Plenary I: Clinical Targets of Tomorrow

Transcription

1 Plenary I: Clinical Targets of Tomorrow Serotonin Biology & Migraine Paul Durham, PhD Distinguished Professor of Cell Biology Director, Center for Biomedical and Life Sciences Missouri State University

2 Disclosures I have received funding for research projects from the following organizations: NIH International ti Dehydrated d Foods electrocore Gelstat Pharmalyte Tuning Elements Tansna DNA BioLabs Banyan

3 Disclosures I have received funding for research projects from the following organizations: NIH International ti Dehydrated d Foods electrocore Gelstat Pharmalyte Tuning Elements Tansna DNA BioLabs Banyan

4 Course Objectives: Serotonin Biology and Migraine 1. Explain the basic mechanism of action of drugs with reported affinity for serotonin receptors. 2. Describe the advantages and disadvantages of emerging therapies with a focus on new methods of delivering drugs that target serotonin receptors. 3. Summarize recent basic science and clinical findings from studies involving serotonergic drugsindevelopment development.

5 Serotonergic System in the Brain Important Role in Migraine Pathology Low cerebral serotonin level between attacks Elevated levels during a migraine i attack Thalamus Hypothalamus Raphe nuclei Cerebellum Dorsal Horn Serotonergic mechanisms in the migraine brain a systematic review. Cephalalgia Mar 23 [Epub] Deen M, Christensen CE, Hougaard A, Hansen HD, Knudsen GM, Ashina M

6 Serotonin Mediates Physiological Effects Via Activation of Different Receptor Subtypes Key role of 5 HT in pain modulation Cephalalgia Mar 23 [Epub]

7 Serotonin Role in Pain Modulating System Dualistic and Complex Migraine A Multiphasic Disorder 5 HT function depends on receptor subtype, availability, and affinity Cephalalgia Mar 23 [Epub]

8 Triptans Target 5 HT 1B/1D Receptors Multiple Sites of Action

9 Activation of 5 HT 1B/1D/1F Receptors Inhibition of Glutamate and CGRP

10 Activation of 5 HT 1B/1D/1F Receptors on Cell Body of Trigeminal Ganglion Neurons CSD/ Hypercortical Activity IL-1, IL-6, NGF PG, ATP, NO Activation/Sensitization of primary afferents NSAIDS Cell Body Neuronal Cell Body Triptan DHE Satellite Glia Trigeminal Nucleus Pain Upper Spinal Cord Meninges Neuropeptide Trigeminal Neuron Release Triptan Mast Cell DHE Triptan Degranulation DHE Activation Of Second Order Neurons and Glia

11 What Acute Treatment of Migraine is Most Effective? Triptans in the Acute Treatment of Migraine: A Systematic Review and Network Meta Analysis BACKGROUND: We conducted systematic reviews and network meta analyses to compare the relative efficacy of triptans (alone or in combination with other drugs) for acute treatment of migraines compared with other triptan agents, non steroidal anti inflammatory drugs (NSAIDs), acetylsalicylic acid (ASA), acetaminophen, ergots, opioids, or anti emetics. METHODS: The Cochrane Library, MEDLINE, and EMBASE were searched for randomized controlled trials that compared triptans (alone or in combination with other drugs) with placebo controlled or active migraine treatments. RESULTS: A total of 133 randomized controlled trials met the inclusion criteria. For 2 hour headache relief, standard dose triptan achieved better outcomes (42 to 76% response) than ergots (38%); equal or better outcomes than NSAIDs, ASA, and acetaminophen (46 to 52%); and equal or slightly worse outcomes than combination therapy (62 to 80%). Among individual triptans, sumatriptan subcutaneous injection, rizatriptan ODT, zolmitriptan ODT, and eletriptan tablets were associated with the most favorable outcomes. Cameron C et al., Headache Jul Aug;55 Suppl 4:

12 What Acute Treatment of Migraine is Most Effective? INTERPRETATION/CONCLUSIONS: Triptans are effective for migraine relief. Standard dose triptans are associated with better outcomes than ergots, and most triptans are associated with equal or better outcomes compared with NSAIDs, ASA, andacetaminophen. acetaminophen. Use of triptans in combination with ASA or acetaminophen, or using alternative modes of administration such as injectables, may be associated with slightly better outcomes than standard dose triptan tablets. Cameron C et al., Headache Jul Aug;55 Suppl 4:

13 Can We Predict Which Triptan Would be Most Effective? Theory Based Analysis of Clinical Efficacy of Triptans Using Receptor Occupancy Background: Triptans exert their action by targeting serotonin 5 HT1B/1D receptors, are used for treatment of migraine attack. Presently, 5 different triptans, namely sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan, are marketed din Japan. In the present study, we retrospectively analyzed the relationships of clinical i l efficacy (headache relief) in Japanese and 5 HT1B/1D receptor occupancy. Methods: To evaluate the total amount of exposure to drug, we calculated the area under the plasma concentration time curve (AUCcp) and the areas under the time curves for Ф1B and Ф1D (AUCФ 1B and AUCФ 1D). Results: Our calculations showed that Фmax 1B and Фmax 1D were relatively high at % and %, respectively, suggesting that it is likely that a high occupancy is necessary to attain the clinical effect. Conclusions: These results suggest that receptor occupancy can be used as a parameter for a common index to evaluate the therapeutic effect. We considered that the present findings provide useful information to support the proper use of triptans. In a future study, we intend to develop a system for clinical application. Tokuoka et al (Yamada). The Journal of Headache and Pain 2014, 15:85

14 Why Are Triptans Selective for Headache and Migraine? Triptan Induced Disruption of Trigemino Cortical Connectivity OBJECTIVE: The 5 HT1B/D agonists (triptans) are specific headache medications that have no effect on pain as such. Yet, underlying mechanisms of action are still a matter of debate. METHODS: Forty three healthy participants underwent fmri while receiving trigemino nociceptive stimulation and control stimuli in a standardized fmri paradigm. Using a crossover, double blind, placebo controlled design, 21 participants (10 women, mean age 26.9, range years) received sumatriptan and 22 participants (11 women, mean age 25.5, 5 range years) received acetylsalicylic li li acid (ASA). RESULTS: We found a significant blood oxygen level dependent signal increase in the trigeminal nuclei and the thalamus after sumatriptan treatment compared with placebo or ASA. In addition, we found a strong coupling during the saline condition, i which h was altered by sumatriptan but not after ASA administration. i i CONCLUSION: These data suggest that a specific functional inhibition of trigemino cortical projections pojecto ss is one eof the reasons s that attriptans, s,unlike epain killers, es,act highly yspecifically ca on headache and migraine but not pain as such. Kröger IL, May A Neurology 2015 May 26;84(21):

15 Sumatriptan Induces Type I Hyperalgesic Priming Gi Protein Coupled 5 HT1B/D Receptor Agonist Sumatriptan Induces Type I Hyperalgesic Priming Like mu opioids, the anti migraine triptans, which act at 5 HT1B/D Gi GPCRs have been implicated in pain chronification. We determined if sumatriptan, a prototypical 5 HT1B/D agonist produces hyperalgesic type II priming. Characteristic of hyperalgesic priming, intradermal injection of sumatriptan (10 ng) induced a change in nociceptor function such that a subsequent injection of prostaglandin E2 (PGE2) induces prolonged mechanical hyperalgesia. Onset to priming was delayed 3 days characteristic oftype I priming. Finally, as observed for other agonists that induce type I priming, sumatriptan did not induce priming in female rats. The prolongation of PGE2 hyperalgesia induced by sumatriptan was partially prevented by co injection of antagonists for the 5 HT1B and 5 HT1D, but not 5 HT7,serotonin receptors, and completely prevented by co administration of a combination of the 5 HT1B and 5 HT1D antagonists. Moreover, the injection of selective agonists, for 5 HT1B and 5 HT1D receptors, also induced hyperalgesic priming. Conclusion: Our results suggest that sumatriptan induces type I hyperalgesic priming, unlike agonists at other Gi GPCRs, which induce type II priming. Araldi, Ferrari, Levine Pain Apr 12. [Epub ahead of print]

16 Putative Role of 5 HT2B Receptors in Migraine Pathology Activation of meningeal 5 HT2B receptors: an early step in the generation of migraine headache? Objective: Several pharmaceuticals are frequently dispensed to prevent or reduce the occurrence of migraine attacks. The prophylactic effect of these drugs has been suggested to be caused through blockade of serotonin (5 HT) receptors of type 5 HT2B or 5 HT2C. Methods: We first used radioligand binding assays to determine the pharmacological profile of the human and rat 5 HT2B receptor. Utilized RT PCR to investigate 5 HT receptor expression in human meningeal tissues. Results: Correlation of the receptor affinities with the potencies used in migraine prophylaxis showed significant correlations, which were better for the 5 HT2B (P = 0.001) 001) than for the 5 HT2C receptor (P = 0.005). 005) All human meningeal tissues expressed 5 HT1D/1B, 5 HT2A, 5 HT2B, 5 HT4 and 5 HT7 mrnas. Only trace amounts of 5 HT2C receptor mrna were found. Conclusion: Our data support the hypothesis that 5 HT2B receptors located on endothelial cells of meningeal blood vessels trigger migraine headache through the formation of nitric oxide. Conclusion: Our literature review suggests an important role of 5 HT2B receptor activation in meningeal nociception and the generation of migraine pain. Schmuck K et al., Eur J Neurosci May;8(5): Segelcke and Messlinger, Cephalalgia Apr 28 [Epub].

17 Selective 5 HT2B Antagonist: Potential Prophylactic Migraine Treatment BF 1 a Novel Selective 5 HT2B Receptor Antagonist Blocking Neurogenic Neural Plasma Protein Extravasation in Guinea Pigs Objective: Serotonin 5 HT2B receptor antagonists have been proposed as migraine prophylactic drugs, but previously available 5 HT2B receptor antagonists displayed multiple monoaminergic side effects and had to be withdrawn from the market. Here, we set out to identify a novel antagonist with high affinity and selectivity towards 5 HT2B receptors. Methods: To test the affinity of new compounds towards various receptors, we generated a broad series of cells functionally coupling human monoaminergic receptors to luciferase. Results: BF 1 was significantly ifi more potent tin this assay compared to the well known non selective 5 HT2B antagonists, methysergide or pizotifen. Conclusion: Therefore, we propose BF 1as a new compound that may be developed for prophylactic migraine treatment without the typical monoaminergic side effects. Schmitz Bet al., Eur J Pharmacol Mar 15;751:73 80.

18 Do Changes in the 5 HT Receptor Sequence Increase the Risk of Migraine? Molecular Factors in Migraine Pathophysiological mechanism of migraine is still unknown, but it is thought that both genetic and environmental factors are involved in this pathological process. The first genetic studies of migraine were focused on the rare subtype of MA: familial hemiplegic migraine (FHM). Migraine is a multifactorial disease with polygenic influence. Recent studies migraine involves both factors responsible for immune response and oxidative stress such as: cytokines, tyrosine metabolism, homocysteine; and factors associated with pain transmission and emotions e.g.: serotonin, hypocretin 1, calcitonin gene related peptide, glutamate. The correlations between genetic variants of the HCRTR1 gene, the polymorphism 5 HTTLPR and hypocretin 1, and serotonin were observed. It is known that serotonin inhibits the activity of hypocretin neurons and may affect the appearance of the aura during migraine attack. Serotoninergic system plays an important role in the pathogenesis of migraine. 5 HT1B and 5 HT1D receptor agonists (triptans) are effective in migraine pharmacotherapy, whereas influence of numerous polymorphisms in 5 HT1A, 5 HT1B, 5 HT2A and 5 HT2C in this disease is still being investigated. Mostofof thecurrent resultsdeny thatchanges inthe5 5 HT receptor sequence increase the risk of migraine. Kowalska et. al., (Dorszewska) Oncotarget, 2016

19 New Formulations and Dli Delivery Methods

20 Zembrace SYMTOUCH Dr. Reddy's Laboratories announced that FDA has approved ZembraceSymTouch (sumatriptan succinate) injection, a drug device combination product intended for the treatment of acute migraine episodes, with or without aura, in adults who are inadequately managed with existing treatment regimens. ZembraceSymTouch is available as a prefilled, ready to use, single dose disposable autoinjector containing 3 mg of sumatriptan, a selective 5 HT1B/ID receptor agonist. The injection is intended to be given subcutaneously. Dr. Reddy s Laboratories Ltd. receives FDA approval for ZEMBRACESymTouch (sumatriptan succinate) injection for the acute treatment of migraines in adults.

21 ONZETRA Xsail ONZETRA Xsail (sumatriptan nasal powder), formerly AVP 825, for the acute treatment of migraine with or without aura in adults New Treatment for Acute Migraine Using Bi Directional Breath Powered Technology Highlyeffective effective, well tolerated alternative to oral triptans Cady, Expert Opin Pharmacother 2015

22 Zecuity Sumatriptan Iontophoretic Transdermal System ZECUITY is a disposable, single use system designed to deliver sumatriptan through the skin using iontophoresis. Iontophoresis is a non invasive method of delivering a drug through the skin using a low electrical current. The ZECUITY electronics, powered by two coin cell lithium batteries, control the amount of current applied and the rate and amount of sumatriptan delivered.

23 Intranasal Sumatriptan for Migraine in Children Acute migraine headache among children and adolescents is common and treatment is challenging. hll Intranasal sumatriptan is a safe and mostly effective option for children and adolescents. Currently the recommended dose is 20 mg for children who weigh more than 40 kg and 10 mg for children who weigh between 20 and 39 kg. Larger trials il should ldbe conducted dto overcome the limitations of small sample sizes, potential low plasma concentration, and placebo effects witnessed in studies to date. Goldman RD, Meckler GD; Can Fam Physician May;61(5):435 7.

24 Zolmitriptan Oral Dispersible Film (ODF) Europe MonoSol Rx and APR are reviewing their options in the Unites States to complete the required steps to obtain Marketing Approval by the FDA under a 505(b) 2 procedure. Zolmitriptan Oral Dispersible Film ( ODF ) is a unique formulation of Zolmitriptan based on the RapidFilm technology, an APR and Labtec s novel and proprietary oral drug delivery technology platform. Once placed in the mouth, it dissolves in a few seconds and is swallowed with the saliva without the need of water. The Zolmitriptan ODF not only avoids the risk of aspiration but also improves patient compliance by reducing swallowing difficulties experienced by many patients taking other oral Zolmitriptan formulations currently available.

25 5 HT Drugs in the Pipeline

26 Levadex (Semprana) Orally Inhaled DHE

27 ZP Triptan Patch Potential for Fast Relief

28 ZP Triptan Patch High Relative Bioavailability

29 ZP Triptan Patch Timeline for Development

30 Lasmiditan Targets 5 HT1F Receptors on Trigeminal Ganglion Neurons Phase III No vasoconstrictor effects However, number of AE including dizziness Reuter, Israel, Neeb Ther Adv Neurol Disord : 46 54

31 CoLucid has reached agreement with the FDA on a Special Protocol Assessment for SAMURAI, our first Phase 3 pivotal trial of Lasmiditan migraine. The trial will include patients with risk factors for cardiovascular disease and some forms of stable cardiovascular disease.

32 Summary Serotonin s role in migraine pathology is complex Triptans remain standard for acute treatment of migraine New delivery methods overcome limitations of oral delivery Potential ti therapeutic ti targets t include 5 HT2B and 5 HT1F receptors

33 Future Directions Likely development of new drugs and identification of nutraceuticals that selectively modulate expression and activity of 5 HT receptors involved din descending di inhibition i of nociceptive processing Appreciation of importance of maintaining a healthy gut microbiome since bacteria can produce 5 HT and other neuromodulator molecules