Nektar Therapeutics · NASDAQ:NKTR
Nektar Therapeutics — Investor Day (April 2012)
93 slides from Nektar Therapeutics's investor day presentation, Apr 16, 2012
Slide 1: Leveraging Nektar's Technology Platform with Large and Small Molecules
Leveraging Nektar’s Technology Platform with Large and Small Molecules Stephen Doberstein, PhD Chief Scientific Officer, Nektar Therapeutics Investor and Analyst R&D Day 1
Slide 2: Differentiated New Medicines Based on Innovative Polymer Conjugation Platform
Differentiated New Medicines Based on Innovative Polymer y Conjugation j g Platform Customized polymer chain controls PK, PK distribution, selectivity Platform creates innovative NCEs based on well- understood biology NCE pipeline has grown Nektar proprietary rapidly with high clinical linker ch
Slide 3: Nektar R&D Pipeline
Nektar R&D Pipeline Program Research Preclinical Phase 1 Phase 2 Phase 3 NALOXEGOL (NKTR-118) (OIC) NKTR 102 (Breast NKTR-102 (B t Cancer) C ) NKTR-102 (Ovarian Cancer) CLINICAL BAY41-6551 (Gram-neg. Pneumonia) NKTR-102 (Colorectal Cancer) NKTR-181 (Chronic Pain) BAX-855 (Hemophilia A) Phase 1/2 NKT
Slide 4: Nektar Polymer Conjugation Technology Allows Control of Drug Pharmacology
Nektar Polymer Conjugation Technology Allows Control of Drug Pharmacology Across Multiple Modalities Advanced Polymer y Conjugation Small molecule Protein Therapeutics Therapeutics Control Optimize PK biodistribution Engineer receptor Control metabolic Increase p potency y selecti it selectivity deg
Slide 5: BioSuperiors: The Next Generation of Biologics
BioSuperiors: The Next Generation of Biologics Stephen Doberstein, PhD Chief Scientific Officer, Nektar Therapeutics Investor and Analyst R&D Day 5
Slide 6: Engineering Multiple Properties to Create BioSuperiors
Engineering Multiple Properties to Create BioSuperiors p Optimize pharmacokinetic profile Extend half-life, better dosing schedule, increased efficacy and tolerability R d Reduce immunogenicity i i it Increase solubility, reduce injection site reactions, mask epitopes Target areas of inflammation/tu
Slide 7: Polymer Conjugation Enables Improved Protein Therapeutics in Multiple Major Classes
Polymer Conjugation Enables Improved Protein Therapeutics in Multiple Major Classes Advanced Polymer Conjugation Protein Therapeutics Antibody A tib d Cytokines Peptides Fragments Investor and Analyst R&D Day 7
Slide 8: Enabling Antibody Fragments as Drugs
Enabling Antibody Fragments as Drugs: Engineering PK and Biodistribution with Varied Polymer Architectures Chapman et al. (1999) Nat. Biotech.17:780 Investor and Analyst R&D Day 8
Slide 9: CIMZIA: Targeting Inflamed Tissue Using Polymer Conjugation
CIMZIA®: Targeting Inflamed Tissue Using Polymer y Conjugation j g Ratio of drug distribution to inflamed and non-inflamed tissue R. Palframan et al., Journal of Immunological Methods 348 (2009) 36–41 Investor and Analyst R&D Day 9
Slide 10: Affymax's OMONTYS (peginesatide): Engineered Peptide Therapeutics
Affymax’s OMONTYS® (peginesatide): Engineered g Peptide p Therapeutics p First approved peptide therapy with Nektar proprietary PEGylation technology Synthetic PEGylated peptide-based peptide based erythropoiesis-stimulating erythropoiesis stimulating agent (ESA) Building blocks (amino acids) ar
Slide 11: Enabling Peptides as Pharmaceuticals: Building on the Promise of OMONTYS
Enabling Peptides as Pharmaceuticals: Building g on the Promise of OMONTYS® Multiple polymer sizes and linker chemistries allow tunable pharmacokinetics and pharmacodynamics Relative Polymer Release Rate 1000 T 1/2 (Hours) 100 10 1 Peptide Conjugate Peptide Conjugates with Tuned Release Kinetics Inv
Slide 12: BAX 855: Longer-Acting (PEGylated) rFVIII Program Partnered with Baxter
BAX 855: Longer-Acting (PEGylated) rFVIII Program g Partnered with Baxter ADVATE®: Dosed every other day f hemophilia for h hili A BAX 855: Full-length recombinant Factor VIII conjugated to PEG • Novel advanced PEGylation technology from Nektar • Preclinical collaboration between Baxter and Nekt
Slide 13: BAX 855: Superior Pharmacokinetics to ADVATE in Cynomolgus Monkeys
BAX 855: Superior Pharmacokinetics to ADVATE® In Cynomolgus y g Monkeysy BAX 855 dosed on day 1 and day 8 ADVATE ddosed d on day d 1,1 3 and d5 BAX 855 has improved PK profile compared to ADVATE BAX 855 has 1.8 times longer Mean Residence Time (MRT) than ADVATE after first dose, 2.1 times longer
Slide 14: Baxter/Nektar Collaboration for BAX 855
Baxter/Nektar Collaboration for BAX 855 Based on ADVATE®, world’s leading g Factor VIII therapy py with annual sales >$2 billion Baxter expects to complete Phase 1/2 in 2012 • Targeting start of Phase 3 by year-end Baxter/Nektar hemophilia p A collaboration: • Up to $84 million in development
Slide 15: Engineering Multiple Properties to Create BioSuperiors
Engineering Multiple Properties to Create BioSuperiors p Optimize pharmacokinetic profile Extend half-life, better dosing schedule, increased efficacy and tolerability R d Reduce immunogenicity i i it Increase solubility, reduce injection site reactions, mask epitopes Target areas of inflammation/tu
Slide 16: Immunotherapy for Melanoma
Immunotherapy for Melanoma Agop Bedikian, MD Professor and Deputy Director of the Skin Center Department of Melanoma Medical Oncology, Division of Cancer Medicine The University of Texas M.D. Anderson Cancer Center Investor and Analyst R&D Day 16
Slide 17: Immunotherapy for Melanoma
Immunotherapy for Melanoma By AGOP Y. BEDIKIAN, MD. M D Anderson Cancer Center M.D. 17
Slide 18: Finn OJ NEJM 2008
18 Finn OJ NEJM 2008;358:2704-15
Slide 19: Cancer immunotherapy
Cancer immunotherapy y • Cancer immunotherapy is the use of the immune system to reject cancer. The main p purpose p is to stimulate the patient's p immune system y so that it will attack the malignant tumor cells. It is one of the few treatment modalities that can be curative due to the memory of t
Slide 20: T-cell destruction of tumors
T-cell destruction of tumors When cytotoxic T lymphocytes encounter tumor cells expressing tumor- associated antigens antigens, they kill via three possible mechanisms: 1. they secrete pore-forming and protein-degrading molecules (perforin and granzyme molecules, respectively). The pore-forming mole
Slide 21: Immunotherapy for Cancer
Immunotherapy for Cancer Advantages Types of Immunotherapy • Tumors are • Cytokines immunogenic • Antibody infusion f • Single cell kill • Vaccines • Migrate to tissue • Adoptive Ad ti • Memory immunotherapy • Life Life-long long protection • Immunomodulators 21
Slide 22: Ipilimumab (Yervoy) a CTLA-4 Blocking Antibody Augments T-Cell Activation
Ipilimumab (Yervoy) a CTLA-4 Blocking Antibody g Augments T-Cell Activation T-cell Activation T-cell Remains T-cell Active Inactivation CTLA-4 T-cell resting ti T-cell T cell T-cell TCR CD28 CTLA-4 CTLA-4 HLA B7 Ipilimumab APC APC APC Korman, Peggs and Allison: Adv. In Immunol. 2006;90:297-339
Slide 23: Overall Survival: Ipilimumab + DTIC
Overall Survival 1.0 Ipilimumab + DTIC Placebo + DTIC 09 0.9 0.8 Ipilimumab + DTIC versus Placebo + DTIC HR (95% CI) 0.72 (0.59–0.87) Alive 0.7 Median OS 11.2 vs. 9.1 months P value l 0 0009 0.0009 portion A 0.6 0.5 0.4 Prop 0.3 0.2 01 0.1 0.0 0 1 2 3 4 Years 23
Slide 24: What are Cytokines?
What are Cytokines? y • Cytokines are substances (generally proteins and glycoproteins) which are secreted by immune cells and may function locally, or they may function at a di t distance, either ith tot suppress or augmentt immunity. i it • IL-2 and Interferon-alfa 2b are FDA approved • IL-2 has k
Slide 25: Interleukin-2: T Cell Growth Factor
Interleukin-2: T Cell Growth Factor • A glycoprotein T-cell growth factor that binds to a receptor on T-cells • First tested at the NCI in the early 1980s, • Higher doses of IL-2 appeared to induce significant and durable clinical responses (cured) due to activation of effector (Natural–Killer) T ce
Slide 26: High-Dose IL-2 for Melanoma
High–Dose g IL-2 for Melanoma • Retrospective data from 266 patients in 7 studies from 17 institutions • Overall response rate was 17%; 6% CR and 11% PR • 5-year survival rate for complete responders was 69% • Median duration of responses: 6.5 months. 26
Slide 27: Results of Treatment of Renal Cell Carcinoma with High-Dose Interleukin-2
Results of Treatment of Renal Cell Carcinoma with High-Dose High Dose Interleukin Interleukin-2 2 Therapy IL2 0.72 mlU/kg 15 min IV q 8 hr x 14 doses q 2 wks, 2 studies IL2 0.6 mlU/kg 15 min IV q 8 hr x 14 doses q 2 wks, 5 studies No. of Patients.: 255 Complete Response: 5% Partial Response: 9% Over
Slide 28: High-Dose Bolus Interleukin-2 Survival
HIGH-DOSE BOLUS INTERLEUKIN-2 S Survival i l All Patients 28
Slide 29: High-Dose Bolus Interleukin-2 Survival by Response
HIGH-DOSE BOLUS INTERLEUKIN-2 S Survival i l by b Response R 29
Slide 30: Toxicity associated with interleukin-2 therapy
Toxicity y associated with interleukin-2 therapy y Systemic: malaise * (14.5%), (14 5%) Chills * (18.3%), (18 3%) weight gain >5% (70.9%) (70 9%) Hemodynamic: Hypotension requiring vasopressors (52.1%) Cardiac: Arrhythmia (6.5%), angina (1.1%), myocardial infarction (0.4%) Pulmonary: Respiratory dis
Slide 31: Patient Monitoring with Interleukin-2
PATIENT MONITORING WITH INTERLEUKIN 2 INTERLEUKIN-2 Inpatient Parameter to monitor No vasopressors ICU / with Vasopressors Vital signs every 4 hours every 1 hour I t k and Intake d output t t every 8 hours h every 1 hours h Weight daily daily Mental status every 8 hours every 4 hours IV site every 8
Slide 32: Management of IL-2 toxicities
Management g of IL-2 toxicities • D Dopamine i used d for f low l urine i output; t t dosing d i continues until creatinine is 3.5-4.0 • Neosynephrine® for hypotension resistant to fluid • Indocin® and Tylenol® around the clock for fevers and chills induced by y IL-2 • Cimetidine used for increased
Slide 33: Opportunity for New Cytokine Therapies
Opportunity y for New Cytokine y Therapies • Current therapiesp generally g y block pathways p y of immune inhibition, with the exception of IL-2 • IL-2 usage is limited to specialized centers in ICU setting tti dued to t its it toxicity t i it • Local stimulation of the immune system in the tumor r
Slide 34: NKTR-214: Engineered Selective Cytokine Therapy for Cancer
NKTR-214: Engineered Selective Cytokine Therapy for Cancer Stephen Doberstein, PhD Chief Scientific Officer, Nektar Therapeutics Investor and Analyst R&D Day 34
Slide 35: NKTR-214: Designing a Better Immunotherapy Treatment
NKTR-214: Designing a Better Immunotherapy py Treatment Optimize p PK profile p to allow for less frequent q dosing g and enable therapy to be given in an outpatient setting Avoid systemic immunostimulation through prodrug design Concentrate cytokine in tumor (with EPR effect) to increase effi
Slide 36: IL-2: Pleiotrophic Effects on Multiple Cell Types
IL-2: Pleiotrophic Effects on Multiple Cell Types yp CD122hi CD25- Kill Tumor Cells Natural Killer Cells CD25+ Suppress pp Killing g IL 2 IL-2 of Tumor Cells Treg Cells CD25+ Vascular Leak y Syndrome (side effect) Endothelial Cells Investor and Analyst R&D Day 36
Slide 37: IL-2: Pleiotrophic Effects on Multiple Cell Types
IL-2: Pleiotrophic Effects on Multiple Cell Types yp CD122hi CD25- Kill Tumor Cells Natural Killer Cells NKTR NKTR- CD25+ Suppress pp Killing g 214 of Tumor Cells Treg Cells CD25+ Vascular Leak y Syndrome (side effect) Endothelial Cells Investor and Analyst R&D Day 37
Slide 38: IL-2 Receptors Have Opposing Effects
IL-2 Receptors Have Opposing Effects IL-2 receptor: major stimulator of NK cell proliferation • Leads L d tto ttumor-killing killi IL-2 receptor: immuno- suppression i ththroughh up- regulation of Treg cells • Reduces tumor killing IL-2 receptor also appears to Fig. 1. Structure of
Slide 39: IL-2 Activates Both Receptors on All Cell Types
IL-2 Activates Both Receptors on All Cell Types yp IL-2 IL-2 Treg Cells Natural Killer Cells Endothelial Cells Fig. 1. Structure of the human IL-2/R quaternary signaling complex. complex 1 1. Wang et al., Science Vol 310 18 Nov. 2005 Investor and Analyst R&D Day 39
Slide 40: NKTR-214 Binds Preferentially to the NK Cell IL-2 Receptor
NKTR-214 Binds Preferentially to the NK Cell IL-2 Receptor p NKTR-214 Treg Cells Natural Killer Cells Endothelial Cells Fig. 1. Structure of the human IL-2/R quaternary signaling complex. complex 1 1. Wang et al., Science Vol 310 18 Nov. 2005 Investor and Analyst R&D Day 40
Slide 41: NKTR-214 is an Engineered Cytokine with Optimized Properties
NKTR-214 is an Engineered Cytokine with Optimized p Properties p Proprietary prodrug design results in low systemic immune activation Enhanced tumor concentrations (EPR effect): activates immune cells in the tumor bed PEG release activates cytokine with optimal receptor binding profile Objec
Slide 42: NKTR-214: Sophisticated Polymer Engineering Solves Multiple Therapeutic Problems
NKTR-214: Sophisticated Polymer Engineering Solves Multiple Therapeutic Problems in Immune Stimulation Prodrug is inactive as infused allowing for accumulation in tumors via EPR effect Inactive Prodrug NKTR-214 Proliferation of mouse CTLL2 cells Investor and Analyst R&D Day 42
Slide 43: NKTR-214 Prodrug Accumulates in Tumor Tissue
NKTR-214 Prodrug Accumulates in Tumor Tissue 10 Animal 1 - Tumor Animal 2 - Tumor Animal 3 - Tumor unit/pixel) Animal 1 - Tissue Animal 2 - Tissue 1 Animal 3 - Tissue Signall intensity (u Tumors 0.1 Normal Tissue 0.01 0 24 48 72 96 120 144 H Hours Mouse xenograft; KB Tumor model Investor and Analyst
Slide 44: NKTR-214 Activated Cytokine has Optimal Receptor Binding Selectivity
NKTR-214 Activated Cytokine has Optimal Receptor Binding Selectivity Activated NKTR-214 Single polymer chain masks αßγ IL-2 receptor binding Directs activity to NK cells in tumor reducing Treg suppression of immune system and endothelial cell toxicity Reduced binding to IL-2 ~50pM Activated
Slide 45: Antitumor Efficacy of NKTR-214 at Low Doses in B16 Mouse Melanoma Model
Antitumor Efficacy of NKTR-214 at Low Doses in Highly Resistant B16 Mouse Melanoma Model Mouse B-16 subcutaneous melanoma, n=9 Investor and Analyst R&D Day 45
Slide 46: Antitumor Efficacy of NKTR-214 at Low Doses in B16 Mouse Melanoma Model
Antitumor Efficacy of NKTR-214 at Low Doses in Highly Resistant B16 Mouse Melanoma Model Mouse B-16 subcutaneous melanoma, n=9 Investor and Analyst R&D Day 46
Slide 47: Antitumor Efficacy of NKTR-214 at Low Doses in B16 Mouse Melanoma Model
Antitumor Efficacy of NKTR-214 at Low Doses in Highly Resistant B16 Mouse Melanoma Model Total Dose Over Regimen Proleukin®: 60mpk p NKTR-214: 6mpk Proleukin: Death due to treatment 39% NKTR-214: Death due to treatment <5% Mouse B-16 subcutaneous melanoma, n=9 Investor and Analyst R&D Day 47
Slide 48: BioSuperiors: Next Frontiers
BioSuperiors: Next Frontiers Selective cytokines Capitalizing on a single technology platform that Blood ood clotting c ott g factors acto s can create the next- generation of biologics: Endocrine peptides Extend PK Lower immunogenicity Antibiotic p peptides p Localize drugs to targets Optim
Slide 49: Oral Small Molecules: A Universe of Opportunities
Oral Small Molecules: A Universe of Opportunities Stephen Doberstein, PhD Chief Scientific Officer, Nektar Therapeutics Investor and Analyst R&D Day 49
Slide 50: Nektar Polymer Conjugation Technology Allows Control of Drug Pharmacology
Nektar Polymer Conjugation Technology Allows Control of Drug Pharmacology Across Multiple Modalities Advanced Polymer y Conjugation Small molecule Protein Therapeutics Therapeutics Control Optimize PK biodistribution Engineer receptor Control metabolic Increase p potency y selecti it selectivity deg
Slide 51: Nektar Polymer Conjugate Technology: From Known Mechanism of Action to New Chemical Entity
Nektar Polymer Conjugate Technology: From Known Mechanism of Action to New Chemical Entity Nektar New Chemical Entity Customized polymer chain Proprietary p y stable linker chemistry Retain mechanism of action at receptor site Investor and Analyst R&D Day 51
Slide 52: Innovative NCEs Created by Optimization of Multiple Drug Properties
Innovative NCEs Created by Optimization of Multiple p Drug g Properties p Modulate potency and receptor selectivity Kinase inhibitors, antihistamines Reduced metabolic clearance Opioids Regulated CNS entry Opioids, analgesics for neuropathic pain pain, antihistamines Improved aqueous solubility Kina
Slide 53: NKTR-228: A New Calcimimetic
NKTR-228: A New Calcimimetic Modulate potency and receptor selectivity Kinase inhibitors, antihistamines Reduced metabolic clearance Opioids Regulated CNS entry Opioids, analgesics for neuropathic pain pain, antihistamines Improved aqueous solubility Kinase inhibitors, calcimimetics Optimized PK NKT
Slide 54: Need for an IV Calcimimetic in Chronic Renal Disease
Need for an IV Calcimimetic in Chronic Renal Disease Cinacalcet (Sensipar) • Only approved calcimimetic • Once daily oral drug to reduce parathyroid hormone in renal patients • Very poorly tolerated orally, patient compliance is a major issue – Patients P ti t experience i nausea and d vomiting it
Slide 55: NKTR-228: Simultaneous Optimization of Solubility and Pharmacokinetics
NKTR-228: Simultaneous Optimization of Solubility y and Pharmacokinetics 7.00 6.00 5.00 ng/ml) Lower Cmax Cinacalcet (n 4.00 NKTR-228, 0.5 mg/kg, IV 3.00 Cinacalcet, 2 mg/kg, PO 2.00 Extended Exposure 1.00 0.00 0 50 100 150 Time (hours) Highly soluble enabling IV administration to avoid nausea and
Slide 56: Opportunities in CNS/Blood-Brain Barrier
Opportunities in CNS/Blood-Brain Barrier Modulate potency and receptor selectivity Kinase inhibitors, antihistamines Reduced metabolic clearance Opioids Regulated CNS entry Opioids, analgesics for neuropathic pain pain, antihistamines Improved aqueous solubility Kinase inhibitors, calcimimetics Opti
Slide 57: Influencing Diffusion Across and Efflux From the Blood-Brain Barrier
Influencing Diffusion Across and Efflux From the Blood-Brain Barrier Investor and Analyst R&D Day 57
Slide 58: Nektar Blood-Brain Barrier Platform Enables Fine-Tuning of Brain Penetration
Nektar Blood-Brain Barrier Platform Enables Fine- Tuning of Brain Penetration for Multiple Drug Classes Brain to Plasma Ratio 50 5 0.5 0.05 0.005 Antidepressant Antihistamine Local Anesthetic 1 Opioid Local Anesthetic 2 Anticholinergic Anticonvulsant Parent Molecule Nektar Polymer Drug Conjugate Inv
Slide 59: Antihistamines Highly Effective in Inhibiting Allergic Response
Antihistamines Highly Effective in Inhibiting g Allergic g Response p Investor and Analyst R&D Day 59
Slide 60: Entry of Antihistamines into CNS Leads to Sedation
Entry of Antihistamines into CNS Leads to Sedation Investor and Analyst R&D Day 60
Slide 61: NKTR-125: A New Peripherally-Restricted Antihistamine
NKTR-125: A New Peripherally-Restricted Antihistamine Investor and Analyst R&D Day 61
Slide 62: NKTR-125: Highly Potent Reduction of Allergic Response
NKTR-125: Highly Potent Reduction of Allergic g Response p Histamine-induced bronchoconstriction Promethazine 5 NKTR-125 Diphenhydramine 4 esistance Fold change in 3 lung re 2 1 0 0 0.1 1 10 100 Dose (mg/kg) Guinea pig histamine-induced bronchoconstriction model, PO, n=5 Investor and Analyst R&D Day
Slide 63: NKTR-125: Exclusion from CNS Results in Little to No Sedation
NKTR-125: Exclusion from CNS Results in Little to No Sedation at Therapeutic p Doses Locomotor Activity Assay ars (% vehicle control ovver 20 mins) 120 Promethazine 100 Diphenhydramine p y 80 NKTR-125 60 40 20 0 Rea Vehicle 100 Vehicle 32 64 128 Vehicle 100 50 50 Dose (mg/kg) ( / ) Mice, Oral, n=10
Slide 64: The Spectrum of Pain
The Spectrum of Pain ACUTE SUBACUTE CHRONIC Neuropathic Visceral Nociceptive Mixed Modes Pain Pain Pain Investor and Analyst R&D Day 64
Slide 65: Neuropathic and Visceral Pain
Neuropathic and Visceral Pain Jeffrey Gudin, MD Director, Pain Management and Palliative Care Englewood Hospital & Medical Center Clinical Instructor, Anesthesiology Mt. Sinai School of Medicine Investor and Analyst R&D Day 65
Slide 66: Neuropathic and Visceral Pain
Neuropathic and Visceral Pain JEFF GUDIN, GUDIN MM.D. D Director, Pain Management and Palliative Care Englewood Hospital & Medical Center Clinical Instructor, Anesthesiology Mt. Sinai School of Medicine Board Certified: Pain Management, Anesthesiology, Addiction Medicine, Hospice and Palliative Care
Slide 67: Types of Pain
T Types off Pain P i PAIN Somatic Visceral Neuropathic Psychological
Slide 68: Opioids are Effective Analgesics for Almost All Types of Pain
Opioids are Effective Analgesics for Almost All Types of Pain (Broad Spectrum) There are four main opioid receptors, the mu receptor, t theth delta d lt receptor, t the th kappa k receptor, and the ORL-1 receptor. Pharmacological testing indicated that the sigma receptors were activated by drugs
Slide 69: Pain Classification
Pain Classification Pain Acute Chronic Injury Postoperative pain Neuropathic Mixed Nociceptive Visceral Diabetic neuropathy Cancer pain Osteoarthritis IBS/abdominal Postherpetic Lower back pain Rheumatoid pain neuralgia Fibromyalgia arthritis Pancreatitis Radiculopathy Musculoskeletal Kidney Stone C
Slide 70: Visceral Pain Syndromes
Vi Visceral lPPain i SSyndromes d Bowel Bladder Kidney Liver Pancreas Stomach Uterus
Slide 71: Visceral Pain
Visceral Pain Pain originating from the viscera (usually hollow organs such as bowel, bladder, and uterus) Usually poorly localized and often presenting as referred pain remote from site of injury Can C b be diffi difficultlt tto ttreatt and d when h chronic, h i can be associated with high de
Slide 72: Visceral Pain Syndromes: Unmet Needs
Visceral Pain Syndromes: Unmet N d Needs Pancreatitis pain Dysmennorhea Dysmennorhea,, pelvic pain Irritable I it bl b bowell syndrome d Interstitial cystitis Kidney stones Generally, Generally opioids are not optimal treatment for visceral pain
Slide 73: Pain Classification
Pain Classification Pain Acute Chronic Injury Postoperative pain Neuropathic Mixed Nociceptive Visceral Diabetic neuropathy Cancer pain Osteoarthritis IBS/abdominal Postherpetic Lower back pain Rheumatoid pain neuralgia Fibromyalgia arthritis Pancreatitis Radiculopathy Musculoskeletal Kidney Stone C
Slide 74: Neuropathic Pain
Neuropathic Pain Pain arising from injury to or dysfunction of any part of the nervous system Characterized by abnormal sensations including hyperalgesia and allodynia Difficult Diffi lt tto ttreatt Current therapy often suboptimal
Slide 75: Neuropathic Pain: Patient Experience
Neuropathic Pain: Patient Experience “Shock-like” Shock like
Slide 76: Treatments for Neuropathic Pain
TREATMENTS FOR NEUROPATHIC PAIN Topical Antidepressants Anticonvulsants Opioids agents t Eg. Eg. Eg. Eg. Amitriptyline Gabapentin Oxycodone Lidocaine patch Duloxetine Pregabalin Morphine Capsaicin Oxcarbazepine IImplantable l t bl analgesic devices
Slide 77: Herpes Zoster
Herpes Zoster Post-herpetic p neuralgia
Slide 78: Neuropathic Pain
Neuropathic Pain Ion channels are a target of interest for the h treatment off neuropathic hi pain i Drugs that block voltage- voltage-gated sodium channels h l are efficacious ffi i iin th the management of neuropathic pain This Thi class l off iion channels h l h has bbeen a major focus of a
Slide 79: The Role of Sodium Channels in Neuropathic Pain
The Role of Sodium Channels in N Neuropathic thi P Pain i Minimal changes from their normal state [plasticity] can lead to ‘neuropathic pain’ The physiology of sodium channels and their role in p pain transmission suggest gg these channels are a good place to investigate g a better treatment for
Slide 80: Slide 80
Slide 81: Sodium Channel Blockers Reduce Spontaneous Firing of Neurons
Sodium Channel Blockers Reduce Spontaneous Firing of Neurons Carbamazepine Lamotrigine Tricyclic Antidepressants Local anesthetics/ anesthetics/antiarrhythmics antiarrhythmics Lidocaine, Mexiletine (oral) Many patients fail sodium channel blockers because of dose- dose-limiting central n
Slide 82: Slide 82
Slide 83: The Trouble With Multimodal Analgesia
The Trouble With Multimodal Analgesia Ok, take the 12 hour for all day long pain take the pain, 3 hour for flare,, take the rapid onset for rescue, take the sedating nerve pain pill at night for sleep, use the muscle relaxant for spasm put on this patch for 12 hours, spasm, hours then try this cream
Slide 84: NKTR-171: A New Approach to Treating Neuropathic Pain
NKTR-171: A New Approach to Treating Neuropathic Pain Stephen Doberstein, PhD Chief Scientific Officer, Nektar Therapeutics Investor and Analyst R&D Day 84
Slide 85: Sodium Channels are Upregulated in Peripheral Nerve Injury
Sodium Channels are Upregulated in Peripheral Nerve Injury, a Source of Neuropathic Pain Investor and Analyst R&D Day 85
Slide 86: Traditional Sodium Channel Blockers Reduce Neuropathic Pain, but Cause Central Side Effects
Traditional Sodium Channel Blockers Reduce Neuropathic Pain, but Cause Central Side Effects Investor and Analyst R&D Day 86
Slide 87: NKTR-171: A New Peripherally Restricted Sodium Channel Blocker
NKTR-171: A New Peripherally Restricted Sodium Channel Blocker Investor and Analyst R&D Day 87
Slide 88: NKTR-171 Shows Comparable Analgesia to Pregabalin in Preclinical Models
NKTR-171 Shows Comparable Analgesia to Pregabalin (Lyrica®) in Preclinical Models of Neuropathic Pain 70 Vehicle (25% hpBCD) w Flinches 60 Morphine 6 mg/kg SC Pregabalin 100 mg/kg PO 50 NKTR-171 200 mg/kg IP # Formalin-iinduced Paw 40 30 20 10 0 0 10 20 30 40 50 60 Time post-formalin injection (min)
Slide 89: NKTR-171 Shows Comparable Analgesia to Pregabalin in Preclinical Models
NKTR-171 Shows Comparable Analgesia to Pregabalin (Lyrica®) in Preclinical Models of Neuropathic Pain 2500 200 mg/kg NKTR-171 is equianalgesic to 100 mg/kg pregabalin (oral) ber of flinches 2000 1500 *** Cumulative numb 1000 *** *** 500 *** ***p<0 p<0.0001, 0001 One One-way way ANOVA w/ Dunnett's Du
Slide 90: Oral NKTR-171 is Efficacious in a Standard Model of Neuropathic Pain
Oral NKTR-171 is Efficacious in a Standard Model of Neuropathic p Pain NKTR-171 significantly reduced mechanical allodynia 0% Paw Withdraw al Th reshold (g) 15 Normal animal response 12 9 ** * Vehicle 6 Vehicle100 mg/kg Pregabalin NKTR-171 300 mg/kg 3 0 50 0 1 Time post-dose (h) *p<0.05, **p<0.01, T
Slide 91: NKTR-171: No Significant CNS Sedative Effects at Equianalgesic Doses
NKTR-171: No Significant CNS Sedative Effects at Equianalgesic Doses to Pregabalin (Lyrica®) 150 on Rotarod 100 c) (sec T ime Spent o 50 * * * p<0.001 <0 001 TTwo-way RM ANOVA 0 significance w.r.t. vehicle motrigine, 60 mg/kg Vehicle mg/kg mg/kg mg/kg Pregabalin, 100 m 100 m 200 m V NKTR-171 Lam Rat
Slide 92: Next Frontiers: Neuroscience/Pain
Next Frontiers: Neuroscience/Pain ACUTE SUBACUTE CHRONIC Neuropathic Visceral Nociceptive Mixed Modes Pain Pain Pain Painful Diabetic IBS OA Cancer Pain Neuropathy Crohn’s Disease HIV Neuropathy Pancreatitis RA Low Back Pain Radicular R di l IInterstitial t titi l Musculo-skeletal Fibromyalgia Pain
Slide 93: Nektar R&D Pipeline
Nektar R&D Pipeline Program Research Preclinical Phase 1 Phase 2 Phase 3 NALOXEGOL (NKTR-118) (OIC) NKTR 102 (Breast NKTR-102 (B t Cancer) C ) NKTR-102 (Ovarian Cancer) CLINICAL BAY41-6551 (Gram-neg. Pneumonia) NKTR-102 (Colorectal Cancer) NKTR-181 (Chronic Pain) BAX-855 (Hemophilia A) Phase 1/2 NKT