DOCSLIB.ORG

In the Circuit Court

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

1 1 FOOD AND DRUG ADMINISTRATION 2 CENTER FOR DRUG EVALUATION AND RESEARCH 3 4 5 6 JOINT MEETING OF THE PSYCHOPHARMACOLOGIC DRUGS AND 7 DRUG AND RISK MANAGEMENT ADVISORY COMMITTEES 8 (PDAC and DSaRM) 9 10 11 12 13 Thursday, November 1, 2018 14 8:00 a.m. to 5:01 p.m. 15 16 17 18 19 FDA White Oak Campus 20 Building 31, the Great Room 21 10903 New Hampshire Avenue 22 Silver Spring, Maryland A Matter of Record (301) 890-4188 2 1 Meeting Roster 2 DESIGNATED FEDERAL OFFICER (Non-Voting) 3 Kalyani Bhatt, BS, MS 4 Division of Advisory Committee and Consultant 5 Management 6 Office of Executive Programs, CDER, FDA 7 PSYCHOPHARMACOLOGIC DRUGS ADVISORY COMMITTEE 8 MEMBERS (Voting) 9 10 Walter S. Dunn, MD, PhD 11 Staff Psychiatrist and Assistant Clinical Professor 12 West Los Angeles Veterans Administration Medical 13 Center 14 University of California Los Angeles 15 Department of Psychiatry 16 Los Angeles, California 17 18 19 20 21 22 A Matter of Record (301) 890-4188 3 1 Jess G. Fiedorowicz, MD, PhD 2 Associate Professor 3 Departments of Psychiatry, Epidemiology and 4 Internal Medicine 5 University of Iowa Carver College of Medicine 6 Iowa City, Iowa 7 8 Satish Iyengar, PhD 9 Chair and Professor of Statistics 10 Department of Statistics 11 University of Pittsburgh 12 Pittsburgh, Pennsylvania 13 14 Felipe A. Jain, MD 15 Assistant Clinical Professor of Psychiatry 16 Department of Psychiatry 17 University of California, San Francisco 18 401 Parnassus Avenue, Langley Porter 19 San Francisco, California 20 21 22 A Matter of Record (301) 890-4188 4 1 Rajesh Narendran, MD 2 (Chairperson) 3 Attending Psychiatrist 4 Re:solve Crisis Network 5 Western Psychiatric Institute and Clinics 6 Associate Professor in Radiology and Psychiatry 7 Psychiatric Molecular Imaging Program 8 University of Pittsburgh 9 Pittsburgh, Pennsylvania 10 11 Kim O. Wictzak 12 (Consumer Representative) 13 Co-Founder, Executive Director 14 Woodymatters 15 Minneapolis, Minnesota 16 17 18 19 20 21 22 A Matter of Record (301) 890-4188 5 1 PSYCHOPHARMACOLOGIC DRUGS ADVISORY COMMITTEE MEMBER 2 (Non-Voting) 3 Robert R. Conley, MD 4 (Industry Representative) 5 Global Development Leader 6 Pain and Core Therapeutic 7 Team and Distinguished Scholar 8 Eli Lilly and Company 9 Lilly Corporate Center 10 Indianapolis, Indiana 11 12 DRUG SAFETY AND RISK MANAGEMENT ADVISORY COMMITTEE 13 MEMBERS (Voting) 14 Kelly Besco, PharmD, FISMP, CPPS 15 Health-System Medication Safety Officer 16 OhioHealth Pharmacy Services 17 Dublin, Ohio 18 19 20 21 22 A Matter of Record (301) 890-4188 6 1 Marie R. Griffin, MD, MPH 2 Professor, Health Policy and Medicine 3 Director, Vanderbilt MPH Program 4 Department of Health Policy 5 Vanderbilt University Medical Center 6 Nashville, Tennessee 7 8 Laurel A. Habel, MPH, PhD 9 Associate Director, Cancer Research 10 Division of Research 11 Kaiser Permanente Northern California 12 Oakland, California 13 14 Sonia Hernandez-Diaz, MD, MPH, DrPH 15 Professor of Epidemiology 16 Department of Epidemiology 17 Harvard T.H. Chan School of Public Health 18 Boston, Massachusetts 19 20 21 22 A Matter of Record (301) 890-4188 7 1 Martin Kulldorff, PhD 2 Professor of Medicine and Biostatistician 3 Division of Pharmacoepidemiology and 4 Pharmacoeconomics 5 Department of Medicine 6 Harvard Medical School and Brigham & Women's 7 Hospital 8 Boston, Massachusetts 9 10 Steven B. Meisel, PharmD 11 System Director of Patient Safety 12 Fairview Health Services 13 Minneapolis, Minnesota 14 15 Anne-Michelle Ruha, MD, FACMT 16 Director, Medical Toxicology Fellowship Program 17 Department of Medical Toxicology 18 Banner University Medical Center 19 Clinical Associate Professor of Emergency Medicine 20 University of Arizona College of Medicine 21 Phoenix, Arizona 22 A Matter of Record (301) 890-4188 8 1 Terri L. Warholak, PhD, RPh, CPHQ, FAPhA 2 Professor and Assistant Dean 3 Academic Affairs and Assessment 4 College of Pharmacy 5 University of Arizona 6 Tucson, Arizona 7 8 TEMPORARY MEMBERS (Voting) 9 Jane B. Acri, PhD 10 Chief, Medication Discovery & Toxicology 11 Branch 12 Division of Therapeutics and Medical 13 Consequences 14 National Institute on Drug Abuse 15 National Institutes of Health (NIH) 16 Bethesda, Maryland 17 18 19 20 21 22 A Matter of Record (301) 890-4188 9 1 David Cella, PhD 2 Professor Chairperson 3 Medical Social Sciences 4 Northwestern University Feinberg School of 5 Medicine 6 Chicago, Illinois 7 8 Stephanie Y. Crawford, PhD, MPH 9 Department of Pharmacy Systems 10 Outcomes and Policy 11 University of Chicago 12 Chicago, Illinois 13 14 Harriet de Wit, PhD 15 Department of Psychiatry and Behavioral 16 Neuroscience 17 The University of Chicago 18 Chicago, Illinois 19 20 21 22 A Matter of Record (301) 890-4188 10 1 Kathryn E. Flynn, PhD 2 Associate Professor of Medicine 3 Division of Hematology and Oncology 4 Senior Scientific Director for Patient-Reported 5 Outcomes 6 Center for International Blood & Marrow Transplant 7 Research 8 Milwaukee, Wisconsin 9 10 Roxanne E. Jensen, PhD 11 Program Director 12 Outcomes Research Branch 13 Health Care Delivery Research Program 14 Division of Cancer Control and Population Sciences 15 National Cancer Institute, NIH 16 Bethesda, Maryland 17 18 Elizabeth Joniak-Grant 19 (Patient Representative) 20 Holly Springs, North Carolina 21 22 A Matter of Record (301) 890-4188 11 1 Brandon D.L. Marshall, PhD 2 Associate Professor 3 Department of Epidemiology 4 Brown University School of Public Health 5 Providence, Rhode Island 6 7 William T. Riley, PhD 8 Director 9 Office of Behavioral and Social Sciences Research 10 NIH 11 Bethesda, Maryland 12 13 FDA PARTICIPANTS (Non-Voting) 14 Robert Temple, MD 15 Deputy Director for Clinical Science 16 CDER FDA 17 Deputy Director (Acting) 18 Office of Drug Evaluation I (ODE I) 19 Office of New Drugs (OND), CDER, FDA 20 21 22 A Matter of Record (301) 890-4188 12 1 Ellis Unger, MD 2 Director 3 ODE I, OND, CDER, FDA 4 5 Mitchell Mathis, MD 6 Division Director 7 Division of Psychiatry Products (DPP) 8 ODE I, OND, CDER, FDA 9 10 Judy Staffa, PhD, RPh 11 Associate Director for Public Health Initiatives 12 Division of Epidemiology II (DEPI-II) 13 Office of Pharmacovigilance and Epidemiology 14 Office of Surveillance and Epidemiology 15 CDER, FDA 16 17 Tiffany Farchione, MD 18 Deputy Director 19 DPP, ODE I, OND, CDER, FDA 20 21 22 A Matter of Record (301) 890-4188 13 1 Dominic Chiapperino, PhD 2 Director 3 Controlled Substance Staff 4 Office of the Center Director, CDER, FDA 5 6 Daniel J. Lee, MD 7 Clinical Reviewer 8 DPP, ODE I, OND, CDER, FDA 9 10 Semhar Ogbagaber, PhD 11 Statistician 12 Division of Biometrics I 13 Office of Biostatistics 14 Office of Translational Sciences, CDER, FDA 15 16 17 18 19 20 21 22 A Matter of Record (301) 890-4188 14 1 C O N T E N T S 2 AGENDA ITEM PAGE 3 Call to Order and Introduction of Committee 4 Raj Narendran, MD 17 5 Conflict of Interest Statement 6 Kalyani Bhatt, BS, MS 23 7 FDA Opening Remarks 8 Mitchell Mathis, MD 27 9 Applicant Presentations - Alkermes, Inc. 10 Introduction 11 Lisa von Moltke, MD 40 12 The Unmet Need in MDD and Challenges in 13 MDD Clinical Trials 14 George Papakostas, MD 51 15 Clinical Efficacy 16 Jerald Schindler, DrPH 65 17 Clinical Safety, and Risk Mitigation 18 Strategies 19 Gary Bloomgren, MD 97 20 21 22 A Matter of Record (301) 890-4188 15 1 C O N T E N T S (continued) 2 AGENDA ITEM PAGE 3 Clinical Perspective and Benefit-Risk 4 Profile 5 Sanjay Mathew, MD 116 6 Conclusion 7 Lisa von Moltke, MD 122 8 Clarifying Questions to Applicant 123 9 FDA Presentations 10 Regulatory History 11 Tiffany Farchione, MD 155 12 Clinical Efficacy and Safety Overview 13 Semhar Ogbagaber, PhD 166 14 Daniel Lee, MD 181 15 Abuse Potential of 16 Buprenorphine/Samidorphan (BUP/SAM) 17 Edward Hawkins, PhD 187 18 FDA Review of the Epidemiologic and 19 Surveillance Data 20 Celeste Mallama, PhD, MPH 197 21 22 A Matter of Record (301) 890-4188 16 1 C O N T E N T S (continued) 2 AGENDA ITEM PAGE 3 University of Washington Medical School 4 Department of Psychiatry and 5 Behavioral Sciences Presentation 6 Depression Effects on Long-Term 7 Prescription Opioid Use, Abuse and 8 Addiction 9 Mark Sullivan, MD, PhD 207 10 FDA Presentations (continued) 11 Risk Management for 12 Buprenorphine/Samidorphan 13 Somya Dunn, MD 221 14 Clarifying Questions to FDA and 228 15 Dr. Sullivan 16 Open Public Hearing 268 17 Clarifying Questions (continued) 332 18 Charge to the Committee 19 Mitchell Mathis, MD 335 20 Questions to the Committee and Discussion 336 21 Adjournment 446 22 A Matter of Record (301) 890-4188 17 1 P R O C E E D I N G S 2 (8:01 a.m.) 3 Call to Order 4 Introduction of Committee 5 DR. NARENDRAN: I would first like to remind 6 everyone to please silence your cell phones, 7 smartphones, other devices if you have not already 8 done so. I would also like to identify the FDA 9 press contact, Sandy Walsh. If you're there, 10 please stand. She's over there. 11 My name is Raj Narendran. I'm the 12 chairperson for today's meeting. I will now call 13 the Joint Meeting of the Psychopharmacology Drug 14 Advisory Committee and the Drug Safety and Risk 15 Management Advisory Committee to order. 16 We'll start by going around the table and 17 introduce ourselves.
Recommended publications
  • United States Securities and Exchange Commission Form

    United States Securities and Exchange Commission Form

    UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 FORM 8-K CURRENT REPORT Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934 Date of report (date of earliest event reported): May 9, 2016 TONIX PHARMACEUTICALS HOLDING CORP. (Exact name of registrant as specified in its charter) Nevada 001-36019 26-1434750 (State or Other Jurisdiction (Commission (IRS Employer of Incorporation) File Number) Identification No.) 509 Madison Avenue, Suite 306, New York, New York 10022 (Address of principal executive offices) (Zip Code) Registrant’s telephone number, including area code: (212) 980-9155 Copy of correspondence to: Marc J. Ross, Esq. James M. Turner, Esq. Sichenzia Ross Friedman Ference LLP 61 Broadway, 32nd Floor New York, New York 10006 Tel: (212) 930-9700 Fax: (212) 930-9725 Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below): o Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) o Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) o Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) o Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) Item 2.02 Results of Operations and Financial Condition. On May 9, 2016, Tonix Pharmaceuticals Holding Corp. (the “Company”) announced its operating results for the first fiscal quarter ended March 31, 2016.
  • United States Securities and Exchange Commission Form

    United States Securities and Exchange Commission Form

    UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 FORM 8-K CURRENT REPORT Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934 Date of report (date of earliest event reported): February 16, 2016 TONIX PHARMACEUTICALS HOLDING CORP. (Exact name of registrant as specified in its charter) Nevada 001-36019 26-1434750 (State or Other Jurisdiction (Commission (IRS Employer of Incorporation) File Number) Identification No.) 509 Madison Avenue, Suite 306, New York, New York 10022 (Address of principal executive offices) (Zip Code) Registrant’s telephone number, including area code: (212) 980-9155 Copy of correspondence to: Marc J. Ross, Esq. James M. Turner, Esq. Sichenzia Ross Friedman Ference LLP 61 Broadway New York, New York 10006 Tel: (212) 930-9700 Fax: (212) 930-9725 Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below): o Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) o Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) o Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) o Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) Item 5.05 Amendments to the Registrant’s Code of Ethics, or Waiver of a Provision of the Code of Ethics. On February 9, 2016, the Board of Directors of Tonix Pharmaceuticals Holding Corp.
  • Summary Analgesics Dec2019

    Summary Analgesics Dec2019

    Status as of December 31, 2019 UPDATE STATUS: N = New, A = Advanced, C = Changed, S = Same (No Change), D = Discontinued Update Emerging treatments for acute and chronic pain Development Status, Route, Contact information Status Agent Description / Mechanism of Opioid Function / Target Indication / Other Comments Sponsor / Originator Status Route URL Action (Y/No) 2019 UPDATES / CONTINUING PRODUCTS FROM 2018 Small molecule, inhibition of 1% diacerein TWi Biotechnology / caspase-1, block activation of 1 (AC-203 / caspase-1 inhibitor Inherited Epidermolysis Bullosa Castle Creek Phase 2 No Topical www.twibiotech.com NLRP3 inflamasomes; reduced CCP-020) Pharmaceuticals IL-1beta and IL-18 Small molecule; topical NSAID Frontier 2 AB001 NSAID formulation (nondisclosed active Chronic low back pain Phase 2 No Topical www.frontierbiotech.com/en/products/1.html Biotechnologies ingredient) Small molecule; oral uricosuric / anti-inflammatory agent + febuxostat (xanthine oxidase Gout in patients taking urate- Uricosuric + 3 AC-201 CR inhibitor); inhibition of NLRP3 lowering therapy; Gout; TWi Biotechnology Phase 2 No Oral www.twibiotech.com/rAndD_11 xanthine oxidase inflammasome assembly, reduced Epidermolysis Bullosa Simplex (EBS) production of caspase-1 and cytokine IL-1Beta www.arraybiopharma.com/our-science/our-pipeline AK-1830 Small molecule; tropomyosin Array BioPharma / 4 TrkA Pain, inflammation Phase 1 No Oral www.asahi- A (ARRY-954) receptor kinase A (TrkA) inhibitor Asahi Kasei Pharma kasei.co.jp/asahi/en/news/2016/e160401_2.html www.neurosmedical.com/clinical-research;
  • Tonix Pharmaceuticals Plans to Expand TNX-102 SL Phase 3 Program Beyond PTSD to Include Fibromyalgia

    Tonix Pharmaceuticals Plans to Expand TNX-102 SL Phase 3 Program Beyond PTSD to Include Fibromyalgia

    April 4, 2019 Tonix Pharmaceuticals Plans to Expand TNX-102 SL Phase 3 Program Beyond PTSD to Include Fibromyalgia Encouraging FDA Meeting Minutes Support Phase 3 Development of TNX-102 SL 5.6 mg in Fibromyalgia NEW YORK, April 04, 2019 (GLOBE NEWSWIRE) -- Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a clinical-stage biopharmaceutical company focused on developing pharmaceutical products to treat serious neuropsychiatric and central nervous system conditions, and biological products to improve biodefense, announced today the expansion of the TNX-102 SL 5.6 mg program beyond posttraumatic stress disorder (PTSD) to include Phase 3 development for TNX-102 SL* in fibromyalgia. TNX-102 SL or Tonmya®** is Tonix’s lead Phase 3 program in PTSD with the Phase 3 RECOVERY trial actively enrolling military and civilian PTSD participants. In a recent Clinical Guidance meeting with the U.S. Food and Drug Administration (FDA), Tonix received clear guidance and support to advance the development of TNX-102 SL, a non-opioid centrally-acting analgesic, for the management of fibromyalgia. Acceptable study design features were discussed to establish the safety and efficacy of TNX-102 SL 5.6 mg in a pivotal study to support the fibromyalgia indication. A lower dose of TNX-102 SL (2.8 mg) taken daily at bedtime was studied previously in fibromyalgia in a Phase 2 study and a Phase 3 study. Both studies showed clinical benefits especially in the quality of sleep improvement, however, primary analyses on pain reduction were not statistically significant. Additional data developed by Tonix in the PTSD program showed that TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) demonstrated acceptable tolerability with additional clinical benefit in pain reduction for trial participants with PTSD.
  • 52Nd Annual Meeting

    52Nd Annual Meeting

    ACNP 52nd Annual Meeting Final Program December 8-12, 2013 The Westin Diplomat Resort & Spa Hollywood, Florida President: David A. Lewis, M.D. Program Committee Chair: Randy D. Blakely, Ph.D. Program Committee Co-Chair: Pat R. Levitt, Ph.D. This meeting is jointly sponsored by the Vanderbilt University School of Medicine Department of Psychiatry and the American College of Neuropsychopharmacology. Dear ACNP Members and Guests, It is a distinct pleasure to welcome you to the 2014 meeting of the American College of Neuropsychopharmacology! This 52nd annual meeting will again provide opportunities for the exercise of the College’s core values: the spirit of Collegiality, promoting in each other the best in science, training and service; participation in Community, pursuing together the goals of understanding the neurobiology of brain diseases and eliminating their burden on individuals and our society; and engaging in Celebration, taking the time to recognize and enjoy the contributions and accomplishments of our members and guests. Under the excellent leadership of Randy Blakely and Pat Levitt, the Program Committee has done a superb job in assembling an outstanding slate of scientific presentations. Based on membership feedback, the meeting schedule has been designed with the goals of achieving an optimal mix of topics and types of sessions, increasing the diversity of participating scientists and creating more time for informal interactions. The presentations will highlight both the breadth of the investigative interests of ACNP membership
  • Behavioral and Brain Sciences Plasticity: Implications for Opioid

    Behavioral and Brain Sciences Plasticity: Implications for Opioid

    Behavioral and Brain Sciences http://journals.cambridge.org/BBS Additional services for Behavioral and Brain Sciences: Email alerts: Click here Subscriptions: Click here Commercial reprints: Click here Terms of use : Click here Plasticity: Implications for opioid and other pharmacological interventions in specific pain states Anthony H. Dickenson Behavioral and Brain Sciences / Volume 20 / Issue 03 / September 1997, pp 392 ­ 403 DOI: null, Published online: 08 September 2000 Link to this article: http://journals.cambridge.org/abstract_S0140525X97241488 How to cite this article: Anthony H. Dickenson (1997). Plasticity: Implications for opioid and other pharmacological interventions in specific pain states. Behavioral and Brain Sciences,20, pp 392­403 Request Permissions : Click here Downloaded from http://journals.cambridge.org/BBS, IP address: 144.82.107.43 on 10 Aug 2012 BEHAVIORAL AND BRAIN SCIENCES (1997) 20, 392±403 Printed in the United States of America Plasticity: Implications for opioid and other pharmacological interventions in specific pain states Anthony H. Dickenson Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom Electronic mail: anthony.dickenson6ucl.ac.uk Abstract: The spinal mechanisms of action of opioids under normal conditions are reasonably well understood. The spinal effects of opioids can be enhanced or reduced depending on pathology and activity in other segmental and nonsegmental pathways. This plasticity will be considered in relation to the control of different pain states using opioids. The complex and contradictory findings on the supraspinal actions of opioids are explicable in terms of heterogeneous descending pathways to different spinal targets using multiple transmitters and receptors ± therefore opioids can both increase and decrease activity in descending pathways.
  • UNITED STATES SECURITIES and EXCHANGE COMMISSION Washington, D.C

    UNITED STATES SECURITIES and EXCHANGE COMMISSION Washington, D.C

    UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 FORM 8-K CURRENT REPORT Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934 Date of report (date of earliest event reported): October 24, 2012 TONIX PHARMACEUTICALS HOLDING CORP. (Exact name of registrant as specified in its charter) Nevada 333-150419 26-1434750 (State or Other Jurisdiction (Commission (IRS Employer of Incorporation) File Number) Identification No.) 509 Madison Avenue, Suite 306, New York, New York 10022 (Address of principal executive offices) (Zip Code) Registrant’s telephone number, including area code: (212) 980-9155 Copy of correspondence to: Marc J. Ross, Esq. Harvey Kesner, Esq. James M. Turner, Esq. Sichenzia Ross Friedman Ference LLP 61 Broadway New York, New York 10006 Tel: (212) 930-9700 Fax: (212) 930-9725 Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below): o Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) o Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) o Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) o Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) ITEM 8.01 Other Events. On October 24, 2012, Tonix Pharmaceuticals Holding Corp. (the “Company”) issued a press release announcing that it has it recently held a pre-Investigational New Drug (“IND”) meeting with the U.S.
  • Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands

    Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands

    Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands By Stephanie Nicole Johnson Submitted to the graduate degree program in Medicinal Chemistry and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Masters in Science. Chairperson: Dr. Thomas E. Prisinzano Dr. Apurba Dutta Dr. Jeffrey P. Krise Date Defended: May 2, 2017 The Thesis Committee for Stephanie Nicole Johnson certifies that this is the approved version of the following thesis: Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands Chairperson: Dr. Thomas E. Prisinzano Date approved: May 4, 2017 ii Abstract The ability of ligands to differentially regulate the activity of signaling pathways coupled to a receptor potentially enables researchers to optimize therapeutically relevant efficacies, while minimizing activity at pathways that lead to adverse effects. Recent studies have demonstrated the functional selectivity of kappa opioid receptor (KOR) ligands acting at KOR expressed by rat peripheral pain sensing neurons. In addition, KOR signaling leading to antinociception and dysphoria occur via different pathways. Based on this information, it can be hypothesized that a functionally selective KOR agonist would allow researchers to optimize signaling pathways leading to antinociception while simultaneously minimizing activity towards pathways that result in dysphoria. In this study, our goal was to alter the structure of U50,488 such that efficacy was maintained for signaling pathways important for antinociception (inhibition of cAMP accumulation) and minimized for signaling pathways that reduce antinociception. Thus, several compounds based on the U50,488 scaffold were designed, synthesized, and evaluated at KORs. Selected analogues were further evaluated for inhibition of cAMP accumulation, activation of extracellular signal-regulated kinase (ERK), and inhibition of calcitonin gene- related peptide release (CGRP).
  • FORM 8-K CURRENT REPORT Pursuant T

    FORM 8-K CURRENT REPORT Pursuant T

    UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 _____________________ FORM 8-K CURRENT REPORT Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934 Date of report (date of earliest event reported): September 3, 2020 _____________________ TONIX PHARMACEUTICALS HOLDING CORP. (Exact name of registrant as specified in its charter) Nevada 001-36019 26-1434750 (State or Other Jurisdiction (Commission (IRS Employer of Incorporation) File Number) Identification No.) 509 Madison Avenue, Suite 1608, New York, New York 10022 (Address of principal executive offices) (Zip Code) Registrant’s telephone number, including area code: (212) 980-9155 Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below): ☐ Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) ☐ Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) ☐ Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) ☐ Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) Securities registered pursuant to Section 12(b) of the Act: Title of each class Trading Symbol(s) Name of each exchange on which registered Common Stock TNXP The NASDAQ Global Market Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§ 240.12b-2 of this chapter).
  • 2019 Tonix Pharmaceuticals Holding Corp. – Confidential – Do Not

    2019 Tonix Pharmaceuticals Holding Corp. – Confidential – Do Not

    © 2019 Tonix Pharmaceuticals Holding Corp. – Confidential – Do not duplicate or distribute 1 November 1, 2019 Investor Presentation Issuer Free Writing Prospectus Filed Pursuant to Rule 433 Registration No. 333 - 234263 2 © 2019 Tonix Pharmaceuticals Holding Corp. – Confidential – Do not duplicate or distribute Cautionary Note on Forward - Looking Statements Certain statements in this presentation regarding strategic plans, expectations and objectives for future operations or results are “forward - looking statements” as defined by the Private Securities Litigation Reform Act of 1995 . These statements may be identified by the use of forward - looking words such as “anticipate,” “believe,” “forecast,” “estimate” and “intend,” among others . These forward - looking statements are based on Tonix’s current expectations and actual results could differ materially . There are a number of factors that could cause actual events to differ materially from those indicated by such forward - looking statements . These factors include, but are not limited to, substantial competition ; our need for additional financing ; uncertainties of patent protection and litigation ; uncertainties of government or third party payor reimbursement ; limited research and development efforts and dependence upon third parties ; and risks related to failure to obtain U . S . Food and Drug Administration clearances or approvals and noncompliance with its regulations . As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products . The forward - looking statements in this presentation are made as of the date of this presentation, even if subsequently made available by Tonix on its website or otherwise . Tonix does not undertake an obligation to update or revise any forward - looking statement, except as required by law .
  • TNX-102 SL for PTSD: Phase 3 P302/RECOVERY Study Expecting Interim Analysis Results in 1Q 2020 16

    TNX-102 SL for PTSD: Phase 3 P302/RECOVERY Study Expecting Interim Analysis Results in 1Q 2020 16

    Investor Presentation 1 January 2020 Version P0214 1-6-20 (Doc 0579) © 2020 Tonix Pharmaceuticals Holding Corp. Cautionary Note on Forward-Looking Statements 2 Certain statements in this presentation regarding strategic plans, expectations and objectives for future operations or results are “forward-looking statements” as defined by the Private Securities Litigation Reform Act of 1995. These statements may be identified by the use of forward-looking words such as “anticipate,” “believe,” “forecast,” “estimate” and “intend,” among others. These forward-looking statements are based on Tonix’s current expectations and actual results could differ materially. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. These factors include, but are not limited to, risks related to failure to obtain U.S. Food and Drug Administration clearances or approvals and noncompliance with its regulations; our need for additional financing; substantial competition; uncertainties of patent protection and litigation; uncertainties of government or third party payor reimbursement; limited research and development efforts and dependence upon third parties. As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products. The forward-looking statements in this presentation are made as of the date of this presentation, even if subsequently made available by Tonix on its website or otherwise. Tonix does not undertake an obligation to update or revise any forward-looking statement, except as required by law. Investors should read the risk factors set forth in the Annual Report on Form 10-K for the year ended December 31, 2018, as filed with the Securities and Exchange Commission (the “SEC”) on March 18, 2019, and periodic reports and current reports filed with the SEC on or after the date thereof.
  • Opioids Regulate Cgmp Formationin Cloned Neuroblastoma Cells

    Opioids Regulate Cgmp Formationin Cloned Neuroblastoma Cells

    Proc. NatL. Acad. Sci. USA Vol. 79, pp. 690-694, January 1982 Neurobiology Opioids regulate cGMP formation in cloned neuroblastoma cells (cyclic nucleotides/opiate receptor/desensitization) GERMAINE J. GWYNN AND ERMINIO COSTA* Laboratory of Preclinical Pharmacology, National Institute of Mental Health, Saint Elizabeths Hospital, Washington, D.C. 20032 Communicated by Floyd E. Bloom, October 8, 1981 ABSTRACT Opioid agonists caused a rapid dose-related el- cumulation in rat striatal slices with characteristics that fulfill evation of the cGMP content of N4TG1 murine neuroblastoma the criteria for a specific narcotic action (6). In contrast, the cells. An excellent correlation was found between the rank order decrements in the cGMP content ofcerebellar tissue observed of potency of agonists in stimulating cGMP accumulation and in after morphine administration are probably indirect effects of displacing [3H]etorphine ([H]ETP) bound to intact cells. The nar- opioid receptor stimulation mediated by the modulation of y- cotic antagonists naloxone and diprenorphine failed to increase aminobutyric acid or acetylcholine collateral neuronal loops (7, cGMP content; moreover, in the presence of 5 ,IM naloxone, the 8). A functional role for cGMP in opioid action is further sug- EC50 of ETP increased from w9 nM to >1 ,uM. N4TG1 cells that had been incubated for 20 min with 0.32 ItM ETP and thoroughly gested by the pivotal role that calcium ions play both in regu- washed displayed a marked loss in sensitivity to subsequent ETP lating cGMP formation (for review, see refs. 9, 10) and in me- challenge. This desensitization was characterized by a 40-50% diating the acute and chronic effects ofopioids (for review, see decrease in maximal response and an increase in the apparent Ka refs.