Calcitonin Gene-related Peptide Research Articles

Protectin D1 ameliorates non-compressive lumbar disc herniation through SIRT1-mediated CGRP signaling.

Background. Neuro-inflammatory response promotes the initiation and sustenance of lumbar disc herniation (LDH). Protectin D1 (PD1), as a new type of specialized pro-resolving mediator (SPM), can improve the prognosis of various inflammatory diseases. Recent studies have shown that over representation of calcitonin gene-related peptides (CGRP) may activate nociceptive signaling following nerve injury. Silent information regulator 1 (SIRT1) is ubiquitously expressed in the dorsal horn of the spinal cord and plays a role in the pathogenesis of LDH. In this study, we investigated the analgesic effects of PD1 and elucidated the impact of neurogenic inflammation in the pathogenesis of neuropathic pain induced by non-compressive lumbar disc herniation (NCLDH) in a rat model. Methods. NCLDH models were established by applying protruding autologous nucleus pulposus to the L5 Dorsal root ganglion (DRG). PD1, SIRT1 antagonist or agonist, CGRP or antagonist were administered as daily intrathecal injections for three consecutive days postoperatively. Behavioral tests were conducted to assess mechanical and thermal hyperalgesia. The ipsilateral lumbar (L4-6) segment of the spinal dorsal horn was isolated for further analysis. Alterations in the release of SIRT1 and CGRP were explored using western blot and immunofluorescence. Results. Application of protruded nucleus (NP) materials to the DRG induced mechanical and thermal allodynia symptoms, and deregulated the expression of pro-inflammatory and anti-inflammatory cytokines in rats. Intrathecal delivery of PD1 significantly reversed the NCLDH-induced imbalance in neuro-inflammatory response and alleviated the symptoms of mechanical and thermal hyperalgesia. In addition, NP application to the DGRs resulted the spinal upregulation of CGRP and SIRT1 expression, which was almost restored by intrathecal injection of PD1 in a dose-dependent manner. SIRT1 antagonist or agonist and CGRP or antagonist treatment further confirmed the result. Conclusion. Our findings indicate PD1 has a potent analgesic effect, and can modulate neuro-inflammation by regulating SIRT1-mediated CGRP signaling in NCLDH.

Calcitonin gene-related peptide receptor antagonism reduces motion sickness indicators in mouse migraine models.

Migraine and vestibular migraine are disorders associated with a heightened motion sensitivity that provoke symptoms of motion-induced nausea and motion sickness. VM affects ∼3% of adults in the USA and affects three-fold more women than men. Triptans (selective serotonin receptor agonists) relieve migraine pain but lack efficacy for vertigo. Murine models of photophobia and allodynia have used injections of calcitonin gene-related peptide (CGRP) or other migraine triggers, such as sodium nitroprusside (SNP), to induce migraine sensitivities in mice to touch and light. Yet, there is limited research on whether these triggers affect motion-induced nausea in mice, and whether migraine blockers can reduce these migraine symptoms. We hypothesized that systemic delivery of CGRP or SNP will increase motion sickness susceptibility and motion-induced nausea in mouse models, and that migraine blockers can block these changes induced by systemically delivered CGRP or SNP. We investigated two measures of motion sickness assessment [motion sickness index (MSI) scoring and motion-induced thermoregulation] after intraperitoneal injections of either CGRP or SNP in C57BL/6J mice. The drugs olcegepant, sumatriptan and rizatriptan were used to assess the efficacy of migraine blockers. MSI measures were confounded by CGRP's effect on gastric distress. However, analysis of tail vasodilatations as a surrogate for motion-induced nausea was robust for both migraine triggers. Only olcegepant treatment rescued tail vasodilatations. These preclinical findings support the use of small molecule CGRP receptor antagonists for the treatment of motion-induced nausea of migraine, and show that triptan therapeutics are ineffective against motion-induced nausea of migraine.Trial Registration: Not Applicable.

Calcitonin Gene-Related Peptide Monoclonal Antibodies for Cluster Headache

Cluster headache is a disabling neurologic disorder that is characterized by daily, attacks of very severe, strictly unilateral pain occurring over a period of weeks or months. Recently, calcitonin gene-related peptide and its receptor complex have garnered attention as promising targets for treating primary headache disorders: particularly migraine and cluster headache. Calcitonin gene-related peptide is found in the trigeminal sensory innervation of major cerebral vessels thought to carry nociceptive information during a headache. Increased levels of calcitonin gene-related peptide have been seen in the ipsilateral jugular venous outflow during an attack phase, and indeed, calcitonin gene-related peptide itself can trigger an attack if administered to a patient in bout, suggesting its distinct role in the generation of attacks. Various monoclonal antibodies targeting calcitonin gene-related peptide and its receptor are emerging as a new frontier in migraine with potential further therapeutic use in cluster headache. This review summarizes the current therapeutic approaches of cluster headache before sharing the potential future role of calcitonin gene-related peptide and its relevance in cluster headache pathology and as targets for future treatment.

Spinal cord injury-induced neurogenic bowel: A role for host-microbiome interactions in bowel pain and dysfunction

Background and aimsSpinal cord injury (SCI) affects roughly 300,000 Americans with 17,000 new cases added annually. In addition to paralysis, 60% of people with SCI develop neurogenic bowel (NB), a syndrome characterized by slow colonic transit, constipation, and chronic abdominal pain. The knowledge gap surrounding NB mechanisms after SCI means that interventions are primarily symptom-focused and largely ineffective. The goal of the present studies was to identify mechanism(s) that initiate and maintain NB after SCI as a critical first step in the development of evidence-based, novel therapeutic treatment options. MethodsFollowing spinal contusion injury at T9, we observed alterations in bowel structure and function reflecting key clinical features of NB. We then leveraged tissue-specific whole transcriptome analyses (RNAseq) and fecal 16S rRNA amplicon sequencing in combination with histological, molecular, and functional (Ca2+ imaging) approaches to identify potential mechanism(s) underlying the generation of the NB phenotype. ResultsIn agreement with prior reports focused on SCI-induced changes in the skin, we observed a rapid and persistent increase in expression of calcitonin gene-related peptide (CGRP) expression in the colon. This is suggestive of a neurogenic inflammation-like process engaged by antidromic activity of below-level primary afferents following SCI. CGRP has been shown to disrupt colon homeostasis and negatively affect peristalsis and colon function. As predicted, contusion SCI resulted in increased colonic transit time, expansion of lymphatic nodules, colonic structural and genomic damage, and disruption of the inner, sterile intestinal mucus layer corresponding to increased CGRP expression in the colon. Gut microbiome colonization significantly shifted over 28 days leading to the increase in Anaeroplasma, a pathogenic, gram-negative microbe. Moreover, colon specific vagal afferents and enteric neurons were hyperresponsive after SCI to different agonists including fecal supernatants. ConclusionsOur data suggest that SCI results in overexpression of colonic CGRP which could alter colon structure and function. Neurogenic inflammatory-like processes and gut microbiome dysbiosis can also sensitize vagal afferents, providing a mechanism for visceral pain despite the loss of normal sensation post-SCI. These data may shed light on novel therapeutic interventions targeting this process to prevent NB development in patients.

Real-world effectiveness of add-on fremanezumab in patients receiving onabotulinumtoxinA for the prevention of chronic migraine in a US tertiary headache center: A retrospective chart review study

Background: Concomitant fremanezumab, a calcitonin gene-related peptide (CGRP) pathway monoclonal antibody (mAb), and onabotulinumtoxinA (onabotA) improve treatment response compared with onabotA alone in patients with chronic migraine (CM). Methods: This was a single-center, retrospective, observational study that assessed treatment response (change over time in monthly headache days [MHD] and pain intensity [PI]) in adult patients with CM receiving fremanezumab as add-on therapy to onabotA for CM prevention. Results: In the study population ( N = 116, age 50.0 ± 13.1, female 85.3%, pre-index onabotA use 46.5 ± 34.2 months) receiving concurrent onabotA and fremanezumab for 17.5 ± 11.6 months, MHD decreased by 3.60 days (95% confidence interval [CI]: −5.26, −1.94, p < 0.001) and PI was reduced by 0.43 (95% CI: −0.77, −0.09, p = 0.012) at the final visit. Statistically significant reductions were seen in both MHD (−4.61, 95% CI: −6.84, −2.39; p < 0.001) and PI (−0.52, 95% CI: −0.84. −0.09; p = 0.017) among patients naïve to mAbs against CGRP or its receptor. No unexpected adverse events were observed. Conclusion: Concomitant fremanezumab and onabotA for CM prevention were effective at reducing the number of MHD and lessening PI, particularly in patients with difficult-to-treat CM who are naïve to mAbs against CGRP or its receptor.

Changes of Trigeminal Ganglion Neurons Innervating the Temporomandibular Joint in Chronic Pain Rat Model.

Background: Phenotype alterations of nociceptive neurons have been shown to be a key step in the pathogenesis of many pain-related diseases. However, it is unclear if the characteristic changes of temporomandibular joint (TMJ) primary afferent neurons are related to the pathogenesis of temporomandibular joint osteoarthritis (TMJOA) chronic pain. This study aimed to determine the morphological and neurochemical changes in trigeminal ganglion (TG) neurons innervating the TMJ in TMJOA chronic pain rats. Materials and Methods: Monosodium iodoacetate (MIA)-induced TMJOA chronic pain rat model was established (n = 6), and saline was injected in rats of the control group (n = 6). TMJ primary afferent neurons were labeled with retrograde tracing (Dil). The spatial distribution and the expression of calcitonin gene-related peptide (CGRP), isolectin B4 (IB4), and neurofilament 200 (NF200) of TMJ primary afferent neurons in TG were investigated using immunofluorescence. Intracellular calcium signaling was recorded by calcium imaging (n = 20). Results: TMJ primary afferent neurons were located only in the V3 region of the TG from both saline- and MIA-injected rats. The number of TG neurons innervating the TMJ was increased in MIA-injected rats. Elevated number and intracellular calcium concentration of small- and medium-sized instead of large-sized Dil+ TG neurons were found in MIA-injected rats. The upregulated expression of CGRP and IB4, but not NF200, in TG neurons innervating the rat TMJs was accompanied by TMJOA chronic pain. Conclusion: This study suggests that sensitization of small- to medium-sized Dil+ TG neurons and CGRP- and IB4-positive Dil+ TG neurons might contribute to the development of TMJOA chronic pain in rats. This will provide valuable information for more efficient control of TMJOA chronic pain.

Atogepant: Mechanism of action, clinical and translational science.

Since the discovery of calcitonin gene-related peptide (CGRP) in 1982, its integral role in migraine pathophysiology, specifically migraine pain, has been demonstrated through cumulative scientific discoveries that have led to the development and approval of migraine-specific therapeutics. Today, eight drugs, including monoclonal antibodies and small molecule CGRP receptor antagonists, known as gepants, have received approval for acute or preventive treatment of migraine. The primary mechanism of these drugs is to block CGRP signaling, thus preventing CGRP-mediated nociception and neurogenic inflammation. Here, we focus on atogepant, a highly potent and selective gepant and the first and only oral medication approved for the preventive treatment of both episodic and chronic migraine in adults. In this article, we summarize the role of CGRP in migraine pathophysiology and the mechanism of action of atogepant. In addition, we provide an overview of atogepant's pharmacology and the key clinical trials and outcomes that have demonstrated the safety and efficacy of atogepant.

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

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

Pulmonary neuroendocrine cells: crucial players in respiratory function and airway-nerve communication.

Pulmonary neuroendocrine cells (PNECs) are unique airway epithelial cells that blend neuronal and endocrine functions, acting as key sensors in the lung. They respond to environmental stimuli like allergens by releasing neuropeptides and neurotransmitters. PNECs stand out as the only lung epithelial cells innervated by neurons, suggesting a significant role in airway-nerve communication via direct neural pathways and hormone release. Pathological conditions such as asthma are linked to increased PNECs counts and elevated calcitonin gene-related peptide (CGRP) production, which may affect neuroprotection and brain function. CGRP is also associated with neurodegenerative diseases, including Parkinson's and Alzheimer's, potentially due to its influence on inflammation and cholinergic activity. Despite their low numbers, PNECs are crucial for a wide range of functions, highlighting the importance of further research. Advances in technology for producing and culturing human PNECs enable the exploration of new mechanisms and cell-specific responses to targeted therapies for PNEC-focused treatments.

Ubrogepant: Mechanism of action, clinical and translational science.

In recent years, the treatment of migraine has experienced a breakthrough in the development of drugs that target the calcitonin gene-related peptide (CGRP) signaling pathway. Monoclonal antibodies against the receptor or ligand have been developed for the preventive treatment of migraine; whereas, orally administered small molecule CGRP receptor antagonists, called gepants, have been developed for both acute and/or preventive treatment. Both modalities have demonstrated safe and effective treatment of migraine, reducing the number of migraine days for patients as well as reducing symptoms and improving patient function and overall quality of life. Here, we provide an abridged review of ubrogepant, an oral CGRP receptor antagonist, approved for the acute treatment of migraine. We briefly summarize the role of CGRP in migraine pathophysiology, describing the mechanism of action of ubrogepant in the context of this pathway, the clinical pharmacology properties and the clinical development and outcomes, including safety, efficacy, pharmacokinetics, and pharmacodynamics, that supported ubrogepant's approval.

Using tissue clearing and light sheet fluorescence microscopy for the three-dimensional analysis of sensory and sympathetic nerve endings that innervate bone and dental tissue of mice.

Bone and dental tissues are richly innervated by sensory and sympathetic neurons. However, the characterization of the morphology, molecular phenotype, and distribution of nerves that innervate hard tissue has so far mostly been limited to thin histological sections. This approach does not adequately capture dispersed neuronal projections due to the loss of important structural information during three-dimensional (3D) reconstruction. In this study, we modified the immunolabeling-enabled imaging of solvent-cleared organs (iDISCO/iDISCO+) clearing protocol to image high-resolution neuronal structures in whole femurs and mandibles collected from perfused C57Bl/6 mice. Axons and their nerve terminal endings were immunolabeled with antibodies directed against protein gene product 9.5 (pan-neuronal marker), calcitonin gene-related peptide (peptidergic nociceptor marker), or tyrosine hydroxylase (sympathetic neuron marker). Volume imaging was performed using light sheet fluorescence microscopy. We report high-quality immunolabeling of the axons and nerve terminal endings for both sensory and sympathetic neurons that innervate the mouse femur and mandible. Importantly, we are able to follow their projections through full 3D volumes, highlight how extensive their distribution is, and show regional differences in innervation patterns for different parts of each bone (and surrounding tissues). Mapping the distribution of sensory and sympathetic axons, and their nerve terminal endings, in different bony compartments may be important in further elucidating their roles in health and disease.

Calcitonin gene-related peptide in pathophysiology of migraine

Calcitonin gene-related peptide in pathophysiology of migraine

Rimegepant as an acute treatment in a refractory migraine patient non-responder to two anti-CGRP monoclonal antibodies and triptans: Case report and pharmacological considerations

Background: Small molecule receptor antagonists (gepants), or monoclonal antibodies (mAbs) against calcitonin gene-related peptide (CGRP) have recently become available for migraine prophylaxis and/or acute treatment. Considering their shared mechanisms of action, if the failure to an anti-CGRP(R) mAbs preclude the effectiveness of gepants or vice versa is still unknown. Herein, we report the first case of a patient with refractory migraine responsive to the acute use of rimegepant that previously failed two different anti-CGRP(R) mAbs and with no response to other acute treatments. Finally, we performed a literature review on the use of gepants in patients that failed other anti-CGRP and/or triptans. Case: A 56-year-old female with a long history of chronic migraine without aura, fulfilling the EHF definition for a diagnosis of refractory migraine. Overall, the patient treated five not-consecutive migraine attacks. All of them were treated according to the predefined criteria. The mean (±SD) NRS before rimegepant assumption was 7.8 ± 0.9, all attacks cause at least severe impairment at onset, and no rescue medications were used. Pain free at 2 hours was achieved in three out of five attacks (60.0%), with no recurrence of migraine in the following 24 hours. The patient reported also a sustained benefit the day after the drug assumption. The response pain free was achieved after a mean time of 13.3 ± 4.5 minutes considering only attacks successfully treated (three out of five attacks). No adverse events were reported. Conclusions: In conclusion, rimegepant for acute treatment may be a viable option in patients with partial or no response to triptans that failed preventive treatments targeting the CGRP pathway, regardless to ligand or receptor. The failure of anti-CGRP(R) mAbs does not necessarily preclude the use of gepants (acute and/or preventive), but further studies are urgently needed to provide evidence on the efficacy of these treatments in managing drug-resistant migraine and to identify novel treatments for patients.

Real-world Efficacy of Erenumab on Migraine-associated Symptoms and Patient-reported Satisfaction Levels: A Retrospective Study in Japan.

Objective In randomized clinical trials and real-world studies, calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs), including erenumab, have demonstrated efficacy for migraine prevention. However, there have been no real-world studies focusing on erenumab in East Asia that investigated its efficacy on migraine-associated symptoms and patient-reported satisfaction levels. Methods This single-center, observational, retrospective, real-world study examined patients who received at least three doses of erenumab at Keio University Hospital, Tokyo, Japan, between December 2021 and March 2023 as their first CGRP mAb treatment in a real-world setting. The patients were administered 70 mg of erenumab monthly. We assessed changes in monthly migraine days (MMDs), responder rates, migraine-associated symptoms including photophobia, phonophobia, nausea/vomiting, and patient-reported satisfaction levels. In addition, injection site reactions and other adverse events were recorded to investigate safety. Results Nineteen patients were considered eligible for the analysis. At 3 months, erenumab decreased MMDs by 6.6 (95% confidence interval, 2.3-10.8; p<0.01). The 50% responder rate was 42%. A total of 83% (n=15), 56% (n=10), and 71% (n=10) of patients reported either improvement in or disappearance of photophobia, phonophobia, and nausea/vomiting, respectively, and 44% (n=8) and 28% (n=5) answered "very satisfied" and "somewhat satisfied", respectively, with erenumab treatment, leaving only 28% (n=5) as "unsatisfied". Injection site reactions (n=6, 32%) and constipation (n=4, 21%) were frequent adverse events. Conclusion In a real-world setting in Japan, erenumab proved to be effective in not only reducing migraine and headache frequency but also improving migraine-associated symptoms and satisfying the majority of patients.

Efficacy of Shu-yi-ning-chang decoction on IBS-D: Modulating Nr4a3 pathway to reduce visceral hypersensitivity.

To evaluate the therapeutic effect of SYNC in diarrhea irritable bowel syndrome (IBS-D) and explore its underlying mechanism through transcriptomic sequencing (RNA-Seq). A rat model of IBS-D was constructed to elucidate the effects of SYNC. Abdominal withdrawal reflex (AWR), fecal water content (FWC), and recording body weight were calculated to assess visceral sensitivity in rats. Histopathological changes in the colon and alterations in mast cell (MC) count were determined. Immunohistochemistry was employed to assess mast cell tryptase (MCT) expression in rat colons. Serum levels of corticotropin-releasing Hormone (CRH), interleukin-6 (IL-6), calcitonin gene-related peptide (CGRP), and 5-hydroxytryptamine (5-HT) were quantified using ELISA. RNA-Seq of colon tissue was performed, followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Western blot analysis was conducted to quantify the expression levels of key proteins in the Nr4a3 pathway in the colon and hypothalamus tissues of rats. SYNC alleviated visceral hypersensitivity and mood disorders in rats with IBS-D. Moreover, it was positively correlated with its dosage and the observed effects, such as the enhancement of the colon's mucosal lining condition and reduction in the number and activation of MCs within the model group. SYNC reduced the expression levels of factors related to the brain-gut axis and inflammatory markers in the bloodstream. RNA-Seq analysis indicated that SYNC down-regulated the expression of Nr4a3 and PI3K. These SYNC-targeted genes primarily played roles in immune regulation and inflammatory responses, correlating with the modulation of Nr4a3 and the PI3K/AKT pathway. Western blot analysis further confirmed SYNC's influence on inflammation-related MC activation by downregulating key proteins in the Nr4a3/PI3K pathway. SYNC inhibited mast cell activation and attenuated visceral hypersensitivity in the colon tissues of IBS-D rats. These effects were mediated by the Nr4a3/PI3K signaling pathway.

Lack of RAMP1 Signaling Suppresses Liver Regeneration and Angiogenesis Following Partial Hepatectomy in Mice.

The liver effectively restores both size and function following partial hepatectomy (PHx). Angiogenesis is crucial for the repair and regeneration of liver tissue post-PHx. Calcitonin gene-related peptide (CGRP) released from sensory nerves and its receptor-receptor activity-modifying protein 1 (RAMP1) are involved in angiogenesis. This study aimed to assess the role of RAMP1 signaling in angiogenesis during liver regeneration following PHx. RAMP1 deficient (RAMP1-/-) and wild-type (WT) mice were subjected to PHx. RAMP1-/- mice demonstrated delayed liver regeneration, indicated by lower liver-to-body weight ratios compared to WT mice. This was associated with lower levels of Ki67+ hepatocytes and hepatic trophic growth factors. Additionally, RAMP1-/- mice exhibited lower levels of endothelial cell markers, including CD31, compared to WT mice. This reduction was associated with reduced levels of vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor 3 (VEGFR3). In WT mice with PHx, the administration of a VEGFR3 inhibitor reduced the liver-to-body weight ratio, Ki67+ hepatocytes, and VEGF-C/VEGFR3 expression levels in the liver compared to those in the vehicle-treated group. The deletion of RAMP1 signaling suppresses liver regeneration and angiogenesis through VEGFR3. Specific activation of RAMP1 signaling may represent a potential therapeutic strategy for liver regeneration following PHx.

Quercetin and ibuprofen combination displayed anti-inflammatory effects and also extenuates the enteric neurons damage of arthritic rats.

This study aimed to investigate the antioxidant and anti-inflammatory properties of quercetin on the cellular components of the Enteric Nervous System in the ileum of rats with arthritis. Rats were distributed into five groups: control (C), arthritic (AIA), arthritic treated with ibuprofen (AI), arthritic treated with quercetin (AQ) and arthritic treated with both ibuprofen and quercetin (AIQ). The ileum was processed for immunohistochemical techniques for HuC/D, calcitonin gene-related peptide, and vasoactive intestinal polypeptide. Measurements in histological sections, chemiluminescence assays, and total antioxidant capacity were also performed. Rheumatoid arthritis resulted in a decrease in neuronal density, yet neuroplasticity mechanisms were evident through observed changes in varicosities size and neuronal area compared to the control group. Reduced paw edema and neuroprotective effects were predominantly noted in both plexuses, as evidenced by the increased density preservation of HuC/D-IR neurons in the AIQ group. The increase of lipoperoxidation levels and paw edema volume in the AQ group was observed compared to the arthritic, whereas the AIQ group mainly showed similar results to those observed in the control. The enteropathy associated with arthritis proved to be significant in the field of gastroenterology, and the combination of quercetin and ibuprofen demonstrated promising anti-inflammatory and neuroprotective effects.

Treatment Outcome After Switching From Galcanezumab to Fremanezumab in Patients With Migraine.

Monoclonal antibodies (mAbs) targeting calcitonin-gene-related peptide (CGRP) or its receptor (anti-CGRP-R) have been widely administered to patients with migraine who show inadequate responses to preventive medications. Among patients in whom a particular anti-CGRP-R mAb is ineffective, switching between different anti-CGRP-R mAbs can be the next option. Few studies have investigated treatment outcomes for antibody switching, especially between mAbs with the same target of the CGRP ligand. We aimed to determine the treatment outcome after switching between two anti-CGRP mAbs (galcanezumab to fremanezumab). We identified migraine patients in a prospective headache clinic registry who received galcanezumab for ≥3 months and were switched to fremanezumab for a further ≥3 months at a single university hospital. We defined a treatment response as a ≥50% reduction in the number of days with a moderate or severe headache at the third month of treatment relative to baseline. The treatment response after switching to fremanezumab was compared with the initial treatment response to galcanezumab. Among 21 patients identified in the registry, 7 (33.3%) were initial responders to galcanezumab. After switching to fremanezumab, 7 (33.3%) showed a treatment response. The treatment response rate was 28.6% in the initial responders and 71.4% in the nonresponders to galcanezumab (p>0.999). Switching between anti-CGRP mAbs (galcanezumab to fremanezumab) yielded a treatment outcome comparable to that reported previously when switching from an anti-CGRP-R mAb (erenumab) to an anti-CGRP mAb (galcanezumab or fremanezumab). The treatment response to fremanezumab seems to be independent of the prior treatment response to galcanezumab. Our findings suggest that switching to another anti-CGRP mAb can be considered when a particular anti-CGRP mAb is ineffective or intolerable.

Comparison of Treatment Patterns in Patients with Migraine Initiating Calcitonin Gene-Related Peptide Monoclonal Antibodies: A Retrospective Real-World US Study.

Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are indicated for migraine prevention in the United States. Limited data comparing real-world treatment patterns for CGRP mAbs are available. To compare the treatment patterns among patients with migraine initiating galcanezumab, fremanezumab, and erenumab. This retrospective study included adult patients with one or more claims for a self-injectable CGRP mAb (galcanezumab, fremanezumab, or erenumab), with continuous enrollment in medical and pharmacy benefits for 12 months pre-index and 6 and 12 months post-index using MerativeTM MarketScan® Commercial and Medicare databases from May 2017 through March 2021. Propensity-score matching was used to address confounding by observed covariates. Outcomes analyzed included proportion of days covered (PDC), medication-possession ratio (MPR), persistence (≤60-day gap), treatment discontinuation, and switch to a non-index drug. Descriptive X2 and t-test analyses were conducted. At the 12-month follow-up, matched galcanezumab and fremanezumab cohorts each comprised 2674 patients and the galcanezumab and erenumab cohorts 3503 each. The mean (SD) PDC and MPR were both 0.6 (0.3) across all cohorts. Based on PDC ≥0.80 and MPR ≥0.80, a greater proportion of galcanezumab vs fremanezumab (46.2% vs 43.7%, p=0.053; 46.8% vs 44.3%, p=0.053) and galcanezumab vs erenumab (46.2% vs 44%, p=0.156; 46.7% vs 44.5%, p=0.262), respectively, initiators were adherent. Compared to galcanezumab, fremanezumab (248.0 days vs 236.5 days, p=0.001), and erenumab (247.8 days vs 241.7 days, p=0.061) initiators had lower mean persistence. Galcanezumab initiators were less likely to discontinue treatment than fremanezumab (47.8% vs 51.7%, p=0.005) and erenumab (47.7% vs 50.2%, p=0.040) initiators. Across cohorts, most switchers initiated onabotulinum toxin A as subsequent treatment. Similar results were observed for 6-month follow-up cohorts. Patients with migraine who initiated treatment with galcanezumab showed higher persistence and lower treatment discontinuation rates than those initiating either fremanezumab or erenumab.

Tolerability of calcitonin gene-related peptide monoclonal antibodies and other monoclonal antibodies in adults with concurrent migraine and other medical conditions

Background/Hypothesis: Calcitonin gene-related peptide monoclonal antibodies (CGRP mabs) are relatively new preventive treatments in adult migraine. Co-morbid medical conditions such as autoimmune or other neurologic/oncologic disorders are not uncommon in migraine patients and some exhibit notable co-morbidity such as asthma. These clinical conditions may necessitate concomitant treatment with another monoclonal antibody with a different mechanism of action other than the CGRP pathway in some individuals with migraine. Methods: We report a retrospective case series in 23 patients identified from our headache clinic treated concurrently with a CGRP monoclonal antibody and other monoclonal antibody for another medical condition. These other medical conditions were neurologic, oncologic, or autoimmune conditions. These patients were evaluated for tolerability, safety, and stability of disease processes including their migraine response. Results/Conclusion: We did not find evidence of new adverse or serious adverse side effects with coadministration of CGRP and non-CGRP monoclonal antibodies during our study time period of 13 months, for the duration of overlap between treatments (between 3 and 12 months).