive effect in patients with EM and CM. Eptinezumab has also shown to be well tolerated, supporting its use in the treatment of patients with migraine and inclusion in the current migraine therapeutic options.

Monoclonal Antibody Targeting CGRP Relieves Cisplatin-Induced Neuropathic Pain by Attenuating Neuroinflammation.

Chemotherapy-induced neuropathic pain (CIPN) is a common side effect of antitumor chemotherapeutic agents. It describes a pathological state of pain related to the cumulative dosage of the drug, significantly limiting the efficacy of antitumor treatment. Sofas strategies alleviating CIPN still lack. Calcitonin gene-related peptide (CGRP) is a neuropeptide involved in many pathologic pains. In this study, we explored the effects of CGRP blocking on CIPN and potential mechanisms. Total dose of 20.7mg/kg cisplatin was used to establish a CIPN mouse model. Mechanical and thermal hypersensitivity was measured using von Frey hairs and tail flick test. Western blot and immunofluorescence were utilized to evaluate the levels of CGRP and activated astrocytes in mouse spinal cord, respectively. In addition, real-time quantitative PCR (RT-qPCR) was used to detect the level of inflammatory cytokines such as IL-6, IL-1β, and NLRP3 in vitro and in vivo. There are markedly increased CGRP expression and astrocyte activation in the spinal cord of mice following cisplatin treatment. Pretreatment with a monoclonal antibody targeting CGRP (ZR8 mAb) effectively reduced cisplatin-induced mechanical hypersensitivity and thermal nociceptive sensitization and attenuated neuroinflammation as marked by downregulated expression of IL-6, IL-1β, and NLRP3 in the mice spinal cord and spleen. Lastly, ZR8 mAb does not interfere with the antitumor effects of cisplatin in tumor-bearing mice. Our findings indicate that neutralizing CGRP with monoclonal antibody could effectively alleviate CIPN by attenuating neuroinflammation. CGRP is a promising therapeutic target for CIPN.