C. Simone Fishburn, Ph.D.

Dr. Fishburn has over 20 years’ experience in preclinical sciences, research biology and molecular genetics, and she has specific expertise in the mechanistic basis of drug action and in translational research.

Dr. Fishburn’s experience includes both small molecule therapeutics and biologics; she is a recognized expert on the effect of polyethylene glycol (PEG) polymer conjugation on the pharmacodynamics and pharmacokinetics of drug molecules. Prior to joining Exponent, Dr. Fishburn worked at Nektar Therapeutics where she led the pain program and directed the preclinical development of a low abuse opioid (NKTR-181) from idea stage to IND filing. In addition she led other early stage preclinical programs on compounds for neuropathic pain, Crohn’s disease, allergic rhinitis and HIV. At Inhale Therapeutics (later Nektar) Dr. Fishburn established an in vitro biology group focused on the cellular nature and biological mechanisms operating at the respiratory mucosa, and investigated the mechanisms of drug absorption across the nasal and pulmonary epithelium. In her doctoral and post-doctoral academic work, Dr. Fishburn performed DNA cloning of dopamine receptors and other signaling proteins, and studied their post-translational modifications and activities in signal transduction pathways.

Dr. Fishburn has directed discovery stage and preclinical pharmacology programs, been responsible for experimental design, data analysis, interpretation of results and lead candidate selection decisions; in addition, she has directed the strategy and execution of preclinical studies to support IND submissions and Phase I clinical trials. She has authored regulatory documents for IND filings and investigator brochures and has worked extensively with marketing and investor relations departments to develop communication strategies and materials describing pipeline drug compounds.

Dr. Fishburn is currently a visiting scholar at the University of Arizona, College of Pharmacy. She has authored over 20 manuscripts in peer-reviewed journals and is an inventor on 6 published patent applications. She has presented her work at both national and international meetings and is a member of the Society for Neuroscience and the American Society for Pharmacology and Experimental Therapeutics. She provides support for patent litigation matters, in addition to support for product liability cases related to pharmaceutical products and devices.

Dr. Fishburn obtained an honors degree in Pharmacology from Cambridge University, a Ph.D. in immunology from the Weizmann Institute of Science in Israel, and performed post-doctoral research on GPCR-based signal transduction at the University of California, San Francisco, for which she was awarded a Fulbright scholarship and fellowships from the Damon Runyon Cancer Research Foundation and American Heart Association.

Gursahani H, Riggs-Sauthier J, Pfeiffer J, Lechuga-Ballesteros D, Fishburn CS. Absorption of Polyethylene Glycol (PEG) polymers: The effect of PEG size on permeability. Journal of Pharmaceutical Sciences 2009; 98:2847–2856.

Fishburn CS. The Pharmacology of PEGylation: Balancing PD with PK to generate improved therapeutics. (Review). Journal of Pharmaceutical Sciences 2008; 97:4167–4183.

Patton JS, Fishburn CS, Weers, JG. The lungs as a portal of entry for systemic drug delivery. Proceedings, American Thoracic Society 2004; 1–338–344.

Leach CL, Kuo M-C, Bueche B, Fishburn CS, Viegas T, Bossard M, Guo M, Bentley MD, Hobbs CH, Cherrington AD, Patton JS. Modifying the pulmonary absorption and retention of proteins through PEGylation. Respiratory Drug Delivery IX 2004; 1:69–78.

Ilani T, Fishburn CS, Levavi-Sivan B, Carmon S, Raveh L, Fuchs S. Coupling of dopamine receptors to G proteins: studies with chimeric D2/D3 dopamine receptors. Cellular and Molecular Neurobiology 2002; pp. 47–56.

Gordon AS, Yao L, Jiang Z, Fishburn CS, Fuchs S, Diamond I. Ethanol acts synergistically with a D2 dopamine agonist to cause translocation of protein kinase C. Molecular Pharmacology 2001; 59:153–160.

Fishburn CS, Pollitt SK, Bourne HR. Localization of a peripheral membrane protein Gbg targets Ga_z. Proceedings, National Academy of Sciences 2000; 97:1085–1090.

Obadiah J, Avidor-Reiss T, Fishburn CS, Carmon S, Bayewitch M, Vogel Z, Fuchs S, Levavi-Sivan B. Adenylyl cyclase interaction with the D2 dopamine receptor family; differential coupling to Gi, Gz, and Gs. Cellular and Molecular Neurobiology 1999; 19:653–664.

Fishburn CS, Herzmark P, Morales J, Bourne HR.Gbg and palmitate target newly synthesized Ga _z to the plasma membrane. The Journal of Biological Chemistry 1999; 274:793–800.

Levavi-Sivan B, Park BH, Fuchs S, Fishburn CS. Human D3 dopamine receptor in the medulloblastoma TE671 cell line: Cross-talk between D1 and D3 receptors. FEBS Letters 1998; 439:138–142.

Morales J, Fishburn CS, Wilson PT, Bourne HR. Plasma membrane localization of Ga_z requires two signals. Molecular Biology of the Cell 1998; 9:1–14.

Skaaning Jensen B, Levavi-Sivan B, Fishburn CS, Fuchs S. Functional expression of the murine D2, D3, and D4 dopamine receptors in Xenopus laevis oocytes. FEBS Letters 1997; 420:191–195.

Accili D, Fishburn CS, Drago J, Steiner H, Lachowicz JE, Park BH, Gauda EB, Lee EJ, Cool MH, Sibley DR, Gerfen CR, Westphal H, Fuchs S. A targeted mutation of the D3 dopamine receptor gene is associated with hyperactivity in mice. Proceedings, National Academy of Sciences 1996; 93:945–949.

Fishburn CS, Bedford M, Lonai P, Fuchs S. Early expression of D3 dopamine receptors in murine embryonic development. FEBS Letters 1996; 381:257–261.

Fishburn CS, Elazar Z, Fuchs S. Differential glycosylation and intracellular trafficking for the long and short isoforms of the D2 dopamine receptor. The Journal of Biological Chemistry 1995; 270:29819–29824.

Fishburn CS, Carmon S, Fuchs S. Molecular cloning and characterisation of the gene encoding the murine D4 dopamine receptor. FEBS Letters 1995; 361:215–219.

Park BH, Fishburn CS, Carmon S, Accili D, Fuchs S. Structural organization of the murine D3 dopamine receptor gene. Journal of Neurochemistry 1995; 64:482–486.

Fishburn CS, David C, Carmon S, Wein C, Fuchs S. In vitro translation of D2 dopamine receptors and their chimaeras; analysis by subtype-specific antibodies. Biochemical and Biophysical Research Communications 1994; 205:1460–1466.

Fishburn CS, David C, Carmon S, Fuchs S. The effect of haloperidol on D2 dopamine receptor subtype mRNA levels in the brain. FEBS Letters 1994; 339:63–66.

David C, Fishburn CS, Monsma FJ Jr, Sibley DR, Fuchs S. Synthesis and processing of D2 dopamine receptors. Biochemistry 1993; 32:8179–8183.

Fishburn CS, Belleli D, David C, Carmon S, Fuchs S. A novel short isoform of the D3 dopamine receptor generated by alternative splicing in the third cytoplasmic loop. The Journal of Biological Chemistry 1993; 268:5872–5878.

Fishburn CS, Slaney JM, Carman RJ, Curtis MA. Degradation of plasma proteins by the trypsin-like enzyme of Porphyromonas gingivalis and inhibition of protease activity by a serine protease inhibitor of human plasma. Oral Microbiology and Immunology 1991; 6:209–215.

Selected Invited Presentations and Published Abstracts

Fishburn CS. Translational research: How to turn an idea into a drug. Invited presentation at the University of Arizona, College of Pharmacy, October 11, 2011.

Harrison S, et al. NKTR-181: A novel opioid analgesic that exhibits reduced abuse potential and maintains full analgesic activity following repeat dosing in preclinical rodent models. Poster presentation at the American Academy of Pain Management 22nd Annual Clinical Meeting, Las Vegas, NV, September 20–23, 2011.

Fishburn CS. NKTR-181: A novel opioid with slowed brain entry shows low abuse liability and reduced CNS side effects. Oral Presentation at 5th Annual Frontiers of Clinical Investigation Symposium – Pain 2010: From Bench to Bedside, October 14–16, 2010.

Fishburn CS, Bergman J, Gursahani H, Riggs J, Riley TA. NKTR-181, a novel opioid analgesic with slow entry into CNS and markedly reduced CNS side-effects. Poster presentation at the 2010 Annual Meeting of the American Society Anesthesiologist, Poster # A509.

Fishburn CS, Wong S, Tonkin L, Pfeiffer J, Gursahani H, Muthukrishnan E, Ali C, Choi I, McWeeney D, Riggs-Sauthier J, Riley TA, Sweeney T, Harrison SD, Doberstein SK. NKTR-181: A novel opioid analgesic with slowed CNS entry shows reduced abuse liability and CNS side effects. Poster presentation at the Society for Neuroscience 40th Annual Meeting: Neuroscience 2010, San Diego, CA, November 13–17, 2010, Poster #HHH11.

Gurshani H, Wong S, Riggs-Sauthier J, Pfeiffer J, Allums S, Zhang W, Deng B-L, Trinchero P, Quach P, Brew C, Evans J, Harrison SD, Doberstein SK, Riley TA, Fishburn CS. Controlling the rate of entry to the CNS by polymer conjugation. Poster presentation at Society for Neuroscience 40th Annual Meeting: Neuroscience 2010, San Diego, CA, November 13–17, 2010, Poster #HHH13.

Fishburn CS. The pharmacology of PEGylation: How slow can you go? Invited presentation at the University of Southern California, School of Pharmacy, March 28, 2008.

Fishburn CS. The pharmacology of PEGylation. Invited presentation at Kings’ College London, School of Pharmacy, November 7, 2006.

• Nektar Therapeutics, 2005–2010
  • Director, Translational Research, and Research Head of Pain program, 2009–2010
  • Associate Director, New Product Strategies, 2008–2009
  • Senior Scientist and Head of in vitro Biology, 2005–2007
• Inhale Therapeutics*, 2002–2004 (*later Nektar Therapeutics)
  • Scientist, Life Sciences
• Academic and Postdoctoral Research Experience
  • Weizmann Institute of Science, Israel, Department of Membrane Biophysics, 1999–2001
  • University of California, Department of Molecular and Cellular Pharmacology, 1995–1999
  • Weizmann Institute of Science Ph.D. program, 1995–1999

Inhalation

Directed and performed studies investigating mechanisms of absorption of drugs and particles across the pulmonary epithelium and nasal epithelium following delivery of aerosols by inhalation, or following intratracheal administration.

Examined the effects of molecule size and other physicochemical properties on the fate of molecules delivered to the lung. Characterized the respective roles of tight junctions, passive and active transepithelial transport, and clearance by alveolar macrophages.

Performed studies on small molecules, peptides and proteins, to determine systemic bioavailability following pulmonary delivery (flip-flop kinetics) compared with other routes of administration.

Polymer Conjugation

Investigated the pharmacological effects of polymer conjugation to drugs, using in vitro and in vivo experimental approaches.

Directed studies to characterize mechanisms of gastrointestinal (GI) absorption of drugs following oral administration, using in vitro models such as Caco-2 cells, in situ studies such as single pass intestinal perfusion (SPIP) and standard in vivo IV/PO pharmacokinetic studies.

Investigated the effect of polymer conjugation on the First Pass Effect (hepatic and GI) of small molecule drugs; Directed studies on phase I and II metabolism (CYP450, glucuronidation) and on P-glycoprotein (PgP) and other efflux transporter systems.

Examined clearance mechanisms for polymers and polymer-conjugated drugs. Studied the effect of polymer size on clearance by the kidney and liver, and on other clearance mechanisms such as macrophage uptake.

Directed studies on blood-brain barrier (BBB) exclusion or penetration of drugs, to investigate how polymer conjugation affects the ability of drugs to enter the CNS. Employed multiple experimental approaches in preclinical species, including in situ brain perfusion, microdialysis and determination of brain:plasma ratios in extracted tissues, following IV, subcutaneous or oral delivery of drugs.

In vitro and in vivo Pharmacology

Directed and performed standard in vitro pharmacology assays: (i) receptor binding properties (Kd, Ki, IC50) (ii) receptor functional assays, in particular second messenger assays for hormones and neurotransmitters working through G protein coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) or steroid hormone signaling pathways. In addition, characterized subcellular localization of different proteins in cells and tissues using fluorescence microscopy and biochemical methods of subcellular fractionation.

Directed in vivo pharmacology assays using animal models of pain to assess the analgesic efficacy of drugs in preclinical species; directed studies using the acetic acid writhing test, hot plate withdrawal response, formalin paw test and CFA-induced or carrageenan-induced paw inflammation assay.

Directed programs to develop opioid drugs with very low abuse properties, based on slowed entry to the CNS; managed CRO studies on abuse liability, such as reinforcing behavior assessed by self-administration properties (substitution tests, progressive ratio tests) in addition to drug discrimination experiments. Performed analyses relating dose required for abuse potential to analgesic potency, in order to demonstrate separation of analgesic properties from abuse potential.

Directed studies on CNS side effects of drugs, such as sedation and changes in motor co-ordination. Managed internal and CRO-based studies using multiple experimental paradigms such as the rotorod assay, locomotor activity in open field tests, and modified Irwin assays.

Directed programs on cytokine drug candidates; examined immunological responses to cytokines in non-human primates by following differential blood counts and cytokine responses over time.

Directed studies on antiviral drug compounds; managed CRO-based studies using in vitro antiviral assays to characterize the antiviral activity of novel anti-HIV drug candidates.

• Society for Neuroscience—SfN (2010–present)
• American Society for Pharmacology and Experimental Therapeutics—ASPET (2002–present)
• American Association for the Advancement of Science—AAAS (2003–present)
• American Association of Pharmaceutical Scientists—AAPS (2004–2009)
• American Society for Cell Biology—ACSB (1999–2008)