Analyst & Investor Briefing
American College of Rheumatology
           October 28, 2008
Forward-Looking Statements and
Non-GAAP Financial Information
• Discussions at this meeting will include forward-looking
 ...
Ken Verburg, Ph.D.
Development Head for Pain Therapeutics
              October 28, 2008
Chronic Pain Population Continues to Expand
     While Unmet Needs Continue to Increase
               Prevalence of Chron...
Few Existing Therapeutic Classes
 >50% of Patients Report These Therapies to Be Suboptimal
                  in Relieving ...
Going Beyond Traditional
 Analgesic Drugs
                                         •                       • Modulation
  ...
Pain Portfolio: Oct ’08
Progress to Innovative Medicines
                                                                 ...
Tanezumab: Overview

• Nerve growth factor (NGF)
                                                    Heavy
  – Key pain me...
Neurotrophic Factors (Neurotrophins)

• A substance that controls neuronal maturation & survival during
  development of f...
Neurotrophins and Their Receptors on
Sensory Neurons

                            BDNF



         NGF                NT4/...
NGF: Pain Signaling




• NGF sensitizes TRPV1 ion channels
   – Noxious heat/acidity (capsaicin receptor)
   – NGF causes...
Anti-NGF Treatment Does Not Affect Acute Pain
Sensation or Neuron Survival in Animals
                            Heat Pai...
Clinical Program Overview
• Exposure
   – >675 patients treated with at least 1 dose
   – ~250 patients → 6 months treatme...
Dose-Ranging Knee OA Study 1008:
Study Design

                                                   placebo (n=75)

        ...
WOMAC Pain Scale (VAS 0-100 mm)

                                                                                    tanez...
WOMAC Function Scale (VAS 0-100 mm)

                                                                                tanez...
Pain Responder Rates at Week 12
                                                                                         p...
Pain Responder Rates With an NSAID in
Phase 3 OA Trials at Week 12
                        100                            ...
Summary of Safety
                                                                                                 placebo...
Summary of Safety
                                                                • Most frequent adverse events across
  ...
Summary of Safety

                                                                • Only arthralgia and worsening
       ...
Summary of Safety

                                                                                • Only 7 patients in to...
Adverse Events Related to Abnormal
Peripheral Sensation

• Allodynia
  – Clothing/touch evoke pain sensation
• Dysesthesia...
Adverse Events Related to Abnormal
Peripheral Sensation
                                                            (µ
   ...
Tanezumab: Summary

• Therapeutic potential in a number of pain conditions
• Fixed low doses administered 6 times per year...
Management of Fibromyalgia
    with Esreboxetine
Fibromyalgia: Clinical Characteristics

• A syndrome characterized by:
    – Widespread soft tissue and muscular pain
    ...
Esreboxetine: Unmet Patient Needs

                        % of Fibromyalgia Patients with Symptoms*

                    ...
Esreboxetine

• Selective norepinephrine reuptake
  inhibitor (NRI)                                    O
                 ...
Putative Site and Mechanism of Action:
Enhancing Norepinephrine (NE) Transmission at
Spinal Cord Dorsal Horn
             ...
Phase 2 Study Design: Study 1034

Eligible Patients Had ACR Defined Fibromyalgia; Score                     8 mg qd
≥40 mm...
Efficacy in Fibromyalgia
                                                                                                 ...
Efficacy in Fibromyalgia
                                                                                                 ...
Time Course of Pain Relief
                     0.0                                                      placebo (n=133)
 ...
Responder Rates: Reductions in Pain
                                                                placebo (n=133)
      ...
Summary of Safety
                                                                     placebo (n=133)
                   ...
Incidence of Adverse Events (≥5%)

                  placebo (n=133)   esreboxetine (n=134)
                       n (%)  ...
Effects on Blood Pressure and Heart Rate

                                  placebo (n=133)              esreboxetine (n=1...
Esreboxetine: Summary

• Therapeutic potential in fibromyalgia
   –   Pain, function, fatigue and cognition
   –   Potenti...
CP-690,550 Update
             Ethan Weiner, M.D.
Development Head for Inflammation Therapeutics
                 October ...
CP-690,550 Update

• Significant Unmet Need
• Mechanism of Action
• Review of Program and Previous RA Data
• New Presentat...
CP-690,550 Update

• Significant Unmet Need
• Mechanism of Action
• Review of Program and Previous RA Data
• New Presentat...
Unmet Need in RA Market

• Limitations of current products

• Needs of physicians and patients

• A significant need exist...
CP-690,550 – A Exciting Potential New
Development in the Treatment of RA
• If successful, CP-690,550 could be the first ne...
CP-690,550 Update

• Significant Unmet Need
• Mechanism of Action
• Review of Program and Previous RA Data
• New Presentat...
Cytokine Signaling of JAK
                        Common γ chain shared by
                        receptors for: IL-2R, I...
CP-690,550 Update

• Significant Unmet Need
• Mechanism of Action
• Review of Program and Previous RA Data
• New Presentat...
Study 1019: Design
                                                1o
                                               anal-...
The ACR 20/50/70
               ACR-20/50/70 Criteria Achieved
              When All of the Following Are True:

• 20/50/...
Study 1019: Week 6 ACR Response Rates

                                                             Placebo
              ...
CP-690,550 RA Program
       2006   2007            2008              2009               2010


1019          1025 (MTX)

...
CP-690,550 Update

• Significant Unmet Need
• Mechanism of Action
• Review of Program and Previous RA Data
• New Presentat...
A3921025 Study Design
                                                       Interim
                                     ...
Study 1025: Week 12 ACR Response Rates
                                                                                   ...
Study 1025: ACR 20 Response Rates Over Time
                          Placebo
                100
                        ...
Study 1025: Week 12 Efficacy Summary

• All doses except 1 mg bid showed a
  significantly better response than placebo,
 ...
Study 1025: Serious Infections

                                CP-690,550                  MTX Weekly
Event              ...
Study 1025: Mean Changes from Baseline
in HGB and ANC at Week 12
                           HGB Change                ANC ...
Study 1025: Severe Anemia and Neutropenia

                                 Incidence Through Week 12 of
• 3 subjects had ...
Study 1025: Incidence of Transaminase
Elevations (Subjects with Normal BL)

                                           AST...
Study 1025: Mean Changes from Baseline
in HDL and LDL at Week 12
                           HDL Change                   L...
Study 1025: Safety Summary (Week 12)

• Serious infections were few and not dose responsive

• Dose related changes in hem...
Study 1025: Overall Conclusions

• An efficacy and safety profile justifying
  progression to Phase III was observed
• The...
CP-690,550 Update

• Significant Unmet Need
• Value Proposition and Mechanism
• Review of Program and Previous RA Data
• N...
Study A3921024: Open-label, Long-term,
Multicenter Study
   Months                     0   3         6         9          ...
Study 1024: Interim Analysis

• An interim analysis was conducted of all
  safety data for all 129 patients enrolled as
  ...
Study 1024: Adverse Events* in 129 Subjects


• Total AEs = 160
   – Mild = 93
   – Moderate = 64
   – Severe = 3 (myocard...
Study 1024: Laboratory Values at 6 Months


                                             CP-690,550 5 mg BID
             ...
Study 1024: DAS28-3 (CRP)
                                         Study 1025       Study 1019      All Patients
         ...
Study 1024: DAS28-4 (ESR)
                                         Study 1025      Study 1019      All Patients
          ...
Study 1024: Conclusions

• CP-690,550 5 mg BID was well tolerated and
  efficacious in patients with moderate to severe
  ...
CP-690,550 Update

• Significant Unmet Need
• Value Proposition and Mechanism
• Review of Program and Previous RA Data
• N...
Study 1013: MTX DDI Study Summary

• Study Objectives:
   – To estimate the effects of MTX on the pharmacokinetics (PK) of...
CP-690,550 RA Program
       2006   2007            2008              2009               2010


1019          1025 (MTX)

...
Conclusion

• Current products for RA have significant
  limitations
• CP-690,550 may offer benefits of both a small
  mol...
Q&A
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Pfizer Analyst and Investor Meeting at the American College of Rheumatology (ACR) Annual Meeting

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Pfizer Analyst and Investor Meeting at the American College of Rheumatology (ACR) Annual Meeting

  1. 1. Analyst & Investor Briefing American College of Rheumatology October 28, 2008
  2. 2. Forward-Looking Statements and Non-GAAP Financial Information • Discussions at this meeting will include forward-looking statements. Actual results could differ materially from those projected in the forward-looking statements. The factors that could cause actual results to differ are discussed in Pfizer’s 2007 Annual Report on Form 10-K and in our reports on Form 10-Q and Form 8-K • Also, discussions during this meeting may include certain financial measures that were not prepared in accordance with generally accepted accounting principles. Reconciliations of those non-GAAP financial measures to the most directly comparable GAAP financial measures can be found in Pfizer’s Current Report on Form 8-K dated October 21, 2008 • These reports are available on our website at www.pfizer.com in the “Investors—SEC Filings” section
  3. 3. Ken Verburg, Ph.D. Development Head for Pain Therapeutics October 28, 2008
  4. 4. Chronic Pain Population Continues to Expand While Unmet Needs Continue to Increase Prevalence of Chronic Pain • Steady growth in patients in Major Global Markets (2011) chronic pain reflects aging population 160MM 40 ~250 million patients • Physicians express displeasure 35 with the current therapies 30 – “Currently medications have very 25 low efficacy – only 1/5 patients are MM treated successfully – if you had 20 this type of efficacy in another 15 field of medicine, it would NOT be 10 accepted. We accept it because we 5 have nothing better.” 0 • Onset of chronic pain can be n A P e A ia ai ch in LB O R life-altering and long lasting lg rP Pa da ya C ce ea ic om an – Arthritis and back pain are the th H br pa C Fi ro leading causes of disability eu N Decision Resources Stewart et al., Lost Productive Time and Costs Due to Common Pain Conditions in the US Pain Workforce. JAMA 2003;290:2443-2454 2003;290:2443-
  5. 5. Few Existing Therapeutic Classes >50% of Patients Report These Therapies to Be Suboptimal in Relieving Their Pain* • Acute Pain/ • Neuropathic Pain Musculoskeletal Pain – Anti-depressants – Acetaminophen – Anti-epileptics – NSAIDs – Topical capsaicin – Opiates – Local anesthetics – Local anesthetics – Muscle relaxants * Mantyselka et al., JAMA 2003;290:2435-2442 2003;290:2435- Stewart et al., JAMA 2003:290:2443-2454 2003:290:2443- Decision Resources Report, Chronic Pain – Key Populations, Market Size and the Driving Force for Drug Reformulations. Oct, 2005 Oct,
  6. 6. Going Beyond Traditional Analgesic Drugs • • Modulation Transduction • • Sensitization Conduction • Transmission • Processing/perception Neuron Microglia Astrocyte Sensitization/ Transduction Conduction Transmission Inhibition TRPV1, TRPV2, TRPV3, NGF, TrkA, TRPV1, NaV1.8, NaV1.7, CaV2.2, mGluR, TRPM8, TRPA, TRPV4, NaV1.8, CXCR3, P2X4, NaV1.3, NaV1.9, NMDA-R, NaV1.3, NMDA- ASIC, TREK-1, P2X3, TREK- p38, GABA-A, GABA- K Channels K Channels, NK1, CGRP NaV1.7 CCR2 Opioid-R, CB1, Opioid-
  7. 7. Pain Portfolio: Oct ’08 Progress to Innovative Medicines NeP Pain Arthritis Pain Fibromyalgia Broad Pain PF-3557156 PF- Sev Chr Pain PDE7i Acute Pain PF-4191834 PF- PF-4480682 PF- PDE5i + α2δ 5-LO inhibitor 4 Compounds PF-3864086 PF- Lyrica PH-797804 PH- & Unique P38 kinase i TRPV1 antag post-op pain post- Targets Beyond PF-4457845 PF- PF-4136309 PF- tanezumab* Celebrex Clinical FAAH inhibitor CCR2 antag Anti-NGF mAb Anti- gout Candidates ADL-5747 ADL- ADL-5859 ADL- esreboxetine Lyrica (FM) DOR agonist DOR agonist NRI EU Ph 3 Ph 3b Ph 1 Ph 2 Pre-Clin *Projected start 4Q; OA
  8. 8. Tanezumab: Overview • Nerve growth factor (NGF) Heavy – Key pain mediator in pain Chain • Humanized, IgG2 monoclonal antibody – High specificity and affinity for NGF – Fc mutation limits Ab-dependent cell mediated toxicity & complement activation NGF • Efficacy in multiple preclinical models of pain • Clinical efficacy demonstrated in OA – 5 min IV administration – (slow IV push) – Low projected dose ≤10 mg q 8 wks – Phase 3 (IV) Program: on plan to start 2008 • Program Objectives – Initial path to approval with OA (IV) Light • Projected BLA submission; 2011/12 Chain – Followed by OA (SC) & Chronic Pain (SC)
  9. 9. Neurotrophic Factors (Neurotrophins) • A substance that controls neuronal maturation & survival during development of functional contacts (neuronal circuits) But practically, • Neurotrophic factors have effects on adult neurons – Upregulate sensitivity, transmitter synthesis/release – Protect from metabolic, chemical, viral or physical insult – Induce/increase sprouting/regeneration
  10. 10. Neurotrophins and Their Receptors on Sensory Neurons BDNF NGF NT4/5 NT3 trkA trkB trkC Nociceptors/ Slowly adapting Proprioceptors/ thermoreceptors Mechanoreceptors large cutaneous Pain/temperature Proprioception, Light touch sensitivity vibration
  11. 11. NGF: Pain Signaling • NGF sensitizes TRPV1 ion channels – Noxious heat/acidity (capsaicin receptor) – NGF causes phosphorylation of TRPV1 which leads to increased transport to cell surface and increased channel activity • NGF activates mast cells • NGF triggers changes in gene expression – Increases expression of proteins that further sensitize these neurons
  12. 12. Anti-NGF Treatment Does Not Affect Acute Pain Sensation or Neuron Survival in Animals Heat Pain 12 Latency (sec.) 8 4 0 Mechanical Pain 6 50% Threshold 4 • 26-week study in adult cynomolgous monkeys with 0, 1, 10 & 30 mg/kg/week 2 – No target organ toxicities – Extensive evaluation of nervous system 0 14 0 10 Days Naive + Vehicle Naive + anti-NGF anti-
  13. 13. Clinical Program Overview • Exposure – >675 patients treated with at least 1 dose – ~250 patients → 6 months treatment – ~60 patients → 12 months treatment • Osteoarthritis – Phase 2 program complete – Encouraging open-label data ≤1 yr with 50 µg/kg IV q 8 wks • Phase 2 studies – Chronic low back pain (CLBP) – completed – Neuropathic pain (PHN) – enrollment completed – Visceral pain • Interstitial cystitis – enrollment ongoing • Endometriosis (4Q), prostatitis (1Q) – Cancer Pain (metastatic bone pain – 1Q) • SC Route of administration – IV/SC BE study (4Q) • RTU liquid formulation developed (refrigerated)
  14. 14. Dose-Ranging Knee OA Study 1008: Study Design placebo (n=75) tanezumab 10 µg/kg (n=75) tanezumab 25 µg/kg (n=75) Screening tanezumab 50 µg/kg (n=75) tanezumab 100 µg/kg (n=75) tanezumab 200 µg/kg (n=75) Study Day -30 -3 1 14 28 42 56 70 84 112 136 182 Visits Randomization Baseline Pain 2nd Dose 1st Dose Days -3 to -1 Study Study (Diary) Medication Medication
  15. 15. WOMAC Pain Scale (VAS 0-100 mm) tanezumab 50 µg/kg (n=72) placebo (n=73) tanezumab 10 µg/kg (n=74) tanezumab 100 µg/kg (n=74) tanezumab 25 µg/kg (n=75) tanezumab 200 µg/kg (n=72) -5 -15 Mean change (se) * -25 ** *** *** *** *** *** * *** *** -35 *** *** *** *** *** *** *** *** -45 *** *** *** *** *** -55 *** *** 0 2 4 6 8 10 12 14 16 Infusion #1 Infusion #2 Week *p≤ p≤ ***p≤ *p≤0.05 ** p≤0.01 ***p≤0.001 vs. placebo Baseline Scores = 62.1 – 69.2 mm
  16. 16. WOMAC Function Scale (VAS 0-100 mm) tanezumab 50 µg/kg (n=72) placebo (n=73) tanezumab 10 µg/kg (n=74) tanezumab 100 µg/kg (n=74) tanezumab 25 µg/kg (n=75) tanezumab 200 µg/kg (n=72) -5 -15 Mean change (se) * ** -25 *** *** *** ** *** *** *** * -35 *** *** *** *** *** *** *** *** -45 *** *** *** *** *** *** *** -55 0 2 4 6 8 10 12 14 16 Infusion #1 Infusion #2 Week *p≤ p≤ ***p≤ *p≤0.05 ** p≤0.01 ***p≤0.001 vs. placebo Baseline Scores = 62.1 – 69.2 mm
  17. 17. Pain Responder Rates at Week 12 placebo (n=73) tanezumab 10 µg/kg (n=74) 100 tanezumab 25 µg/kg (n=75) 90 tanezumab 50 µg/kg (n=72) *** *** tanezumab 100 µg/kg (n=74) 80 *** *** tanezumab 200 µg/kg (n=72) *** *** * Percent of Patients 70 * 60 ** ** 50 40 *** *** 30 ** 20 * * 10 0 30% Responders 50% Responders 90% Responders *p≤ p≤ ***p≤ Active treatment group vs. placebo: *p≤0.05 ** p≤0.01 ***p≤0.001 Dworkin RH, Turk DC, Wywrich KW, et al. Interpreting the clinical importance of treatment outcomes clinical in chronic pain clinical trials: IMMPACT recommendations. J Pain 2008; 9: 105-121 105-
  18. 18. Pain Responder Rates With an NSAID in Phase 3 OA Trials at Week 12 100 placebo (n=660) 90 Dose 1 (n=671) Dose 2 (n=641) 80 Percent of Patients Dose 3 (n=646) 70 60 * * 50 * 40 * * * 30 20 10 0 90% Responders 30% Responders 50% Responders p≤ *Active treatment group vs. placebo: p≤0.05
  19. 19. Summary of Safety placebo (n=74) tanezumab 10 µg/kg (n=74) tanezumab 25 µg/kg (n=74) 90 tanezumab 50 µg/kg (n=74) 80 78 tanezumab 100 µg/kg (n=74) Incidence (% of Patients) tanezumab 200 µg/kg (n=74) 69 70 69 66 60 60 55 50 40 30 20 11 8 10 5 4 3 3 3 1 1 0 0 0 0 Adverse Events Serious Adverse Withdrawals due to Events Adverse Events
  20. 20. Summary of Safety • Most frequent adverse events across tanezumab groups: – Headache (8.9%) 90 – URTI (7.3%) – Paresthesia (6.8%) 80 78 – Hypoesthesia (5.7%) Incidence (% of Patients) – Arthralgia (5.7%) 69 70 69 66 • Infusion site reactions (pain or burning) 60 60 were rare (0.5% each) 55 • Incidence of abnormal neurological exams 50 similar to pbo 40 • No effects on HR, BP, ECGs, labs • No evidence of anti-tanezumab antibodies 30 20 11 8 10 5 4 3 3 3 1 1 0 0 0 0 Adverse Events Serious Adverse Withdrawals due to Events Adverse Events
  21. 21. Summary of Safety • Only arthralgia and worsening diabetes led to withdrawal in more 90 than one patient • Arthralgia – 2 patients (100, 200 80 78 ug/kg doses) Incidence (% of Patients) 69 70 69 • Diabetes – 3 patients (10, 50 and 66 200 ug/kg) 60 60 55 • One patient discontinued the 50 study due to abnormal cutaneous sensation (hyperesthesia) 40 30 20 11 8 10 5 4 3 3 3 1 1 0 0 0 0 Adverse Events Serious Adverse Withdrawals due to Events Adverse Events
  22. 22. Summary of Safety • Only 7 patients in total 90 experienced serious adverse 80 78 events (all considered unrelated to study medication) Incidence (% of Patients) 69 70 69 66 • Chest pain (pbo) cellulitis, appendicitis (10µg/kg) 60 60 55 breast cancer, bacterial arthritis (50µg/kg) syncope, lumbar spine 50 stenosis (200µg/kg) 40 30 20 11 8 10 5 4 3 3 3 1 1 0 0 0 0 Adverse Events Serious Adverse Withdrawals due to Events Adverse Events
  23. 23. Adverse Events Related to Abnormal Peripheral Sensation • Allodynia – Clothing/touch evoke pain sensation • Dysesthesia: – Sensitivity to touch and clothing – Sunburn/hot sensation • Paresthesia – Tingling, pricking, or pins & needles sensation • Hyperesthesia (Hypoesthesia) – High (low) sensitivity to touch, pain, or other sensory stimuli
  24. 24. Adverse Events Related to Abnormal Peripheral Sensation (µ tanezumab (µg/kg) placebo 10 25 50 100 200 Combined n (%) N=74 N=74 N=74 N=74 N=74 N=74 N=370 Any AE 2 (2.7) 4 (5.4) 4 (5.4) 4 (5.4) 13 (17.6) 12 (16.2) 37 (10.0) Allodynia 0 0 0 0 1 (1.4) 1 (1.4) 2 (0.5) Dysesthesia 0 0 0 0 1 (1.4) 1 (1.4) 2 (0.5) Hyperesthesia 0 0 0 3 (4.1) 4 (5.4) 4 (5.4) 11 (3.0) Paresthesia 2 (2.7) 4 (5.4) 4 (5.4) 1 (1.4) 8 (10.8) 8 (10.8) 25 (6.8) Hypoesthesia 0 1 (1.4) 7 (9.5) 2 (2.7) 5 (6.8) 6 (8.1) 21 (5.7) Early, Transient, Mild-to-Moderate, Normal/Minor Changes on Neurological Exams; Not Consistent with Structural Damage
  25. 25. Tanezumab: Summary • Therapeutic potential in a number of pain conditions • Fixed low doses administered 6 times per year • Encouraging safety profile to date • Dose-related transient abnormal cutaneous sensations have been observed – not treatment limiting • Long-term effects on sensory and autonomic function to be investigated in Phase 3 – Large safety database – Neurological Impairment Score – Routine neurological exams – Nerve conduction velocity assessment – Autonomic function testing – Cutaneous peripheral nerve density • Upcoming milestones
  26. 26. Management of Fibromyalgia with Esreboxetine
  27. 27. Fibromyalgia: Clinical Characteristics • A syndrome characterized by: – Widespread soft tissue and muscular pain Fibromyalgia Tender Points – Decreased pain threshold (tenderpoints) Fatigue: 81% – “usually or always too tired”1 – – Disturbed sleep: 75% consider their sleep nonrestorative1 – Anxiety or depression – IBS, Raynaud’s, headache, paresthesias • Prevalence 2.0% (U.S.); 3–6 million people – Diagnosed ~1 million – 3.4% for women, 0.5% for men – Most common in women ages ≥50 years • Difficult condition for patients – diagnosis and treatment 1 Wolfe et al. Arthritis Rheum 1990 2 Hudson et al. Rheumatic Dis Clin N A 1996 3 Dwight et al. Pychosomatics 1998 4 Epstein et al. Pychosomatics 1999
  28. 28. Esreboxetine: Unmet Patient Needs % of Fibromyalgia Patients with Symptoms* 97% 91% 90% 67% 36% Depressive Pain Fatigue Poor Difficulty Symptoms Sleep Concentrating Key Value Drivers Widespread Difficulty Fatigue Poor Sleep Function Depression Pain Concentrating Lyrica Unmet Unmet duloxetine Need Need Gap Gap milnacipran esreboxetine Pfizer Internal Marketing Research Data, 2008
  29. 29. Esreboxetine • Selective norepinephrine reuptake inhibitor (NRI) O H O • More selective isomer of Edronax (racemic reboxetine) – Approved for depression in over O 40 countries outside the US H NH MeSO3H • Different pharmacologic approach than Lyrica Esreboxetine • Once daily administration [S,S] - reboxetine PNU-165442E • In Phase 3 development for fibromyalgia NET:SERT selectivity Esreboxetine >>>racemic reboxetine>>milnacipran>duloxetine>fluoxetine
  30. 30. Putative Site and Mechanism of Action: Enhancing Norepinephrine (NE) Transmission at Spinal Cord Dorsal Horn Cortex Esreboxetine Increases Descending Brainstem NE Inhibition for Pain Relief Dorsal Root nociceptor Ganglia Spinal cord Specific knock-out of NE transporter reuptake mechanism enhances endogenous knock- and exogenous opioid analgesia (Bohn et al., J. Neurosci., 20: 9040, 2000) Neurosci.,
  31. 31. Phase 2 Study Design: Study 1034 Eligible Patients Had ACR Defined Fibromyalgia; Score 8 mg qd ≥40 mm on 100 mm Pain Visual Analog Scale and Mean Score ≥4 on a 0-10 Numerical Pain Rating Scale One-step dose reduction One- 6 mg qd esreboxetine (n=134) One-step dose reduction One- 4 mg qd One-step dose reduction One- 2 mg qd Single-blind Single- placebo placebo (n=133) Randomization -3 -2 0 2 4 6 8 Weeks
  32. 32. Efficacy in Fibromyalgia placebo (n=133) esreboxetine (n=134) Pain Reduction Improvement in Function 0 0 Mean Change In NRS Score Mean Change in FIQ Score -0.5 -5 -1.0 -10 -8.1 -1.0 -1.5 -15 -1.6 -15.6 -20 -2.0 * * Scale 0 (no pain) to 10 (worst pain) Scale 0 (none) to 100 (max impairment) Baseline Scores: 6.8 (both groups) Baseline Scores: 62.8 (placebo) 61.4 (esreboxetine) *p<0.01 vs. placebo
  33. 33. Efficacy in Fibromyalgia placebo (n=133) esreboxetine (n=134) Improvement in Fatigue Patient Global Impression 0 60 * Mean Change in MAF Score 42.6 50 -2 Percent of Patients 40 23.4 -4 30 * -2.8 17.1 20 -6 10 3.8 0 -8 -6.4 Very Much/ Very Much * Much Improved Improved Scale 0 (none) to 50 (maximum) Baseline Scores: 37.8 (placebo) 37.6 (esreboxetine) *p<0.01 vs. placebo
  34. 34. Time Course of Pain Relief 0.0 placebo (n=133) esreboxetine (n=134) -0.4 Mean Change from Baseline Score -0.8 * * -1.2 * * * * -1.6 -2.0 1 2 3 4 5 6 7 8 Study week * p<0.05 vs. placebo Mean (SD) Baseline Score; placebo = 6.8 (1.4); esreboxetine = 6.8 (1.4) 6.8
  35. 35. Responder Rates: Reductions in Pain placebo (n=133) esreboxetine (n=134) * 40 37.6 35 30 (% of patients) Responders 25 22.6 ** 20 18.1 15 8.3 10 5 0 30% Response Rate 50% Response Rate (Clinically Important) (Substantial Improvement) *p=0.004; **p=0.01 vs. placebo
  36. 36. Summary of Safety placebo (n=133) esreboxetine (n=134) 100 Incidence (% of Patients) 80 72 57 60 40 20 8.2 3.0 0.7 0.7 0 Adverse Withdrawals Serious Adverse Events due to Events Adverse Events
  37. 37. Incidence of Adverse Events (≥5%) placebo (n=133) esreboxetine (n=134) n (%) n (%) Constipation 7 (5.3) 26 (19.4) Insomnia 5 (3.8) 24 (17.9) Dry mouth 3 (2.3) 22 (16.4) Headache 5 (3.8) 19 (14.2) Nausea 4 (3.0) 12 (9.0) URTI 7 (5.3) 6 (4.5) Dizziness 2 (1.5) 9 (6.7) Nasopharyngitis 6 (4.5) 5 (3.7) Fatigue 6 (4.5) 2 (1.5) Hyperhidrosis 2 (1.5) 7 (5.2) Palpitations 2 (1.5) 6 (4.5)
  38. 38. Effects on Blood Pressure and Heart Rate placebo (n=133) esreboxetine (n=134) Baseline At 8 weeks Baseline At 8 weeks Parameter Mean (SD) Mean (SD) Mean (SD) Mean (SD) Systolic BP (mmHg) 123.6 (13.7) 123.8 (14.1) 120.6 (14.4) 120.9 (14.5) Diastolic BP (mmHg) 77.0 (8.5) 76.7 (9.1) 76.3 (8.4) 77.7 (8.6) Sitting heart rate (bpm) 74.1 (9.4) 75.5 (9.7) 73.2 (9.8) 81.6 (10.7) • No clinically relevant difference in systolic or diastolic BP was observed between esreboxetine and placebo • Esreboxetine-treated exhibited a mean increase in heart rate of 8 bpm
  39. 39. Esreboxetine: Summary • Therapeutic potential in fibromyalgia – Pain, function, fatigue and cognition – Potential for study with Lyrica – Differentiation from mixed reuptake inhibitors – Benefit: risk optimized in phenotypic subgroups • Encouraging safety profile to date – Differentiation from mixed reuptake inhibitors • Mechanism-based safety and tolerability to be investigated in Phase 3 – Cardiovascular safety – Anticholinergic-like effects: constipation, urinary retention • Upcoming milestones
  40. 40. CP-690,550 Update Ethan Weiner, M.D. Development Head for Inflammation Therapeutics October 28, 2008
  41. 41. CP-690,550 Update • Significant Unmet Need • Mechanism of Action • Review of Program and Previous RA Data • New Presentations at ACR – 12 week dose response data (study 1025) – Open Label Extension (study 1024) – MTX DDI Study (study 1013) • Summary
  42. 42. CP-690,550 Update • Significant Unmet Need • Mechanism of Action • Review of Program and Previous RA Data • New Presentations at ACR – 12 week dose response data (study 1025) – Open Label Extension (study 1024) – MTX DDI Study (study 1013) • Summary
  43. 43. Unmet Need in RA Market • Limitations of current products • Needs of physicians and patients • A significant need exists for new oral treatments beyond the treatments of the last three decades
  44. 44. CP-690,550 – A Exciting Potential New Development in the Treatment of RA • If successful, CP-690,550 could be the first new oral DMARD to be marketed in more than 10 years • CP-690,550 is the first Janus Kinase inhibitor, a novel immune pathway mechanism that has the potential to treat patients afflicted by a number of autoimmune diseases • A significant need exists for new treatments beyond the current paradigm of methotrexate (and other older DMARDs), and injectable TNF inhibitors
  45. 45. CP-690,550 Update • Significant Unmet Need • Mechanism of Action • Review of Program and Previous RA Data • New Presentations at ACR – 12 week dose response data – Open Label Extension – MTX DDI Study • Summary
  46. 46. Cytokine Signaling of JAK Common γ chain shared by receptors for: IL-2R, IL-4R, IL- IL- IL-7R, IL-9R, IL-15R, IL-21R IL- IL- IL- IL- NK Cell IL- 2 Cytokine Effector IL- 4 X IL- 21 T Cell X Expansion IL- 2 Expansion IL- 15 T CP-690,550 Cell JAK 1 JAK 3 blocks this point in the P Monocyte P signaling B cell cascade, P before STAT X X IL- 4 IL- 4 is activated IL- 7 STAT P Differentiation P Activation STAT STAT Current Opinion in Rheumatology 2005: 17; 305 - reproduced with permission.
  47. 47. CP-690,550 Update • Significant Unmet Need • Mechanism of Action • Review of Program and Previous RA Data • New Presentations at ACR – 12 week dose response data (study 1025) – Open Label Extension (study 1024) – MTX DDI Study (study 1013) • Summary
  48. 48. Study 1019: Design 1o anal- ysis Weeks 0 1 2 3 4 5 6 7 8 9 10 11 12 5 mg BID (N=64) Screening 15 mg BID (N=61) Days -28 to 0 30 mg BID (N=61) Informed Placebo (N=68) Follow-Up Consent Double-Blind Off Drug • Subjects with active RA who had failed either methotrexate ≥ 15 mg/wk or a TNF- inhibitor, but currently were on no DMARDs or biologics • At least 9 tender and 6 swollen joints PLUS 2 of: – ≥45 minutes AM stiffness; ≥28 mm/hr ESR; ≥10 mg/L CRP • Background NSAIDs, analgesics, low-dose glucocorticoids allowed • Equal randomization • Study approved by local IRBs/ECs and all subjects provided written informed consent
  49. 49. The ACR 20/50/70 ACR-20/50/70 Criteria Achieved When All of the Following Are True: • 20/50/70% improvement from baseline in the tender joint count • 20/50/70% improvement from baseline in the swollen joint count • 20/50/70% improvement from baseline in at least 3 of the 5 variables: 1 Patient Global Assessment 2 Physician Global Assessment 3 Patient Pain Visual Analog Score (VAS) 4 HAQ disability index 5 C-Reactive Protein / Erythrocyte Sedimentation Rate (ESR)
  50. 50. Study 1019: Week 6 ACR Response Rates Placebo 81% 77% 5 mg 70% 15 mg 30 mg 54% 51% 33% 29% 28% 22% 13% 6% 3% ACR 20 ACR 50 ACR 70
  51. 51. CP-690,550 RA Program 2006 2007 2008 2009 2010 1019 1025 (MTX) Phase III RA Program RA POC 1035 (Monotherapy) 1029 (F/U off Drug) Open Label Extension Studies (1024) P2 1039 (Japan MTX) ACR 2006 P2 1040 (Japan Monotherapy) ACR 2008
  52. 52. CP-690,550 Update • Significant Unmet Need • Mechanism of Action • Review of Program and Previous RA Data • New Presentations at ACR – 12 week dose response data (study 1025) – Open Label Extension (study 1024) – MTX DDI Study (study 1013) • Summary
  53. 53. A3921025 Study Design Interim Analysis Week 0 2 4 6 8 10 12 14 16 18 20 22 24 20 mg QD (N=80) 15 mg BID (N=75) 10 mg BID (N=75) Methotrexate 5 mg BID (N=71) 3 mg BID (N=68) 1 mg BID (N=71) Placebo (N=69) Efficacy (Primary) Durability (Secondary) Safety Signals • Subjects with RA and inadequate response to stable dose (at least 6 weeks) MTX 7.5–25 mg/wk; if dosed <15 least 7.5– mg/wk, must have documented intolerance to or toxicity from higher doses higher • At least 6 tender and 6 swollen joints and either CRP >7 mg/L OR ESR > ULN locally • Background NSAIDs, analgesics, low-dose glucocorticoids allowed; DMARDs other than MTX washed out low- • Equal randomization • Subjects assigned to placebo, 1 mg BID, 3 mg BID or 20 mg QD who did not achieve at least 20% reduction in TJC and SJC at week 12 automatically advanced to 5 mg BID • This study was approved by local IRBs/ECs and all subjects provided written informed consent provided
  54. 54. Study 1025: Week 12 ACR Response Rates Placebo 70% ACR Week 12 Responder Rates, LOCF (%) 1 mg BID ** * * * 60% 3 mg BID 5 mg BID 50% ** 10 mg BID 15 mg BID 40% * * 20 mg QD 30% ** * * 20% 10% 0% ACR20 ACR50 ACR70 * p≤0.05 ** p≤0.0001
  55. 55. Study 1025: ACR 20 Response Rates Over Time Placebo 100 1 mg BID 90 3 mg BID 5 mg BID 80 10 mg BID 15 mg BID 70 20 mg QD Response Rate P<=0.05 60 (nominal significance vs. Placebo) 50 40 30 20 10 0 0 2 4 6 8 10 12 Week
  56. 56. Study 1025: Week 12 Efficacy Summary • All doses except 1 mg bid showed a significantly better response than placebo, confirming efficacy from earlier 1019 study • Efficacy generally improved with higher doses with maximal effects generally observed at 15 mg bid • Onset of efficacy was as early as 2 weeks, peaked at 8 weeks and was maintained at 12 weeks
  57. 57. Study 1025: Serious Infections CP-690,550 MTX Weekly Event Dose Dose Age Pneumonia 3 mg BID 15 mg 40 Urinary tract 3 mg BID 15 mg 52 infection Pneumonia 5 mg BID 15 mg 56 Respiratory 10 mg BID 20 mg 68 tract infection Pneumonia 20 mg QD 17.5 mg 53 Serious infection was defined as one requiring hospitalization or parenteral antibiotic therapy; or any subject with a serious infection was withdrawn from the study. All serious infections were study. observed in female study participants.
  58. 58. Study 1025: Mean Changes from Baseline in HGB and ANC at Week 12 HGB Change ANC Change k/µl Dose g/dl Dose 1 mg BID 0.02 1 mg BID -0.80 3 mg BID 0.11* 3 mg BID -0.50 5 mg BID 0.14* 5 mg BID -0.82 10 mg BID -0.42 10 mg BID -0.83 15 mg BID -0.40 15 mg BID -1.18* 20 mg QD -0.12 20 mg QD -0.32 placebo -0.18 placebo -0.35 * P < 0.05 compared to placebo
  59. 59. Study 1025: Severe Anemia and Neutropenia Incidence Through Week 12 of • 3 subjects had ANC’s Subjects with Anemia That Is less than 1000 k/µl Severe or Life Threatening Anemia Rates – 15 mg bid Above – 15 mg bid Dose N n Observed Placebo placebo 67 2 3.0% – 1 mg bid 1 mg BID 69 3 4.4% 1.4% • No potentially life 3 mg BID 67 2 3.0% 0.0% threatening cases 5 mg BID 70 1 1.4% -1.6% of neutropenia (< 500 10 mg BID 73 5 6.9% 3.9% k/µl) 15 mg BID 73 6 8.2% 5.2% 20 mg QD 79 2 2.5% -0.5% Severe or Life-threatening Anemia (combined), defined by Life- OMERACT as a decrease of at least 2.1 G/dL or a hemoglobin < 8 G/dL
  60. 60. Study 1025: Incidence of Transaminase Elevations (Subjects with Normal BL) AST > 3 X ULN ALT > 3 X ULN 1 mg BID 0 0 3 mg BID 0 0 5 mg BID 0 0 10 mg BID 1 (1%) 1 (1%) 15 mg BID 2 (3%) 4 (5%) 20 mg QD 2 (3%) 1 (1%) placebo 0 1 (2%) No subject met “Hy’s rule”: ALT > 3 X ULN and Bilirubin > 2 X ULN Hy’ rule”
  61. 61. Study 1025: Mean Changes from Baseline in HDL and LDL at Week 12 HDL Change LDL Change Dose mg/dl Dose mg/dl 1 mg BID 2.22* 1 mg BID 6.31** 3 mg BID 3.63** 3 mg BID 8.14** 5 mg BID 6.11** 5 mg BID 12.97** 10 mg BID 2.71* 10 mg BID 16.17** 15 mg BID 4.74** 15 mg BID 15.23** 20 mg QD 5.78** 20 mg QD 9.61** placebo -1.32 placebo -5.15 * P < 0.05 compared to placebo ** P < 0.005 compared to placebo
  62. 62. Study 1025: Safety Summary (Week 12) • Serious infections were few and not dose responsive • Dose related changes in hemoglobin and neutrophils were seen. Incidences of OMERACT severe or life-threatening anemia and neutropenia were low. No subject was withdrawn for protocol specified hemoglobin or neutrophil levels • Small increases in serum creatinine over baseline were seen in all dose groups, including placebo. No increases were progressive over time compared to placebo • Dose dependent increases in LDL, HDL and total cholesterol were observed, but increases appeared to plateau by week 6 • Increased incidences of potentially significant ALT increases were observed in the 15 mg BID dose
  63. 63. Study 1025: Overall Conclusions • An efficacy and safety profile justifying progression to Phase III was observed • The data presented, plus the 24 week data from this study, plus data anticipated from study 1035 will provide a robust database to inform Phase III dosing
  64. 64. CP-690,550 Update • Significant Unmet Need • Value Proposition and Mechanism • Review of Program and Previous RA Data • New Presentations at ACR – 12 week dose response data (study 1025) – Open Label Extension (study 1024) – MTX DDI Study (study 1013) • Summary
  65. 65. Study A3921024: Open-label, Long-term, Multicenter Study Months 0 3 6 9 12 Study A3921025 24 weeks, background MTX Screening CP-690,550 5 mg BID Days -28 to 0 Study A3921019 6 Weeks, Monotherapy • Patients could continue their stable background RA therapy, including approved DMARDs and glucocorticoids • Specific rescue medications and adjustments of background therapy were allowed • Study approved by local IRBs / ECs. All subjects gave written informed consent
  66. 66. Study 1024: Interim Analysis • An interim analysis was conducted of all safety data for all 129 patients enrolled as of 22-Feb-2008 • Comparisons in laboratory data and DAS were made at 1 and 6 months – 40 patients had completed 6 months in study as of 22-Feb-2008
  67. 67. Study 1024: Adverse Events* in 129 Subjects • Total AEs = 160 – Mild = 93 – Moderate = 64 – Severe = 3 (myocardial infarction, RA, acne) • Infections = 32 – Mild = 13 – Moderate = 19 – Severe = 0 – No serious AE’s related to infection by data cut * At time of Feb 22, 2008 data cut
  68. 68. Study 1024: Laboratory Values at 6 Months CP-690,550 5 mg BID 1025 1019 All 0.92 ± 0.23 0.86 ± 0.20 0.88 ± 0.21 Serum creatinine, mg/dL 5.27 ± 1.56 5.01 ± 1.81 5.09 ± 1.73 Neutrophil count, 103/mm3 12.31 ± 0.91 13.70 ± 1.30 13.28 ± 1.35 Hemoglobin, g/dL 117.02 ± 34.36 145.45 ± 34.90 136.92 ± 36.74 LDL, mg/dL 69.43 ± 27.30 62.44 ± 15.81 64.54 ± 19.84 HDL, mg/dL Data presented as mean ± SD
  69. 69. Study 1024: DAS28-3 (CRP) Study 1025 Study 1019 All Patients 6.0 5.0 Mean (SD) DAS28-3 Score 4.0 3.0 2.0 1.0 0.0 N=68 N=32 N=100 N=12 N=27 N=39 Month 1 Month 6
  70. 70. Study 1024: DAS28-4 (ESR) Study 1025 Study 1019 All Patients 7.0 6.0 Mean (SD) DAS28-4 Score 5.0 4.0 3.0 2.0 1.0 0.0 N=69 N=6 N=75 N=12 N=20 N=32 Month 1 Month 6
  71. 71. Study 1024: Conclusions • CP-690,550 5 mg BID was well tolerated and efficacious in patients with moderate to severe active RA over a median of 109.0 days • DAS 28 was similar in all patients at 6 months, regardless of prior study experience • Mean laboratory values remained within normal limits at 6 months; no patient required discontinuation due to individual changes in laboratory values
  72. 72. CP-690,550 Update • Significant Unmet Need • Value Proposition and Mechanism • Review of Program and Previous RA Data • New Presentations at ACR – 12 week dose response data (study 1025) – Open Label Extension (study 1024) – MTX DDI Study (study 1013) • Summary
  73. 73. Study 1013: MTX DDI Study Summary • Study Objectives: – To estimate the effects of MTX on the pharmacokinetics (PK) of CP-690,550 when administered to subjects with RA – To estimate the effects of multiple doses of CP-690,550 (30 mg Q 12 h) on the PK of MTX – To evaluate the short-term safety and tolerability of co-administration of CP-690,550 (30 mg Q 12 h) and MTX • Conclusions: – Co-administration of CP-690,550 and MTX in RA subjects appeared to be safe and well tolerated – MTX had no clinically relevant effect on the CP-690,550 PK – CP-690,550 had no clinically relevant effect on MTX AUC values and the observed 10% increase in MTX Cmax value when co-administered with CP-690,550 is not expected to be clinically important – Therefore, based on the PK results from this study, no dosage adjustment is needed when co-administering CP-690,550 and MTX
  74. 74. CP-690,550 RA Program 2006 2007 2008 2009 2010 1019 1025 (MTX) Phase III RA Program RA POC 1035 (Monotherapy) 1029 (F/U off drug) 1024 (Open Label Extension) P2 1039 (Japan MTX) ACR 2006 P2 1040 (Japan Monotherapy) ACR 2008
  75. 75. Conclusion • Current products for RA have significant limitations • CP-690,550 may offer benefits of both a small molecule and a biologic • Data to date for CP-690,550 has demonstrated a promising profile • Robust clinical program underway / Plans for Phase III trial progressing
  76. 76. Q&A

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