Nektar Therapeutics · NASDAQ:NKTR
Nektar Therapeutics — Investor Day (April 2012)
179 slides from Nektar Therapeutics's investor day presentation, Apr 16, 2012
Slide 1: Products and Platforms for Growth
Products and Platforms for Growth Nektar Investor and Analyst R&D Day April 16, 2012
Slide 2: Welcome
Welcome Jennifer Ruddock, Ruddock VP Investor Relations Nektar Therapeutics Investor and Analyst R&D Day 2
Slide 3: Forward-looking statements
During our presentations today, we expect to make forward-looking statements regarding our business including our technology, technology drug candidates, candidates research plans, plans clinical development plans, regulatory strategy, and the market potential of our drug candidates. Actual results
Slide 4: Welcome
Welcome Jennifer Ruddock, Ruddock VP Investor Relations Nektar Therapeutics Investor and Analyst R&D Day 4
Slide 5: Nektar: Products and Platforms for Growth
NEKTAR: Products and Platforms for Growth Stephen Doberstein Doberstein, PhD PhD, Chief Scientific Officer Nektar Therapeutics Investor and Analyst R&D Day 5
Slide 6: Nektar: Strong Foundation for Continued Growth
Nektar: Strong Foundation for Continued Growth Potential for Four Phase 3 Pipeline Programs by Year-End • Naloxegol for OIC – AstraZeneca on track for mid-2013 filings in US & EU • NKTR-102 for metastatic breast cancer – Phase 3 study initiated Dec 2011 • BAY45-4661/NKTR-061 for pneumonia – Bayer ta
Slide 7: Corporate Profile – Who We Are
Corporate Profile – Who We Are Biopharmaceutical p company p y leveraging polymer conjugation technologies to develop new therapies in multiple areas ~ 425 employees • R&D Center and HQ in San Francisco, CA • Manufacturing i Huntsville, in H ill AL • R&D support in Hyderabad, India Investor and
Slide 8: Differentiated New Molecules Based on Innovative Polymer Conjugation Platform
Differentiated New Molecules 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 9: Nektar is the Global Leader in Polymer Conjugation Technology
Nektar is the Global Leader in Polymer Conjugation j g Technology gy Long track record of success with proteins and small molecules Deep internal experience understanding polymer-related structure- activity relationships with extensive know-how in conjugation chemistry h i t across many chemical
Slide 10: Polymer Conjugation 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 11: Proven Track Record of Enabling Biologics
Proven Track Record of Enabling Biologics Partner Product Engineered Antibody Class Cytokine Cytokine Cytokine Cytokine Cytokine Fragment Peptide Renal Renal Crohn's Indication Hepatitis C Neutropenia Hepatitis C Acromegaly Anemia Disease Anemia in CKD (dialysis) FDA 2001 00 2002 00 2002 00 2003 003
Slide 12: Evolution of Nektar Technology Platform in Biologics
Evolution of Nektar Technology Platform in Biologics g Optimize pharmacokinetic profile Extend half-life, half life better dosing schedule schedule, increased efficacy and tolerability Reduce immunogenicity Increase solubility, reduce injection site reactions, mask epitopes Target areas of inflammat
Slide 13: The Revolution: Small Molecule Polymer Conjugates
The Revolution: Small Molecule Polymer Conjugates Oral Modulate Bioavailability Potency Extend Target Small Molecule Half-Life Tumors Polymer Conjugates Increase Target Solubility Inflamed Tissue Regulate Lower Cmax CNS Entry Investor and Analyst R&D Day 13
Slide 14: Targeted Prodrug Technology
Targeted Prodrug Technology Oral Modulate Bioavailability Potency Extend Target Small Molecule Half-Life Tumors Polymer Conjugates Increase Target Solubility Inflamed Tissue Regulate Lower Cmax CNS Entry Investor and Analyst R&D Day 14
Slide 15: Targeted Prodrug Technology: Optimizing Pharmacological Parameters
Nektar Targeted Prodrug Technology: Optimizing Multiple Pharmacological Parameters in Parallel Targeted g Prodrug g PK/PD Effect Clinical Effect Conjugate Property Target g Increase Tumor Increase Efficacy y Tumor Concentration Reduce Toxicity Extend Consistent Improve Half-Life Exposure Efficacy In
Slide 16: Targeted Prodrugs in Oncology
Targeted Prodrugs in Oncology Prodrug enters tumor tissue through leaky vasculature Nektar Confidential 16
Slide 17: The Revolution: Small Molecule Polymer Conjugates
The Revolution: Small Molecule Polymer Conjugates Oral Modulate Bioavailability Potency Extend Target Small Molecule Half-Life Tumors Polymer Conjugates Increase Target Solubility Inflamed Tissue Regulate Lower Cmax CNS Entry Investor and Analyst R&D Day 17
Slide 18: Polymer Conjugation Can Regulate CNS Entry
Polymer Conjugation Can Regulate CNS Entry y Oral Modulate Bioavailability Potency Extend Target Small Molecule Half-Life Tumors Polymer Conjugates Increase Target Solubility Inflamed Tissue Regulate Lower Cmax CNS Entry Investor and Analyst R&D Day 18
Slide 19: Polymer Drug Conjugates Tuned to Diffuse at Different Rates
Nektar Polymer Drug Conjugates Can Be Tuned to Diffuse At Different Rates Investor and Analyst R&D Day 19
Slide 20: 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 20
Slide 21: Controlling CNS Entry Through Permeability and Efflux Modulation
Controlling CNS Entry Through Simultaneous Modulation of Permeability and Efflux Transport Effl A Efflux Activity ti it Permeability 15 40 ve permeabiliity 30 10-6(cm/s) Efflux ratio 10 20 *1 5 Passiv E 10 0 0 I G A B C D E H ld F I G A B C D E H ld F fo fo af af Sc Sc Conjugate Series Conjugate Ser
Slide 22: Tuning Brain Uptake Rate for Identical Scaffold
Tuning Brain Uptake Rate for Identical Scaffold Brain Uptake Rate Relative to Antipyrene Source: Nektar Therapeutics Investor and Analyst R&D Day 22
Slide 23: 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 24: Blood-Brain Barrier Platform Has Enabled New Drug Candidates
Blood-Brain Barrier Platform Has Enabled a Range g of New Drug g Candidates Opioid-induced constipation • Naloxegol (NKTR-118) Phase III Opioid Analgesics • NKTR-181 NKTR 181 Ph Phase II begins b i mid-year id • NKTR-192 Phase I Neuropathic Pain • NKTR-171 Preclinical • Other scaffolds Aller
Slide 25: The Spectrum of Pain
The Spectrum of Pain Robert Medve Medve, MD MD, Chief Medical Officer Nektar Therapeutics Investor and Analyst R&D Day 25
Slide 26: The Spectrum of Pain
The Spectrum of Pain ACUTE SUBACUTE CHRONIC Investor and Analyst R&D Day 26
Slide 27: 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 27
Slide 28: Unmet Needs in Opioid Therapy
Unmet Needs in Opioid Therapy Currently available opioids have a narrow Side Effects therapeutic index and produce dose-limiting side Tolerability effects including somnolence, dizziness, sedation, respiratory depression, and constipation Investor and Analyst R&D Day 28
Slide 29: Unmet Needs in Opioid Therapy
Unmet Needs in Opioid Therapy Currently available opioids have a narrow Side Effects therapeutic index and produce dose-limiting side Tolerability effects including somnolence, dizziness, sedation, respiratory depression, and constipation Currently available opioids associated with high risk Abuse o
Slide 30: Unmet Needs in Opioid Therapy
Unmet Needs in Opioid Therapy Currently available opioids have a narrow Side Effects therapeutic index and produce dose-limiting side Tolerability effects including somnolence, dizziness, sedation, respiratory depression, and constipation Side effects and prescriber and patient anxiety regarding abu
Slide 31: The Pain Market: Multiple Opportunities for Nektar
The Pain Market: Multiple Opportunities for Nektar B Barry Flannelly, Fl ll PharmD Ph D VP Global Product Strategy, Nektar Therapeutics Investor and Analyst R&D Day 31
Slide 32: Naloxegol (NKTR-118)
Naloxegol (NKTR-118) Once-Daily Oral Tablet in Development to Treat Chronic OIC Comprehensive Phase 3 program underway • AZ on track for regulatory filings in mid-2013 in US and EU For naloxegol, naloxegol Nektar eligible for up to: • $95 million in milestones upon US/EU acceptance of filings • $140
Slide 33: Opioid-Induced Constipation Market
Opioid-Induced Constipation Market Opioids work by blocking receptors in the brain, resulting in pain control, and in the gut, causing OIC and other GI symptoms1 The global opioid market encompasses over 100 million patients.2 • For those patients who take opiates for long-term pain management u
Slide 34: AstraZeneca: Strong Position in Primary Care
AstraZeneca: Strong Position in Primary Care and Covers Full Spectrum of Opioid Prescribers Primary Care Ph i i Physicians 250 Million Opioid Prescriptions Written Annually in the U.S.1 Pain Specialists Other Specialties 0.3% p GI Specialists 1. By type of prescriber, 2010 IMS Health Investor and An
Slide 35: NKTR-181: New Opioid Molecule for Chronic Pain
NKTR-181 New Opioid Molecule for Chronic Pain US 2011 Opioid Sales Revenue > $8 Billion NKTR-181 NKTR 181 designed to target chronic pain market with novel opioid: Chronic • Slow rate of entry into CNS Acute Pain Pain designed to: $6 9B $6.9B $1 3B $1.3B – Reduce abuse liability – Reduce drowsiness
Slide 36: Million People in the U.S. Received at Least One Opioid Prescription
Last Year 70 Million People in the U.S. Received at Least One Opioid p Prescription p Total Patients Total Prescriptions Chronic 90+ days of 160 therapy 12.1M 140 148.3M s) ptions (millions 17% 120 Acute 100 103.4M < 90 days of 80 therapy py Prescrip 60 57M 40 83% 20 0 Acute Chronic 69.1M Unique Opi
Slide 37: Significant Opportunity for NKTR-181 in U.S.
Significant Opportunity for NKTR-181 in U.S. Chronic Pain Patient Population p Total Prescriptions Chronic Patient Opioid Treatment Days of Therapy 160 140 148.3M Long- scriptions (millions) 120 Acting 100 556 7M 556.7M 103.4M 80 Short- 60 Acting Pres 40 2 6B 2.6B 20 0 Acute Chronic Total of 3.2 Bil
Slide 38: Significant Opportunity for NKTR-181: Peak Share Estimate
Significant Opportunity for NKTR-181 in U.S. Chronic Pain Patient Population p Opioid Rx / Year Cost Per Day of Branded Chronic Pain Patients % Peak Share Length of Rx Long-Acting Opioids: 5 – 15% ~ 30 D Days Current C t price i 148.3M Share of Therapy Range $8 – $16 $2.8B – $5.7B Source: Nektar The
Slide 39: NKTR-192: New Opioid Molecule for Acute Pain
NKTR-192 New Opioid Molecule for Acute Pain US 2011 Opioid Sales Revenue NKTR-192 targets acute pain > $8 Billion* Billion market with highly differentiated opioid: • Slow rate of entry into CNS Chronic designed to: Acute Pain Pain – Reduce abuse liability $6 9B $6.9B $1 3B $1.3B – Reduce drowsiness
Slide 40: Million People in the U.S. Received at Least One Opioid Prescription
Last Year 70 Million People in the U.S. Received at Least One Opioid p Prescription p Total Patients Total Prescriptions Chronic 90+ days of 160 Chronic therapy 12.1M 140 148.3M s) ptions (millions 17% 120 Acute 100 < 90 days of 80 103.4M Acute therapy py Prescrip 60 57M 40 83% 20 0 Chronic Acute 69
Slide 41: Significant Opportunity for NKTR-192 in U.S.
Significant Opportunity for NKTR-192 in U.S. Acute Pain Patient Population p Total Prescriptions Acute Patient Opioid Treatment Days of Therapy 160 Long- 140 Acting 148.3M ns) 20.1M Prescriptions (million 120 100 80 103.4M Short- 60 Acting 40 734.5M 20 0 Chronic Acute U.S. 251.7M Total Rx’s 755 Mill
Slide 42: Significant Opportunity for NKTR-192: Peak Share Estimate
Significant Opportunity for NKTR-192 in U.S. Acute Pain Patient Population p Opioid Rx / Year Cost Per Day of Branded Acute Pain Patients % Peak Share Length of Rx Short-Acting Opioids: 10 – 20% 20 D Days off Current C t price i 103.4M Share Therapy Range $8 – $16 $2.0B – $4.0B Source: Nektar Therap
Slide 43: Nektar: Capturing Multiple Opportunities in Pain Market
Nektar: Capturing Multiple Opportunities in Pain Market Osteoarthritis Chronic pain: Lower back pain Rheumatoid arthritis NKTR-181 Spinal stenosis Cancer pain Muscle injuries, sprains and strains Acute pain: Post operative pain Kidney stones NKTR-192 Pancreatitis a c eat t s Diabetic neuropathy Neur
Slide 44: Pain Management and Addiction: Expert Panel
Pain Management and Addiction: Expert p Panel Lynn R. Webster, Sidney Schnoll, Richard Rauck, MD Steven Passik, PhD Jeffrey Gudin, MD MD MD, PhD Founder and Executive Professor of Psychiatry Medical Director, Clinical Instructor, VP of Pharmaceutical Director, and Anesthesiology, Anesthesiology, Ris
Slide 45: Opioid-Induced Constipation
Opioid-Induced Constipation Richard Rauck, MD Founder and Executive Director, C li Carolinas P Paini IInstitute tit t anddC Center t ffor Cli Clinical i lR Research h Clinical Associate Professor, Department of Anesthesiology, Wake Forest University School of Medicine Investor and Analyst R&D Day 45
Slide 46: Richard Rauck, MD
Richard Rauck, MD Founder and Executive Director, Carolinas Pain Institute and Center for Clinical Research Clinical Associate Professor of the Department of Anesthesiology, Wake Forest University School of Medicine
Slide 47: Opioid Pharmacology
Opioid Pharmacology Pharmacologic effects of opioids are diverse Not confined to central nervous system Opioid receptors are present throughout the body ○ Distribution and density may change over time and in different states (inflammation, etc.) Endogenous g opioids p may y have a role in no
Slide 48: Opioid Dysmotility of GI
oPioiD @ anatcesia DYSMOTILITY OF GI: @ constipation ——oo"> circular muscle myenteric plexus
Slide 49: Opioid receptors in the GI tract
Opioid receptors are present throughout the GI tract Peristalsis is the normal forward- propulsive muscle activity of the gut Opioid effects on smooth muscle in the wall of the bowel decrease peristalsis Decreased peristalsis means decreased movement of bowel contents Decreased secretion (
Slide 50: Reversal of Dysmotility: Relief of Constipation
OPIOID @ anatcesia *. REVERSAL OF DYSMOTILITY: -.) RELIEF OF CONSTIPATION PNS —_—_—_—_—> PERIPHERALLY-RESTRICTED 4 . OPIOID ANTAGONIST y SS Mi mucosa circular muscle myenteric plexus
Slide 51: Opioid antagonists
Opioid antagonists are competitive inhibitors of the mu-receptor -- compete with opioids to occupy the binding site Reversing opioid effects on the smooth muscle of the bowel may restore normal motility y to reverse OIC
Slide 52: Opioid-Induced Constipation
Opioid--Induced Constipation Opioid Tolerance Does D ttolerance l d develop l tto opioid i id effects ff t on GI motility? tilit ? ○ Probably not – at least not in a relevant time frame for most patients ○ A patient on opioids is prone to OIC as long as they continue on opioids. In fact, fact
Slide 53: Prevalence of Opioid-Induced Constipation
Prevalence of Opioid-Induced Constipation Up to 40-50 percent of patients who take opiates for long term pain management, will develop constipation2 Approximately 40-50 percent of those patients experience ineffecti e relief from ccurrent ineffective rrent treatment options including incl ding p
Slide 54: Naloxegol (NKTR-118): Phase 3 Development Program
Naloxegol (NKTR-118): Phase 3 Development Program R b tM Robert Medve, d MD MD, Chi Chieff Medical M di l Officer Offi Nektar Therapeutics Investor and Analyst R&D Day 54
Slide 55: Design of naloxegol 12-Week Efficacy Studies
Design of naloxegol 12-Week Efficacy Studies in Non-Cancer Pain Subjects for Treatment of OIC Two Randomized, Double-Blind, Placebo-Controlled 12-Week Studies in Patients With Non-Cancer-Related Pain and Opioid-Induced Constipation (OIC) NKTR-118 Patients with Arm A: Primary Endpoint 12.5 mg oral ta
Slide 56: Design of 52-Week Safety Study
Design of 52-Week Safety Study to Assess the Long-Term g Safety y of naloxegol g An Open-Label 52-week Study to Assess the Long-Term Safety of naloxegol in Opioid-Induced Constipation (OIC) in Patients With Non-Cancer-Related Pain Primary Outcome Measures NKTR-118 • Incidence, Nature, and Randomized
Slide 57: Substance Abuse and Opioid Analgesics
Substance Abuse and Opioid Analgesics Steve Passik, PhD Professor of Psychiatry and Anesthesiology Vanderbilt University School of Medicine Psychosomatic Medicine Investor and Analyst R&D Day 57
Slide 58: NKTR-181 in Development for Chronic Pain: Clinical Profile
NKTR-181 in Development for Chronic Pain: Clinical Profile Lynn Webster, MD Medical Director, CRI-Lifetree Investor and Analyst R&D Day 58
Slide 59: Prescription Opioid Abuse Presents a Major Health Problem
Prescription Opioid Abuse Presents a Major Health Problem Current Formulation Approaches to Abuse include Long-Acting g g Formulations and Tamper-Resistant Formulations NKTR NKTR-181 181 Time Release y, • NKTR-181 is a new molecular entity, Deterrent Coatings and cannot be converted to a rapid- acti
Slide 60: NKTR-181: Reduced Rate of Entry into the Brain vs Oxycodone
NKTR-181: Preclinical Data Shows Reduced Rate of Entry into the Brain Compared to Oxycodone 1.4 Reduced brain entry rate lowers potential for euphoria, liking, sedation 1.2 90% reduced and respiratory depression entry rate g/g/hr 1 NKTR NKTR-181 181 peak in vivo efficacy Brain uptake rate ug 0.8
Slide 61: Source: Volkow, National Drug Abuse Summit
Source: Volkow, N., National Drug Abuse Summit, April 2012 61
Slide 62: NKTR-181: Less Abuse Potential vs. Oxycodone in Primates
NKTR-181: Preclinical Primate Model Shows Less Abuse Potential of NKTR-181 vs. Oxycodone Equianalgesic Oxycodone O d 100% 100% NKTR-181 oosing Drug Over 80% 60% 50% od Foo 40% Animals Cho 25% 25% 25% 20% 0% % % 0% 0% % % of A 0% 0 0.003 0.01 0.03 0.1 0.3 1 3 IV Unit Dose Per Lever Push (mg/kg/inject
Slide 63: NKTR-181 Wide Therapeutic Index in Preclinical Models
NKTR-181 Exhibited a Wide Therapeutic Index in Preclinical Models ` ANALGESIA RATIO ABUSE POTENTIAL Acetic Acid Writhing (m) Drug Discrimination (r) Abuse Potential: Analgesia ED50 (μmol/kg ) Min AE Dose (μmol/kg) 14 790 56 NKTR-181 7.6 28.4 4 Oxycodone Ratio 1.8 28 NKTR-181: Oxycodone ANALGESIA SED
Slide 64: NKTR-181: Less CNS Coordination Effects and Respiratory Depression
NKTR-181: Preclinical Models Exhibit Less CNS Coordination Effects and Less Respiratory Depression Compared to Standard Opioids CNS Motor Coordination/ Respiratory Distress Sedative Potential Equianalgesic q g Doses 100 Saline 100 saline NKTR-181 (100 mg/kg, po) 80 ax Effect 60 % Ma Oxycodone O d 40
Slide 65: Demonstration of the Abuse Quotient
Demonstration of the Abuse Quotient Webster et. al., Expert Opin. Investig. Drugs (2009) 18(3) 65
Slide 66: Pharmacokinetics of Oxycodone Formulations
Pharmacokinetics of Oxycodone Formulations Webster et. al., 25th AAPM Meeting, February 2009 66
Slide 67: NKTR-181 Shows Dose-linearity, Cmax at 2-4 Hours
NKTR-181 Shows Dose-linearity, with Cmax at 2-4 Hours Post-dose Mean (±SEM) Plasma NKTR-181 Concentration-Time Profiles in Healthy Subjects (n=12 per dose level) NKTR 181 demonstrates predictable dose NKTR-181 dose-linear linear pharmacokinetics over a 50-fold 50 fold range of single oral doses in h
Slide 68: NKTR-181 Shows Dose-Linear Kinetics with Steady State
NKTR-181 Shows Dose-Linear Kinetics with Steady State Mean Plasma NKTR-181 Trough Concentrations in Healthy Subjects Mean Plasma Pre-dose (or 12 hrs post-dose) concentrations 1000 ma NKTR-181 Conc. (ng/mL) PK Parameters a a ete s After te OOral a Dosing of NKTR-181 100 Tmax ~2 hours 100 mg 200 mg t½
Slide 69: Pupillometry – What does it tell us?
Pupillometry – What does it tell us? 69
Slide 70: NKTR-181 Demonstrates Significant Central Effect Over Hours
NKTR-181 Demonstrates Significant Central Effect Over 12 Hours Peak central effect occurs ~4 hours following oral dosing Mean Pupil Diameter (% Change from Baseline) Day 1 nge from baseline) 0 -10 ameter (% chan -20 Mean Pupil Dia -30 Placebo 100 mg 200 mg 300 mg 400 mg M -40 40 0 4 8 12 Day 1 Time
Slide 71: NKTR-181 Sustained Dose-dependent Central Effect with Twice Daily Dosing
NKTR-181 Displays Sustained Dose-dependent Central Effect with Twice Daily Dosing Central effect (miosis) of NKTR-181 maintained with repeated dosing The mean change in pupil diameter from baseline on days 1, 2, 4, and 6. Results show that there is a dose- proportional NKTR-181 effect on the CNS and
Slide 72: Oxycodone: Human Pupillometry Data Show Rapid CNS Uptake
Oxycodone: Human Pupillometry Data Demonstrate Rapid Uptake into CNS OxycodoneHistorical Comparison Oxycodone enters the brain rapidly and extensively from the plasma Rapid rate of entry leads to liki / liking/euphoria h i and d other th CNS side effects Source: Kharash et. al, Clinical Pharmaco
Slide 73: NKTR-181: Human Pupillometry Confirms Slow Rate of Entry into CNS
NKTR-181: Human Pupillometry Data Confirm Slow Rate of Entry into CNS NKTR-181 enters the brain slowly from plasma Slow rate of entry into brain designed to reduce liking/euphoria g p and other CNS side effects Source: Webster et. al., 2012 AAPM 73
Slide 74: Human Pain Models: Cold Pressor Test
Human Pain Models Cold Pressor Test – What does it tell us? 74
Slide 75: NKTR-181 Single Ascending Dose Study, Cold-Pressor Test
NKTR-181 in Phase 1 Single Ascending Dose Study Cold-Pressor Test Single Ascending Dose Trial 2500 2500 2500 2500 80 mg 160 mg 320 mg 500 mg Plasma Conc. (ng/mL) Plasma Conc. (ng/mL) Plasma Conc. (ng/mL) Plasma Conc. (ng/mL) 2000 2000 2000 2000 1500 1500 1500 1500 1000 1000 1000 1000 500 500 500 500
Slide 76: Human Pain Models: UV-B Burn Test
Human Pain Models UV-B Burn Test – What is it? 76
Slide 77: Human Pain Models: UV-B Burn Test
Human Pain Models UV-B Burn Test – What is it? 77
Slide 78: NKTR-181 Displays Analgesic Activity in Peripheral Analgesic Model
NKTR-181 Displays Analgesic Activity in Peripheral Analgesic Model NKTR-181 demonstrates analgesia and anti-hyperalgesia activity following UVB injury Mechanical Evoked Pain Response P-value P value <0.0309 P-value <0.0092 In an experimental model of induced UVB injury, NKTR-181 had significant anti
Slide 79: NKTR-181 Well-Tolerated Throughout 8-Day Dosing Period
NKTR-181 Well-Tolerated in Phase 1 Throughout 8-Day Dosing Period (n=48) No serious or severe adverse events or dose-limitingg toxicities observed in healthy volunteers throughout 8-day dosing period Up to 400 mg twice-daily No observed respiratory depression Only one report of mild elevated
Slide 80: Conclusions
Conclusions NKTR-181 is an orally-available new mu-opioid agonist molecule l l designed d i d to t have h a slower l rate t off brain b i uptake t k compared with standard opioid therapies • Human data confirm 10-fold reduced rate of CNS entry from plasma as compared to oxycodone NKTR-181 produc
Slide 81: Conclusions (continued)
Conclusions (continued) The PK profile of NKTR-181 is well suited for the treatment off chronic h i pain i • Peak plasma level ~2 hours following dosing with an oral liquid. • Plasma half-life ~12 hours • Plasma levels reach steady state after Day 3 Responses in the pharmacodynamic models and th
Slide 82: NKTR-181 and NKTR-192 Development Programs
NKTR-181 and NKTR-192 Development Programs Robert Medve Medve, MD MD, Chief Medical Officer Nektar Therapeutics Investor and Analyst R&D Day 82
Slide 83: NKTR-181 Clinical Development Program
NKTR-181 Clinical Development Program Sample Primary Study Stage Study Population Study Design Size Endpoints Status Single ascending oral Analgesic dose dose over an 8-day range associated Phase 1 Healthy subjects 105 Complete treatment period in with minimal CNS healthy y subjects j side effects M
Slide 84: NKTR-181 Designed to Treat Chronic Pain
NKTR-181 Designed to Treat Chronic Pain Phase 2 Study will evaluate NKTR-181 oral tablets dosed twice daily to treat chronic pain from osteoarthritis of the knee Utilizing well-established clinical trial design • Placebo-controlled, randomized withdrawal design used sed as pi pivotal otal effica
Slide 85: Tablet Preparation for Phase 2 Development is Complete
Tablet Preparation for Phase 2 Development is Complete Tablets bioequivalent q to oral liquid dosed in Phase 1 No food effect observed with either liquid or tablets No gender effect observed Final Phase 2 preparation underway for start mid-year Investor and Analyst R&D Day 85
Slide 86: Primary Objectives of Phase 2 Study for NKTR-181
Primary Objectives of Phase 2 Study for NKTR-181 in Chronic Pain Patients Efficacy y Objectives j Determine the analgesic efficacy of NKTR-181 in subjects with osteoarthritis of the knee Primary Pi Endpoint: E d i t • The mean change from Baseline Pain Score to pain score at the end of the doubl
Slide 87: Phase 2 Study Design: Randomized Withdrawal Study
Phase 2 Study Design: Randomized Withdrawal Study in Osteoarthritis Patients Screening/ Titration to Maintenance Subject Baseline Effect Phase Population ≤ 28 days ≤ 28 days 21 days Optimal D Dose Establish (100 patients) Baseline Inclusion Opioid Naïve Placebo (100 patients) OA Knee Dropouts Subjec
Slide 88: Human Abuse Liability Assessment
Human Abuse Liability Assessment Human Abuse Liability (HAL) Assessment is a required element in the clinical development of opioids and for many other centrally-acting drugs • FDA gguidance document is available and p provides current standards and expectations Use of recreational prescription
Slide 89: NKTR-192: Next Mu-Opioid Analgesic for Acute Pain
NKTR-192: Next Mu-Opioid Analgesic to Address Acute Pain Conditions ACUTE SUBACUTE CHRONIC • Designed to have short-acting short acting profile with rapid onset of action • Also designed to have a slower rate of entry into CNS as compared to other short-acting opioids: – Reduce abuse liability – Red
Slide 90: NKTR-192 Crosses Slowly into the Brain
NKTR-192 Crosses Slowly into the Brain Reducing g Its Potential to Create Euphoria p NKTR-192 has much NKTR-192 shows virtually the same slower uptake into the potential for abuse as saline and brain than oxycodone in less potential than oxycodone in preclinical model preclinical abuse liability mod
Slide 91: NKTR-192 Rapid Analgesic Response in Preclinical Model
NKTR-192 Has Rapid Analgesic Response in Preclinical Model of Pain Orally-administered NKTR-192 shows RAPID analgesic response in a model of pain in rats Rats N = 10 per group NKTR-192 NKTR 192 also showed good analgesic response in models of inflammatory and visceral pain Harrison et. al., Neurosci
Slide 92: NKTR-192 Low Levels of Sedation in Preclinical Models
NKTR-192 Shows Low Levels of Sedation in Preclinical Models at Doses Effective for Pain Relief NKTR-192 Demonstrates A Wide Therapeutic Window Between Effective Pain Relief and its Potential to Cause Sedation or Drowsiness Increasing A l Analgesia i Decreased Sedation Analgesia: Mice N = 5-20 per gr
Slide 93: NKTR-192 Low Sedation Compared to Oxycodone
NKTR-192 Shows Low Levels of Sedation Compared to Oxycodone at Equianalgesic Doses 100 ation 80 (% maximum m) Motorr coordina 60 40 20 Rats 0 N = 5-10 per group 0 30 60 Time (min) Vehicle 30m g/kg Oxycodone (p.o.) 100 m g/kg NKTR-192 (p.o.) Harrison et. al., Neuroscience 2011: Society for Neuroscien
Slide 94: Pain Management and Addiction: Expert Panel
Pain Management and Addiction: Expert p Panel Lynn R. Webster, Sidney Schnoll, Richard Rauck, MD Steven Passik, PhD Jeffrey Gudin, MD MD MD, PhD Founder and Executive Professor of Psychiatry Medical Director, Clinical Instructor, VP of Pharmaceutical Director, and Anesthesiology, Anesthesiology, Ris
Slide 95: Etirinotecan pegol (NKTR-102): Commercial Opportunity
Etirinotecan pegol (NKTR-102): Commercial Opportunity B Barry Flannelly, Fl ll PharmD Ph D Vice President, Global Product Strategy Investor and Analyst R&D Day 95
Slide 96: NKTR-102 Phase 1 Study: Broad Activity in Solid Tumors
Etirinotecan pegol (NKTR-102) Phase 1 Study: y Broad Activity y in Solid Tumors RECIST Response / Tumor Prior Agents Tumor Reduction Breast Doxil, bevacizumab, docetaxel, carboplatin, tamoxifen, PR: ↓41% (triple negative) paclitaxel, cisplatin Investigational agent, docetaxel, carboplatin, tamoxifen
Slide 97: NKTR-102: Single Agent with New Mechanism of Action in MBC
Etirinotecan pegol (NKTR-102): Highly Active Single Agent with New Mechanism of Action in Metastatic Breast Cancer • Most M t drugs d usedd iin MBC di disruptt microtubules and have overlapping toxicities The Challenge of T ti Treating Metastatic M t t ti • In Phase 2, NKTR-102 had excellent Breast
Slide 98: Breast Cancer Market Overview
Breast Cancer Market Overview Worldwide Incidence: 1.3 Million | Annual Deaths: 465,000 7 Major Markets 7 Major Markets Incidence and Mortality Sales of Current Breast Cancer Therapies New Country Deaths Cases $0 96B $0.96B US 211,000 40,000 EU-5 238,000 58,000 U.S. Japan 55,000 12,000 $5.12B EU5 $3
Slide 99: Treatment of Breast Cancer in U.S.
Treatment of Breast Cancer in U.S. A Heterogeneous Patient Population Hormone-unresponsive or 113k high risk of progression •Visceral Vi l di disease OR •Organ threatening disease burden with moderate to severe symptoms HER2+ (25%) HER2- (75%) 25% 15% 60% 28k 17k 68k Triple HER2+ HER2- (ER/PR +/-) N
Slide 100: Single Agent Approach in HER2 Negative Metastatic Breast Cancer
Single Agent Approach in HER2 Negative (-) Metastatic Breast Cancer is Significant g Approximately 51% of HER2 - mBrC Regimens are Single Agents Investigational Drugs 5% Other Combo 30% Single Agents 51% Bev Regimens 14% All Metastatic Lines of Therapy Source: IntrinsiQ IntelliView Investor and Anal
Slide 101: NKTR-102 in Recurrent Metastatic Breast Cancer Peak Sales Potential
Etirinotecan pegol’s (NKTR-102) First Indication in Recurrent Metastatic Breast Cancer Could Exceed $500M in Peak Sales in US and EU-5 Annual Treatments in U.S. & EU5 % Peak Share 4th Line + 10 – 15% Share 25 700 25,700 Lines 2 - 4+ 4 3rd Line , 37,600 1st Line 95,600 2nd Line 62,300 $500 – $700M So
Slide 102: Etirinotecan pegol in Ovarian Cancer
Etirinotecan pegol (NKTR-102) in Ovarian Cancer • Few options for late stage disease in No drug approved the platinum-resistant setting for platinum- • Unmet medical need for woman who resistant ovarian have been treated with Doxil® and cancer since i h have platinum-resistant l ti i t t and d Doxil
Slide 103: Ovarian Cancer Market Overview
Ovarian Cancer Market Overview Worldwide Incidence: 225,000 | Annual Deaths: 140,000 7 Major Markets S l off C Sales Current O i Ovarian 7 Major Markets Cancer Therapies Incidence and Mortality C Country t N New C Cases D th Deaths $67M US 21,000 15,000 $182M US EU-5 EU 5 28,000 18,000 EU 5 Japan 8,
Slide 104: NKTR-102 in Platinum Resistant Ovarian Cancer Opportunity
Etirinotecan pegol (NKTR-102) Could Help Fill the Unmet Medical Need in Platinum Resistant Ovarian Cancer Annual Treatments in U.S. & EU5 % Peak Share 3rd Line 20 – 25% Share Platinum Resistant Lines 2 – 3+ 3 37,600 2nd 2 d Line Li Platinum Resistant 1st Line 62,300 95,600 $175 – $225M Source: US In
Slide 105: Unlocking Etirinotecan pegol Growth Potential
Unlocking etirinotecan pegol Growth Potential Brain Cancer REVENUE Gastric Cancer Lung Cancer Colorectal Cancer Ovarian Cancer Metastatic Breast Cancer TIME Investor and Analyst R&D Day 105
Slide 106: Oncology: Expert Panel
Oncology: Expert p Panel Ahmad Awada, Ignace B. Vergote, Edith A. Perez, MD Agop Bedikian, MD MD, PhD MD, PhD Deputy Director, Mayo Clinic Head of the Medical Oncology Professor & Head of the Professor and Deputy Director Cancer Center Clinic, Institut Jules Bordet, Department of Obstetrics and of t
Slide 107: Treatment of Metastatic Breast Cancer
Treatment of Metastatic Breast Cancer Edith A. Perez, M. D. Deputy Director, Mayo Clinic Cancer Center Group Vice Chair, Alliance for Clinical Trials in Oncology Serene M. and Frances C. Durling Professor of Medicine Investor and Analyst R&D Day 107
Slide 108: Management of Metastatic Breast Cancer
Management of Metastatic Breast Cancer April 2012 Edith A. Perez, M.D. S Serene M M. anddFFrances C C. D Durling li P Professor f off M Medicine di i Deputy Director, Mayo Clinic Comprehensive Cancer Center Group Vice Chair Chair, Alliance for Clinical Trials in Oncology Mayo Clinic Jacksonville, Fl
Slide 109: Outline: MBC
Outline: MBC • Overview of MBC • Molecular epidemiology • Current and future therapeutic approaches • Management of ER+ disease • Management of HER2+ disease • Chemotherapy • Summary
Slide 110: Metastatic Disease 2012
Metastatic Disease 2012 • Survival depends mostly on tempo • Biology of tumor key • Median remains approx 18- 18-24 months • 20 20--25% alive at 5 years • Goals of treatment • Control of disease and symptoms • Maximizing quality of life • Extend time to progression • Improve survival
Slide 111: Lines of Chemotherapy Received Before Death from MBC
“Approx how Many Lines of ChemoRx were Received by the Last 5 pts you Treated who Died of MBC (average)?” 2 0% 6% 3 5% 19% 28% Therapy 4 29% 5 37% 31% Lines of T 6 21% 10% 7 2% 3% 8 7% 1% 9 0% 0% 10 0% 1% 0% 5% 10% 15% 20% 25% 30% 35% 40% Clinical Investigators Practicing Oncologists N Love, Researc
Slide 112: Trends in the Use of Adjuvant Chemotherapy Over Time
Trends in the Use of Adjuvant Chemotherapy Over Time Source: Gradishar, W., 2011 ASCO Breast Cancer Symposium: Oral Abstract Session B Discussion.
Slide 113: New Therapeutic Targets in Trials
New Therapeutic Targets in Trials • PARP • mTOR • PI3K • MEK • Topoisomerase I
Slide 114: Hormone Receptor Positive MBC
Hormone Receptor Positive MBC • ER and/or d/ PRPR+ • 60 60--70% of breast cancers
Slide 115: Hormone Receptor Positive MBC in 2012
Hormone Receptor (HR)+ MBC i 2012 in HR+, MBC HER2+ HER2‐ 1L: Anastrozole Letrozole Tamoxifen Ovarian function suppression 2L: Exemestane +/- everolimus Fulvestrant Chemotherapy ± targeted Rx
Slide 116: HR+ MBC in 2013-4: Patient flow and treatment paradigm
HR+ MBC in 2013-4: P ti t flow Patient fl t t t paradigm & treatment di HR+, MBC Two phase III HER2+ HER2‐ trials ongoing in CT + HER2 HR+ BC HR targeted Rx 1L: 1L: AI + HER2 Anastrozole, 1L: Let or targeted Rx Letrozole Tam + Tamoxifen bevacizumab 2L: 2L: AI + HER2 Exemestane targeted Rx +/‐everoli
Slide 117: HER2+ Breast Cancer
HER2+ Breast Cancer • 15 - 20% off iinvasive i b breastt cancers • 50 50%% ER+, 50% ER ER-- • Therapeutic decision based on tumor’s HER2 testing • Other markers under evaluation, including immune--related immune • Several agents in the clinic and under study Perez EA, et al. JCO 2010; Perez EA, et a
Slide 118: HER2+ MBC: Therapeutic Options (1)
HER2+ MBC: Therapeutic Options (1) • First- Fi t-line First li th therapy • Trastuzumab with • Paclitaxel ± carboplatin • Docetaxel • Vinorelbine • Clinical trials • Pertuzumab • T-DM1 Perez EA and Spano JP, Cancer 2011. NCCN 2011 v.2
Slide 119: HER2+ MBC: Therapeutic Options (2)
HER2+ MBC: Therapeutic Options (2) • Second- S Second d-line li ththerapy • Lapatinib + capecitabine • Trastuzumab + other chemoRx • Trastuzumab + capecitabine • Trastuzumab + lapatinib • Clinical trials • EMILIA (T-(T-DM1) --- expected ASCO 2012 Perez EA and Spano JP, Cancer 2011. NCCN 2011 v.2
Slide 120: Triple Negative
Triple Negative • ER ER,, PR, PR HER2 ““negative” ti ” • What are the targets in the different subsets of “triple negative” disease?
Slide 121: Triple Negative Breast Cancer
“Triple Negative” Breast Cancer Immunohistochemistry • ER and PR <1% ER PR HER2 nuclear • HER2 “negative negative””: IHC 0 or 1+ staining or 2+ IHC staining g with Histology negative FISH • High grade ductal
Slide 122: Evolution of Chemotherapy for Metastatic Breast Cancer
Evolution of Chemotherapy for Metastatic Breast Cancer Mid 20th Late 20th Late 20th century century century y 21st century Early y Early Biological Novel antitubulins Anthracyclines Taxanes era chemotherapy py Vi Vinorelbine lbi C Capecitabine it bi begins Advanced cytotoxics CMF (VP) CMF = cyclopho
Slide 123: Microtubule Targeted Agents for MBC
Microtubule Targeted Agents for MBC • Microtubule destabilizers : inhibit polymerization, loss of cellular microtubules • Vinca alkaloids • Vinorelbine • Halichondrins:Eribulin • Microtubule stabilizers : stimulate polymerization, increase density of cellular microtubules • Taxanes • Paclitaxel, doc
Slide 124: Expected Clinical Outcomes with Single-agent ChemoRx in MBC
Expected Clinical Outcomes with ith Single-agent Si l t ChemoRx Ch R in i MBC Response Rate Time to Progression 1stt line li 25 - 40% 5 - 8 mo 2nd line 15 - 30% 2 - 5 mo 3rd line 0 - 20% 1 - 4 mo 4th line Few data 5th line Fewer data 6th liline, etc N No d data
Slide 125: Single Agent Chemotherapy Outcomes in Refractory MBC
Single Agent Chemotherapy Outcomes i Refractory in R f t MBC Prior Therapy Author Agent RR PFS A T C Perez Ixabepilone ✓ ✓ ✓ 11% 3 mo JCO 2007 Cortes Eribulin ✓ ✓ ✓/- 12% 3.7 mo Lancet 2011 NKTR--102 NKTR ✓ ✓ ✓/- 30% 4.6 mo Awada (Q14 + Q 21) SABCS 2010 NKTR--102 NKTR ✓ ✓ ✓/- 26% 5.3 mo (Q 21 only)
Slide 126: 'Omic' Approaches to Preventing or Managing MBC
‘Omic’ Approaches to Preventing or Managing MBC Griffith OL and Gray JW. Breast Cancer Res. 2011 Dec 8;13(6):230
Slide 127: Improving Therapy for MBC
Improving Therapy for MBC research tumor biopsies) (via research, • Develop D l more effective ff ti ways tto enhance h apoptosis • Understand U d t d mechanisms h i off resistance i t and d develop strategies to overcome them • Develop D l b better tt bibiomarkers k tto predict di t response to the
Slide 128: Collaborators
Collaborators NIH F b 16- Feb 16-17, 17 2013 NCI 5K, relay, half and full marathon breastcancermarathon.com BCRF 26.2 with Donna Foundation
Slide 129: Etirinotecan pegol (NKTR-102) in Metastatic Breast Cancer
Etirinotecan pegol (NKTR-102) in Metastatic Breast Cancer Ahmad Awada, MD, PhD Medical Oncology Clinic Institut Jules Bordet Université Libre de Bruxelles (U.L.B.) Brussels, Belgium Investor and Analyst R&D Day 129
Slide 130: Etirinotecan Pegol in Metastatic Breast Cancer
Etirinotecan Pegol in Metastatic Breast Cancer Ahmad Awada, MD, PhD Medical Oncology Clinic Institut Jules Bordet Université Libre de Bruxelles (U.L.B.) Brussels Belgium Brussels,
Slide 131: Etirinotecan Pegol: A Tumor-Targeted Topoisomerase I Inhibitor
Etirinotecan Pegol: A Tumor-Targeted Topoisomerase I Inhibitor
Slide 132: Etirinotecan Pegol: A Tumor-Targeted Topoisomerase I Inhibitor
Etirinotecan Pegol: A Tumor-Targeted Topoisomerase I Inhibitor
Slide 133: Polymer Conjugates Target Tumor Tissues
Polymer Conjugates Target Tumor Tissues T Tumors Dye‐Polymer Conjugate Nude mouse, KB tumor xenograft, dorsal view: Four‐arm IR dye conjugate, stable linkage Tumors Dye‐Polymer Conjugate Free Dye Nude mouse, A375 tumor xenograft, dorsal view Mouse was co‐injected with conjugate and free dye to demon
Slide 134: NKTR-102 Mechanism of Action
NKTR-102 Mechanism of Action First-generation Topo-I inhibitors have a high initial peak concentration and short half-life 100 Plasma Active 10 Metabolite Concentration (ng/ml) Dose Schedule (weeks)
Slide 135: NKTR-102 Mechanism of Action
NKTR-102 Mechanism of Action NKTR-102’s design results ~, in a lower initial peak concentration . of active Topo [ inhibitor in the blood nora Active 10 Metabolite Concentration (ng/ml) 3 6 Dose Schedule (weeks)
Slide 136: NKTR-102 Mechanism of Action
NKTR-102 Mechanism of Action i : a 4 | r che >. s Due to an extended half life of 50 days, active drug remains in circulation throughout the entire chemotherapy cycle
Slide 137: Increased and Prolonged SN38 Tumor Exposure of Etirinotecan Pegol
Increased and Prolonged SN38 Tumor Exposure of Etirinotecan Pegol Correlates with Improved Tumor Growth Suppression Compared to Irinotecan Irinotecan Etirinotecan Pegol g N38 Concenntration (ng/mL) Tumor Weigh T (mg) SN ht Tumor growth recommences within Suppression of tumor growth 2 days after last
Slide 138: Etirinotecan Pegol: Clinical Overview in Metastatic Breast Cancer
Etirinotecan Pegol: Clinical Overview in Metastatic Breast Cancer Final Results of a Phase 2 Study of Etirinotecan Pegol, a Topoisomerase I Inhibitor-Polymer Conjugate, in Patients with Pretreated Metastatic Breast Cancer Demonstrating Significant Antitumor Activity
Slide 139: Background: Need For New Therapeutic Options in Breast Cancer
Background: Need For New Therapeutic Options p in Breast Cancer •Resistance to taxanes and anthracyclines is a significant cause of treatment failure in breast cancer1, 2 ,3 — Limiting quality of life and survival •Topoisomerase I inhibition with irinotecan in MBC showed rather limited activity (q3w
Slide 140: Phase 2 Study Design: Randomized to Two Schedules
Phase 2 Study Design: Randomized to Two Schedules of Etirinotecan Pegol g •Primary Efficacy Objective: — Determine the objective response rate (ORR) by RECIST v 1.0 — Determine the optimal schedule of NKTR-102 in breast cancer •Secondary Objectives: PFS, OS and safety Metastatic 145 mg/m2 q14d Breas
Slide 141: Demographics
Demographics NKTR-102 NKTR-102 145 mg/m2 145 mg/m2 q14 days q21 days N 35 N=35 N 35 N=35 Age (years) Median (Range) 53 (33-83) 56 (37-77) ECOG PS 0 15 (43%) 13 (37%) 1 20 (57%) 22 (63%) Receptor Status* ER+ or PR+ 22 (63%) 21 (60%) ER-/PR-/HER2- (triple negative) 11 (31%) 10 (29%) HER2+ 5 (14%) 1 (3
Slide 142: Objective Tumor Response Rate by RECIST
Objective Tumor Response Rate by RECIST ((Investigator g Assessment)) Response by RECIST v 1.0 NKTR-102 NKTR-102 TOTAL g 2 145 mg/m g 2 145 mg/m q14 days q21 days n 31* 35 66 ORR 10 (32%) 9 (26%) 19 (29%) CR 2 (7%) 0 2 (3%) PR 8 (26%) 9 (26%) 17 (26%) SD 12 (39%) 16 (46%) 28 (42%) PD 9 (29%) 10 (29%
Slide 143: Response Rate By Prior Therapy
Response Rate By Prior Therapy Prior Therapy Subgroup* Overall Response by RECIST v 1.0 n/N (%) Evaluable Patients NKTR-102 NKTR-102 145 mg/m2 145 mg/m2 TOTAL q14 days q21 days Prior A/T only 7/22 (32%) 5/21 (24%) 12/43 (28%) Prior A/T in MBC 3/7 (43%) 2/9 (22%) 5/16 (31%) P i A/T/C Prior 2/6 (33%)
Slide 144: Maximum Decline in Tumor Measurements
Maximum Decline in Tumor Measurements* 100 80 6 patients ti t with ith 100% resolution l ti off ttargett llesions i • 2 CRs • 4 near CRs (unresolved non-target lesions) 60 00603: unresolved pleural thickening; bone metastases 02117: unresolved pleural effusion 40 02106: unresolved sclerotic bone met
Slide 145: Progression-Free Survival (All Patients)
Progression-Free Survival ((All Patients)) Median PFS: of progression-free Overall: 4.6 months (95% CI: 2.6 – 5.7) Q14d: 3.5 months Q21d: 5.3 months Proportion o P Time From Cycle1/Day1 (months) Source: Data as of 09May2011 145
Slide 146: Overall Survival (All Patients)
Overall Survival (All Patients) Median OS: Overall: 10 10.3 3 months (95% CI: 8 8.7-15.0) 7-15 0) Q14d: 8.8 months Q21d: 13.1 months Probability of Survvival Time From Cycle1/Day1 (months) Source: Data as of 09May2011 146
Slide 147: Summary of Drug-Related Adverse Events
Summary of Drug-Related Adverse Events 145 mg/m2 145 mg/m2 Most Common Drug-Related Grade 3 q14 days* q21 days and 4 Adverse Events > 5% N=35 N=35 N (%) Grade 3 Grade 4 Grade 3 Grade 4 Diarrhea 6 (17%) 1 (3%) 8 (23%) 0 Neutropenia 2 (6%) 2 (6%) 3 (9%) 1 (3%) Dehydration 3 (9%) 0 4 (11%) 0 Fatigue 4
Slide 148: Time Course of Diarrhea and Neutropenia
Time Course of Diarrhea and Neutropenia NKTR-102 NKTR-102 145 mg/m2 q14d 145 mg/m2 q21d N=35 N=35 Diarrhea (≥Grade 3) Cycle 1 and/or 2 9% 3% Cycle 3 and/or 4 0% 6% Cycle 4+ 11% 14% Onset Time, Median (Range) days [# cycle] 88 (1-121) [6] 93 (8-107) [5] Duration, Median (Range) days 8.5 (1-16) 14 (2-
Slide 149: Etirinotecan Pegol MBC Data Competitive
Etirinotecan Pegol MBC Data Competitive NKTR-102 Irinotecan Irinotecan Eribulin Physician Eribulin Eribulin Ixabepilone Pemetrexed Awada Q 3wk Qwk (EMBRACE) Choice (EMBRACE) Single Perez Prior ATC q21d Perez Perez Cortes Cortes ATC subset arm JCO N=80 ASCO JCO JCO Lancet Lancet Lancet phase II 2007
Slide 150: Etirinotecan Pegol: Conclusions
Etirinotecan Pegol: Conclusions • Single-agent etirinotecan pegol demonstrated a 29% ORR in heavily pretreated advanced breast cancer (median p ( 3rd line MBC)) — PFS: 4.6 months — Preliminary estimate for median OS: 10.3 months — Progression Progression-free free at 6 months: 35.5% • ORR was mainta
Slide 151: Clinical case 1
Clinical case 1 • 49 year-old patient • Estrogen receptor positive breast cancer with bone metastases 6 years ago • Previous treatments: • Goserelin + tamoxifen • Anastrozole + gefitinib • Exemestane • Liver metastases in 2009 docetaxel • October 2009: progressive disease in the liver • Etirinotec
Slide 152: Clinical case 1
Clinical case 1 Baseline After 6 cycles of etirinotecan pegol 152
Slide 153: Clinical case 1
Clinical case 1 • Treatment interruption after 12 cycles due to AE • Disease stabilisation and normal tumor marker for 17 months of therapy • Progressive disease in the liver • Re-treatment with etirinotecan pegol (q 2 weeks)) is still ongoing: g g 4+ months 153
Slide 154: Clinical case 1: Rechallenge with etirinotecan pegol
Clinical case 1: Rechallengeg with etirinotecan p pegol g Baseline After 10 cycles 154
Slide 155: Clinical case 1: Rechallenge with etirinotecan pegol
Clinical case 1: Rechallengeg with etirinotecan p pegol g CA 15 15‐3 3 CEA Treatment ongoing with no side effects except alopecia grade 1 and fatigue grade 1 155
Slide 156: Clinical case 2
Clinical case 2 • 41 year-old patient • Triple negative breast cancer 3 years earlier • Supra-clavicular nodes, mediastinal nodes and lung metastases • Previous treatments: • FEC • Docetaxel • Weekly paclitaxel • Capecitabine p • PR after 2 cycles of etirinotecan pegol (q3 weeks) • Stop after 6 cycl
Slide 157: Clinical case 2
Clinical case 2 Baseline After 4 cycles of etirinotecan pegol 157
Slide 158: Clinical case 2
Clinical case 2 Baseline After 4 cycles of etirinotecan pegol 158
Slide 159: BEACON Phase 3 Study in Metastatic Breast Cancer
BEACON Phase 3 Study in Metastatic Breast Cancer
Slide 160: Phase 3 BEACON Study: Design and Endpoints
Phase 3 BEACON Study: Design and Endpoints 160
Slide 161: Phase 3 BEACON Study: Secondary Objectives
Phase 3 BEACON Study: Secondary Objectives • Objective response rate • Progression-free Progression free survival • Clinical benefit rate • Duration of response p • Safety profiles of etirinotecan pegol and TPC • Health-related Quality of Life • Additional pharmacokinetic data • Evaluate the pharmac
Slide 162: Phase 3 BEACON Study: Exploratory Objectives
Phase 3 BEACON Study: Exploratory Objectives • Correlate specific biomarker data with outcome • Baseline and serial assessment of circulating tumor cells (CTCs) using ApoCell’s ApoStream technology • CTCs will be examined for various proteins (topoisomerase 1 and 2), DNA damageg (such ( as double-st
Slide 163: Steering Committee
Steering Committee Role of the committee is to provide oversight on study design, monitor patient enrollment, review DMC minutes and provide recommendations to Nektar regarding any suggested change in the protocol Edith Perez, M.D. Javier Cortés , M.D. Ahmad Awada, M.D. Joyce O'Shaughnessy, M.D. May
Slide 164: NKTR-102: Development Program
NKTR-102: Development Program R b tM Robert Medve, d MD MD, Chi Chieff Medical M di l Officer Offi Nektar Therapeutics Investor and Analyst R&D Day 164
Slide 165: Etirinotecan pegol (NKTR-102) Clinical Development Program
Etirinotecan pegol (NKTR-102) Clinical Development p Program g Sample Primary Stage Disease State Study Design Study Status Size Endpoint Phase 1 Advanced Solid Tumors NKTR-102 weekly, q2w, q3w 76 MTD Complete Phase 1 Advanced Solid Tumors NKTR-102 + 5-FU/Leucovorin ~30 MTD Enrolling/Ongoing Phase 2
Slide 166: Etirinotecan pegol (NKTR-102) in Ovarian Cancer
Etirinotecan pegol (NKTR-102) in Ovarian Cancer Sample Primary Stage Disease State Study Design Study Status Size Endpoint Phase 1 Advanced Solid Tumors NKTR-102 weekly, q2w, q3w 76 MTD Complete Phase 1 Advanced Solid Tumors NKTR-102 + 5-FU/Leucovorin ~30 MTD Enrolling/Ongoing Phase 2a Advanced Soli
Slide 167: Ovarian Cancer Treatment Algorithm
Ovarian Cancer Treatment Algorithm Evaluate surgery 1st line therapy 1st-line Pl ti Platinum-sensitive iti (prim or IDS) Carboplatin / Re-challenge: (relapse > 12 mo) Platinum- based combination Paclitaxel iv chemotherapy Platinum partially - • PLD/carbo regimen sensitive •g gemcitabine/carbo (relap
Slide 168: Original and Extended Phase 2 Studies in Platinum Resistant Ovarian Cancer
Original and Extended Phase 2 Studies in Platinum Resistant Ovarian Cancer Original Study: Randomized Simon Two-Stage Design NKTR-102 145 mg/m2 Platinum- q14d Primary Endpoint: resistant ovarian Objective cancer patients Response Rate N=71 NKTR-102 By RECIST 145 mg/m2 q21d N=106 N 106 Platinum-resis
Slide 169: Demographics for Ovarian Cancer Patients Treated with NKTR-102
Demographics for All Patients With Ovarian Cancer Treated with Etirinotecan pegol (NKTR-102) NKTR-102 NKTR-102 Total Q14d Q21d (N = 167) (N = 38) (N = 129) Median Platinum 14 5 wks 14.5 10 0 wks 10.0 10 9 wks 10.9 Free Interval Median Prior 3.0 (1, 7) 3.0 (1, 15) 3.0 (1, 15) Therapies (range) Median
Slide 170: Highly Platinum-Resistant/Refractory Patients by Platinum-Free Interval
Patients in Etirinotecan pegol (NKTR-102) Ovarian Cancer Study Highly Platinum-Resistant/Refractory Patients by Platinum-Free Interval (PFI) 37% 44% PFI < 1 month PFI 1 - 3 months PFI 3 - 6 months 19% Median Platinum-Free Interval of 10.9 weeks Investor and Analyst R&D Day 170
Slide 171: Preliminary Topline Response Rate
Preliminary Topline Response Rate ((Confirmed and Unconfirmed)) Total (N=162*) Confirmed ORR 28 (17%) 95% CI for RR (12%, 24%) Confirmed + 40 (25%) Unconfirmed ORR (18%, 32%) 95% CI for RR Confirmed GCIG response 46 (30%) 95% CI for GCIG response (23% 38%) (23%, 21 Patients Still on Study Drug (Marc
Slide 172: NKTR-102 Response Rate vs. Historical Comparisons
Etirinotecan pegol (NKTR-102) Response p Rate vs. Historical Comparisons p Better Response Rate than Historical Comparisons in Platinum-Resistant Ovarian Cancer Etirinotecan pegol (NKTR-102) (NKTR 102) studied in more advanced and heavily pretreated disease than other agents Median Prior Median Prio
Slide 173: Reduction in Tumor Burden with Single-Agent NKTR-102 (by RECIST)
Dramatic Reduction in Tumor Burden with Single- Agent Etirinotecan pegol (NKTR-102) (by RECIST) 60 Maximum % Change in SLD Target Lesions 40 20 20% Increase (RECIST) 0 -20 20 30% Decrease -40 (RECIST) -60 60 -80 -100 N = 140; includes all patients for which RECIST assessment was available as of 1/14
Slide 174: Reduction in Tumor Burden with Single-Agent NKTR-102 (by CA125)
Dramatic Reduction in Tumor Burden with Single-Agent Etirinotecan pegol (NKTR-102) (by CA125) 100 80 60 50% Increase 40 (CA-125) 20 0 -20 -40 50% Decrease (CA-125) -60 60 -80 -100 N = 123; includes all patients for which CA-125 was available as of 1/14/12 Investor and Analyst R&D Day 174
Slide 175: NKTR-102: Side Effect Profile in Platinum-Resistant Ovarian Cancer
Etirinotecan pegol (NKTR-102): Side Effect Profile in Platinum-Resistant Ovarian Cancer Q14d Q21d Total Most Common Drug-Related (N=38) (N=128) (N=166) Grade 3 and Grade 4 AE’s (>5% overall) Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 (%) (%) (%) (%) (%) (%) Diarrhea 26 3 17 0 19 1 Dehydration 2
Slide 176: Ovarian Cancer Program Next Steps
Ovarian Cancer Program Next Steps High response rate in poor prognosis and heavily pre-treated patients ti t with ith platinum-resistant/refractory l ti i t t/ f t ovarian i cancer • Response rates higher than historical comparisons for PLD and topotecan • Patients enrolled in NKTR-102 study were
Slide 177: Etirinotecan pegol (NKTR-102) Clinical Development Program
Etirinotecan pegol (NKTR-102) Clinical Development Program Sample Primary Stage Disease State Study Design Study Status Size Endpoint Phase 1 Advanced Solid Tumors NKTR-102 weekly, q2w, q3w 76 MTD Complete Phase 1 Advanced Solid Tumors NKTR-102 + 5-FU/Leucovorin ~30 MTD Enrolling/Ongoing Phase 2a Ad
Slide 178: Oncology: Expert Panel
Oncology: Expert p Panel Ahmad Awada, Ignace B. Vergote, Edith A. Perez, MD Agop Bedikian, MD MD, PhD MD, PhD Deputy Director, Mayo Clinic Head of the Medical Oncology Professor & Head of the Professor and Deputy Director Cancer Center Clinic, Institut Jules Bordet, Department of Obstetrics and of t
Slide 179: Coffee Break
COFFEE BREAK Investor and Analyst R&D Day 179