telcagepant (MK-0974) / Merck (MSD) - LARVOL DELTA

Application of quantitative systems toxicology and machine learning models in the assessment of drug-induced liver injury (ACS-Fall 2025) - "In this case study, DILIsym predicted clinical elevations of liver enzymes and bilirubin for telcagepant, correctly recapitulating the clinically observed DILI liability of the first-generation compound...These modes will empower QST modeling of DILI at early discovery stages, without the need for typical in vitro mechanistic toxicity assays. Case studies demonstrating lower relative clinical hepatotoxic risk of compounds vs other in-class compounds will be presented."

Machine learning • Hepatology • Liver Failure • Metabolic Disorders

Pharmacological characterization of ubrogepant and atogepant in cAMP assays at human, rat and mouse calcitonin family receptors in transfected cells (AHS 2024) - "Two other gepants (rimegepant and telcagepant) were also studied as comparators in some experiments. Ubrogepant and atogepant are capable of antagonizing additional receptors in the calcitonin receptor family, beyond the canonical CGRP receptor."

Preclinical • CNS Disorders • ADM

CGRP receptor antagonists (gepants). (PubMed, Handb Clin Neurol) - "More than 15 years later, the first second generation of gepants, ubrogepant and rimegepant, are now approved for the acute treatment of migraine with or without aura. Furthermore, a novel and promising third-generation gepant, zavegepant, has recently been approved as well. In this chapter, we review the evidence supporting the effectiveness, safety, and tolerability of gepants for the acute treatment of migraine. Furthermore, we discuss the potential limitations and future directions of this class of migraine-specific medication."

Journal • CNS Disorders • Hepatology • Migraine • Pain

Blocking the CGRP Receptor: Differences across Human Vascular Beds. (PubMed, Pharmaceuticals (Basel)) - "Interestingly, olcegepant, atogepant and rimegepant, with a Schild plot slope 1 log unit more potent in HMMAs than in HCAs, while telcagepant, ubrogepant and zavegepant, with a Schild plot slope not different from unity, showed similar (<1 log difference) potency across both tissues. As a Schild plot slope < 1 may point to the involvement of multiple receptors, it is important to further identify the receptors involved in the relaxation to CGRP in HCAs, which may be used to improve the cardiovascular safety of future antimigraine drugs."

Journal • Cardiovascular • CNS Disorders • Migraine • Pain

Focus on zavegepant: the first intranasal third-generation gepant. (PubMed, Pain Manag) - "Newly approved small molecules that antagonize the CGRP receptor, gepants, have advanced from the hepatotoxic first-generation telcagepant to third-generation intranasal zavegepant; during this process of drug development, rimegepant, ubrogepant and atogepant, which are orally administered, have been launched and approved for clinical use with no warning for hepatotoxicity. Real-world, long-term postmarketing data about the efficacy and safety of gepants are awaited. The aim of the present drug evaluation study was to provide an overview of the novel, third-generation intranasal Zavegepant, encompassing its development and future perspectives."

Journal • Review • CNS Disorders • Hepatology • Migraine

The CGRP Receptor Antagonist MK0974 Induces EVI1 AML Cell Apoptosis by Disrupting ERK Signaling. (PubMed, Anticancer Res) - "MK0974, a CGRP receptor antagonist, inhibits the CRLR/RAMP1 complex and induces apoptosis, making it a potential therapeutic agent for CRLR/RAMP1 AML."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CALCRL • MECOM

Characterization of transit rates in the large intestine of mice following treatment with a CGRP antibody, CGRP receptor antibody, and small molecule CGRP receptor antagonists. (PubMed, Headache) - "These results are consistent with reported clinical data. Selectively blocking the CGRP receptor may have a greater impact on gastrointestinal transit than attenuating the activity of the ligand CGRP. This differential effect may be related to physiologically opposing mechanisms between the CGRP and AMY1 receptors, as the CGRP ligand antibody could inhibit the effects of CGRP at both the CGRP and AMY1 receptors."

Journal • Preclinical • CNS Disorders • Constipation • Gastroenterology • Gastrointestinal Disorder • Migraine

Safety evaluation of oral calcitonin-gene-related peptide receptor antagonists in patients with acute migraine: a systematic review and meta-analysis. (PubMed, Eur J Clin Pharmacol) - "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."

Journal • Retrospective data • Review • CNS Disorders • Fatigue • Migraine • Pain • Xerostomia

A systematic review with expert opinion on the role of gepants for the preventive and abortive treatment of migraine. (PubMed, Expert Rev Neurother) - "The available data on the efficacy and safety of gepants suggest they may represent an abortive, and to some extent, preventive treatment option for migraine, in patients who do not respond or have adverse effects to first/second line treatments or at high risk for medication overuse headache. Some gepants have been approved as third-line treatments for migraine, thus opening new therapeutic horizons."

Journal • Review • CNS Disorders • Migraine • Pain

Comparing the Liver Safety Profiles of Four Next-Generation CGRP Receptor Antagonists to the Hepatotoxic CGRP Inhibitor Telcagepant Using Quantitative Systems Toxicology Modeling. (PubMed, Toxicol Sci) - "Subsequently, while four next-generation CGRP receptor antagonists (rimegepant, zavegepant, atogepant, and ubrogepant) were being advanced into late-stage clinical trials, due to telcagepant's failure, more confidence in the liver safety of these compounds was needed. Subsequent clinical trials have validated these predictions for each of the four compounds, and all 3 of the compounds submitted to FDA to date (rimegepant, ubrogepant and atogepant) have since been approved by the FDA with no warning for hepatotoxicity. This work demonstrates the potential for QST modeling to prospectively differentiate between hepatotoxic and non-hepatotoxic molecules within the same class."

Journal • CNS Disorders • Hepatology • Liver Failure • Metabolic Disorders • Migraine

Molecular simulations reveal the impact of RAMP1 on ligand binding and dynamics of calcitonin gene-related peptide receptor (CGRPR) heterodimer. (PubMed, Comput Biol Med) - "Here in this study, with several molecular modeling approaches and molecular dynamics (MD) simulations, the structural and dynamical effects of RAMP1 on the binding of small molecule CGRPR inhibitors (namely rimegepant and telcagepant) to the CGRPR extracellular ectodomain complex site (site 1) and transmembrane binding site (site 2) are investigated. Results showed that although these molecules stay stable at site 1, they can also bind to site 2, which may be interpreted as non-specificity of the ligands, however, most of these interactions at transmembrane binding site are not sustainable or are weak. Furthermore, to examine the site 2 for gepant binding, different in silico experiments (i.e., alanine scanning mutagenesis, SiteMap, ligand decomposition binding free energy analyses) are also conducted and the results confirmed the putative binding pocket (site 2) of the gepants at the CGRPRs."

Journal • CNS Disorders • Migraine • CALCRL

[VIRTUAL] ADVANCING CALCITONIN GENE-RELATED PEPTIDE RECEPTOR (CGRP) ANTAGONISTS USING QUANTITATIVE SYSTEMS TOXICOLOGY MODELING TO CHARACTERIZE NEXT-IN-CLASS COMPOUNDS COMPARED TO THE HEPATOTOXIC FIRST IN CLASS TELCAGEPANT (AASLD 2021) - "Background: CGRP inhibitors have shown promise in the treatment of migraine. DILIsym correctly predicted the DILI liability of the first generation compound telcagepant. The four next-in-class compounds did not show the same signal for liver safety concerns as telcagepant . Subsequent clinical trials have validated these results, and both rimegepant and ubrogepant have been approved by the FDA with no warning for hepatotoxicity ."

CNS Disorders • Hepatology • Liver Failure • Metabolic Disorders • Migraine

Exploring Ligand Binding to Calcitonin Gene-Related Peptide Receptors. (PubMed, Front Mol Biosci) - "We also evaluated the association and dissociation of the antagonist telcagepant from the extracellular domain (ECD) of CGRPR and the water network perturbation upon binding. This study, which represents the first example of dynamic docking of a class B1 GPCR peptide, delivers insights on several aspects of ligand binding to CGRPR, expanding understanding of the role of the ECD and the receptor-activity modifying protein 1 (RAMP1) on agonist selectivity."

Journal • Cardiovascular • Diabetes • Heart Failure • Metabolic Disorders • Oncology • CALCRL

[VIRTUAL] Central sensitization and migraine treatments impact on thalamic metabolism: MR study at 21.1 T (AHS 2021) - "For treatment groups, drugs were injected (0.3 mg/kg sumatriptan, 0.3 mg/kg telcagepant or 0.1 mg/kg ouabain) prophylactically 5 min prior to NTG. Thalamic metabolite concentrations during migraine onset reveal that recruited neural structures undergo a state of ATP deprivation possibly due to NKAT over-activity at the CP, which may be mitigated by migraine treatments. The neuroprotective response (elevated Gly and Tau) to NTG-triggered sensitization is reduced but not eliminated by treatment with either sumatriptan, telcagepant or ouabain."

CNS Disorders • Migraine

[VIRTUAL] Cerebral hemodynamics with migraine onset and intervention (AHS 2021) - "While anesthetized in the MR scanner, the rats (n=6/group) were administered an in situ IP injection of either NTG (10 mg/kg) to trigger the migraine or saline to serve as control, with and without the prior injection (5 min) of either sumatriptan or telcagepant (both 0.3 mg/kg). Cerebral microcirculation showed altered perfusion significantly impacting the NTG-triggered brainstem, an integrating gateway to nociceptive inputs. However, CBF increases are largely subsequent to both ionic and metabolic changes. Prophylactic drugs impact early perfusion only in the brainstem, reversing the CBF enhancement of NTG alone."

CNS Disorders • Migraine • Pain

Migraine therapeutics differentially modulate the CGRP pathway. (PubMed, Cephalalgia) - "The therapeutic effect of agents targeting the CGRP ligand versus receptor for migraine prevention (antibodies) or acute treatment (gepants) may involve distinct mechanisms of action. These findings suggest that differing mechanisms could affect efficacy, safety, and/or tolerability in migraine patients."

Journal • CNS Disorders • Migraine • ADM

Recent Advances in Pharmacotherapy for Episodic Migraine. (PubMed, CNS Drugs) - "In 2018, three calcitonin gene-related peptide (CGRP) pathway monoclonal antibodies, erenumab, fremanezumab and galcanezumab, were approved in various parts of the world, including Europe and the US, and another, eptinezumab, is pending, for the prevention of migraine...Rimegepant, ubrogepant and lasmiditan are migraine-specific acute therapies yet to be approved by regulators...Beyond this, gepants will see the most disruptive development in migraine management in generations with medicines that can have both acute and preventive effects, the latter evidenced by data from the discontinued drug telcagepant and the early-phase drug atogepant...Clinicians will be able to offer treatment patients want rather than trying to fit migraineurs into therapeutic boxes for their management. Despite pessimistic susurrations of a largely addlepated form, many patients, and physicians, will welcome new options, and the challenges of new treatment paradigms, with optimism."

Journal • Cardiovascular • CNS Disorders • Migraine

Novel migraine treatment with CGRP-related monoclonal antibodies (PubMed, Rinsho Shinkeigaku) - "Among them, telcagepant, was shown to exert a significant migraine prophylactic action as well...Furthermore, emerging data support the long-term safety and efficacy of these antibodies. In this review article, the development and perspective of anti-migraine therapeutic strategies using CGRP-related antibodies are discussed."

Journal • CNS Disorders • Hepatology • Migraine • Pain

Use of a Bile Salt Export Pump Knockdown Rat Susceptibility Model to Interrogate Mechanism of Drug Induced Liver Toxicity. (PubMed, Toxicol Sci) - "Benzbromarone, lopinavir, and simeprevir caused smaller increases in plasma T3-BA, but did not result in hepatotoxicity in Bsep KD rats. Bosentan, cyclosporine A, and ritonavir, however, showed no enhancement of T3-BA in plasma in Bsep KD rats, as well as Bsep noninhibitors acetaminophen, MK-0974, or clarithromycin...Bsep KD also altered liver and/or plasma levels of asunaprevir, TAK-875, TAK-875 acyl-glucuronide, benzbromarone, and bosentan. The Bsep KD rat model has revealed differences in the effects on bile acid homeostasis among Bsep inhibitors that can best be monitored using measures of T3-BA and TCA-d4 in plasma. However, the phenotype caused by Bsep inhibition is complex due to the involvement of several compensatory mechanisms."

Journal • Preclinical

Calcitonin Gene-Related Peptide Modulators - The History and Renaissance of a New Migraine Drug Class. (PubMed, Headache) - "These included the anatomic colocalization of CGRP and its receptor in sensory fibers innervating pain-producing meningeal blood vessels, its release by trigeminal stimulation, the observation of elevated CGRP in the cranial circulation during migraine with normalization concomitant with headache relief by sumatriptan, and translational studies with intravenous (IV) CGRP that evoked migraine only in migraineurs...More recently, CGRP target engagement imaging studies using a CGRP receptor PET ligand [ C]MK-4232 demonstrated that there was no brain CGRP receptor occupancy at clinically effective antimigraine doses of telcagepant, a prototypic CGRP-RA...Large molecule biologic antibody (mAb) approaches that are given subcutaneously to neutralize circulating CGRP peptide (fremanezumab, galcanezumab) or block CGRP receptors (erenumab) have shown consistent efficacy and tolerability in multicenter migraine prevention trials and are now approved for clinical use...."

Journal • CNS Disorders • Migraine • Pain

Gepants for abortive treatment of migraine: A network meta-analysis. (PubMed, Brain Behav) - "Gepants were effective for abortive treatment of migraine. The most effective treatment of gepants for migraine might be olcegepant which were administrated transvenously. And all of gepants were safe for migraine treatment with single dose."

Journal • Retrospective data • CNS Disorders • Migraine • Pain

The locus of action of CGRPergic monoclonal antibodies against migraine: peripheral over central mechanisms. (PubMed, CNS Neurol Disord Drug Targets) - "Unfortunately, further pharmaceutical development (for olcegepant and telcagepant) was interrupted due to pharmacokinetic issues observed during the randomized clinical trials (RCT)...Presently, the U.S. Food and Drug Administration approved four mAbs, namely: (i) erenumab; (ii) fremanezumab; (iii) galcanezumab; and (iv) eptinezumab...Since these mAbs have a molecular weight of 150 kDa, some studies rule out the relevance of their central actions as they seem unlikely to cross the blood-brain barrier (BBB). Considering the therapeutic relevance of this new class of antimigraine compounds, the present review has attempted to summarize and discuss the current evidence on the probable sites of action of these mAbs."

Journal • CNS Disorders • Migraine • Pain

The role of CGRP as targeted treatment for migraine - Introduction (YouTube) - "Stewart J. Tepper, MD, provides his perspectives on the clinical impact of 4 recently published studies involving the management of patients with migraines."

Video

Mechanistic Investigations Support Liver Safety of Ubrogepant. (PubMed, Toxicol Sci) - "In contrast, DILIsym predicted no hepatotoxicity during treatment with ubrogepant, even at daily doses up to 1000 mg (10-fold higher than the proposed clinical dose of 100 mg). These predictions are consistent with clinical trial experience showing that ubrogepant has lower potential to cause hepatotoxicity than has been observed with telcagepant and MK-3207."

Clinical • Journal • CNS Disorders • Migraine

Efficacy, safety, and tolerability of telcagepant in the treatment of acute migraine: A meta-analysis (Pain Pract) - P=NA, N=NA; "The difference in pain freedom at 2 hours significantly favored telcagepant over placebo (...P < 0.001) and triptans over telcagepant (...P < 0.001). The difference in pain relief at 2 hours significantly favored telcagepant over placebo (...P < 0.001). The difference in pain relief at 2 hours did not significantly favor telcagepant over triptans or vice versa (... P = 0.061)."

Retrospective data • Migraine