Ubrogepant for the Treatment of Migraine.

BACKGROUND: Ubrogepant is an oral, small-molecule calcitonin gene-related peptide receptor antagonist for acute migraine treatment. METHODS: We conducted a randomized trial to evaluate the efficacy, safety, and side-effect profile of ubrogepant. We assigned adults with migraine, with or without aura, in a 1:1:1 ratio to receive an initial dose of placebo, ubrogepant at a dose of 50 mg, or ubrogepant at a dose of 100 mg for treatment of a single migraine attack, with the option to take a second dose. The coprimary efficacy end points were freedom from pain at 2 hours after the initial dose and absence of the most bothersome migraine-associated symptom at 2 hours. Secondary end points included pain relief (at 2 hours), sustained pain relief (from 2 to 24 hours), sustained freedom from pain (from 2 to 24 hours), and absence of symptoms associated with migraine (photophobia, phonophobia, and nausea) at 2 hours. RESULTS: A total of 1672 participants were enrolled; 559 were assigned to receive placebo, 556 to receive 50 mg of ubrogepant, and 557 to receive 100 mg of ubrogepant. The percentage of participants who had freedom from pain at 2 hours was 11.8% in the placebo group, 19.2% in the 50-mg ubrogepant group (P = 0.002, adjusted for multiplicity, for the comparison with placebo), and 21.2% in the 100-mg ubrogepant group (P<0.001). The percentage of participants who had freedom from the most bothersome symptom at 2 hours was 27.8% in the placebo group, 38.6% in the 50-mg ubrogepant group (P = 0.002), and 37.7% in the 100-mg ubrogepant group (P = 0.002). Adverse events within 48 hours after the initial or optional second dose were reported in 12.8% of participants in the placebo group, in 9.4% in the 50-mg ubrogepant group, and in 16.3% in the 100-mg ubrogepant group. The most common adverse events were nausea, somnolence, and dry mouth (reported in 0.4 to 4.1%); these events were more frequent in the 100-mg ubrogepant group (reported in 2.1 to 4.1%). Serious adverse events reported within 30 days in the ubrogepant groups included appendicitis, spontaneous abortion, pericardial effusion, and seizure; none of the events occurred within 48 hours after the dose. CONCLUSIONS: A higher percentage of participants who received ubrogepant than of those who received placebo had freedom from pain and absence of the most bothersome symptom at 2 hours after the dose. The most commonly reported adverse events were nausea, somnolence, and dry mouth. Further trials are needed to determine the durability and safety of ubrogepant for acute migraine treatment and to compare it with other drugs for migraine. (Funded by Allergan; ClinicalTrials.gov number, NCT02828020.).

Safety evaluation of oral calcitonin-gene-related peptide receptor antagonists in patients with acute migraine: a systematic review and meta-analysis.

OBJECTIVE: Calcitonin gene-related peptide (CGRP) receptor antagonists have been suggested as novel treatments for acute migraine. This study aimed to use meta-analysis to compare the safety and tolerability of five existing oral CGRP receptor antagonists (BI44370TA, MK-3207, rimegepant, telcagepant, and ubrogepant) with that of a placebo or triptans against acute migraine. METHODS: Five prominent databases were searched to identify randomized controlled trials on this topic. The primary safety outcomes of interest were any adverse events (AEs) and treatment-related adverse events (TRAEs), and secondary outcomes were individual events, namely diarrhea, dizziness, dry mouth, fatigue, nausea, paresthesia, somnolence, upper abdominal pain, and vomiting. RESULTS: Fifteen studies met the eligibility criteria and were examined in detail. Although, compared to placebo, oral CGRP receptor antagonists significantly increased the incidence of any AEs (risk ratio [RR] = 1.15; 95% confidence interval [CI] = 1.07-1.23), there was no difference in the incidence of TRAEs (RR = 1.18; 95% CI = 1.00-1.38). Moreover, CGRP receptor antagonists were safer than triptans with respect to primary safety outcomes, such as any AEs (RR = 0.78; 95% CI = 0.63-0.98) and TRAEs (RR = 0.68; 95% CI = 0.58-0.79). CONCLUSION: Despite oral CGRP receptor antagonists posing a significantly higher risk of AEs when compared to placebo, CGRP receptor antagonists have a favorable safety profile compared to triptans. Our findings inform strategies to enhance safety and tolerability in the treatment of acute migraine.

Two possible cases of erenumab-induced xerostomia.

WHAT IS KNOWN AND OBJECTIVE: Erenumab is a monoclonal antibody for the prophylactic treatment of migraine. We describe the first cases of xerostomia probably induced by this drug. CASE SUMMARY: We present two patients diagnosed with chronic migraine who started treatment with erenumab and presented with dry mouth after the first and second dose. WHAT IS NEW AND CONCLUSION: Xerostomia is not described as an adverse reaction in the drug's technical datasheet. A search was made in PubMed including 'erenumab', 'fremanezumab', 'galcanezumab', 'xerostomia', and no results were found. It is necessary to identify this potential adverse reaction in order to estimate its prevalence and possible impact on patients' quality of life.

Real-world efficacy, tolerability, and safety of ubrogepant.

OBJECTIVE: To assess the real-world efficacy, tolerability, and safety of ubrogepant in a tertiary headache center. BACKGROUND: The efficacy and safety of ubrogepant for the acute treatment of migraine were established in phase 3 randomized controlled trials. However, there is no real-world data of patient experience with ubrogepant in a population in which the majority of patients have chronic migraine, multiple prior unsuccessful treatments, complex medical comorbidities, and concurrent use of other migraine-specific medications. METHOD: This was a post-market cohort study conducted at Mayo Clinic Arizona. All patients prescribed ubrogepant were tracked and contacted 1-3 months after the prescription to answer a list of standardized questions. Demographic information and additional headache history were obtained from chart review. RESULTS: We obtained eligible questionnaire responses from 106 patients. Chronic migraine accounted for 92/106 (86.8%) of the population. Complete headache freedom (from mild/moderate/severe to no pain) and headache relief (from moderate/severe to mild/no pain or mild to no pain) for ≥75% of all treated attacks at 2 hours after taking ubrogepant were achieved in 20/105 (19.0%) and 50/105 (47.6%) patients, respectively. A total of 33/106 (31.1%) patients reported being "very satisfied" with ubrogepant. Adverse events were reported in 42/106 (39.6%) patients, including fatigue in 29/106 (27.4%), dry mouth in 8/106 (7.5%), nausea/vomiting in 7/106 (6.6%), constipation in 5/106 (4.7%), dizziness in 3/106 (2.8%), and other adverse events in 7/106 (6.6%). Predictive factors for being a "good responder" to ubrogepant, defined as headache relief for ≥75% of all treated attacks at 2 hours after taking ubrogepant, included migraine with aura, episodic migraine, <5 prior unsuccessful preventive or acute treatment trials. Additionally, prior treatment responses to a CGRP monoclonal antibody and onabotulinumtoxinA injections are predictive of treatment responses and patient satisfaction to ubrogepant. For the 62/106 (58.5%) patients concurrently using a CGRP monoclonal antibody, there was no difference in the "good responder" rate or adverse event rate compared to those who were not on a CGRP monoclonal antibody, though the rate of moderate, as opposed to mild adverse events was higher, 11/62 (47.8%) versus 3/44 (17.6%), p = 0.048. Additionally, 16 patients had a history of significant cardiovascular or cerebrovascular diseases. No severe adverse events were reported in any patient. CONCLUSION: Our study confirms and extends the efficacy profile and tolerability of ubrogepant in a real-world tertiary headache clinic and identifies factors that may predict efficacy. Adverse event rates were higher than reported in clinical trials. Further studies are needed to confirm these findings and to evaluate the long-term efficacy and safety of ubrogepant.

Diagnosis and Management of Headache: A Review.

IMPORTANCE: Approximately 90% of people in the US experience headache during their lifetime. Migraine is the second leading cause of years lived with disability worldwide. OBSERVATIONS: Primary headache disorders are defined as headaches that are unrelated to an underlying medical condition and are categorized into 4 groups: migraine, tension-type headache, trigeminal autonomic cephalalgias, and other primary headache disorders. Studies evaluating prevalence in more than 100 000 people reported that tension-type headache affected 38% of the population, while migraine affected 12% and was the most disabling. Secondary headache disorders are defined as headaches due to an underlying medical condition and are classified according to whether they are due to vascular, neoplastic, infectious, or intracranial pressure/volume causes. Patients presenting with headache should be evaluated to determine whether their headache is most likely a primary or a secondary headache disorder. They should be evaluated for symptoms or signs that suggest an urgent medical problem such as an abrupt onset, neurologic signs, age 50 years and older, presence of cancer or immunosuppression, and provocation by physical activities or postural changes. Acute migraine treatment includes acetaminophen, nonsteroidal anti-inflammatory drugs, and combination products that include caffeine. Patients not responsive to these treatments may require migraine-specific treatments including triptans (5-HT1B/D agonists), which eliminate pain in 20% to 30% of patients by 2 hours, but are accompanied by adverse effects such as transient flushing, tightness, or tingling in the upper body in 25% of patients. Patients with or at high risk for cardiovascular disease should avoid triptans because of vasoconstrictive properties. Acute treatments with gepants, antagonists to receptors for the inflammatory neuropeptide calcitonin gene-related peptide, such as rimegepant or ubrogepant, can eliminate headache symptoms for 2 hours in 20% of patients but have adverse effects of nausea and dry mouth in 1% to 4% of patients. A 5-HT1F agonist, lasmiditan, is also available for acute migraine treatment and appears safe in patients with cardiovascular risk factors. Preventive treatments include antihypertensives, antiepileptics, antidepressants, calcitonin gene-related peptide monoclonal antibodies, and onabotulinumtoxinA, which reduce migraine by 1 to 3 days per month relative to placebo. CONCLUSIONS AND RELEVANCE: Headache disorders affect approximately 90% of people during their lifetime. Among primary headache disorders, migraine is most debilitating and can be treated acutely with analgesics, nonsteroidal anti-inflammatory drugs, triptans, gepants, and lasmiditan.

Gαs-Coupled CGRP Receptor Signaling Axis from the Trigeminal Ganglion Neuron to Odontoblast Negatively Regulates Dentin Mineralization.

An inflammatory response following dental pulp injury and/or infection often leads to neurogenic inflammation via the axon reflex. However, the detailed mechanism underlying the occurrence of the axon reflex in the dental pulp remains unclear. We sought to examine the intracellular cyclic adenosine monophosphate (cAMP) signaling pathway in odontoblasts via the activation of Gs protein-coupled receptors and intercellular trigeminal ganglion (TG) neuron-odontoblast communication following direct mechanical stimulation of TG neurons. Odontoblasts express heterotrimeric G-protein α-subunit Gαs and calcitonin receptor-like receptors. The application of an adenylyl cyclase (AC) activator and a calcitonin gene-related peptide (CGRP) receptor agonist increased the intracellular cAMP levels ([cAMP]i) in odontoblasts, which were significantly inhibited by the selective CGRP receptor antagonist and AC inhibitor. Mechanical stimulation of the small-sized CGRP-positive but neurofilament heavy chain-negative TG neurons increased [cAMP]i in odontoblasts localized near the stimulated neuron. This increase was inhibited by the CGRP receptor antagonist. In the mineralization assay, CGRP impaired the mineralization ability of the odontoblasts, which was reversed by treatment with a CGRP receptor antagonist and AC inhibitor. CGRP establishes an axon reflex in the dental pulp via intercellular communication between TG neurons and odontoblasts. Overall, CGRP and cAMP signaling negatively regulate dentinogenesis as defensive mechanisms.

Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial.

OBJECTIVE: To evaluate the long-term tolerability of telcagepant for acute treatment of intermittent migraine attacks. Background.- Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being investigated for the acute treatment of migraine. METHODS: Migraine patients were randomized 2:1 to double-blind treatment with telcagepant 280/300 mg or rizatriptan 10 mg for an acute mild, moderate, or severe migraine. Patients could administer a second dose within 2-24 hours for nonresponse or migraine recurrence. Patients could treat up to 8 attacks per month for up to 18 months. Safety assessments included spontaneous reports of adverse events and collection of vital signs, electrocardiograms, and laboratory assessments. The primary endpoint was the percentage of patients with ≥ 1 triptan-related adverse events in the 14-day period post dose. RESULTS: Of 1068 patients randomized, 641 (90%) patients treated ≥ 1 attack with telcagepant and 313 (88%) treated ≥ 1 attack with rizatriptan. A total of 19,820 attacks were treated with telcagepant (mean per patient = 31) and 10,981 with rizatriptan (mean per patient = 35). Fewer triptan-related adverse events (difference: -6.2%; 95% CI -10.4, -2.6; P < .001) and drug-related adverse events (difference: -15.6%; 95% CI -22.2, -9.0) were reported for telcagepant vs rizatriptan. The most common adverse events appeared to have generally similar incidence proportions between the treatment groups. Those with an incidence > 5% in the telcagepant group were dry mouth (9.7%, rizatriptan = 13.7%), somnolence (9.2%, rizatriptan = 16.6%), dizziness (8.9%, rizatriptan = 10.2%), and nausea (9.0%, rizatriptan = 6.4%). CONCLUSIONS: Telcagepant was generally well tolerated when administered for the acute intermittent treatment of migraine for up to 18 months. The incidences of triptan-related and drug-related adverse events favored telcagepant over rizatriptan.

Randomized controlled study of telcagepant plus ibuprofen or acetaminophen in migraine.

OBJECTIVE: To evaluate the efficacy and tolerability of telcagepant when co-administered with ibuprofen or acetaminophen for the acute treatment of migraine. BACKGROUND: Telcagepant is an oral calcitonin gene-related peptide receptor antagonist which is being evaluated for the acute treatment of migraine. Combining telcagepant with analgesics that have a different mechanism of action could produce greater efficacy. METHODS: Randomized, double-blind, placebo-controlled study. Patients were randomized to treat a moderate or severe migraine headache with either telcagepant 280 mg + ibuprofen 400 mg (N = 171), telcagepant 280 mg + acetaminophen 1000 mg (N = 171), telcagepant 280 mg (N =170), or placebo (N = 171). The primary efficacy endpoint was 2-hour pain freedom. The study had approximately 88% power to detect an additive effect of at least 15 percentage points (telcagepant combination vs telcagepant monotherapy) and 48% power to detect an additive effect of at least 10 percentage points. Safety and tolerability were assessed by adverse events and laboratory tests. RESULTS: The percentages of patients with 2-hour pain freedom were greater in each active treatment group compared to placebo (P < .001): telcagepant + ibuprofen = 35.2%, telcagepant + acetaminophen = 38.3%, telcagepant = 31.2%, placebo = 10.9%. No significant differences were seen for either of the combination groups vs telcagepant monotherapy, but both were numerically larger than telcagepant monotherapy. All the active treatments were generally well tolerated. The percentage of patients reporting any adverse event within 48 hours was higher in the active treatment groups than placebo: telcagepant + ibuprofen = 30.3%, telcagepant + acetaminophen = 31.6%, telcagepant = 24.8%, placebo = 18.2%. The most common adverse events reported by ≥ 4 patients in one or more of the treatment groups that included telcagepant were fatigue, nausea, dizziness, somnolence, dry mouth, and tremor. CONCLUSIONS: The combination of telcagepant 280 mg with either ibuprofen 400 mg or acetaminophen 1000 mg did not show a statistically significant difference from telcagepant alone. Numerically greater treatment effects in the combination treatment groups over the telcagepant 280 mg monotherapy suggest that telcagepant combination treatments may merit further evaluation in studies powered to detect smaller additive benefits. (Clinicaltrials.gov; NCT00758836).

Inferior alveolar nerve transection disturbs innate immune responses and bone healing after tooth extraction.

Coordination between the nervous and innate immune systems to maintain bone homeostasis is largely uncharacterized. The present study investigated the sensory-immune interaction in resting alveolar bone and healing socket by surgical sensory denervation. Bone histomorphometry and immunohistochemistry showed that sensory denervation resulted in moderate suppression of bone remodeling, with a proinflammatory milieu manifested by increased neutrophil recruitment and possible alternations in macrophage phenotypes along the resting bone surface. This denervation effect intensified when bone remodeling was triggered by tooth extraction, as revealed by disrupted temporospatial variations in macrophage subpopulations and neutrophil infiltration, which were closely associated with a dramatic decline in socket bone filling and residual ridge height. Antagonism of calcitonin gene-related peptide (CGRP) brought about similar antianabolic and proinflammatory effects as sensory denervation, suggesting that sensory nerves may monitor the bony milieu by CGRP. Depletion of macrophages, rather than neutrophils, ruled out CGRP effects, illustrating that macrophages were the primary immune mechanism that linked sensory innervation, innate immunity, and bone. The data support that sensory innervation is required for control of innate immune responses and maintenance of bone homeostasis. Sensory neuropeptides, such as CGRP, are a possible target for the development of proanabolic treatments in bone disease by modulating innate immune responses.

Calcitonin-gene related peptide is a potent inducer of oedema in rat orofacial tissue.

BACKGROUND AND AIMS: This study aimed to assess the potential of calcitonin-gene related peptide (CGRP), a neuropeptide released from sensory nerves, to induce oedema in orofacial tissue. EXPERIMENTAL APPROACH: Wistar rats (150-200 g) anesthetized with isoflurane were injected intraorally with CGRP (100 µl; 8-33 pmol) in the right side of the mouth. The contralateral side was injected with the same volume of physiological saline. Increased cheek thickness (in mm), as a measure of oedema formation, was assayed bilaterally with a digital caliper before (T = 0) and up to 24 h following injection of CGRP. Pretreatment with antagonists (CGRP8-37, 10 nmol; pizotifen, 2 mg/kg) was given by intra-oral or subcutaneous injection, 10 or 30 min, respectively, before the inflammatory stimulus. CGRP and CGRP8-37 were also injected into the rat hind paw to induce oedema. Data are presented as the mean (±SEM) difference in thickness between the right and the left sides at each time. RESULTS: Following intra-oral injection, CGRP induced a rapidly developing (5-15 min) and long-lasting (6 h), dose-dependent oedema in the rat cheek, blocked by pre-treatment with CGRP8-37 or pizotifen. CGRP induced a smaller oedematogenic effect in the rat hind paw also blocked by the CGRP antagonist. CGRP (16 pmol) potentiated the oedema induced by co-injected substance P (3.7 nmol) and contributed to the oedema following intraoral injection of carrageenan (100 µg). Injection of CGRP8-37 alone induced an early but short-lasting oedema. CONCLUSION: Local injection of CGRP potently induced oedema in the orofacial tissue of rats which was blocked by a CGRP receptor antagonist. The overall inhibition of carrageenan-induced oedema by CGRP8-37 suggests that endogenous CGRP contributes to an oedematogenic response in orofacial tissues.

Effect of the sensory neuropeptide antagonists h-CGRP((8-37)) and SR 140.33 on pulpal and gingival blood flow in ferrets.

In a previous study, it was concluded that the neuropeptides calcitonin gene-related peptide (CGRP) and substance P are released during resting conditions in the (exposed) ferret dental pulp, contributing to a basal vasodilator tone in the pulpal vessels. In order to exclude the possibility that the method used elicited axon reflexes, which might be responsible for neuropeptide release, the present study was designed without pulp exposure. Non-invasive laser-Doppler flowmetry was used to measure the effects of intra-arterial infusions of the antagonists h-CGRP((8-37)) and SR 140.33 (neurokinin 1-receptor antagonist) on pulpal and gingival blood flow before, during and after electrical tooth stimulation. Infusions of h-CGRP((8-37)) reduced the basal blood flow in the pulp by 31.4+/-5.2% (p<0.001) and in the gingiva by 22.6+/-4.8% (p<0.05). A further significant decrease in basal blood flow was measured in both pulp and gingiva following SR 140.33 administration. The reduction in blood flow was 16.9+/-1.9% (p<0.005) in the pulp and 19. 3+/-5.6% (p<0.05) in the gingiva. The systemic arterial pressure remained unchanged both during and after the periods of infusion. Tooth stimulation before the antagonist infusion significantly increased the pulpal blood flow by 71.9+/-15.3% (p<0.005). Infusion of h-CGRP((8-37)) greatly reduced this electrically induced vasodilatation, indicating that CGRP is the principal factor responsible for the vasodilatation observed after tooth stimulation. This study confirms the previous finding that a resting vasodilator tone due to the release of CGRP and SP exists in the ferret dental pulp. It is concluded that spontaneous, basal release of the neuropeptides CGRP and substance P exists both in dental pulp and gingiva in the ferret.

Direct quantitative analysis of a 20 kDa PEGylated human calcitonin gene peptide antagonist in cynomolgus monkey serum using in-source CID and UPLC-MS/MS.

PEGylation is a successful strategy to improve the pharmacokinetic and pharmaceutical properties of therapeutic peptides. However, quantitative analysis of PEGylated peptides in biomatrix by LC-MS/MS poses significant analytical challenge due to the polydispersity of the polyethylene glycol (PEG), and the multiple charge states observed for both the peptide and PEG moieties. In this report, a novel LC-MS/MS method for direct quantitative analysis of 20 kDa PEGylated CGRP[Cit, Cit] in cynomolgus monkey serum is presented. CGRP[Cit, Cit] is an investigational human calcitonin gene peptide receptor antagonist with amino acid sequence Ac -WVTH[Cit]LAGLLS[Cit]SGGVVRKNFVPT DVGPFAF-NH(2). In-source collision-induced dissociation (in-source CID) of 20 kDa PEGylated peptide was used to generate CGRP[Cit, Cit] fragment ions, among which the most abundant b(8)(+) ion was selected and measured as a surrogate for the 20 kDa PEGylated peptide. A solid phase extraction (SPE) method was used to extract the PEGylated peptides from the biomatrix prior to the UPLC-MS/MS analysis. This method achieved a lower limit of quantitation (LLOQ) of 5.00 ng/mL with a serum sample volume of 100 µL, and was linear over the calibration range of 5.00 to 500 ng/mL in cynomolgus monkey serum. Intraday and interday accuracy and precision from QC samples were within ±15%. This method was successfully applied to a pharmacokinetic study of the 20 kDa PEGylated CGRP[Cit, Cit] in cynomolgus monkeys.

Mechanism of CGRP-induced vasodilation in the rat isolated perfused kidney.

We investigated the intracellular mechanisms involved in calcitonin gene-related peptide (CGRP)-induced vasodilation in rat isolated perfused kidney. CGRP-1 receptor antagonist, CGRP-8-37, abolished the responses. Endothelial denudation by Triton X-100 or nitric oxide (NO) synthase inhibition by NG-nitro-L-arginine attenuated the maximum dilation by about 63 and 55%, respectively. Protein kinase A inhibitor, KT-5720, caused an about 72% inhibition in CGRP-induced maximum dilation. Soluble guanylate cyclase inhibitor, ODQ, and ATP-sensitive potassium channel blocker, glibenclamide, inhibited the CGRP-induced maximum responses by 75 and 55%, respectively. Cyclooxygenase inhibitor, indomethacin, had no effect. Our data suggest that CGRP-1 receptors, endothelium, NO synthase, protein kinase A, soluble guanylate cyclase, and ATP-sensitive potassium channels, but not the cyclooxygenase pathway, may play a role in CGRP-induced vasodilation in rat isolated perfused kidney.