Faculty David M. Pariser, MD Professor Eastern Virginia Medical School Norfolk, VA

Transcription

1

2 Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current as of May The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of Creative Educational Concepts or the supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

3 Usage Rights This slide deck is provided for educational purposes and slides may be used for personal, non-commercial presentations only as long as content and references remain the same. No part of this slide deck may be published or distributed in print or electronic format without prior written permission from Creative Educational Concepts.

4 Learning Objectives Analyze the pathogenesis of psoriasis, focusing on the inflammatory cascade and corresponding therapeutic targets for traditional non-biologic systemic agents as well as novel biologic therapies in development. Explore current treatment paradigms for psoriasis using traditional biologic agents and examine potential place in therapy for newer emerging biologic therapies, appraising the predicted benefits of these emerging agents based on novel therapeutic targets. Using real-world, case-based patient scenarios, effectively integrate strategies and develop treatment plans for patients with psoriasis that address practical issues in the use of traditional biologic agents, and potential place in therapy for emerging biologic agents

5 Faculty David M. Pariser, MD Professor Eastern Virginia Medical School Norfolk, VA Please refer to your handout for a full list of disclosures.

6

7 Psoriasis: Clinical Decision Making for the Nurse Practitioner Complete skin and joint assessment Diagnosing Initiating therapy Managing patient over time Adjusting therapy Monitoring for adverse events and comorbidities

8 Limited Forms of Psoriasis

9 Widespread Plaque Psoriasis

10 Dermatology s New View on Psoriasis 1 o skin disorder 20 years Immunologic dysfunction

11 Healthy Skin Immunology of Psoriasis Injury or Inflammation Steady-state Immunity (tolerance) Immune Amplification (active effector immunity) Lowes MA, et al. Annu Rev Immunol

12 Clinical and Histological Picture Non-Lesional Lesional Lowes MA, et al. Annu Rev Immunol

13 Increasing Risk Prior Treatment Paradigm Process: Psoriasis therapy followed stepwise progression Patients must fail the previous step of therapy before initiating a more aggressive therapy OTC Products Emollients Other Rx Topical Agents Topical steroids Vitamin D analogs Topical retinoids Other Rx topicals Phototherapy UVB Broadband UVB Narrowband PUVA Laser Systemic Therapy Cyclosporine Methotrexate Acitretin Systemic steroids Order of Treatment Progression Lebwohl M, et al. J Am Acad Dermatol

14 Shifting the Treatment Paradigm Treatment Toolbox for Moderate to Severe Disease Topicals for mild disease Phototherapy Laser PUVA UVB Systemic Agents Acitretin Apremilast Cyclosporine Methotrexate Biologic Agents Adalimumab Etanercept Infliximab Secukinumab Ustekinumab

15 Who Says So? AAD Consensus Statement on Psoriasis Therapies (J Am Acad Dermatol, November, 2003): Systemic therapy may be considered for patients with psoriasis on the palms, soles, head and neck, genitalia or when 5% or more of skin surface is involved Biologics should be considered among the first-line treatment options in a patient who is a candidate for systemic therapy AAD=American Academy of Dermatology Callen JP, et al. J Am Acad Dermatol

16 Determining Severity Pariser, et al. (2007) NPF Med Ad Board Consensus on Disease Severity This clinical consensus statement proposes a 2-tiered system for plaque psoriasis therapy that reflects more accurately than the current system how patients are treated in clinical practice. American Academy of Dermatology Work Group, et al. (2011) Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. The severity of psoriasis is defined not only by extent of body surface area (BSA) involvement (<5% being considered mild, 5% but <10% moderate, and 10% severe), but also by involvement of the hands, feet, facial, or genital regions, by which, despite involvement of a smaller BSA, the disease may interfere significantly with activities of daily life. NPF=National Psoriasis Foundation Pariser DM, et al. Arch Dermatol. 2007; Menter A, et al. J Am Acad Dermatol

17 When to Select a Systemic Effective and manageable risk if used correctly Variable cost to patient Not all are candidates for biologic therapy Biologic therapies may fail as monotherapy, and succeed in combination with systemics Rescue therapies in tough clinical scenarios Options Methotrexate, Cyclosporine (CyA), Acitretin, Apremilast

18 Percentage of Patients Methotrexate and Cyclosporine: PASI 75 Response at Week % 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Double-blind, active-controlled (no placebo) Dose adjustments allowed for each drug 71% Cyclosporine (N=42) Dose mg/kg 60% Methotrexate (N=43) Dose mg/kg Vera MR, et al. N Engl J Med

19 Percentage of Patients Responding Methotrexate Efficacy vs. Infliximab For all visits: P< Weeks Infliximab (N=653) MTX (N=215) PASI 75 response by visit (intent-to-treat population). Patients achieving <PASI 50 by Week 16 (grey line) were permitted to switch treatment groups MTX=methotrexate Barker J, et al. Br J Dermatol

20 Area-Severity Index Cyclosporine: Dose Dependent Efficacy Fixed-Dose Phase Adjusted-Dose Phase Week of Study Placebo 3 mg/kg/day 5 mg/kg/day 7.5 mg/kg/day Solid symbols indicate significantly different values vs. before treatment (week 0) (P<.005) All groups receiving cyclosporine had significant improvement vs. placebo (P<.001) The groups receiving 5 mg/kg/day and 7.5 mg/kg/day had significant improvement vs. the group receiving 3 mg/kg/day (P<.01) but not as compared with each other (P>.4) Ellis CN, et al. N Engl J Med

21 Acitretin % BSA Involvement Reduction Group Double-Blind Daily Dose, mg Open-Label Daily Dose, mg Mean % BSA % BSA Reduction at Week 8 % BSA Reduction at Week 24 (N=19) 25 (Lo) (N=52) 25 (Lo) (N=23) 50 (Hi) (N=77) 50 (Hi) Placebo (N=101) 0 (mean, 43) (worse disease) 43 Mean % BSA involvement at baseline. After DBL phase, placebo patients were allowed into open-label phase to receive treatment. Haushalter K, et al. J Dermatolog Treat

22 Limitations of Conventional Systemic Therapies Agent Adverse Event Contraindications Methotrexate Cyclosporine Acitretin Hepatotoxicity, drug interactions, immunosuppression, bone marrow suppression, pneumonitis, birth defects, decreased sperm count, miscarriage Immunosuppression, impaired renal function, hypertension, malignancies, drug interactions Birth defects, mucocutaneous effects, dyslipidemia Pregnancy (category X) a, breastfeeding, renal impairment, hepatitis, cirrhosis, leukopenia, thrombocytopenia, regular alcohol use, unreliability in patients Acute infections, active malignancies, uncontrolled hypertension, impaired renal function Pregnancy b, breastfeeding a Rule out pregnancy in women of childbearing potential; avoid pregnancy if either partner is receiving methotrexate; contraception: women, during therapy and at least 1 ovulatory cycle afterward; men, at least 3 months after therapy. b Patients should not become pregnant for at least 3 years following drug discontinuation. Menter A, et al. J Am Acad Dermatol

23 Advantages of Conventional Systemic Therapies Agent Methotrexate Cyclosporine Acitretin Advantages Fast acting Good efficacy Effective in psoriasis and psoriatic arthritis FDA approved for psoriasis and psoriatic arthritis Long track record in rheumatoid arthritis Combination data available with biologics Least expensive Very fast acting Very high efficacy FDA approved for psoriasis and psoriatic arthritis Long track record in rheumatoid arthritis and Crohn s disease Pregnancy class B Oral agent Side effects not serious and manageable Use in pustular psoriasis Hands and feet Pathirana D, et al. J Eur Acad Dermatol Venereol. 2009; Menter A, et al. J Am Acad Dermatol

24 Small Molecules

25 Apremilast Novel, oral small molecule Inhibits PDE-4 Anti-inflammatory properties Reduces TNF-α, IL-2, IFN-γ, several leukotrienes and NO synthase Recently FDA approved for PsA and PsO in adult patients with moderate to severe plaque No recommended laboratory or TB monitoring PDE-4=phosphodiesterase-4; PsA=psoriatic arthritis; PsO=psoriasis; TB=tuberculosis Reich K, et al. Presented at AAD Annual Meeting; 2013.

26 Apremilast Mechanism of Action Reich K, et al. Presented at AAD Annual Meeting; 2013.

27 Patients Achieving PASI 75 (%) Apremilast Phase III (ESTEEM 1): PASI 75 by Prior Treatment Experience at Week N= Overall LOCF, Full Analysis Set (N=844) No Prior Systemic No Prior Biologic P<.0001; P=.0273 vs. placebo. Conventional +/or biologics. Prior Biologic Placebo Apremilast 30 mg BID Failed Prior TNF Reich K, et al. Presented at AAD Annual Meeting; 2013.

28 Apremilast Phase III (ESTEEM 1): AEs in 5% of Any Treatment (Weeks 0-16) Adverse Event (AE) N(%) Placebo (N=282) Apremilast 30 mg BID (N=560) Diarrhea 20(7.1) 105(18.8) Nausea 19(6.7) 88(15.7) URTI 21(7.4) 57(10.2) Nasopharyngitis 23(8.2) 41(7.3) Tension headache 12(4.3) 41(7.3) Headache 13(4.6) 31(5.5) >96% of patients had mild/moderate or no AEs. 1 (0.4%) placebo and 2 (0.4%) apremilast 30 mg twice daily patients reported severe diarrhea or nausea. Diarrhea includes loose stools and increased urgency. URTI=upper respiratory tract infection Reich K, et al. Presented at AAD Annual Meeting; 2013.

29 Patient Case

30 Case 27 year old female, psoriasis onset early 20sbetter but never clear or comfortable with topical agents Only health issue- 5 3 and 185 lbs Strong family history of psoriasis CyA used to quickly clear her for her wedding with transition to adalimumab 90% clear for 2 years-became pregnant Elected not to discontinue while pregnant Moved to East Coast in first trimester

31 Returned to Dallas Case-Updated History East Coast Derm withheld adalimumab throughout first pregnancy-topicals helped miminally Post-partum flare-started on etanercept, some improvement, another pregnancy, held drug until post-partum flare then moved back to Dallas Presented with very inflammatory, pruritic large plaques almost 30% BSA, no arthralgia Restarted adalimumab-regained 75% clearance

32

33 Case Continued Adalimumab less effective than first experience Options: Continue, increase dose, add another agent, or change biologics Ustekinumab 45 mg utilized Better, not clear, with flare 1-2 weeks pre-dosing, occasional hand stiffness and tender joints Options: Continue, increase dose, decrease interval, add another agent, or change biologics

34 Better but Flares Pre-Dosing

35 Better vs. Almost Clear vs. Clear Should we consider combination therapy (adding methotrexate or apremilast) or changing biologic agents? Can we get her closer to PASI 90 or 100? Does it matter?

36 Case Current Treatment Plan Secukinumab was presented as an option as monotherapy with continuation of current regimen until new drug approved OR increase dose of ustekinumab to 90 mg every 12 weeks OR decrease interval to every 8 week dosing Patient elected to attempt dosing at every 8 week interval if approved, if not, we will transition to secukinumab

37 When to Select a Biologic Patient needs more effective therapy (MTX, CyA, Acitretin) not an option Previous sub-optimal experience ( failure ) Contraindication Phototherapy not an option Unavailability or inconvenient Cost prohibitive Failure or risk of skin cancer Pathirana D, et al. J Eur Acad Dermatol Venereol. 2009; Menter A, et al. J Am Acad Dermatol. 2008; Menter A, et al. J Am Acad Dermatol

38 Which Biologic to Select Self injectable vs. in office injection or infusion Rapid onset of therapeutic effect needed Prior biologic use Medical history and concomitant illnesses Arthralgia Malignancy history or risk Infection-TB Multiple sclerosis or other demyelinating disease Congestive heart failure And, unfortunately Provider comfort level Insurance formulary status Patient copayments Pathirana D, et al. J Eur Acad Dermatol Venereol. 2009; Menter A, et al. J Am Acad Dermatol. 2008; Menter A, et al. J Am Acad Dermatol

39 T-Cell Inhibitors 1st Generation Biologics

40 Screening Prior to Starting a Biologic Initial Assessment of Immunization Status or Disease History Haemophilus influenzae Diphtheria Tetanus Pertussis Varicella zoster Hepatitis A and B Human papillomavirus Influenza Herpes Zoster MMR Meningococcal Streptococcus pneumoniae TNF-α blockers: Adalimumab, Etanercept, Infliximab Complete blood cell count + platelets: baseline and every 2-6 months Chemistry screen + LFT: baseline and every 2-6 months TB skin test: baseline and annually thereafter Ustekinumab TB skin test: baseline Lebwohl M, et al. J Am Acad Dermatol. 2008; Wine-Lee L, et al. J Am Acad Dermatol. 2013; FDA Prescribing Information.

41 Cytokines and Cytokine Inhibitors in Chronic Inflammation TNF-α IL-1 IFN- IL-8 GM-CSF IL-12 IL-23 Others Pro-inflammatory Adalimumab Etanercept Infliximab Golimumab IL-15 IL-16 IL-17 IL-18 IL-22 TGFβ IL-6 2 nd Generation Biologics IL-1RA sil-1r1 stnf-ri,ii IL-4 IL-10 IL-11 IL-13 IL-18BP Anti-inflammatory Sabat R, et al. Exp Dermatol

42 % Patients Adalimumab Phase III: PASI 75 Response Weeks 0 24 Placebo (N=398) Adalimumab (N=814) Week 4 Week 8 Week 12 Week 16 Week 24 Note: Intention-to-Treat (ITT), patients with missing PASI scores considered non-responders P<.001 adalimumab vs. placebo Menter A, et al. J Am Acad Dermatol

43 PASI 75 Response (% of Patients) Methotrexate Efficacy vs. Adalimumab Placebo Methotrexate Adalimumab # Week 4 Week 8 Week 12 Week 16 # P=.001 adalimumab vs. placebo; P<.001 adalimumab vs. placebo P<.001 adalimumab vs. methotrexate. Note: ITT: pts with missing PASI scores considered non-responders Saurat JH, et al. Br J Dermatol

44 % Patients Etanercept: PASI 75 at 12 Months Etanercept 25 mg BIW Etanercept 50 mg --> 25 mg Etanercept 50 BIW Intent to Treat, LOCF mg BIW mg 25 mg BIW 60% 45% 20 As Treated Weeks BIW=twice weekly; LOFC=last observation carried forward Sterry W, et al. Presented at EADV Annual Congress; 2004; Papp KA. Arch Dermatol Res

45 % Patients Infliximab: PASI 75 Over Time 100 Infliximab 5 mg/kg Non-Responder Imputation Dropouts for lack of efficacy=tx Failure Missed data points=tx Failure Conservative view of data Weeks Reich K, et al. Lancet

46 Cytokines and Cytokine Inhibitors in Chronic Inflammation Tildrakizumab Gesulkumab TNF-α IL-1 IFN- IL-8 GM-CSF IL-12 IL-23 Others Pro-inflammatory Ustekinumab Briakinumab IL-15 IL-16 IL-17 IL-18 IL-22 TGFβ IL-6 Secukinumab Ixekizumab Brodalumab 3 rd Generation Biologics IL-1RA sil-1r1 stnf-ri,ii IL-4 IL-10 IL-11 IL-13 IL-18BP Anti-inflammatory Sabat R, et al. Exp Dermatol

47 Agents Targeting Interleukins Ustekinumab IL-12, IL-23 IL-17A Secukinumab Ixekizumab Brodalumab IL-23 Tildrakizumab Gesulkumab

48 Psoriasis: Targeting the IL-12/23 Pathway IFNγ Th1 IL-2 APC TNF-β Th17 Th22 IL-17a IL-17f IL-6 TNF-α IL-21 IL-22 Fitch E, et al. Curr Rheumatol Rep. 2007; Romagnani S. Inflamm Bowel Dis

49 The p40 Subunit is Shared IL-12 IL-23 p40 p35 p19 p40 Ustekinumab NK or T cell membrane Leonardi CL, et al. Lancet. 2008; Papp KA, et al. Lancet

50 When to Select an IL-12/23 Biologic First-line for any moderate to severe adult patient with psoriasis that is a candidate for a systemic agent or phototherapy Also approved for PsA Inadequate response to systemic or TNF inhibitor Dosing schedule or in office injections preferred

51 Percent of Patients Phoenix 1 & 2: PASI 75 Response at Week PHOENIX PHOENIX Placebo N=255 Ustekinumab 45 mg N=255 Ustekinumab 90 mg N=256 4 Placebo N=410 Ustekinumab 45 mg N=409 Ustekinumab 90 mg N=411 P<.001 vs. placebo Leonardi CL, et al. Lancet. 2008; Papp KA, et al. Lancet

52 Percent of Patients Ustekinumab Phase III PASI Response Over 28 Weeks PHOENIX 1 Week PHOENIX 2 Week PASI 50 PASI 75 PASI 90 0 PASI 50 PASI 75 PASI 90 Ustekinumab 45 mg (N=250) Ustekinumab 90 mg (N=243) Ustekinumab 45 mg (N=397) Ustekinumab 90 mg (N=400) P<.001 vs. placebo for all comparisons Leonardi CL, et al. Lancet. 2008; Papp KA, Lancet

53 Function of Th17 Effector Cytokines IL-17a Expressed by memory T cells and NK cells Increased in psoriatic skin Subcutaneous injection neutrophilia Enhances inflammation Enhances angiogenesis Fitch E, et al. Curr Rheumatol Rep IL-22 Expressed in high levels by Th17 cells Increased in psoriasis (skin and plasma) Levels correspond to disease activity Induces keratinocyte hyperproliferation (in vivo, in vitro) Stimulates keratinocytes to secrete antimicrobial peptides

54 Percent of Subjects Secukinumab Phase III Psoriasis Results ERASURE Results PASI 75 and IGA 0/1 Through 52 Weeks (1/2) PASI 75 Response Secukinumab 300 mg Secukinumab 150 mg IGA 0/1 Response Secukinumab 300 mg Secukinumab 150 mg Placebo Placebo Week Week Secukinumab 150 mg (N=245) Secukinumab 300 mg (N=245) Placebo (N=247) IGA=investigator s global assessment Langley RG, et al. N Engl J Med

55 Secukinumab: Phase II Safety Results Preferred Term 1x25 mg N=29 N(%) Secukinumab 3x25 mg N=26 N(%) 3x75 mg N=21 N(%) 3x150 mg N=27 N(%) Placebo N=22 N(%) Patients with any AE(s) 22(75.9) 19(73.1) 16(76.2) 24(88.9) 16(72.7) Death (4.5) Serious Adverse Events (SAEs) 0 2(7.7) 1(4.8) 0 2(9.1) AEs leading to discontinuation 0 1(3.8) 0 1(3.7) 0 AEs and infections 5% in any treatment group Psoriasis (worsening) 8(27.6) 4(15.4) 4(19.0) 3(11.1) 2(9.1) Nasopharyngitis 1(3.4) 4(15.4) 4(19.0) 4(14.8) 2(9.1) Pharyngitis 0 1(3.8) 0 2 (7.4) 0 Upper respiratory tract infection 3(10.3) 2(7.7) 1(4.8) 2(7.4) 0 Headache 1(3.4) 2(7.7) 1(4.8) 1(3.7) 0 Pruritus 1(3.4) 0 0 1(3.7) 3(13.6) Respiratory tract infection, viral 1(3.4) 1(3.8) 1(4.8) 0 2(9.1) Papp KA, et al. Br J Dermatol

56 Secukinumab: Phase II Safety Results Secukinumab Preferred Term 1x25 mg N=29 N(%) 3x25 mg N=26 N(%) 3x75 mg N=21 N(%) 3x150 mg N=27 N(%) Placebo N=22 N(%) Other AEs of interest Atrial fibrillation 0 1(3.8) 0 0 1(4.5) Acute myocardial infarction (4.5) Arrhythmia 1(3.4) Cardiac failure, congestive 0 1(3.8) Cardiomyopathy 0 1(3.8) Myocardial infarction (4.5) Wolff-Parkinson-White syndrome 0 0 1(4.8) 0 0 Papp KA, et al. Br J Dermatol

57 Percent Improvement in PASI Score Brodalumab: Phase II Efficacy Results Percent Improvement in PASI Scores over Time Week All P<.001 vs. placebo and vs. 70 mg dose of brodalumab P<.001 vs. placebo 210 mg Brodalumab group 140 mg Brodalumab group 280 mg Brodalumab group 70 mg Brodalumab group Placebo group The P value for the comparison of the 70 mg dose of brodalumab with placebo (P<.001) is for all the time points except week 2, for which the P value was.002. PASI denotes psoriasis-area-and-severity index. Papp KA, et al. N Engl J Med

58 Brodalumab: Phase II Safety Results Variable Placebo Brodalumab Adverse events (N=37) 70 mg (N=38) 140 mg (N=39) 210 mg (N=40) Number of Patients(Percent) 280 mg (N=41) Total (N=158) Any 23(62) 26(68) 27(69) 33(82) 30(73) 116(73) Serious 1(3) 1(3) 0 1(2) 0 2(1) Leading to withdrawal from study (2) 1(1) Leading to discontinuation of study drug 1(3) 0 0 2(5) 1(2) 3(2) Grade 3, 4, or 5 2(5) 1(3) 1(3) 3(8) 2(5) 7(4) Common adverse events Nasopharyngitis 3(8) 6(16) 1(3) 4(10) 2(5) 13(8) Upper respiratory tract infection 2(5) 3(8) 3(8) 2(5) 5(12) 13(8) Arthralgia 1(3) 1(3) 2(5) 0 4(10) 7(4) Injection-site erythema 1(3) 1(3) 1(3) 3(8) 4(10) 9(6) Pain in extremity 0 1(3) 0 3(8) 4(10) 8(5) Nausea 1(3) 4(11) 1(3) 1(2) 0 6(4) A serious adverse event was defined as an event that was fatal or life threatening, required or prolonged hospitalization, or caused persistent or substantial disability or incapacity or a congenital anomaly or birth defect or an event that was considered by the investigator to be a medically important event. The severity of adverse events was graded according to the National Cancer Institute s Common Terminology Criteria for Adverse Events, version 4.0. Common adverse events were those that were reported in at least four patients in any treatment group. Papp KA, et al. N Engl J Med

59 Subjects Achieving a PASI Response (% With 95% CI) Results: PASI 75/90/100 in Subjects Treated With Brodalumab from Parent Study Baseline, Observed Data 100 PASI 75 PASI 90 PASI N=173 N=175 N=175 N=175 N=175 N=172 N=168 N=169 N=165 N=159 N= Weeks N=number of subjects who were treated and had an assessment at the specified visit As observed analysis 165 subjects remained on study at week 48 (48 on 140 mg; 117 on 210 mg); 153 remained on study and had an assessment at week 96 (105 on 140 mg; 48 on 210 mg) Papp KA, et al. N Engl J Med

60 Patients (%) Ixekizumab: Phase II Efficacy Results Patients (%) Placebo (N=26) 10 mg Ixekizumab (N=28) 25 mg Ixekizumab (N=30) 75 mg Ixekizumab (N=29) 150 mg Ixekizumab (N=28) 75% Reduction in PASI Score 90% Reduction in PASI Score mg 75 mg 25 mg 10 mg mg 75 mg 25 mg 10 mg Weeks Placebo Weeks Placebo Leonardi C, et al. N Engl J Med

61 Patients (%) Ixekizumab: Phase II Efficacy Results Patients (%) Placebo (N=26) 10 mg Ixekizumab (N=28) 25 mg Ixekizumab (N=30) 75 mg Ixekizumab (N=29) 150 mg Ixekizumab (N=28) 100% Reduction in PASI Score spga Score of 0 or mg 75 mg 25 mg mg 25 mg 75 mg 10 mg Weeks 10 mg Placebo Weeks Placebo Leonardi C, et al. N Engl J Med

62 Ixekizumab: Phase II Adverse Events Adverse Events during the Study Period (through 20 Weeks), According to Study Group. Variable Placebo (N=27) 10 mg (N=28) 25 mg (N=30) 75 mg (N=29) 150 mg (N=28) No. of adverse events No. of serious adverse events Adverse events-no. patients (%) 17(63) 21(75) 21(70) 17(59) 13(46) Adverse events-no. of patients (%) Infection or infestation 7(26) 12(43) 9(30) 9(31) 8(29) Nasopharyngitis 5(19) 3(11) 3(10) 3(10) 4(14) Upper respiratory infection 1(4) 1(4) 3(10) 1(3) 1(4) Injection-site reaction 0 0 3(10) 1(3) 2(7) Headache 1(4) 4(14) 4(13) 1(3) 1(4) Allergy or hypersensitivity 2(7) 1(4) 1(3) 2(7) 1(4) Adverse events were those that first occurred or worsened after randomization. The specific events listed are those that occurred in at least 5% of patients receiving ixekizumab. Allergy or hypersensitivity was defined as that distinct from injection-site reactions. Allergy or hypersensitivity events include those described by reported terms that were consistent with hypersensitivity on the basis of Medical Dictionary for Regulatory Activities Standard Medical Queries for anaphylactic reaction, angioedema, and severe cutaneous adverse reaction. Leonardi C, et al. N Engl J Med

63 Tildrakizumab

64 Selectively Targeting IL-23 The p19 Subunit is NOT Shared IL-12 IL-23 p40 p35 p19 p40 NK or T cell membrane

65 % Patients Tildrakizumab: Phase IIb Psoriasis Trial 100 PASI 75 at 16 Weeks 100 PASI 90 at 16 Weeks PBO 5 mg 25 mg 100 mg 200 mg PBO 5 mg 25 mg 100 mg 200 mg N=41 N=40 N=87 N=88 N=84 N=45 N=42 N=90 N=87 N=86 Note: ITT-NRI analysis P.001 vs. placebo Thaci D, et al. Presented at EADV Annual Congress; 2013.

66 Tildrakizumab: Phase IIb Psoriasis Trial Adverse Events 5% in Any Treatment Group [N(%)] 5 mg (N=42) 25 mg (N=91) 100 mg (N=89) 200 mg (N=86) PBO (N=45) Any AE 30(71) 55(60) 56(63) 53(62) 31(69) Lymphadectomy 2(5) 3(3) 2(2) 1(1) 0 Diarrhea 1(2) 3(3) 6(7) 3(3) 3(7) Dyspepsia 2(5) 1(1) 2(2) 0 0 Toothache 2(5) 1(1) 1(1) 2(2) 1(2) Bronchitis 3(7) 3(3) 1(1) 0 2(4) Gastroenteritis 2(5) 0 3(3) 3(3) 1(2) Nasopharyngitis 8(19) 12(13) 13(15) 10(12) 9(20) URTI 2(5) 0 3(3) 2(2) 0 Arthralgia 2(5) 2(2) 0 2(2) 0 Back pain 1(2) 4(4) 3(3) 4(5) 0 Musculoskeletal pain 2(5) 4(4) 1(1) 2(2) 0 Headache 3(7) 5(5) 5(6) 7(8) 4(9) Cough 3(7) 2(2) 2(2) 1(1) 2(4) Pruritus 1(2) 4(4) 0 4(5) 4(9) Urticaria 2(5) 0 1(1) 0 0 Hypertension 0 2(2) 2(2) 4(5) 0 Papp KA, et al. Presented at AAD Annual Meeting; 2013.

67 CP-690,550 (Tofacitinib) Janus Kinase (JAK) Inhibitor Inhibits JAK 1 and 3 >JAK 2 Rheumatoid Arthritis inflammatory cytokines, chemokines inflammatory cells (Mf, T cells, NK and NKT cells) Recently approved by US-FDA (November 2012) Psoriasis 5 mg twice daily Highly efficacious Relatively well tolerated Papp KA, et al. Br J Dermatol. 2012; Mamolo C, et al. J Eur Acad Dermatol Venereol

68 PASI 75 Response Rate (%) Tofacitinib: PASI 75 Results Over Time 100 Placebo Tofacitinib 5 mg BID Tofacitinib 2 mg BID Tofacitinib 15 mg BID Baseline Week Papp KA, et al. Br J Dermatol

69 Therapeutic End Points in Psoriasis: Why PASI 90 and PASI 100 Matter

70

71 Mean % PASI Estimated Probabilities of Response The positions of ustekinumab 45 mg and ustekinumab 90 mg are reversed when the ustekinumab data are analyzed according to the dosing recommendations listed in the Summary of Product Characteristics (eg 45 mg in patients <100 kg and 90 mg in patients >100 kg). Reich K, et al. Br J Dermatol

72 Mean % PASI Estimated Probabilities of Response The positions of ustekinumab 45 mg and ustekinumab 90 mg are reversed when the ustekinumab data are analyzed according to the dosing recommendations listed in the Summary of Product Characteristics (eg 45 mg in patients <100 kg and 90 mg in patients >100 kg). Reich K, et al. Br J Dermatol

73 Mean % PASI Estimated Probabilities of Response The positions of ustekinumab 45 mg and ustekinumab 90 mg are reversed when the ustekinumab data are analyzed according to the dosing recommendations listed in the Summary of Product Characteristics (eg 45 mg in patients <100 kg and 90 mg in patients >100 kg). Reich K, et al. Br J Dermatol

74

75

76

77

78 Clear is Better Than Almost Clear Reported DLQI indicating treatment failure 20% in patients with Almost Clear skin 2% in patients with Clear skin DLQI=Dermatology Life Quality Index Takeshita J, et al. J Am Acad Dermatol

79 If it becomes realistic to clear most patients with psoriasis...does everyone deserve to be clear?..and at what cost?

80

81

82