Sanofi Could Pursue Other Oncology M&A Targets After Medivation Loss

Total Page:16

File Type:pdf, Size:1020Kb

Sanofi Could Pursue Other Oncology M&A Targets After Medivation Loss With Medivation, Pfizer Sees GSK, J&J And Roche Speak Up Stockwatch A Chance For More Combinations On Women’s Equality Day Last week the increasing volume of Pfizer is relying on future growth of Scrip spoke to big pharma about press backlash against Mylan’s Turing the prostate cancer therapy Xtandi to gender equality issues that need Pharmaceuticals-like pricing policy on justify the $14bn price it will pay to highlighting across the life science EpiPen resulted in another social media buy Medivation (p3) industry (p14) condemnation (p19) 2 September 2016 No. 3818 Scripscrip.pharmamedtechbi.com Pharma intelligence | informa maceutical Inc. as well as a trio of firms that could offer significant cancer assets – Re- generon Pharmaceuticals Inc., Incyte Corp. and Ariad Pharmaceuticals Inc. While BioMarin – an oft-cited takeout target of late – could add heft to the rare disease franchise within Sanofi’s Genzyme Corp. unit and Vertex would bring along a potential blockbuster cystic fibrosis fran- chise, a deal that could spark the established but dwindling cancer business at Sanofi might be the most desirable way to go. A further consideration against pursuing Bio- Marin is the reality that potential interest by rare disease specialist Shire PLC could pro- duce another bidding war like the one that rose up around Medivation. In an Aug. 23 note, Bryan Garnier & Co. ana- Shutterstock: Mmaxer Shutterstock: lyst Eric LeBerrigaud called Pfizer’s acquisition of Medivation “not great news” for Sanofi de- spite the premium price, saying it could have Sanofi Could Pursue Other Oncology “dramatically boosted” the pharma’s cancer franchise and been immediately accretive. “Obviously, the company won’t call it a day M&A Targets After Medivation Loss and will continue to look for other potential JOSEPH HAAS [email protected] targets in the field (and preferably profitable ones, with a promising development pipe- Losing Medivation could end up being a apply that capital now toward another can- line),” he wrote. “And we believe Regeneron, winning proposition for the French phar- cer-focused biotech purchase to bolster its Incyte or Ariad might attract Sanofi’s interest.” ma if it can boost its cancer franchise an- oncology portfolio at a more reasonable cost. Meanwhile, Jefferies Equity Research ana- other way, like by acquiring its partner In the days immediately following Pfizer’s lyst Brian Abrahams named Incyte as one of in multiple collaborations Regeneron or purchase of Medivation – at $81.50 per the most desirable biotech takeout candi- making a less expensive takeout, such as share, an estimated 21% premium over a dates industry-wide in an Aug. 22 note due Incyte or Ariad. share price that already had ballooned since both to its portfolio and pipeline, as well as Sanofi’s buyout interest first became public its “digestible” size. anofi opened the bidding and knowledge in May – analysts speculated drummed up interest in Medivation that Sanofi might be able to get the pipeline A MATURE CANCER SInc., but another suitor – Pfizer Inc. – boost it seeks at a lower price. FRANCHISE AT SANOFI walked off with the prize. While the French Suggested buyout targets for Sanofi or Though Sanofi has a long legacy in cancer pharma may have found the $14bn price tag other big pharmas also competing in the drug development, built around mature, and the share price premium paid by its US Medivation auction include Vertex Pharma- generic-challenged chemotherapy drugs rival too rich for its tastes, it may be able to ceuticals Inc., Biogen Inc. and BioMarin Phar- CONTINUED ON PAGE 7 BROUGHT TO YOU BY THE EDITORS OF PHARMASIA NEWS, START-UP AND SCRIP INTELLIGENCE IN THIS ISSUE More and larger M&A deals could boost public Meulien biopharma companies talks about successes & challenges Phase III Endpoint Hit For of leading IMI Novartis’s Gilenya Follow- 4 On In Progressive MS 13 20 COVER / Sanofi Could Pursue Other Oncology from the US editor M&A Targets After Medivation Loss [email protected] 3 With Medivation, Pfizer Sees A Chance For More Combinations Pfizer’s Aug. 22 acquisition of Medivation put an 4 Pfizer’s Medivation Buyout: end to a long bidding war, but it wasn’t the end of One-Off Deal Or Start Of A Biopharma Spending Spree? the story. Will $81.50 per share – more than dou- 6 Mylan Could Get Out Of EpiPen Price Backlash With ble the trading price before M&A rumors started A Little Contrition, Analyst Says swirling – turn out to be a reasonable price for an established prostate cancer drug and the promise 8 Lundbeck’s Alzheimer’s Strategy Targets of new immuno-oncology combinations? Pfizer Symptoms And Disease Modification will need to push Xtandi to new practitioners and 10 R&D Bites new patients. Medivation has played up its PARP 11 AstraZeneca Sells Small-Molecule Antibiotics inhibitor talazoparib, but there’s little evidence yet. To Pfizer But Still Investing In R&D Pidilizumab has promise too, but Pfizer will have to 12 Pfizer/Celltrion Prep For October Inflectra Launch figure out what it is and how it will help its existing IO plans. What’s next for Sanofi, which started off 13 Phase III Endpoint Hit For Novartis’s Gilenya the frenzy? It could build up its base in oncology, or Follow-On In Progressive MS it could go another direction and double down on 14 GSK, J&J And Roche Speak Up On Women’s Equality Day rare diseases. The question of what’s next for Pfizer 16 Business Bulletin is also still on the table. The $14bn deal was small scale for the pharma giant, so it doesn’t preclude 17 Pharmaceutical R&D In Turkey: the possibilities of a split. Pfizer has promised an Important Steps Forward But A Long Way To Go answer on that by the end of the year. It will take 18 Policy & Regulation Briefs longer than that to see the effect of the Medivation 19 Stockwatch: Teva And Mylan Hit Terminal Velocity deal on the biotech M&A market. 20 Interview: View From The Top Of IMI: Heading Up Life Sciences’ Biggest Public-Private Partnership 22 Pipeline Watch 23 Appointments exclusive online content INTERVIEW: GSK India’s Playbook For Vaccines Dominance Deft pricing and effective physician engagement appear to have helped shape GSK’s sustained dominance in the Indian self-pay vaccines market. GSK Pharmaceuticals India managing director, Annaswamy Vaidheesh, takes Scrip through some of the strategies at play. http://bit.ly/2bSMX03 INTERVIEW: Oscotec Lays Out Global Ambitions For RA, Cancer Drugs Executives from the South Korean bioventure firm Oscotec talk to Scrip about the significance of the recent license agreement for a third-generation EGFR inhibitor by partner Yuhan, and extolled the company’s other core pipeline products, which @scripnews /scripintelligence include novel candidates for rheumatoid arthritis and cancer. http://bit.ly/2bBNTn0 /scripintelligence /scripintelligence 2 | Scrip intelligence | 2 September 2016 © Informa UK Ltd 2016 HEADLINE NEWS With Medivation, Pfizer Sees A Chance For More Combinations Most of the $14bn value Pfizer agreed to pay to buy Medivation is tied to future growth of Xtandi, according to the company, but two pipeline assets and the potential to combine drugs could offer upside. JESSICA MERRILL [email protected] fizer Inc. is relying on future growth of the prostate cancer ther- adding to Lupron or other androgen deprivation therapy, particu- apy Xtandi (enzalutamide) to justify the $14bn price it will pay larly in the urologist’s office, will be a key to growth.” Pto buy Medivation Inc., but two pipeline products and the po- Xtandi generated sales of $1.9bn worldwide in 2015, which Me- tential for developing drugs in combination across pipelines could divation shares with its marketing partner Astellas Pharma Inc., but be longer term growth drivers. it is expected to grow substantially by 2021. Bourla said Pfizer be- “Medivation’s pipeline and innovative assets, including a PARP in- lieves it will own two of the top 10 oncology drugs in the world by hibitor and an immuno-oncology agent, play in the most attractive 2021 with Ibrance and Xtandi. areas in oncology,” CEO Ian Read said during a conference call Aug. Medivation, meanwhile, in the run up to the auction, has been 22, announcing the acquisition. “By combining with Medivation, talking up the potential of talazoparib, which is being studied in we’ll be creating one of the industry’s leading oncology franchises,” a Phase III test in BRCA-mutated breast cancer that is expected to building on the momentum the firm has had with its breast cancer read out in 2017. therapy Ibrance (palbociclib). Medivation believes talazoparib has the potential to be a best- in-class PARP inhibitor. The only approved PARP inhibitor on the Pfizer believes it will own two of the market is AstraZeneca PLC’s Lynparza (olaparib), approved to treat BRCA-mutated ovarian cancer. Clovis Oncology Inc.’s rucaparib is top 10 oncology drugs in the world pending at FDA for ovarian cancer, with action expected in the sec- ond quarter of 2017. by 2021 with Ibrance and Xtandi. Ironically, Pfizer previously owned rucaparib and out-licensed it to Clovis in 2011 for $7m upfront plus $255m in milestones. Man- Pfizer showed just how serious it is about competing in oncology agement said it is confident talazoparib will be best in class when with the pricey buyout. The companies announced Aug. 22 that asked by analysts how the drug might compare to rucaparib. Pfizer was the winner of a competitive bidding process for the San Pidilizumab is an immuno-oncology agent that is being studied Francisco-based biotech. in several Phase I/II studies, including a 150-patient Phase II trial in The crown jewel in Medivation’s portfolio is the hormone thera- patients with diffuse large B-cell lymphoma.
Recommended publications
  • Annual Report
    Zentralinstitut für Seelische Gesundheit Landesstiftung des öffentlichen Rechts 2017 2019 ANNUAL REPORT 2017 2019 ANNUAL REPORT EXECUTIVE BOARD RESEARCH REPORT BY THE EXECUTIVE BOARD, DEPARTMENTS, INSTITUTES DEVELOPMENT FIGURES AND RESEARCH GROUPS Report by the Executive Board 6 The Future of Therapy Research 42 Development Figures 8 Department of Neuropeptide Research 46 in Psychiatry Department of Molecular Neuroimaging 47 Department of Public Mental Health 48 Hector Institute for Translational 50 Brain Research RG Developmental Brain Pathologies 51 Department of Biostatistics 52 PATIENT CARE Institute of Cognitive and 53 Clinical Neuroscience CLINICAL DEPARTMENTS AND INSTITUTES RG Brain Stimulation, Neuroplasticity and 54 Learning RG Psychobiology of Risk Behavior 54 Clinic of Psychiatry and Psychotherapy 12 RG Body Plasticity and Memory Processes 55 Clinic of Child and Adolescent Psychiatry and 20 RG Psychobiology of Pain 56 Psychotherapy RG Psychobiology of Emotional Learning 57 Clinic of Psychosomatic Medicine and 24 Institute for Psychopharmacology 58 Psychotherapy RG Behavioral Genetics 59 RG Translational Addiction Research 60 Clinic of Addictive Behavior and 26 RG Physiology of Neuronal Networks 61 Addiction Medicine RG Molecular Psychopharmacology 62 Adolescent Center for Disorders 29 RG Neuroanatomy 63 of Emotional Regulation RG In Silico Psychopharmacology 64 Adolescent Center for 30 Institute for Psychiatric and 65 Psychotic Disorders – SOTERIA Psychosomatic Psychotherapy RG Experimental Psychotherapy 66 Central Outpatient
    [Show full text]
  • The “Rights” of Precision Drug Development for Alzheimer's Disease
    Cummings et al. Alzheimer's Research & Therapy (2019) 11:76 https://doi.org/10.1186/s13195-019-0529-5 REVIEW Open Access The “rights” of precision drug development for Alzheimer’s disease Jeffrey Cummings1*, Howard H. Feldman2 and Philip Scheltens3 Abstract There is a high rate of failure in Alzheimer’s disease (AD) drug development with 99% of trials showing no drug- placebo difference. This low rate of success delays new treatments for patients and discourages investment in AD drug development. Studies across drug development programs in multiple disorders have identified important strategies for decreasing the risk and increasing the likelihood of success in drug development programs. These experiences provide guidance for the optimization of AD drug development. The “rights” of AD drug development include the right target, right drug, right biomarker, right participant, and right trial. The right target identifies the appropriate biologic process for an AD therapeutic intervention. The right drug must have well-understood pharmacokinetic and pharmacodynamic features, ability to penetrate the blood-brain barrier, efficacy demonstrated in animals, maximum tolerated dose established in phase I, and acceptable toxicity. The right biomarkers include participant selection biomarkers, target engagement biomarkers, biomarkers supportive of disease modification, and biomarkers for side effect monitoring. The right participant hinges on the identification of the phase of AD (preclinical, prodromal, dementia). Severity of disease and drug mechanism both have a role in defining the right participant. The right trial is a well-conducted trial with appropriate clinical and biomarker outcomes collected over an appropriate period of time, powered to detect a clinically meaningful drug-placebo difference, and anticipating variability introduced by globalization.
    [Show full text]
  • Critical Analysis of Valuation and Strategical Orientation of Merger
    EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH, 2018 https://doi.org/10.1080/14737167.2018.1417040 REVIEW Critical analysis of valuation and strategical orientation of merger and acquisition deals in the pharmaceutical industry Raphaela Marie Louisa Dierks, Olivier Bruyère and Jean-Yves Reginster Faculty of Medicine, Department of Public Health, Epidemiology and Health Economics, CHU Sart-Tilman, Liège, Belgium ABSTRACT ARTICLE HISTORY Introduction: The pharmaceutical industry is undergoing major shifts due to changing macro and Received 21 October 2017 micro factors. As the industry is highly capital intensive and patents are expiring, the outlook is on Accepted 11 December 2017 generating inorganic growth, mainly through M&A. Using the income valuation approach, one analyses KEYWORDS two completed deals in 2016 above 1bn USD. Thereafter one outlines the main motives behind M&A Pharmaceutical industry; deals and concluded by discussing whether M&A harms medical innovations. merger and acquisitions Areas covered: The paper is based on empirical study questioning existing literature in order to (M&A); valuation; inorganic critically analyse valuation and the strategical orientation of pharmaceutical companies growth; medical innovation; Expert commentary: Pharmaceutical companies understand the changing market conditions and non-core assets; drug favour their expertise. The restructuring of the industry moves to small niche companies (I.e. pipeline; tax inversion Biopharma or biotech companies) researching key innovations and big companies purchasing them to develop them, create clinical trials and distribute them as this is a costly manner Conclusion: One can expect more M&A deals during the next years focusing on value rather than volume. Pharmaceutical players resilient to the market changes may survive if they change their business model from a traditional vertical one to outsourcing and diversification including external players.
    [Show full text]
  • La Place Des Composés Multi Target Directed Ligands Dans Le Traitement De La Maladie D’Alzheimer Katia Hamidouche
    La place des composés Multi Target Directed Ligands dans le traitement de la maladie d’Alzheimer Katia Hamidouche To cite this version: Katia Hamidouche. La place des composés Multi Target Directed Ligands dans le traitement de la maladie d’Alzheimer. Sciences pharmaceutiques. 2017. dumas-01556379 HAL Id: dumas-01556379 https://dumas.ccsd.cnrs.fr/dumas-01556379 Submitted on 5 Jul 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITE DE CAEN NORMANDIE ANNEE 2017 U.F.R. DES SCIENCES PHARMACEUTIQUES THESE POUR LE DIPLOME D’ETAT DE DOCTEUR EN PHARMACIE PRESENTEE PAR Katia HAMIDOUCHE SUJET : La place des composés "Multi Target Directed Ligands" dans le traitement de la maladie d'Alzheimer SOUTENUE PUBLIQUEMENT LE : 31/03/2017 JURY : Pr. Michel Boulouard PRESIDENT DU JURY Dr. Véronique Lelong Boulouard EXAMINATEUR Dr. Joanna Bourgine EXAMINATEUR Pr. Thomas Freret Remerciements Avant tout, je tiens à dédier ce travail à mes parents , que je remercie également profondément pour leurs longs encouragements et soutien, et à qui je présente toute ma reconnaissance et gratitude pour les sacrifices qu’ils ont choisis de faire afin de nous permettre, ma sœur, mes frères et moi -même de faire ces grandes études, et sans lesquels je n’aurai jamais découvert cet univers de savoir et de science « à la Française ».
    [Show full text]
  • Copyrighted Material
    Index Note: page numbers in italics refer to figures; those in bold to tables or boxes. abacavir 686 tolerability 536–537 children and adolescents 461 acamprosate vascular dementia 549 haematological 798, 805–807 alcohol dependence 397, 397, 402–403 see also donepezil; galantamine; hepatic impairment 636 eating disorders 669 rivastigmine HIV infection 680 re‐starting after non‐adherence 795 acetylcysteine (N‐acetylcysteine) learning disability 700 ACE inhibitors see angiotensin‐converting autism spectrum disorders 505 medication adherence and 788, 790 enzyme inhibitors obsessive compulsive disorder 364 Naranjo probability scale 811, 812 acetaldehyde 753 refractory schizophrenia 163 older people 525 acetaminophen, in dementia 564, 571 acetyl‐L‐carnitine 159 psychiatric see psychiatric adverse effects acetylcholinesterase (AChE) 529 activated partial thromboplastin time 805 renal impairment 647 acetylcholinesterase (AChE) acute intoxication see intoxication, acute see also teratogenicity inhibitors 529–543, 530–531 acute kidney injury 647 affective disorders adverse effects 537–538, 539 acutely disturbed behaviour 54–64 caffeine consumption 762 Alzheimer’s disease 529–543, 544, 576 intoxication with street drugs 56, 450 non‐psychotropics causing 808, atrial fibrillation 720 rapid tranquillisation 54–59 809, 810 clinical guidelines 544, 551, 551 acute mania see mania, acute stupor 107, 108, 109 combination therapy 536 addictions 385–457 see also bipolar disorder; depression; delirium 675 S‐adenosyl‐l‐methionine 275 mania dosing 535 ADHD
    [Show full text]
  • A [18F]Fluoroethoxybenzovesamicol Positron Emission Tomography Study
    Received: 24 May 2018 Revised: 7 September 2018 Accepted: 10 September 2018 DOI: 10.1002/cne.24541 RESEARCH ARTICLE Regional vesicular acetylcholine transporter distribution in human brain: A [18F]fluoroethoxybenzovesamicol positron emission tomography study Roger L. Albin1,2,3,4 | Nicolaas I. Bohnen1,2,3,5 | Martijn L. T. M. Muller3,5 | William T. Dauer1,2,3,6 | Martin Sarter3,7 | Kirk A. Frey2,5 | Robert A. Koeppe3,5 1Neurology Service & GRECC, VAAAHS, Ann Arbor, Michigan Abstract 2Department of Neurology, University of Prior efforts to image cholinergic projections in human brain in vivo had significant technical lim- Michigan, Ann Arbor, Michigan itations. We used the vesicular acetylcholine transporter (VAChT) ligand [18F]fluoroethoxyben- 3University of Michigan Morris K. Udall Center zovesamicol ([18F]FEOBV) and positron emission tomography to determine the regional of Excellence for Research in Parkinson's distribution of VAChT binding sites in normal human brain. We studied 29 subjects (mean age Disease, Ann Arbor, Michigan 47 [range 20–81] years; 18 men; 11 women). [18F]FEOBV binding was highest in striatum, inter- 4Michigan Alzheimer Disease Center, Ann Arbor, Michigan mediate in the amygdala, hippocampal formation, thalamus, rostral brainstem, some cerebellar 18 5Department of Radiology, University of regions, and lower in other regions. Neocortical [ F]FEOBV binding was inhomogeneous with Michigan, Ann Arbor, Michigan relatively high binding in insula, BA24, BA25, BA27, BA28, BA34, BA35, pericentral cortex, and 6Department of Cell and Developmental lowest in BA17–19. Thalamic [18F]FEOBV binding was inhomogeneous with greatest binding in Biology, University of Michigan, Ann Arbor, the lateral geniculate nuclei and relatively high binding in medial and posterior thalamus.
    [Show full text]
  • In Alzheimer Disease: Never Change a Winning Team and Do Not Build Exclusively on Surrogates
    Journal of Pharmacology & Clinical Research ISSN: 2473-5574 Review Article J of Pharmacol & Clin Res Volume 2 Issue 1 - February 2017 Copyright © All rights are reserved by Jan M Keppel Hesselink DOI: 10.19080/JPCR.2017.02.555580 Idalopirdine (LY483518, SGS518, Lu AE 58054) in Alzheimer disease: never change a winning team and do not build exclusively on surrogates. Lessons Learned from Drug Development Trials Jan M Keppel Hesselink* Department of Molecular Pharmacology, University Witten/Herdecke, Germany Submission: January 11, 2017; Published: February 07, 2017 *Corresponding author: Jan M Keppel Hesselink, Department of Molecular Pharmacology, University Witten/Herdecke, Germany, Email: Abstract The effect of Acetylcholinesterase inhibition on Alzheimer’s disease is modest. Augmentation strategies are thus whished for and explored. acetylcholinesterase inhibitors in animal pharmacology. A phase Idalopirdine is a 5HT6 antagonist, and was found to augment the efficacy of II study supported the concept, however the study did not follow a dose-finding design, but focused on one dose only, 90 mg/daily. Currently Wea phase will discussIII program the phase further II andevaluates phase IIIthe program value of ofsuch idalopirdine augmentation in Alzheimer strategy. disease The first and phase outline III thetrial lessons however learned missed for the drug target. development: This first phase III trial was underdosed; maximum dose was 60 mg/daily, possibly based on an overly firm belief in surrogate parameters, a PET study. mg/day). Subsequently do not change the dose-regime from t.i.d. in phase II to once daily in phase III, even if surrogate parameters support always use fixed dose range studies in phase II, first define the lowest effective dose and the no-effect dose, as well as the effective dose (90 conservative drug development pattern and avoid cutting corners seems the lesson of this case of idalopirdine in Alzheimer disease.
    [Show full text]
  • Dietary Restriction of Amino Acids for Cancer Therapy Jian-Sheng Kang
    Kang Nutrition & Metabolism (2020) 17:20 https://doi.org/10.1186/s12986-020-00439-x REVIEW Open Access Dietary restriction of amino acids for Cancer therapy Jian-Sheng Kang Abstract Biosyntheses of proteins, nucleotides and fatty acids, are essential for the malignant proliferation and survival of cancer cells. Cumulating research findings show that amino acid restrictions are potential strategies for cancer interventions. Meanwhile, dietary strategies are popular among cancer patients. However, there is still lacking solid rationale to clarify what is the best strategy, why and how it is. Here, integrated analyses and comprehensive summaries for the abundances, signalling and functions of amino acids in proteomes, metabolism, immunity and food compositions, suggest that, intermittent dietary lysine restriction with normal maize as an intermittent staple food for days or weeks, might have the value and potential for cancer prevention or therapy. Moreover, dietary supplements were also discussed for cancer cachexia including dietary immunomodulatory. Keywords: Amino acid restriction, Cancer, Lysine, Kwashiorkor, Tryptophan, Arginine, Cachexia Introduction common and effective metabolic intervention for cancer? Cancer is a complex disease. There are more than 100 For amino acids (AAs), which is the most heavily used distinct types of cancer but sharing common hallmarks, AA in vivo? Which AA restriction is cell proliferation including sustaining proliferative signaling and evading the most sensitive to? What kind of dietary strategies are growth suppressors [1, 2]. The anabolic and catabolic practically available for cancer control? metabolisms of cancer cells must be reprogrammed to maintain their proliferation and survival, and may even hijack normal cells to create tumor microenvironment AA metabolism is the leading energy-consuming process (TME) for tumorigenesis and avoiding immune destruc- The consumption and release profiles of 219 metabolites tion [2].
    [Show full text]
  • Zebrafish Behavioural Profiling Identifies GABA and Serotonin
    ARTICLE https://doi.org/10.1038/s41467-019-11936-w OPEN Zebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitation Matthew N. McCarroll1,11, Leo Gendelev1,11, Reid Kinser1, Jack Taylor 1, Giancarlo Bruni 2,3, Douglas Myers-Turnbull 1, Cole Helsell1, Amanda Carbajal4, Capria Rinaldi1, Hye Jin Kang5, Jung Ho Gong6, Jason K. Sello6, Susumu Tomita7, Randall T. Peterson2,10, Michael J. Keiser 1,8 & David Kokel1,9 1234567890():,; Anesthetics are generally associated with sedation, but some anesthetics can also increase brain and motor activity—a phenomenon known as paradoxical excitation. Previous studies have identified GABAA receptors as the primary targets of most anesthetic drugs, but how these compounds produce paradoxical excitation is poorly understood. To identify and understand such compounds, we applied a behavior-based drug profiling approach. Here, we show that a subset of central nervous system depressants cause paradoxical excitation in zebrafish. Using this behavior as a readout, we screened thousands of compounds and identified dozens of hits that caused paradoxical excitation. Many hit compounds modulated human GABAA receptors, while others appeared to modulate different neuronal targets, including the human serotonin-6 receptor. Ligands at these receptors generally decreased neuronal activity, but paradoxically increased activity in the caudal hindbrain. Together, these studies identify ligands, targets, and neurons affecting sedation and paradoxical excitation in vivo in zebrafish. 1 Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143, USA. 2 Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
    [Show full text]
  • Radium-223 in Combination with Docetaxel in Patients with Castration
    HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Eur J Cancer Manuscript Author . Author manuscript; Manuscript Author available in PMC 2020 September 06. Published in final edited form as: Eur J Cancer. 2019 June ; 114: 107–116. doi:10.1016/j.ejca.2019.04.007. Radium-223 in combination with docetaxel in patients with castration-resistant prostate cancer and bone metastases: a phase 1 dose escalation/randomised phase 2a trial This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). *Corresponding author: Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Fax: þ1 646 227 2417., [email protected] (M.J. Morris). 1Current address: Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA. 2Current address: Department of Medical Sciences, University of Turin Division of Nuclear Medicine, Turin, Italy. Conflict of interest statement M.J.M. discloses consultancy/advisory roles with Astellas Pharma, Bayer, Endocyte and Advanced Accelerator Applications and has received travel/accommodation expenses from Bayer and Endocyte, and his institution has received research funding from Bayer, Endocyte, Progenics and Sanofi; Y.L. discloses consultancy/advisory roles with Astellas Pharma, AstraZeneca, Janssen, Merck Sharp & Dohme, Pfizer, Roche, Seattle Genetics and Sanofi, and his institution has received research funding from Sanofi; C.J.S. declares stock ownership in relation to Leuchemix, consultancy/advisory roles with Astellas Pharma, AstraZeneca, Bayer, Genentech/Roche, Janssen Biotech, Pfizer and Sanofi and intellectual property interests in relation to Leuchemix and Exelixis, and his institution has received research funding from Astellas Pharma, Bayer, Janssen Biotech, Sanofi and Sotio; K.F.
    [Show full text]
  • GPCR/G Protein
    Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com GPCR/G Protein G Protein Coupled Receptors (GPCRs) perceive many extracellular signals and transduce them to heterotrimeric G proteins, which further transduce these signals intracellular to appropriate downstream effectors and thereby play an important role in various signaling pathways. G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). In unstimulated cells, the state of G alpha is defined by its interaction with GDP, G beta-gamma, and a GPCR. Upon receptor stimulation by a ligand, G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell. These effects include activating the MAPK and PI3K pathways, as well as inhibition of the Na+/H+ exchanger in the plasma membrane, and the lowering of intracellular Ca2+ levels. Most human GPCRs can be grouped into five main families named; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, and Secretin, forming the GRAFS classification system. A series of studies showed that aberrant GPCR Signaling including those for GPCR-PCa, PSGR2, CaSR, GPR30, and GPR39 are associated with tumorigenesis or metastasis, thus interfering with these receptors and their downstream targets might provide an opportunity for the development of new strategies for cancer diagnosis, prevention and treatment. At present, modulators of GPCRs form a key area for the pharmaceutical industry, representing approximately 27% of all FDA-approved drugs. References: [1] Moreira IS. Biochim Biophys Acta. 2014 Jan;1840(1):16-33.
    [Show full text]
  • Summary Conflict of Interest Statements BCC 2021
    Summary conflict of interest statements BCC 2021 Last name First name Type of affiliation/ financial interest Name of commercial company Aapro Matti Receipt of grants/research supports: Amgen, Eisai, Genomic Health, Helsinn, Hospira, Novartis, Merck, Mundipharma, Pfizer, Rache, Sandoz, Tesaro, Teva, Vifor Receipt of honoraria or consultation fees: Accord Pharmaceuticals, Amgen, Astellas, Bayer HealthCare Pharmaceuticals (Schering), Biocon, Boehringer Ingelheim, BMS, Celgene, Cephalon, Chugai Pharmaceutical Co. Ltd., Clinigen Group, Dr.Reddy's Laboratories, Eisai Co. Ltd., Eli Lilly, Genomic Health (Exact Sciences), GlaxoSmithKline (GSK), Glenmark Pharmaceuticals Limited, Gl Therapeutics, lnc., Helsinn Healthcare SA, Hospira (Pfizer), lpsen, Janssen Biotech, Johnson & Johnson, Kyowa Kirin Group, Merck, Merck Serono (Merck KGaA), Mundipharma International Limited, Novartis, Pfizer, Pierre Fabre, Rache, Sandoz, Sanofi, Taiho Pharmaceutical, Tesaro (GSK), Teva Pharmaceutical lndustries Ltd., Vifor Pharma Other support: European Cancer Organisation, SPCC, Cancer Center Genolier Aebi Stephan Receipt of honoraria or consultation fees: Novartis, Roche, Pfizer Other support: Support for CME lectures of the Lucerne Cancer Center: Amgen, Astellas, Bayer, Bristol-Myers Squibb, Debiopharm International SA, Eisai, Ipsen Pharma, Janssen, Merck, MSD, Pfizer, Roche, Sanofi Genzyme, Servier, Takeda André Fabrice Receipt of grants/research supports: Comepensated to the hospital: Roche, AstraZeneca, Daiichi Sankyo, Pfizer, Novartis, Lilly Barrios Carlos
    [Show full text]