This study aims to evaluate the tolerability and effectiveness of the off-label use of rimegepant as acute migraine treatment in adolescents. Calcitonin gene-related peptide (CGRP) levels are elevated during migraine attacks. Gepants, oral CGRP receptor antagonists, have demonstrated effectiveness as acute and preventive migraine treatment in adults. They are generally well tolerated with limited side effects. Their use for migraine is approved by the United States Food and Drug Administration (FDA) in adults; however, data on their use in adolescents remain limited. This is a retrospective chart review of pediatric patients <18 years of age who received at least one dose of rimegepant as acute migraine treatment at Dell Children's Medical Center between 2020 and 2023. Effectiveness was evaluated using patient-reported outcomes during clinic visits. Tolerability was assessed through vital signs, laboratory data, and patient-reported side effects pre- and post-rimegepant use. Data were analyzed using descriptive and inferential statistics. Twelve adolescents who received at least one dose of rimegepant were identified. The mean age at first dose was 15.3 years (SD ± 1.5); nine (75%) were female. Migraine types included episodic migraine without aura (n = 4, 33%), episodic migraine with aura (n = 1, 8%), chronic migraine without aura (n = 4, 33%), and hemiplegic migraine (n = 3, 25%). The mean number of headache days per month at baseline was 11.5 (SD ± 11.8). Patients tried a mean of 3.9 (SD ± 2.4) acute medications prior to rimegepant use. During follow-up, 10 of 12 (83%) patients reported either resolution or improvement of their migraine attacks with rimegepant use. There were no statistically significant height, weight, blood pressure, or laboratory changes after rimegepant use, and no patients reported side effects. Rimegepant may be a safe and effective acute migraine treatment in adolescents. No adverse events occurred, and the medication appears to be safe and well-tolerated. These findings support the need for larger prospective and randomized controlled trials to further evaluate the tolerability and effectiveness of gepants in the pediatric population.

AimThe TACHIS study (from the ancient Greek adjective "tachýs" meaning rapid) aimed to evaluate eptinezumab effectiveness and tolerability in routine clinical practice, integrating patient-reported outcomes and use of International Headache Society (IHS)-endorsed categories of migraine control by treatment.BackgroundEptinezumab is the only intravenous anti-calcitonin gene related peptide (CGRP) monoclonal antibody (mAb) approved for migraine prevention. While its efficacy has been demonstrated in RCTs, real-world evidence in patients with prior preventive treatment failures is still limited.MethodsTACHIS is a prospective, multicenter, observational study conducted in Italy. Adults with episodic or chronic migraine initiating eptinezumab were followed for 24 weeks. Primary outcomes included change from baseline in monthly migraine days (MMDs) and ≥50% responder rate. Secondary outcomes included changes from baseline in acute medication use, Migraine Disability Assessment (MIDAS) and Headache Impact Test-6 (HIT-6) and IHS-defined residual burden categories. Logistic regression identified factors of response status.ResultsA total of 128 patients were included (82% female; 82% chronic migraine). MMDs decreased overall by 5.7 days (95% CI: -7.2 to -4.3) at week 12 and 6.9 (95% CI: -8.5 to -5.2) at week 24 (p < 0.001). A ≥ 50% response was achieved in 43.8% and 48.2% of patients at weeks 12 and 24, respectively. Over 40% of patients achieved optimal or modest migraine control. CGRP targeted therapy-naïve patients experienced significant greater benefit, though non-naïve patients also improved. Female sex and chronic migraine diagnosis were independently associated with response at 12 weeks. Adverse events were infrequent (4.7%) and mild, with no discontinuations due to safety concerns.ConclusionsEptinezumab demonstrated effectiveness and tolerability in a real-world population of patients with migraine and prior preventive treatment failures. The integration of migraine control metrics provides a comprehensive evaluation of therapeutic impact and supports eptinezumab use in routine care.Trial RegistrationThe TACHIS study was preregistered on clinicaltrial.gov, NCT06409845.

Gepants, a novel class of calcitonin gene-related peptide (CGRP) receptor antagonists, are increasingly used for acute and preventive migraine treatment; however, comprehensive real-world safety data are limited. This study is a retrospective disproportionality analysis that evaluates the safety profile of rimegepant, ubrogepant, atogepant, and zavegepant by analyzing adverse events (AEs) reports from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database in patients with migraine. AE reports for rimegepant, ubrogepant, atogepant, and zavegepant from January 2020 to March 2025 were retrieved from the FAERS database using standardized drug names and migraine-related indications. Disproportionality analyses were employed to detect AE signals, classified by system organ class (SOC) and Preferred Term (PT) using MedDRA 27.0. A total of 84, 55, 80, and 31 AE signals were identified for rimegepant, ubrogepant, atogepant, and zavegepant, respectively. Nausea, a gastrointestinal disorder, was the only AE common to all four gepants (4.07%-5.2%). Oral gepants (rimegepant, ubrogepant, atogepant) primarily showed gastrointestinal and nervous system AEs, including constipation (atogepant, reporting odds ratio {ROR} = 11.39 [95% confidence interval {CI}: 10.21-12.71]) and dizziness. Zavegepant was associated with respiratory AEs, notably nasal discomfort (ROR = 718.38 [95% CI: 552.33-934.35]). Potential signals related to pregnancy outcomes were detected for rimegepant and ubrogepant, warranting cautious interpretation and further investigation. Gepants display distinct AE profiles, with oral agents linked to gastrointestinal and neurological effects and intranasal zavegepant associated with respiratory irritation. Continued post-marketing surveillance is essential to inform personalized migraine management and guide future CGRP-targeted drug development.

The Impact of Anti-Calcitonin Gene-Related Peptide Monoclonal Antibodies on Sleep Quality and Daytime Sleepiness in Migraine Patients: A Multicenter Study

Anti-calcitonin gene-related peptide monoclonal antibodies (CGRP-mAbs) are effective injectable medications for the treatment of migraine. This study aimed to evaluate continuation, resumption, and withdrawal rates of CGRP-mAb treatment under real-world clinical conditions. Treatment-naïve patients with at least 3 months of follow-up after starting CGRP-mAb treatment were included. The decision to continue, discontinue, or resume CGRP-mAb treatment was made freely by the patients. Headache Impact Test-6 (HIT-6) and the Migraine-Specific Quality of Life Questionnaire (MSQ) were administered before starting treatment and one month after each CGRP-mAb injection. The endpoints were as follows: continuation rates of CGRP-mAb treatment after treatment initiation; resumption rate; withdrawal rate; changes in HIT-6 and MSQ scores; and differences in background factors between the resumption and withdrawal groups. Of the 1162 migraine patients, 146 were included in the analysis. Continuation rates of CGRP-mAb treatment at 3, 6, 9, 12, 18, and 24 months were 93.2%, 80.2%, 68.9%, 58.8%, 55.4%, and 51.7%, respectively. For the patients who discontinued, the resumption rate was 76.8%, and the withdrawal rate was 20.7%. HIT-6 and MSQ scores were significantly decreased at all assessment points compared with before CGRP-mAb treatment. There were no significant differences in factors between the resumption and withdrawal groups. Under real-world clinical conditions in which patients were free to choose their own treatment, the continuation rate of CGRP-mAb treatment 12 months after treatment initiation was 58.8%, and more than half of patients remained on treatment after 24 months. The resumption rate was 76.8% and the withdrawal rate was 20.7%.

This study aims to investigate the potential risk and possible mechanisms of Raynaud's phenomenon (RP) associated with the use of calcitonin gene-related peptide (CGRP) antagonists through a comprehensive analysis of the FDA Adverse Event Reporting System (FAERS) database combined with drug-gene network analysis methods. In this disproportionality study, we evaluated the adverse event (AE) signal of RP associated with CGRP antagonists from the FAERS covering the quarter 2 of 2018 to quarter 1 of 2025, using four methods. The gene targets of CGRP antagonists and RP targets were predicted using multiple databases and protein-protein interactions (PPI) using the STRING database. Subsequently, Kyoto Encyclopedia of genes and genomes (KEGG) enrichment analysis was performed using R software to identify the potential mechanisms of CGRP antagonists related to RP. This study retrieved a total of 149 AE reports related to CGRP antagonists and RP reports from the FAERS database, involving 7 CGRP antagonists. Erenumab has the highest number of reports. The data mining results indicate that fremanezumab resulted in the strongest AE signals of the four methods. Protein-protein interaction (PPI) network analysis revealed key nodes of non-peptide small molecule CGRP antagonists in RP, such as the key nodes of rimegepant in RP is AKT1, EGFR, ERBB2, and others. The KEGG pathway enrichment analysis showed that the most possible mechanisms of rimegepant, atogepant, and ubrogepant induce RP is the PI3K signaling pathway.Using a novel approach, we systematically integrated the FAERS database with drug-gene network analysis. Our results not only suggest a potential risk of RP associated with CGRP antagonists but also reveal that the PI3K/AKT pathway is the underlying mechanism for non-peptide small molecules. We recommend that patients receiving these antagonists, particularly those with underlying vascular dysfunction, undergo regular monitoring for RP.

Eptinezumab is an anti-calcitonin gene-related peptide monoclonal antibody used for migraine prevention. During clinical trials, hypersensitivity to eptinezumab was described without a clear underlying mechanism. To determine if the reaction was immunoglobulin E-mediated, the team of Nice University Hospital (Nice, France) performed the eptinzeumab skin tests. A 10-step desensitization protocol has been proposed to manage these reactions. Two patients presenting with immediate hypersensitivity reactions underwent the eptinezumab skin test. Neither skin test was positive, suggesting a non-immunoglobulin E-mediated mechanism. The patients then completed the desensitization protocol successfully. This hospital-based 10-step desensitization protocol appears safe and effective.

Inhibition of the calcitonin gene-related peptide (CGRP) pathway offers a novel therapeutic option in the prevention of migraine attacks. The aim of this guideline is to provide practical recommendations for the safe, effective, and personalized use of CGRP inhibitors in episodic and chronic migraine within Hungarian clinical practice. The recommendations were developed based on international guidelines and current clinical trial evidence. The guideline takes into account drug efficacy, side-effect profiles, contraindications, as well as considerations for specific patient populations. CGRP antagonists - including monoclonal antibodies and gepants - may be applied even as first-line acute or preventive treatments owing to their efficacy and favorable safety profiles, particularly when the patient's clinical status, preferences, or comorbidities justify their use. Adverse events are mostly mild, and overall safety is favorable. Therapeutic decisions should be followed by a three-month evaluation period, and in the case of insufficient response, drug switching or combination therapy should be considered. According to international evidence, a structured therapeutic algorithm and a patient-tailored approach may have a beneficial effect and are expected to contribute to improved quality of life in patients with migraine. Orv Hetil. 2025; 166(50): 1963-1974.

BackgroundMigraine is a prevalent and disabling condition affecting one billion people worldwide. calcitonin gene-related peptide (CGRP) inhibitors have transformed migraine management. We describe real-world trends in CGRP inhibitor treatment, switching, discontinuation, and migraine-related health care use (including emergency department, ED, and ambulatory care visits).MethodsWe used the Merative™ MarketScan® Research data, providing data on inpatient and outpatient healthcare use and drug dispensation from a large sample of individuals with employer-sponsored health insurance in the United States. We identified adults using CGRP inhibitors (comprising both monoclonal antibodies, mAbs, and small-molecule CGRP receptor antagonists, gepants) as preventive treatment for migraine between May 2018 and December 2022. We evaluated treatment patterns, including switching between CGRP agents or other prophylactic migraine treatments, and therapy discontinuation. Healthcare and migraine-related medication use were compared one year pre- and post-CGRP inhibitor initiation. Migraine-related medications included preventive migraine-specific treatments (e.g., onabotulinumtoxinA), non-specific preventives (e.g., antidepressants), and acute treatments—both migraine-specific (e.g., triptans) and non-specific (e.g., opioids).ResultsWe studied 148,100 adults with at least one CGRP inhibitor dispensation. CGRP inhibitor use increased over time, with newer agents being more commonly dispensed in recent years. Within the first year, 10.3% of individuals switched between CGRP inhibitors, and an additional 13.5% discontinued their first CGRP inhibitor without switching to another. Post-initiation, there was a 4.5% reduction in migraine-related medication use (95% confidence interval, CI: -4.9% to -4.0%, and 12.8% reduction in healthcare use (95% CI: -13.2% to -12.3%).ConclusionsCGRP inhibitors are increasingly used over time. About 10% switch between CGRP agents within the first year of initiation. There was reduction in other migraine-related medications and healthcare visits following CGRP initiation.Trial registrationN/A.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-025-02167-0.

BackgroundRimegepant is a small-molecule calcitonin gene-related peptide receptor antagonist approved in adults for acute treatment of migraine (with or without aura) and preventive treatment of episodic migraine (EM). Rimegepant is well tolerated at approved doses; 75 mg as needed up to once per day for acute treatment and 75 mg every other day for preventive treatment. This study evaluated long-term safety and tolerability of once-daily (QD) rimegepant 75 mg for EM prevention.MethodsAdults with 4–14 migraine attacks per month received open-label oral rimegepant 75 mg QD for up to 24 weeks. Standard-of-care medications for acute treatment of migraine and stable dosing of preventive migraine medications were permitted. Endpoints included on-treatment adverse events (AEs) occurring in ≥5% of participants, on-treatment serious AEs, on-treatment AEs leading to rimegepant discontinuation, and on-treatment grade 3–4 laboratory test abnormalities. Efficacy was not assessed in this study.ResultsOverall, 250 participants (female = 82.4%, White = 86.4%, mean age = 42.6 years) received ≥1 dose of rimegepant and 74.8% completed open-label treatment. Mean (SD) time on rimegepant was 19.3 (8.7) weeks. Overall, 53.6% of participants had ≥1 on-treatment AE, none had a serious AE, 1.6% had a severe AE, and 2.8% had an AE leading to rimegepant discontinuation. On-treatment AEs occurring in ≥5% of participants included nasopharyngitis (9.2%), COVID-19 (6.4%), and nausea (6.0%). On-treatment grade 3–4 laboratory test abnormalities included low lymphocytes (0.4%), high creatine kinase (3.8%), low glucose (0.4%), high low-density lipoprotein cholesterol (LDL-C; 9.8%), high fasting LDL-C (9.3%), high non-fasting LDL-C (10.2%), high potassium (1.3%), high triglycerides (0.9%), high fasting triglycerides (1.3%), and urine glucose (0.5%). No on-treatment elevations in liver transaminases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) > 5× the upper limit of normal (ULN) or potential Hy’s law cases (ALT or AST > 3× the ULN concurrent with total bilirubin levels > 2× the ULN) were observed.ConclusionRimegepant 75 mg QD for up to 24 weeks had a favorable safety profile for preventive treatment of EM.Trial registrationClinicalTrials.gov NCT05207865 (registered January 12, 2022).Supplementary informationThe online version contains supplementary material available at 10.1186/s10194-025-02225-7.

Osteoarthritis (OA) is a debilitating joint disease affecting over 500 million people globally, characterized by cartilage degradation, chronic pain, and failed tissue repair. Neurogenic inflammation, driven by neuropeptides including Substance P (SP) and calcitonin gene-related peptide (CGRP), plays a key role in the pathogenesis of OA. This study explores the therapeutic potential of extracellular vesicles (EVs) derived from infrapatellar fat pad mesenchymal stem/stromal cells (IFP-MSCs) transduced with CGRP antagonist CGRP8-37 (aCGRP IFP-MSC EVs). These EVs are enriched in anti-inflammatory miRNAs and proteins, and they express neprilysin (CD10), enabling SP degradation. Herein, several LncRNAs were identified, which have been known to interact with miRNAs that affect the knee joint homeostasis. Specifically, 11 LncRNAs (ZFAS1, EMX2OS, HOTAIRM1, RPS6KA2-AS1, DANCR, LINC-ROR, GACAT1, GNAS-AS1, HAR1A, OIP5-AS1, TERC) interact with miRNAs that promote cell proliferation, prevent apoptosis, and preserve homeostasis. In vitro, aCGRP IFP-MSC EVs downregulated pro-inflammatory markers (TNF, TLR4, MAPK8) in dorsal root ganglia and promoted chondrocyte gene expression consistent with anabolism and matrix remodeling. In vivo, intra-articular EV delivery attenuated pain behaviors, preserved the cartilage structure, restored PRG4+ stem/progenitor cell localization, and trended toward reduced SP levels. Histological analysis confirmed improved collagen organization and reduced matrix degradation. These findings suggest that aCGRP IFP-MSC EVs exert multimodal effects on neuroinflammation, cartilage regeneration, and joint homeostasis. This cell-free, gene-enhanced EV therapy offers a promising disease-modifying strategy for the treatment of OA, with the potential to address both structural changes and chronic pain associated with this disease.

BackgroundChronic migraine (CM) is highly disabling, and many patients fail to respond to monotherapy with approved preventive treatments. OnabotulinumtoxinA (BoNTA) and atogepant act on distinct but complementary targets within the trigeminovascular system and may exert additive or synergistic effects when used together. Real-world data on their combination remain scarce.MethodsWe prospectively analyzed adult patients with CM who had received at least three prior BoNTA cycles and initiated atogepant 60 mg/day for a minimum of 24 weeks as add on to BoNTA. Co-primary outcomes were changes in monthly migraine days (MMDs) and ≥50% response rate at 24 weeks. Secondary outcomes included disability, medication use, tolerability and subgroup comparisons by prior monoclonal antibodies exposure.ResultsAmong 101 patients, 82 completed 24 weeks of co-treatment. Mean MMDs decreased by 6.5 days (p < 0.001) and 45.1% of patients achieved a ≥50% reduction. Acute medication days decreased by 6.0 (p < 0.001) and Headache Impact Test-6 scores improved significantly (mean change: -4.0; p < 0.001). Patient's Global Impression of Change scores indicated moderate-to-great improvement. Anti-calcitonin gene-related peptide naïve patients experienced larger reductions in MMDs (-7.75 vs. -5.87) and disability scores compared to non-naïve patients. Multivariable analysis identified only baseline acute medication use as predictor of response. Adverse events were mild and consistent with known safety profiles for both drugs separately; no novel safety concerns emerged.ConclusionsThe addition of atogepant to BoNTA might be effective and well tolerated in real-world setting, including CM patients previously exposed to multiple preventives. Prospective controlled trials and health-economic evaluations are warranted to validate these observations and inform future clinical guidelines.

BackgroundIt is becoming increasingly evident that the vasculature is implicated in migraine pathophysiology. Calcitonin gene-related peptide (CGRP) acts as one of the key migraine mediators through various mechanisms that includes endothelium-mediated cerebral vessel vasodilation. Endothelial cells express mechanosensitive Piezo1 channels and have been suggested to play a role in migraine pathophysiology. However, the crosstalk between these two migraine-related signalling pathways remains unclear.MethodsWe measured intracellular calcium (Ca2+) in human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs), after exposure to Yoda1, a specific Piezo1 channel agonist, with and without CGRP. In addition, we investigated the effects of CGRP and Yoda1 on cellular remodelling by staining for focal adhesion (FA) protein paxillin using immunocytochemistry.ResultsOur data suggest that a one-hour sensitization of hiPSC-ECs with CGRP followed by application of Yoda1 leads to a higher intracellular Ca2+ level compared to when Yoda1 and CGRP are acutely applied separately or combined, suggesting at least indirect crosstalk between the two signalling pathways in the vascular system. CGRP receptor antagonist BIBN4096 significantly reduced the intracellular Ca²+ level under this sensitization protocol, confirming effective CGRP pathway blockade. The results also show that a one-hour sensitization of CGRP and Piezo1 activation affects cellular remodelling as evidenced by an increased number and area size of paxillin FA points per cell in hiPSC-ECs.ConclusionsWe have generated a human cell assay based on iPSC-derived endothelial cells and provided some evidence for crosstalk between mechanosensitive Piezo1 channels and CGRP in our hiPSC-EC system, which shows the potential for in vitro modelling of vascular implications relevant to migraine.

BackgroundThe REVIEW study evaluated the real-world experiences of individuals treated with eptinezumab for chronic migraine (CM) in the outpatient setting. This post hoc analysis explored eptinezumab effectiveness in three participant subgroups: those who had self-reported psychiatric comorbidities, those previously treated with subcutaneous anti-calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies (mAbs) for migraine prevention, or those who had reported ever experiencing symptoms of brain fog.MethodsAdults with a CM diagnosis who completed ≥ 2 eptinezumab infusion cycles provided survey responses that included the number of good days (participant-defined) per month before and after initiating eptinezumab, the presence/absence of comorbid psychiatric conditions, the number and type of subcutaneous anti-CGRP mAbs used prior to initiating eptinezumab, and the presence/absence of brain fog (feeling confused, difficulty learning/remembering, or trouble speaking/reading) and its improvement after initiating eptinezumab.ResultsAmong 94 participants, 61 (65%) reported psychiatric comorbidities, and 84 (89%) had previously used a subcutaneous anti-CGRP mAb. Average increase from baseline in participant-reported total number of good days per month after initiating eptinezumab were 9.8 and 10.1 days for those with the presence or absence of psychiatric conditions at baseline, respectively; based on the type of subcutaneous anti-CGRP mAb, average increase from baseline were, 9.2 days (erenumab), 10.6 days (fremanezumab), and 10.0 days (galcanezumab); and based on the number of prior mAbs, 9.9 days (0 prior), 8.9 days (1 prior), 11.7 days (2 prior), and 8.6 days (3 prior). Participants reporting complete/very much improvement in brain fog had an average 15-day increase in the number of good days per month, while in participants that reported brain fog did not improve, there was a 1-day increase.ConclusionsThis post hoc analysis of REVIEW showed that eptinezumab treatment can provide patient-perceived benefits across a spectrum of individuals with CM, including those with psychiatric comorbidities, in real-world settings. A greater number of good days regardless of number of prior mAb therapy supports the use of eptinezumab earlier for individuals with CM, rather than cycling through multiple anti-CGRP therapies. Furthermore, good days can provide a meaningful and measurable endpoint to assess preventive treatment and is correlated with improvements in brain fog.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-025-02165-2.

The treatment of migraine is hampered by inter-individual variability, leading to an inefficient "trial and error" approach. Artificial intelligence (AI) and machine learning (ML) offer a path towards precision medicine by predicting therapeutic outcomes. This scoping review systematically evaluates the evidence for AI and ML models for predicting pharmacologic response in migraine. A systematic search of four databases (PubMed, Web of Knowledge, Cochrane Library, and OpenGrey) identified 12 eligible studies using AI/ML to predict acute or prophylactic response to migraine treatment. These studies, which date back to articles published in 2006 and have been increasingly published recently, used a wide range of methods, from classical algorithms like support vector machines to deep learning and probabilistic models. The models primarily utilized clinical phenotyping and neuroimaging data and reported high predictive accuracy for novel biologics (e.g., anti-calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs)) and acute treatments (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs)). However, our systematic review finds that this apparent success is undermined by critical and pervasive methodological weaknesses. The central finding is that most studies relied solely on internal validation, carrying a high risk of overfitting, with external validation being exceptionally rare. Furthermore, several publications were based on overlapping patient cohorts, and a complete lack of biomarker or genetic data was noted. Consequently, the clinical application of AI and ML is currently stalled. Future progress depends on overcoming the "crisis of generalizability" by mandating external validation, addressing the "data bottleneck" with large, diverse datasets, and expanding data modalities to include "omic" data. These measures are critical to begin to realize the potential of AI and ML to personalize migraine treatment and significantly improve patient outcomes.

Migraine is a debilitating chronic disorder requiring multifaceted treatment approaches, including acute, preventive, and nonpharmacological interventions. Small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists, also referred to as gepants , provide third-line treatment options for patients refractory to first- and second-line therapies. This study evaluates the cost-effectiveness of 3 CGRP antagonists-ubrogepant (Ubrelvy), rimegepant (Nurtec ODT), and zavegepant (Zavzpret)-compared with usual care. Cost-effectiveness analysis of gepants vs usual care. We used a Markov model to assess the cost-effectiveness from the US payer's perspective, incorporating 5 health states: mild, moderate, and severe pain while on treatment; no pain while on treatment; and off treatment. The analysis was conducted over a 5-year time horizon with a 48-hour cycle length, discounting costs and quality-adjusted life-years (QALYs) annually at 3%. Scenario analyses were used to determine the robustness of the results. None of the gepants were cost-effective at willingness-to-pay thresholds of $50,000, $100,000, or $150,000 per QALY. Among the 3 gepants, rimegepant was the most cost-effective option; it had an incremental cost-effectiveness ratio of $93,700.20 per QALY compared with ubrogepant and was both less costly and more effective than zavegepant. Ubrogepant, rimegepant, and zavegepant are not cost-effective options for acute migraine treatment but may be appropriate for patients experiencing 2 or fewer migraines per month. If a gepant is to be prescribed, rimegepant is the most cost-effective option of the 3.

Macrophages orchestrate the immune microenvironment during skin wound healing. While acupuncture's efficacy in accelerating wound healing is established, its underlying mechanisms, particularly those related to macrophage modulation, remain poorly characterized. This study aimed to investigate how acupuncture modulates macrophage phenotype and inflammatory responses to facilitate skin repair. We established an 8-mm full-thickness dorsal skin defect model in C57BL/6J mice, randomizing them into control and acupuncture groups. To investigate the role of the calcitonin gene-related peptide (CGRP) pathway, the CGRP receptor antagonist BIBN4096 was administered intradermally before each acupuncture treatment. For the acupuncture group, we performed a daily 20-min intervention for 10days, which consisted of oblique manual needling at four predefined locations around the wound. Wound repair quality, inflammatory cytokine levels, and macrophage polarization were assessed using histological analysis (H&E and Masson's staining), flow cytometry, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and reverse transcription quantitative polymerase chain reaction (RT-qPCR). Acupuncture significantly facilitated wound closure, enhanced collagen deposition, and improved tissue repair quality. These benefits were associated with an immunomodulatory effect, characterized by enhanced M2 macrophage polarization within the wounds, a reduction in systemic macrophage load in the spleen, and reduced local and systemic levels of IL-1β and IL-6. Mechanistically, the activation of the CGRP-RAMP1-TSP-1 pathway was critical, as its inhibition with BIBN4096 abrogated the effects of acupuncture on macrophage polarization and wound healing. Notably, the suppression of inflammatory cytokines by acupuncture was only partially dependent on CGRP signaling. Our findings indicate that acupuncture promotes wound healing and inflammation resolution, at least in part, by activating the CGRP-RAMP1-TSP-1 pathway to drive M2 macrophage polarization. Furthermore, the persistence of its anti-inflammatory effects after CGRP inhibition strongly suggests the involvement of additional, non-CGRP-dependent pathways in modulating the immune response.

Background and ObjectiveAtogepant is an oral calcitonin gene-related peptide receptor antagonist developed for the preventive treatment of migraine. This work aimed to develop a population pharmacokinetic (popPK) model to support dosage regimen selection during the clinical development of atogepant in patients with episodic migraine (EM) or chronic migraine (CM) and to guide the dosing recommendations for regulatory approval.MethodsPharmacokinetic data collected from 12 phase 1 studies, 1 phase 2b/3 study, and 1 phase 3 study in healthy participants and patients with EM were used to develop a popPK model that was externally validated with data from a CM phase 3 study and a phase 3 study in patients with EM for whom two to four classes of conventional oral preventive treatments have failed. The model was built and evaluated using nonlinear mixed-effect modeling and diagnostic assessments.ResultsThe final model featured three disposition compartments, with linear elimination from the central compartment and a sequential zero-/first-order lagged absorption process. Formulation, dose, food status, liver function, concomitant medication, and body weight were each found to have a statistically significant influence on atogepant’s pharmacokinetics. Absorption was affected by dose and formulation, the apparent central volume of distribution (V1/F) increased with body weight, relative bioavailability (Frel) modestly increased with dose, and a high-fat meal lengthened absorption lag time. Severe hepatic impairment and coadministration of itraconazole, quinidine, or a single rifampin dose decreased apparent clearance (CL/F) by ~37% and ~66%, ~29%, and ~13%, respectively, while coadministration of multiple rifampin doses increased CL/F by 1.82-fold. Frel increased by 1.95 and 2.4 fold with coadministration of itraconazole and a single rifampin dose, respectively, and decreased by ~25% with multiple rifampin doses. Mild/moderate renal impairment, coadministration of breast cancer resistance protein (BCRP) inhibitors, BCRP substrates and statins, age, and sex had no clinically relevant effect on atogepant pharmacokinetics. No statistically significant differences were observed in atogepant’s pharmacokinetics between healthy participants and patients with migraine.ConclusionsThe pharmacokinetics of atogepant are similar in healthy participants and patients with CM or EM. Dose adjustments owing to intrinsic factors of age, sex, race, and body weight, or owing to concomitant medications consisting of P-glycoprotein (P-gp) inhibitors, BCRP inhibitors, oral contraceptive components (ethinyl estradiol and levonorgestrel), famotidine, esomeprazole, sumatriptan, acetaminophen, and naproxen are not necessary. Atogepant’s popPK model provides a valuable tool for evaluating specific questions for patients, healthcare providers, and regulatory agencies. Integration into other modeling approaches has also aided in model-informed drug development decisions.Clinical Trial RegistrationNCT03855137 (EudraCT number: 2018-004337-32).Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-025-01566-5.

Abstract Glioblastoma (GB) is recalcitrant to immunotherapy due to severe CD8⁺ T cell exclusion and abundance of immunosuppressive tumor-associated macrophages (TAMs). Defining the mechanisms of immune evasion in GB is essential for identifying therapeutic vulnerabilities. Here, we unveil dural nociceptors—pain-sensing sensory neurons—as critical, noncanonical drivers of immune evasion in GB. We demonstrate that dural nociceptors are activated and reprogrammed by soluble factors present in GB-associated cerebrospinal fluid. In syngeneic orthotopic GB murine models, ablation of nociceptors significantly improves survival, enhances anti-tumor immune responses, and sensitizes otherwise unresponsive tumors to immune checkpoint blockade therapy (ICBT). Mechanistically, GB-associated dural nociceptors secrete elevated levels of the immunomodulatory neuropeptide calcitonin gene-related peptide (CGRP). Single-cell RNA-sequencing analyses of human GB samples show that RAMP1, the receptor subunit for CGRP, is selectively expressed on TAM subsets with pronounced immunosuppressive features. Using macrophage-specific RAMP1 conditional knockout (cKO) mice, we found that RAMP1 deletion in TAMs significantly prolongs survival of GB-bearing mice, reduces TAM immunosuppression, and enhances CD8⁺ T cell infiltration and effector function while limiting exhaustion. This survival benefit is lost with CD8⁺ T cell depletion, highlighting the key role of CGRP-driven TAM–T cell crosstalk in shaping anti-tumor immunity. Importantly, GB-bearing cKO mice exhibit markedly improved responsiveness to ICBT. At the molecular level, we uncover a strong reciprocal antagonism between CGRP and interferon-gamma (IFN-γ) signaling that dictates TAM fate. CGRP inhibits IFN-γ–induced STAT1 activation, while IFN-γ blocks CGRP-driven cAMP levels and downregulates RAMP1 expression. CGRP acts as a neural cue that imprints immunosuppressive features in TAMs by blocking their sensitivity to IFN-γ, a critical pro-inflammatory cytokine required for anti-tumor immunity, at transcriptional and epigenetic levels. Thus, the CGRP–RAMP1 axis represents a hijacked neural circuit driving immune evasion in GB and offers a translatable strategy to restore immunotherapy response by repurposing FDA-approved CGRP antagonists.

Background: This observational study presents preliminary real-world evidence on the comparative efficacy and safety of combination therapy with onabotulinumtoxinA and the CGRP receptor antagonist atogepant versus atogepant monotherapy in patients with treatment-refractory chronic migraine. Methods: Twenty adult patients (aged 18-75) meeting ICHD-3 criteria for refractory chronic migraine - defined by 8 monthly migraine days, MIDAS ³11, and inadequate response or intolerance to ³ 3 preventive therapies - were enrolled. Ten patients received atogepant monotherapy, while ten initiated combination therapy with onabotulinumtoxinA and atogepant. Efficacy was assessed over three months using changes in monthly migraine days, headache severity (Numerical Rating Scale, NRS), and disability scores (HIT-6, MIDAS). Acute medication use and tolerability were also evaluated. Results: The combination therapy group demonstrated significantly greater reductions in monthly migraine days, headache intensity, and disability scores compared to the monotherapy group. Responders - defined as patients remaining migraine-free for 36 consecutive weeks - were more frequent in the combination cohort. Both treatments were well tolerated, with no serious adverse events reported. Chronic migraine remains a debilitating condition, often resistant to standard preventive treatments. Dual blockade of the CGRP pathway - via onabotulinumtoxinA and a CGRP receptor antagonist - may offer synergistic benefits by targeting both peripheral and central CGRP mechanisms. Conclusion: These preliminary findings support the enhanced clinical efficacy and safety of combining onabotulinumtoxinA with CGRP receptor antagonists in managing refractory chronic migraine. This multimodal strategy may provide a personalized, mechanism-based approach to care and warrants further investigation in larger, controlled studies.