Ubrogepant: First Approval

Scott, Lesley J.

doi:10.1007/s40265-020-01264-5

Cited by 67 publications

(98 citation statements)

References 15 publications

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“…The small molecule CGRP antagonist, telcagepant, does not appear to act centrally at therapeutic doses [52]. The small molecule GGRP receptor antagonists such as ubrogepant and rimegepant, which were recently approved in the United States for the treatment of migraine attacks [53,54], appear to predominantly function in the PNS [24,55]. While the BBB is relatively impermeable to antibodies [56], it is still possible to detect up to approximately 0.1% of the blood concentration in the cerebrospinal fluid [24,57,58]; thus, the monoclonal antibodies to CGRP peptide (eptinezumab, fremanezumab, and galcanezumab) could potentially have some level of CNS activity, despite not appearing to penetrate the BBB in large concentrations [24,57].…”

Section: Role Of Cgrp In Migrainementioning

confidence: 99%

Lasmiditan mechanism of action – review of a selective 5-HT1F agonist

et al. 2020

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Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second-and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT 1B/1D receptors. The discovery that the serotonin 1F (5-HT 1F) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT 1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT 1B receptors, the activation of 5-HT 1F receptors does not cause vasoconstriction. The potency of different serotonergic agonists towards 5-HT 1F was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT 1F agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites. Lasmiditan activation of CNS-located 5-HT 1F receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT 1F receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT 1F receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT 1F receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT 1F agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.

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Section: Role Of Cgrp In Migrainementioning

confidence: 99%

Lasmiditan mechanism of action – review of a selective 5-HT1F agonist

et al. 2020

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“…With regards to neurology, all CGRP-targeted therapies tested for the acute treatment and prevention of migraine have consistently produced positive results to date, strongly supporting the evolving role of CGRP in migraine pathophysiology. Indeed, the orally administered CGRP receptor antagonist ubrogepant was shown to provide relief from acute migraine attacks [ 34 , 35 ], whereas monoclonal antibodies against either CGRP or CGRP receptor including erenumab, fremanezumab or galcanezumab, applied once monthly by subcutaneous injection, are particularly effective for a long-lasting prevention of episodic or chronic migraine [25] . The drugs currently being developed are well tolerated and exhibit an excellent safety profile free of warnings and precautions about adverse side effects aside from hypersensitivity and injection-site reactions [62] .…”

Section: Discussionmentioning

confidence: 99%

“…Although anti-CGRP and CGRP receptor antibodies have been shown to be an excellent alternative treatment with little or no adverse effects [33] , the fact that CGRP and its receptor are expressed in many different organs, including bone tissue, has raised concerns about hitherto unrecognized side effects, including a negative effect on bone fracture repair. To date, the FDA has approved one gepant (ubrogepant, targeting CGRP receptor) [ 34 , 35 ] and three monoclonal antibodies (erenumab, targeting CGRP receptor; galcanezumab and fremanezumab, targeting CGRP) for the preventive and acute treatment of migraine [36] .…”

Section: Introductionmentioning

confidence: 99%

The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing

et al. 2020

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Background Impaired fracture healing represents an ongoing clinical challenge, as treatment options remain limited. Calcitonin gene-related peptide (CGRP), a neuropeptide targeted by emerging anti-migraine drugs, is also expressed in sensory nerve fibres innervating bone tissue. Method Bone healing following a femoral osteotomy stabilized with an external fixator was analysed over 21 days in αCGRP-deficient and WT mice. Bone regeneration was evaluated by serum analysis, µCT analysis, histomorphometry and genome-wide expression analysis. Bone-marrow-derived osteoblasts and osteoclasts, as well as the CGRP antagonist olcegepant were employed for mechanistic studies. Findings WT mice with a femoral fracture display increased CGRP serum levels. αCGRP mRNA expression after skeletal injury is exclusively induced in callus tissue, but not in other organs. On protein level, CGRP and its receptor, calcitonin receptor-like receptor (CRLR) complexing with RAMP1, are differentially expressed in the callus during bone regeneration. On the other hand, αCGRP-deficient mice display profoundly impaired bone regeneration characterised by a striking reduction in the number of bone-forming osteoblasts and a high rate of incomplete callus bridging and non-union. As assessed by genome-wide expression analysis, CGRP induces the expression of specific genes linked to ossification, bone remodeling and adipogenesis. This suggests that CGRP receptor-dependent PPARγ signaling plays a central role in fracture healing. Interpretation This study demonstrates an essential role of αCGRP in orchestrating callus formation and identifies CGRP receptor agonism as a potential approach to stimulate bone regeneration. Moreover, as novel agents blocking CGRP or its receptor CRLR are currently introduced clinically for the treatment of migraine disorders, their potential negative impact on bone regeneration warrants clinical investigation. Funding This work was funded by grants from the Else-Kröner-Fresenius-Stiftung (EKFS), the Deutsche Forschungsgemeinschaft (DFG), and the Berlin Institute of Health (BIH).

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“…These drugs were promising in trials but were discontinued due to low oral bioavailability (olcegepant) and unexpected hepatotoxicity (telcagepant) [177]. However, ubrogepant and rimegepant tablets have both recently received FDA approval (23rd December 2019 and 27th February 2020) for acute treatment of migraine in adults [178].…”

Section: Acute Treatmentsmentioning

confidence: 99%

The fifth cranial nerve in headaches

et al. 2020

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The fifth cranial nerve is the common denominator for many headaches and facial pain pathologies currently known. Projecting from the trigeminal ganglion, in a bipolar manner, it connects to the brainstem and supplies various parts of the head and face with sensory innervation. In this review, we describe the neuroanatomical structures and pathways implicated in the sensation of the trigeminal system. Furthermore, we present the current understanding of several primary headaches, painful neuropathies and their pharmacological treatments. We hope that this overview can elucidate the complex field of headache pathologies, and their link to the trigeminal nerve, to a broader field of young scientists.

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Ubrogepant: First Approval

Cited by 67 publications

References 15 publications

Lasmiditan mechanism of action – review of a selective 5-HT1F agonist

Lasmiditan mechanism of action – review of a selective 5-HT1F agonist

The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing

The fifth cranial nerve in headaches

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