Annual Rheumatology & Therapeutics Review for Organizations & Societies

Transcription

1 Annual Rheumatology & Therapeutics Review for Organizations & Societies

2 Small Molecule Inhibitors in Rheumatology

3 The Concept of Intracellular Signaling Pathways Cytokine, Immune complex, Antigen Anti-TNF TNF P Transduction eg, STAT, MAPK P Transcription Nucleus P DNA eg, STAT, NF-kB Ligand Binding eg, JAK, SYK, BtK mrna Cell Membrane Release/ Secretion Expressed Translation Effector Protein microrna STAT = signal transducers and activators of transcription; MAPK = mitogen-activated protein kinase; BtK = Bruton s tyrosine kinase; NF-kB = nuclear factor kappa-light-chain-enhancer of activated B cells; mrna = messenger ribonucleic acid; microrna = micro ribonucleic acid. Meinnes IB. Kelly s Textbook of Rheumatology

4 Key Concept: Cascading Events P P Kinase Kinase P Kinase Kinase P Kinase Kinase P Activated Transcription Factors

5 Principles of Signaling Pathways After ligand receptor binding, signal must reach the nucleus Many signaling molecules Multiple redundant pathways Facilitated typically by kinase-mediated phosphorylation of tyrosine, threonine, serine Cross-regulation balance between inhibition and stimulation Different pathways in various cell types

6 The Human Kinome Kinome A subset of the Genome consisting of the protein kinase genes Protein kinases act as key regulators of cell function by catalyzing the addition of a negatively charged phosphate group to proteins Regulates protein function in both normal and disease states Over 500 kinome genes have been identified TK CMGC TKL CK1 STE AGC CAMK

7 Approved Kinase Inhibitors with Experimental Use in Rheumatic Diseases Imatinib: CML, ALL MDS Aggressive systemic mastocytosis Hypereosinophilic syndrome and/or chronic eosinophilic leukemia GIST Sunitinib GIST - gastrointestinal stromal tumor. Advanced renal cell carcinoma Progressive, well-differentiated pancreatic neuroendocrine tumors Erlotinib Advanced or metastatic non-small cell lung cancer Locally advanced or metastatic pancreatic cancer Dasatinib: CML, ALL

8 Targets SYK JAK BTK PDE4 P13K

9 Pertinent Presumed Pathways in RA MAPK signaling cascade SYK (& BTK) signaling cascade Syk P13k P13K P13K signaling cascade Lipid messengers P13k P13k NF K B signaling cascade JAK signaling cascade Kinases Kinases p38 JNK BTK ERK Second messengers IKK NF K B STAT STAT STAT JAK JAK STAT Gene Transcription Cytoplasm Nucleus

10 JAKs Cytokine Cytokine receptor SOCS JAK JAK PTP Ub JAK Proteasome STAT Υ P STAT Υ Υ STAT P PTP P1AS P STAT Υ Υ STAT P Transcription PTP Nucleus

11 Tofacitinib A JAK1/JAK3 Inhibitor Tofacitinib is a reversible competitor of the ATP binding site of JAK 1,2 with a chemical structure related to ATP 3 Half-life of approximately 3 hours 4 Originally developed as a JAK3 inhibitor, tofacitinib was found to inhibit JAK3 and JAK1 with functional specificity over JAK2 2,4 Tofacitinib has demonstrated rapid clinical improvement in patients with RA for whom treatment with csdmards or TNFi have failed 5,6 Tofacitinib became the first JAK inhibitor to gain FDA approval 7 in November 2012 and Swissmedic approval 8 in July 2013 for use in adult patients with moderately to severely active RA who have had an inadequate response to, or who are intolerant of, MTX JAK = Janus kinase; ATP = Adenosine triphosphate; RA = rheumatoid arthritis; csdmard = conventional synthetic disease-modifying antirheumatic drug; TNFi = tumor necrosis factor inhibitor; MTX = methotrexate 1. Jiang JK, et al. J Med Chem. 2008;51: ; 2. Meyer DM, et al. J Inflamm (London). 2010;7:41; 3. ATP Compound Summary, PubChem Accessed November 23, 2013; 4. Xeljanz SmPC, 5. van Vollenhoven RF, et al. N Engl J Med. 2012;367: ; 6. Burmester G, et al. Lancet. 2013;381: ; 7. Drugs@FDA, Xeljanz, [last visited August 2014]; 8. Swissmedic Journal 07/2013, 08/2013:586. N N N H N N N O CN

12 STAT STAT STAT STAT Cytokine Receptor Activation and JAK Pathway Signaling Cytokines bind to cell surface receptors leading to receptor polymerization and activation of associated JAKs. 1 The JAK family includes JAK1, JAK2, JAK3, and TYK2 1-3 Activated JAKs phosphorylate the cytokine receptors. These receptors then dock (bind) STATs 1 Activated JAKS then phosphorylate the docked STATs. The now activated STATs dimerize and move to the nucleus to activate new gene transcription 1,3 Cytokine JAK P P P P P P JAK Phosphate group Gene transcription/ Cytokine production P=phosphate; TYK2=tyrosine kinase 2; JAK = Janus kinase; STAT = signal transducer and activator of transcription 1. Shuai K, Liu B. Nat Rev Immunol. 2003;3(11): ; 2. O Sullivan LA, et al. Mol Immunol. 2007;44: ; 3. O Shea JJ, et al. N Engl J Med. 2013;368:

13 STAT STAT Jakinibs Inhibit JAK Pathway Signaling Cytokine Cytokine binding to its cell surface receptor leads to receptor polymerization 1 Jakinib Jakinibs inhibit the autophosphorylation and activation of JAKs 2 JAK JAK JAKs cannot phosphorylate the cytokine receptors. Therefore, the receptors cannot dock STATs 2 Because the STATs cannot dock, they are not phosphorylated or activated. Gene transcription and cytokine production is thereby inhibited 2 Gene transcription/ Cytokine production JAK = Janus kinase; STAT = signal transducer and activator of transcription 1. Shuai K, Liu B. Nat Rev Immunol. 2003;3(11): ; 2. Jiang JK, et al. J Med Chem. 2008;51(24): ;

14 Tofacitinib Clinical Pharmacology Summary of PK Parameters of Tofacitinib in Human Subjects Parameter Mean (SD) Oral administration: absolute bioavailability (%) 2,3 74 Rapid absorption: T max (h) 1,2, Volume of distribution (L) 3 87 (16) Protein binding to albumin in clinical dose range (%) 1,3 40 Metabolism and elimination 1,3 Hepatic 70%, Renal 30% Rapid elimination: Terminal phase t ½ (h) 1,2,3 3.3 (0.5) Clearance (L/h) Clearance pathways 2 ~53% CYP3A4, ~17% CYP2C19, ~30% renal No major circulating or active metabolites 2 <10% of parent compound Median. AUC=area under the curve; CYP2C19=cytochrome P450 2C19; CYP3A4=cytochrome P450 3A4; PK=pharmacokinetics; SD=standard deviation; t1/2=half life 1. Riese RJ, et al. Best Prac Res Clin Rheumatol. 2010;24: ; 2. Dowty ME, et al. Drug Metab Dispos 2014;42: ; 3. Xeljanz SmPC,

15 Tofacitinib Clinical Development Program

16 5 Randomized Studies in DMARD-IR Tofacitinib efficacy and safety evaluated in treatment settings representative of clinical practice Combination Therapy Monotherapy MTX - inadequate responders (MTX-IR) TNF - inhibitors inadequate responders (TNFi-IR) MTX - inadequate responders (MTX-IR) and other DMARDs TNF - inhibitors inadequate responders (TNFi-IR) Tofacitinib has nearly 13,000 patient-years of drug exposure and was studied in approximately 5700 patients* 1 Approximately 4800 patients have been treated with tofacitinib for 2 years or longer* 2 Tofacitinib 5mg or 10mg twice daily showed a consistent safety profile and sustained efficacy over 5 years in LTE studies Placebo treatment limited to minimize risk of inadequate treatment DMARD = disease modifying antirheumatic drug; IR = inadeqaute responder; MTX = methotrecate; TNF = tumor necrosis factor *Data as of April Mariette X, et al. Arthritis Rheum. 2013;65 (suppl 10):S340, abstract Wollenhaupt J, et al. Arthritis Rheum. 2013a;65(suppl 10):S993, abstract 2328.

17 A Broad Range of Patient Types Was Studied in the Tofacitinib Phase 3 Confirmatory Studies Study Patient Type Patients Enrolled Distinguishing Feature Treatment Study Duration ORAL Solo 1 DMARD-IR 610 Monotherapy Tofacitinib 5 or 10 mg BID 6 months ORAL Sync 2 DMARD-IR 792 Background DMARDs* Tofacitinib 5 or 10 mg BID + nonbiologic DMARD(s) 12 months ORAL Step 3 TNFi-IR 399 TNFi-IR Tofacitinib 5 or 10 mg BID + MTX 6 months ORAL Standard,4 MTX-IR 717 Active control (adalimumab) Tofacitinib 5 or 10 mg BID + MTX 12 months ORAL Scan 5 MTX-IR 797 Radiographic data Tofacitinib 5 or 10 mg BID + MTX 24 months *Nonbiologic DMARDs; Not designed as a head-to-head study between tofacitinib and adalimumab. BID=twice daily; IR=inadequate responder. 1. Fleischmann R, et al. N Engl J Med, 2012;367: ; 2. Kremer J, et al. Ann Intern Med. 2013;159: ; 3. Burmester G, et al. Lancet. 2013;381: ; 4. van Vollenhoven R, et al. N Engl J Med. 2012;367: ; 5. van der Heijde D, et al. Arthritis Rheum. 2013;65(3): ;

18 ORAL Standard: Tofacitinib or Adalimumab in Treating Adult Patients With RA After an Inadequate Response to MTX

19 4:4:1:1:4 Randomization ORAL Standard Study Design Tofacitinib 5 mg BID + MTX Tofacitinib 10 mg BID +MTX Inadequate responders to MTX N=717 Placebo + MTX Placebo + MTX Tofacitinib 5 mg BID + MTX Tofacitinib 10 mg BID + MTX Adalimumab 40 mg Q2W + MTX Baseline Month 6 Co-primary efficacy endpoints ACR20 (month 6) HAQ-DI change from baseline (month 3) DAS28-4 (ESR) <2.6 (month 6) This study was not designed for non-inferiority/superiority comparisons between tofacitinib and adalimumab. Month 12 Study End MTX = methotrexate; BID=twice daily; IR=inadequate responder; Q2W=every 2 weeks; ACR=American College of Rheumatology; HAQ-DI=Health Assessment Questionnaire Disability Index; DAS=disease activity score; ESR = erythrocyte sedimentation rate van Vollenhoven RF, et al. N Engl J Med. 2012;367:

20 ORAL Standard Patient Demographics Characteristic 1 Placebo Tofacitinib Tofacitinib Adalimumab 5 mg BID N=56 10 mg BID N=52 5 mg BID N= mg BID N= mg Q2W N=204 Female (n (%)) 43 (76.8) 39 (75.0) 174 (85.3) 168 (83.6) 162 (79.4) White (n (%))* 40 (71.4) 35 (67.3) 151 (74.0) 143 (71.1) 148 (72.5) Mean age (years) Mean disease duration (years) Region of origin (%),2 All groups (N=717) United States 14.5% Latin America 11.9% Europe 55.8% Rest of world 17.8% BID=twice daily; IR=inadequate responder; Q2W=every 2 weeks *Race was self-reported A total of 21 countries were included in the study; the geographic breakdown is based on the number of patients who had 20% improvement in the ACR20 at Month van Vollenhoven RF, et al. N Engl J Med. 2012;367: ; 2. Arthritis Advisory Committee Meeting presentation deck. Tofacitinib. May 9,

21 ORAL Standard Baseline Disease Characteristics Characteristic Placebo Tofacitinib Tofacitinib Adalimumab Mean tender joints (68) Mean swollen joints (66) 5 mg BID N=56 10 mg BID N=52 5 mg BID N= mg BID N= mg Q2W N= ESR (mm/h) CRP (mg/l) Positive for RF (%) Positive for anti-ccp antibodies (%) Mean DAS28 4(ESR) Mean DAS28-3(CRP) Mean HAQ-DI score BID=twice daily; IR=inadequate responder; Q2W=every 2 weeks; CCP=cyclic citrullinated peptide; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; DAS = DAS, Disease Activity Score; HAQ-DI = HAQ-DI, Health Assessment Questionnaire Disability Index van Vollenhoven RF, et al. N Engl J Med. 2012;367:

22 ORAL Standard Prior DMARD Use Other Than MTX Placebo Tofacitinib Tofacitinib 5 mg BID N=56 10 mg BID N=52 5 mg BID N=204 TNFi 4 (7.1%) 5 (9.6%) 12 (5.9%) Other biologic DMARDs 4 (7.1%) 2 (3.8%) 2 (1.0%) Traditional DMARDs (not including MTX) 30 (53.6%) 29 (55.8%) 109 (53.4%) MTX is a background medication required for all subjects TNFi: certolizumab pegol, etanercept, golimumab, infliximab Other biologic DMARDs: abatacept, anakinra, canakinumab, rituximab, tocilizumab Traditional DMARDs other than MTX: gold preparations, antimalarials, leflunomide, penicillamine, sulfasalazine DMARD = disease modifying antirheumatic drug; MTX = methotrexate; TNF = tumor necrosis factor inhibitor van Vollenhoven RF, et al. N Engl J Med. 2012;367:

23 Patients (%) ORAL Standard ACR20 Primary Endpoint With and Without Advancement Penalty ** 52.6 ** 101/ /196 ACR20 (NRI) at month 6 With Advancement Penalty Without Advancement Penalty 47.2 ** 94/ / / / / Placebo + MTX Tofacitinib 5 mg BID + MTX Tofacitinib 10 mg BID + MTX Adalimumab 40 mg SC Q2W + MTX This study was not designed for non-inferiority/superiority comparisons between tofacitinib and adalimumab. **p<0.001 vs placebo; Primary analysis: NRI (with advancement penalty) NRI (without advancement penalty) ACR=American College of Rheumatology; BID=twice daily; MTX=methotrexate; NRI=non-responder imputation; Q2W=every 2 weeks; SC=subcutaneous. van Vollenhoven RF, et al. N Engl J Med. 2012;367:

24 LSM change from Baseline ORAL Standard HAQ-DI Primary Endpoint 0 HAQ-DI (month 3) MCID = ** ** ** -0.8 Placebo + MTX Tofacitinib 5 mg BID + MTX Tofacitinib 10 mg BID + MTX Adalimumab 40 mg SC Q2W + MTX This study was not designed for non-inferiority/superiority comparisons between tofacitinib and adalimumab. **p<0.001 vs placebo BID=twice daily; HAQ-DI=Health Assessment Questionnaire Disability Index; LSM=least squares mean; MCID=minimum clinically important difference; Q2W=every 2 weeks; SC=subcutaneous. van Vollenhoven RF, et al. N Engl J Med. 2012;367:

25 HAQ-DI (change from baseline) ORAL Standard Mean Change From Baseline in HAQ-DI Month Tofacitinib 5 mg BID + MTX Tofacitinib 10 mg BID + MTX Adalimumab 40 mg SC Q2W + MTX Placebo + MTX Placebo + MTX 5 mg BID + MTX Placebo + MTX 10 mg BID + MTX BID=twice daily; HAQ-DI=Health assessment questionnaire-disability index; Q2W=every 2 weeks; SC=subcutaneous. This study was not designed for non-inferiority/superiority comparisons between tofacitinib and adalimumab. van Vollenhoven RF, et al. N Engl J Med. 2012;367:

26 DAS28-4 (ESR) <2.6 (month 6) patients (%) DAS28-4 (ESR) <2.6 (month 6) patients (%) ORAL Standard DAS28-4(ESR) <2.6 Primary Endpoint DAS28-4 (ESR) <2.6 (Month 6) With Advancement Penalty Without Advancement Penalty ** / / * /177 * / / / / Placebo + MTX Tofacitinib 5 mg BID + MTX Tofacitinib 10 mg BID + MTX Adalimumab 40 mg SC Q2W + MTX *p<0.05, **p<0.001 vs placebo. Primary analysis. NRI (with advancement penalty). Actual response rates at Month 6 for active treatment groups, not penalized for lack of efficacy at Month 3. BID=twice daily; DAS=disease activity score; ESR=erythrocyte sedimentation rate; Q2W=every 2 weeks; SC=subcutaneous; MTX = methotrexate van Vollenhoven RF, et al. N Engl J Med. 2012;367:

27 ORAL Standard Treatment-Emergent AEs and Discontinuations Due to AEs Months 0 to 3 and 3 to 6 Tofacitinib 5 mg BID N=204 Tofacitinib 10 mg BID N=201 Adalimumab 40 mg Q2W N=204 Placebo N=108 Months 0-3 (n (%)) n (%) n (%) n (%) AEs 106 (52.0) 94 (46.8) 105 (51.5) 51 (47.2) Serious AEs 12 (5.9) 10 (5.0) 5 (2.5) 2 (1.9) Serious IEs 3 (1.5) 4 (2.0) 0 1 (0.9) Discontinued due to AEs 14 (6.9) 10 (5.0) 10 (4.9) 3 (2.8) Months 3-6 (n (%)) Placebo tofacitinib 5mg BID N=28 Placebo tofacitinib 10mg BID N=21 Placebo N=59 AEs 67 (32.8) 62 (30.8) 7 (25.0) 9 (42.9) 16 (27.1) Serious AEs 10 (4.9) 7 (3.5) (3.4) Serious IEs 2 (1.0) 1 (0.5) Discontinued due to AEs 5 (2.5) 11 (5.5) 1(3.6) 0 0 AEs=adverse events; IEs = infection events; BID=twice daily; Q2W=every 2 weeks van Vollenhoven RF, et al. N Engl J Med. 2012;367:

28 ORAL Solo: Efficacy and Safety of 2 Doses of Tofacitinib Monotherapy in Patients With Active RA

29 Randomization ORAL Solo Study Design Tofacitinib 5 mg BID (Monotherapy) Inadequate responders to 1 DMARD(s) N=610 Tofacitinib 10 mg BID (Monotherapy) Placebo Tofacitinib 10 mg BID (Mono) Placebo Tofacitinib 5 mg BID (Mono) Baseline Month 3 Co-primary efficacy endpoints (Month 3) ACR20 response (NRI) HAQ-DI change from baseline DAS28-4(ESR)<2.6 Month 6 study end DMARD = disease modifying antirheumatic drug; BID=twice daily; ACR=American College of Rheumatology; NRI=non-responder imputation; HAQ-DI=Health Assessment Questionnaire Disability Index; DAS=disease activity score; ESR = erythrocyte sedimentation rate Fleischmann R, et al. N Engl J Med. 2012;367:

30 Patients (%) ORAL Solo ACR20 ACR20 (NRI) /120 Month 3 (Primary) Month 6 144/ /242 35/60 34/60 167/ /242 Placebo Tofacitinib 5 mg BID Tofacitinib 10 mg BID Placebo 5 mg Tofacitinib BID Placebo Tofacitinib 10 mg BID p< vs placebo; there are no p-values at Month 6 as there is no placebo ACR=American College of Rheumatology; NRI=non-responder imputation; BID=twice daily 1. Fleischmann R, et al. N Engl J Med. 2012;367: ; 2. Fleischmann R., et al. Presentation ACR 2010, Abstract #4352

31 Change in HAQ-DI ORAL Solo HAQ-DI 0.0 Month 3 (Primary) 1 Month MCID = LS mean (Change from Baseline) Placebo Tofacitinib 5 mg BID Tofacitinib 10 mg BID Placebo Tofacitinib 5 mg BID Placebo Tofacitinib 10 mg BID p< vs placebo; there are no p-values at Month 6 as there is no placebo HAQ-DI=Health Assessment Questionnaire Disability Index; LS = least square; BID=twice daily; MCID = minimal clinically important difference; BID=twice daily 1. Fleischmann R, et al. N Engl J Med. 2012;367: ; 2. Fleischmann R., et al. Presentation ACR 2010, Abstract #4352

32 Patients (%) ORAL Solo DAS28-4 (ESR) DAS28-4(ESR) <2.6 (NRI) Month 3 (Primary) Month 6 Placebo Tofacitinib 5 mg BID Tofacitinib 10 mg BID Placebo Tofacitinib 5 mg BID Placebo Tofacitinib 10 mg BID DAS=disease activity score; ESR = erythrocyte sedimentation rate; NRI=non-responder imputation; BID=twice daily Fleischmann R, et al. N Engl J Med. 2012;367:

33 Patients (%) Patients (%) Patients (%) ORAL Solo ACR Scores ** ACR50 (NRI) ACR20 (NRI) Month ** ** Tofacitinib 5 mg BID Tofacitinib 10 mg BID Placebo Placebo 5 mg BID Placebo 10 mg BID All patients randomized to placebo for 3 months were blindly advanced to tofacitinib at Month 3 * ACR70 (NRI) * Month A significant difference from placebo in ACR scores was seen by week 2 ACR=American College of Rheumatology; NRI=non-responder imputation; BID=twice daily *p<0.01,**p<0.001, p< vs placebo Fleischmann R, et al. N Engl J Med. 2012;367:

34 ORAL Solo: Treatment-Emergent AEs and Discontinuations Due to AEs Months 0 to 3 and 3 to 6 Months 0-3, n (%) Tofacitinib 5 mg BID N=243 Tofacitinib10 mg BID N=245 Placebo N=122 AEs 124 (51.0) 139 (56.7) 67 (54.9) Serious AEs 1 (0.4) 5 (2.0) 6 (4.9) Serious IEs 0 1 (0.4) 0 Discontinued due to AEs 2 (0.8) 6 (2.4) 5 (4.1) Months 3-6, n (%) Tofacitinib 5 mg BID N=243 Tofacitinib 10 mg BID N=245 Placebo Tofacitinib 5mg BID N=61 Placebo Tofacitinib 10mg BID N=61 AEs 97 (39.9) 101(41.2) 22 (36.1) 24 (39.3) Serious AEs 5 (2.1) 6 (2.4) 1 (1.6) 0 Serious IEs 1 (0.4) 3 (1.2) 1 (1.6) 0 Discontinued due to AEs 1 (0.4) 5 (2.0) 0 0 There was an increased rate of serious infections with tofacitinib as compared with placebo Over the course of 6 months, there was 1 case of an opportunistic infection in the tofacitinib 10 mg BID group and 2 cases of malignancies in the placebo tofacitinib 10 mg BID group and tofacitinib 10 mg group 1 death occurred during months 3 to 6 in the in the tofacitinib 10 mg BID group AEs=adverse events; IEs = infection events; BID=twice daily Fleischmann R, et al. N Engl J Med. 2012;367:

35 ORAL Scan: Efficacy and Safety of 2 Doses of Tofacitinib in Patients With Active RA on Background MTX

36 Randomization ORAL Scan Study Design Inadequate responders to MTX N=797 Placebo + MTX Tofacitinib 5 mg BID + MTX Tofacitinib 10 mg BID +MTX Tofacitinib 10 mg BID + MTX Placebo + MTX Tofacitinib 5 mg BID + MTX Baseline Month 6 Month 12 Month 18 Month 24 Co-primary efficacy endpoints ACR20 (Month 6) Mean change from baseline in mtss (Month 6) Mean change from baseline in HAQ-DI (Month 3) DAS28-4 (ESR) <2.6 (Month 6) MTX = methotrexate; BID=twice daily; ACR=American College of Rheumatology; NRI=non-responder imputation; HAQ-DI=Health Assessment Questionnaire Disability Index; DAS=disease activity score; ESR = erythrocyte sedimentation rate van der Heijde D, et al. Arthritis Rheum. 2013;65:

37 ACR20 response, Patients (%) ORAL Scan ACR20 Primary Endpoint 80 ACR20 (NRI, Month 6) Placebo + MTX Tofacitinib 5 mg BID + MTX Tofacitinib 10 mg BID + MTX n= 39/ / /309 p<0.001 vs placebo ACR=American College of Rheumatology; NRI=non-responder imputation; BID=twice daily; MTX = methotrexate van der Heijde D, et al. Arthritis Rheum. 2013;65:

38 LSM change From Baseline Patients (%) ORAL Scan HAQ-DI and DAS28-4(ESR)<2.6 Primary Endpoints HAQ-DI Improvement (Month 3) MCID = DAS28-4(ESR)<2.6 (NRI, Month 6) Placebo + MTX Tofacitinib 5 mg BID + MTX Tofacitinib 10 mg BID + MTX p<0.001 vs placebo; Step-down procedure does not allow for declaring significance. HAQ-DI=Health Assessment Questionnaire Disability Index; DAS=disease activity score; ESR = erythrocyte sedimentation rate; MTX = methotrexate; BID=twice daily; LSM = least square mean; MCID = minimal clinically important difference; NRI=non-responder imputation van der Heijde D, et al. Arthritis Rheum. 2013;65:

39 Patient Response Rates (%) Efficacy of Tofacitinib as Monotherapy and Combination Therapy Demonstrated Statistically Significant ACR Response Rates ORAL Solo 1 3-Month Primary Endpoint (DMARD-IR) * ORAL Scan 2 6-Month Primary Endpoint 71.0 (MTX-IR; bkgrd MTX) ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 Placebo Without background DMARDs (Solo) Plus background MTX (Scan and Standard) Tofacitinib 5 mg twice daily Monotherapy (Solo) Plus background MTX (Scan and Standard) Tofacitinib 10 mg twice daily Monotherapy (Solo) Plus background MTX (Scan and Standard) ORAL Standard 3 6-Month Primary Endpoint (MTX-IR; bkgrd MTX) ** * 9.1 Adalimumab 40 mg Q2W Plus background MTX (Standard) *p<0.01; **p<0.001; p< vs placebo; All response rates are calculated using NRI. DMARD-IR=DMARD-inadequate responder; MTX-IR-methotrexate-inadequate responder. 1. Fleischmann R, et al. N Engl J Med. 2012;367: ; 2. van der Heijde D, et al. Arthritis Rheum. 2013;65: ; 3. van Vollenhoven RF, et al. N Engl J Med. 2012;367:

40 Efficacy Summary Identification of the JAK pathway and its role in inflammatory cytokine production led to the development of JAK inhibitors by multiple companies Cytokines that are modulated by a JAK inhibitor are determined by the binding affinity of the inhibitors to each of the 4 JAK isozymes Therefore the clinical efficacy, safety, and utility of a Jakinib is determined by the relative affinities with which it binds to JAK isozymes and is able to modulate cytokine synthesis and secretion Tofacitinib studies enrolled a range of patients, including inadequate responders to nonbiologic and biologic DMARDs and patients who were MTX naïve In the phase 3 clinical development program, patients treated with tofacitinib experienced reduced signs and symptoms and improved physical function as measured by: ACR20 responses at Months 3 and 6 Mean changes from baseline in HAQ-DI scores at Month 3 Reduced disease activity was observed in the development program as measured by: DAS28-4 (ESR) of <2.6 at Month 3 and Month 6

41 Safety Summary for Tofacitinib 5 mg versus 10 mg BID Endpoint All Cause Mortality Serious Infection Malignancy (excl. NMSC) NMSC Lung Cancer MACE GI Perforation Herpes Zoster Comparison P3ALL LTE P3ALL LTE P3ALL LTE P3ALL LTE P3ALL LTE P3ALL LTE P3ALL LTE P3ALL LTE Risk Ration (95% Cl) 10 mg /5 mg NA Incidence Rate (events/100 PY) 5 mg 10 mg Data as of 29SEP2011 P3ALL LTE Favors 10 mg Favors 5 mg GI, gastrointestinal; LTE, long-term extension; MACE, major adverse cardiac events; NMSC, non-melanoma skin cancer; PY, patient year. FDA Advisory Committee Meeting, 9 May 2012 (NDA ). Presentation [Accessed December 2012]

42 Safety Conclusions Safety profile of tofacitinib Well described, based on nearly 13,000 patient years of exposure 1 Similar to existing immunomodulatory therapies for rheumatoid arthritis (RA), with specific differences as described 2 Rheumatologists are familiar with the appropriate management of patients treated with these RA therapies 1. Mariette X, et al. Arthritis Rheum. 2013;65 (suppl 10):S340, abstract FDA Advisory Committee Meeting, 9 May 2012 (NDA ). Presentation [Accessed August 2014]

43 Apremilast

44 There Are 11 Distinct Families of PDEs PDE1A, B,C PDR2A PKA, CaMK Ca/CaM Ca/CaM cgmp cgmp camp cgmp PDE3A,B PKA, PKB Membrane-associated domain insert PDE4A,B,C,D PDE5A PDE6A,B,C PDE7A,B PDE8A,B PDE9A PDE10A PDE11A Targeting domain cgmp GAF A GAF A Targeting domain GAF A GAF A GAF B GAF B PAS domain REC GAF B GAF B ERK2 PDE = phosphodiesterase. Lugnier C. Pharmacol Ther. 2006;109:

45 Total PDE Activity, % PDE4 Is the Predominant PDE in Immune Cells In Vitro PDE4 Activity in Monocytes and DCs 1 PDE4 is the Predominant PDE in inflammatory Cells based on an in Vitro analysis 1,2 80 PDE1 PDE3 PDE4 PDE total PDE 1/3/ Monocyte Immature DC Mature DC (LPS) Mature DC (LPS/IFN-ϒ) DC = dendritic cells; LPS = lipopolysaccharide; IFN = interferon; PDE = phosphodiesterase. 1. Heystek HC, et al. Int Immunol. 2003;15: Gottlieb AB, et al. J Drugs Dermatol. 2013;12:

46 Enzyme Inhibition by Apremilast In Vitro Is Specific for PDE4 and Does Not Significantly Affect the Function of Other PDEs Apremilast selectively inhibits PDE4A, B, C, and D in vitro PDE = phosphodiesterase. Schafer PH, et al. Cell Signal. 2014;26:

47 Apremilast Has No Other Known Targets The effects of apremilast on binding to 68 cell surface receptors and for inhibition of 17 enzymes were tested Receptors tested included adenosine, adrenergic, angiotensin, benzodiazepine, bradykinin, cannabinoid, cholecystokinin, corticotrophin releasing factor, dopamine, etc Enzymes included phosphodiesterases, adenylyl cyclase, guanylyl cyclase, protein kinase C, etc The investigators of this in vitro analysis concluded that no significant binding or effects other than PDE4 inhibition have been observed PDE = phosphodiesterase. Schafer PH, et al. Cell Signal. 2014;26:

48 Apremilast Mechanism of Action Schafer PH, et al. Biochem Pharmacol. 2012;83:

49 Cytokine Production (% of Control) Cytokine Production (% of Control) Apremilast Regulates the Production of Pro- and Anti-Inflammatory Cytokines In Vitro IC 50 (μm) GM-CSF 7.8 IL-12p TNF-α IFN-γ Apremilast (μm) 1 10 Effect of apremilast on cytokine and Chemokine production IL-10 IL-6 IL-8 IL-1β RANTES Apremilast (μm) Apremilast 30 mg BID human plasma mean C max = (1.5 μm) GM-CSF = granulocyte macrophage colony-stimulating factor; IL = interleukin; TNF = tumor necrosis factor; IFN = interferon. 1. Schafer P, et al. Br J Pharmacol. 2010;159: Schafer P. Biochem Pharmacol. 2012;83:

50 Cytokine Production (% of control, Mean ± SEM) Apremilast Limits Cytokine Production by Human T Cells In Vitro IC 50 (μm) 100 RANTES IL IFN-γ GM-CSF TNF-α IL IL-10 IL [apremilast] (μm) IL Apremilast inhibits production of Th1, Th2, and Th17 cytokines IL = interleukin; IFN = interferon; GM-CSF = granulocyte macrophage colony-stimulating factor; TNF = tumor necrosis factor. Schafer PH, et al. Cell Signal. 2014;26:

51 IgG Production (% of Control) IL-2 Production (% of Control) TNF-α Production (% of Control) IFN-α Production (% of Control) Apremilast Shows Selectivity for Suppressing Innate Immune Responses In Vitro TLR4-Stimulated PBMC apremilast pomalidomide IC 50 (μm) > [Compound] (μm) apremilast lenalidomide pomalidomide 1 B-Cell Stimulation [Compound] (μm) IC 50 (μm) apremilast lenalidomide TLR9-Stimulated pdc apremilast pomalidomide TLR = toll-like receptor; PBMC = peripheral blood mononuclear cells; pdc = plasmacytoid dendritic cells. Schafer PH, et al. Cell Signal. 2014;26: IC 50 (μm) 0.62 > [Compound] (μm) 1 T-Cell Stimulation IC 50 =2.4 μm EC 50 = μm [Compound] (μm) 10

52 Apremilast Mechanism of Action Summary Mechanism of Action Apremilast Is a Selective Inhibitor of PDE4 Inhibits all PDE4 subtypes (A, B, C, and D) Does not inhibit other PDEs, kinases, or other known receptors or enzymes Does not bind to cereblon, the target of thalidomide Regulates Cellular Signaling Elevates intracellular camp Activates protein kinase A, resulting in phosphorylation and activation of CREB/ATF-1 transcription factors Inhibits NF-κB-driven transcription Regulates cytokine expression, inhibiting TNF, IL-23, and IL-17, and increasing expression of anti-inflammatory mediators such as IL-10 Has Greater Effects on Innate vs. Adaptive Immunity Inhibits toll-like receptor activation in monocytes, dendritic cells, and neutrophils Does not affect B-cell or T-cell expansion or immunoglobulin production PDE = phosphodiesterase; camp = cyclic adenosine monophosphate; CREB = camp responsive element binding protein; ATF-1 = activating transcription factor 1; NF-κB = nuclear factor kappa B; TNF = tumor necrosis factor; IL = interleukin. Schafer PH, et al. Cell Signal. 2014;26: Schafer P. Biochem Pharmacol. 2012;83:

53 PALACE 1 Biomarker Subset Demographics Baseline Demographic and Clinical Characteristics of Biomarker Substudy Patients (N=150) Placebo n=51 20 mg BID n=51 Apremilast 30 mg BID n=48 Age, mean (SD), years 49.7 (12.4) 47.3 (11.2) 52.3 (11.2) Female, n (%) 20 (39.2) 25 (49.0) 23 (47.9) White, n (%) 49 (96.1) 46 (90.2) 47 (97.9) Body mass index, mean (SD), kg/m (7.4) 33.0 (7.1) 32.8 (6.8) Duration, mean (SD), years Psoriatic arthritis 6.5 (5.7) 4.9 (4.6) 10.1 (8.3) Psoriasis 13.5 (11.7) 13.1 (11.9) 19.0 (13.5) Swollen joint count (0-76), mean (SD) 13.0 (8.2) 12.7 (10.4) 13.9 (8.7) Tender joint count (0-78), mean (SD) 27.9 (17.8) 22.4 (15.6) 27.4 (16.5) HAQ-DI (0-3), mean (SD) 1.1 (0.59) 1.0 (0.55) 1.2 (0.61) Physician s global assessment of disease activity (0-100 mm visual analog scale), mean (SD) 58.0 (20.4) 59.4 (18.9) 57.9 (17.4) Prior use of biologics, n (%) 24 (47.1) 24 (47.1) 25 (52.1) Prior use of methotrexate, n (%) 41 (80.4) 40 (78.4) 39 (81.3) Prior biologic failure, n (%) 11 (21.6) 10 (19.6) 10 (20.8) The n reflects the number of patients included in the biomarker substudy; actual number of patients available for each parameter may vary. Investigators concluded that baseline characteristics of the biomarker subset were similar to those of the full study population, except that prior exposure to a biologic DMARD, such as a TNF blocker, was higher in the biomarker subset (48.8%) than in the full analysis set (23.6%) HAQ-DI = Health Assessment Questionnaire-Disability Index; DMARD = disease-modifying anti-rheumatic drug; TNF = tumor necrosis factor. Schafer PH, et al. EULAR 2014 [poster SAT0402].

54 Percent Change From Baseline (Mean± SEM) Percent Change From Baseline (Mean± SEM) Change in Biomarkers at Weeks 4 and 16 Week 4 (Data as Observed) Week 16 (LOCF) Placebo Apremilast 20 mg BID Apremilast 30 mg BID Placebo Apremilast 20 mg BID Apremilast 30 mg BID TNF-α IL-8 MIP-1β TNF-α IL-8 IL-6 Ferritin vwf *P<0.05 vs. placebo (rank ANCOVA 2-sided P value). P= LOCF = last observation carried forward; TNF = tumor necrosis factor; IL = interleukin; MIP-1 = macrophage inflammatory protein beta; vwf = von Willebrand factor; ANCOVA = analysis of covariance. Schafer PH, et al. EULAR 2014 [poster SAT0402].

55 Apremilast Induced Changes in Plasma Biomarkers in Psoriatic Arthritis (PALACE 1) at Week 16 Association Between ACR20 Response and Biomarker Change at Week 16 Univariate Analysis 1* Multivariate Analysis 2 Biomarker TNF-α (pg/ml) IL-8 (pg/ml) IL-6 (pg/ml) Ferritin (ng/ml) vwf (μg/ml) Odds Ratio (2-Sided 95% CI) (0.986, 1.003) (0.990, 1.010) (0.992, 1.004) (0.974, 1.019) (0.985, 1.040) Placebo n=51 *Odds ratios, confidence intervals (CIs), and P values were calculated from a logistic regression model with percent change from baseline biomarker value at Week 16 (last observation carried forward [LOCF]) as a covariate. P values were calculated from a logistic regression model with treatment as a factor, percent change from baseline biomarker value at Week 16 (LOCF) as a covariate, and interaction of treatment and percent change from baseline value at Week 16 (LOCF). At Week 16 (LOCF) for the biomarkers with a significantly (P<0.05) different percent change from baseline in the between-treatment comparisons (apremilast 20 mg BID vs. placebo or apremilast 30 mg BID vs. placebo), the ACR20 (NRI) and ACR20 (LOCF) datasets were identical. NS represents P TNF = tumor necrosis factor; IL = interleukin; vwf = von Willebrand factor. The change in plasma TNF levels at Week 16 was significantly associated with clinical response (ACR20) at both dose levels of apremilast Schafer PH, et al. EULAR 2014 [poster SAT0402]. P Value NS NS NS NS NS Apremilast 20 mg BID n=51 Odds Ratio (2-Sided 95% CI) (1.001, 1.011) (0.985, 1.008) (0.991, 1.013) (0.984, 1.018) (0.938, 0.996) P Value NS NS NS Apremilast 30 mg BID n=48 Odds Ratio (2-Sided 95% CI) (0.960, 0.996) (0.984, 1.004) (0.977, 1.002) (0.969, 1.016) (0.992, 1.022) P Value Interaction P Value NS NS NS NS NS NS NS

56 Percent Change From Baseline (Mean±SEM) Change in Biomarkers at Week Week 24 (LOCF) Placebo Apremilast 20 mg BID Apremilast 30 mg BID *P<0.05 vs. placebo (rank ANCOVA 2-sided P value). TNF-α IL-8 MIP-1β MCP-1 IL-6 Ferritin vwf Schafer PH, et al. EULAR 2014 [poster SAT0402]. TNF = tumor necrosis factor; IL=interleukin; MIP-1β=macrophage inflammatory protein beta; MCP-1=monocyte chemotactic protein 1; vwf=von Willebrand factor; ANCOVA = analysis of covariance.

57 Percent Change From Baseline (Mean±SEM) Mean Percent Change in Biomarkers at Week Apremilast 20 mg BID Apremilast 30 mg BID IL-6 IL-23 IL-17 Ferritin IL-10 IL-1RA *P<0.05 Wilcoxon signed rank test (2-sided P value for testing median of zero). Investigator conclusions: Significant reduction of circulating IL-6, IL-23, and IL-17 with apremilast 30 mg BID treatment suggests that longer-term therapy inhibits components of the systemic Th17 immune response in patients with psoriatic arthritis Significant increases were observed in the anti-inflammatory mediators IL- 10 and IL-1RA with APR 30 mg BID IL = interleukin; IL-1RA = interleukin 1 receptor antagonist. Schafer PH, et al. EULAR 2014 [poster SAT0402].

58 PALACE 1 Pharmacodynamic Conclusions Investigator conclusions: Treatment with apremilast for 4 to 24 weeks was associated with significant reductions in circulating levels of TNF-α, IL-8, IL-6, MIP-1β, MCP-1, and ferritin, representing partial decreases in components of pro-inflammatory innate Th1 immunity The change in TNF-α was significantly associated with clinical ACR 20 response to apremilast at Week 16 After 40 weeks, there was a significant reduction of circulating IL-6, IL-23, and IL-17 on apremilast 30 mg BID treatment, suggesting that longterm apremilast therapy inhibits components of the systemic Th17 immune response in patients with psoriatic arthritis After 40 weeks, there were also significant increases in the anti-inflammatory mediators IL-10 and IL-1RA with apremilast 30 mg BID TNF = tumor necrosis factor; IL=interleukin; MIP-1β=macrophage inflammatory protein beta; MCP-1=monocyte chemotactic protein 1. Schafer PH, et al. EULAR 2014 [poster SAT0402].

59 Psoriatic Arthritis: Synovial Infiltration Is Associated With Cytokine Upregulation Synovial biopsies from PsA patients are comparable to those from RA patients with regards to the number of macrophages and fibroblasts 1 CD3+ T cell numbers were significantly lower in PsA than in RA 1 Synovial tissue in PsA is also characterized by the expression of pro-inflammatory cytokines including 2,3 : TNF-α IL-12 IFN-g IL-15 IL-6 IL-17 IL-1 IL-18 PsA = psoriatic arthritis; RA = rheumatoid arthritis; TNF = tumor necrosis factor; IFN = interferon; IL=interleukin. 1. van Kuijk AWR, et al. Ann Rheum Dis. 2006;65: Fitzgerald O, Winchester R. Arthritis Res Ther. 2009;11: van Baarsen LGM, et al. Ann Rheum Dis. 2011;70(Suppl 2):A79.

60 TRAP5+ Cell Count (% of Control) Apremilast Inhibits Osteoclastogenesis In Vitro 150 Dex + Vit.D Human osteoclast resorbing bone 0 No Dex/ No Vit.D Vit.D only Dex only Control APR 0.1 APR 1 APR 10 ROL 10 ALEN 10 SULF 30 *P<0.05, **P<0.01, P<0.001 vs control by one-way ANOVA followed by Dunnett s post test. Investigator conclusions: Corticosteroids such as dexamethasone contribute to osteoclast formation, leading to bone resorption Apremilast inhibits the formation of osteoclasts, suggesting that it may help counteract the bone catabolic effects of corticosteroids in diseases ANOVA = analysis of variance Adams M. Arthritis Rheum ;64:10(Suppl)S17 [abstract 45]. Adams M, Schafer PH. ACR 2012 [poster].

61 PDE4 Expression Is Elevated in Psoriatic Skin Schafer P, et al. AAD 2013 [e-poster 6634].

62 Table 1: Dosage Titration Schedule Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 & thereafter AM AM PM AM PM AM PM AM PM AM PM 10 mg 10 mg 10 mg 10 mg 20 mg 20 mg 20 mg 20 mg 30 mg 30 mg 30 mg 2.2 Dosage Adjustment in Patients with Severe Renal Impairment

63 Table 3: Proportion of Patients with ACR Responses in Studies PsA-1, PsA-2 and PsA-3 Placebo ± N a DMARDs ACR 20 Week 16 ACR 50 Week 16 Reference ID: N=168 PsA 1 PsA 2 PsA 3 Otezla 30 mg twice daily ± DMARDs N=168 Placebo ± DMARDs N=159 Otezla 30 mg twice daily ± DMARDs N=162 Placebo ± DMARDs N=169 Otezla 30 mg twice daily ± DMARDs N=167 19% 38% 19% 32% b 18% 41% b 6% 16% 5% 11% 8% 15% ACR 70 Week 16 1% 4% 1% 1% 2% 4% a N is number of randomized and treated patients b Statistically significantly different from placebo (p<0.05)

64 Table 2: Adverse Reactions Reported in 2% of Patients on OTEZLA 30 mg Twice Daily And 1% Than That Observed in Patients on Placebo For Up To Day 112 (Week 16) Placebo OTEZLA 30 mg BID Day 1 to 5 Preferred Term (N=495) N(%) c Day 6 to Day 112 (N=490) n(%) Day 1 to 5 (N=497) N(%) Day 6 to Day 112 (N=493) n(%) 5.1 Depression Diarrhea a 6 (1.2) 8 (1.6) 46 (9.3) 38 (7.7) Nausea a 7 (1.4) 15 (3.1) 37 (7.4) 44 (8.9) Headache a 9 (1.8) 11 (2.2) 24 (4.8) 29 (5.9) Upper respiratory tract infection a 3 (0.6) 9 (1.8) 3 (0.6) 19 (3.9) Vomiting a 2 (0.4) 2 (0.4) 4 (0.8) 16 (3.2) Nasopharyngitis a 1 (0.2) 8 (1.6) 1 (0.2) 13 (2.6) Abdominal pain upper a 0 (0.0) 1 (0.2) 3 (0.6) 10 (2.0) a Of the reported gastrointestinal adverse reactions, 1 subject experienced a serious adverse reaction of nausea and vomiting OTEZLA 30 mg twice daily; 1 subject treated with OTEZLA 20 mg twice daily experienced a serious adverse reaction b Of the reported adverse drug reactions none were serious. c n (%) indicated number of patients and percent. Treatment with OTEZLA is associated with an increase in adverse reactions of depression. During the 0 to 16 weeks placebo-controlled period of the 3 controlled clinical trials, 1.0% (10/998) of patients treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1441) of patients treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated patients (0.495). Depression was reported as serious in 0.2% (3/1441) of patients exposed to OTEZLA, compared to none in placebo treated patients (0/495). Instances of suicidal ideation and behavior have been observed In 0.2% (3/1441) of patients while receiving OTEZLA, compared to none in placebo treated patients (0/495). In the clinical trials, two patients who received placebo committed suicide compared to none in OTEZLA treated patients. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. Patients, their caregivers,and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur. 5.2 Weight Decrease During the controlled period of the studies, weight decrease between 5-10% of body weight was reported in 10% (49/497) of patients treated with OTEZLA s 30 mg twice daily compared to 3.3% (16/495) treated with placebo [see Adverse Reactions (6.1)]. Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered. 5.3 Drug Interactions Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilat, which may result in a loss of efficacy of OTEZLA. Therefore, the use of cytochrome P450 enzyme inducers (e.g. rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not recommended [ see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

65 Apremilast PSA 3 Infliximab RESPOND ACR 20 ACR 50 ACR % 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% ACR20 ACR50 ACR70 MTX MTX + INF Apremilast 30 BID

66 Patients Achieving ACR20 Response (%) ACR20 Response Over 52 Weeks PALACE 1, 2, and Patients Receiving Apremilast From Baseline (Data as Observed) Apremilast 20 mg BID PALACE 1 Apremilast 30 mg BID mg BID, n/m 51/158 59/145 75/129 75/ mg BID, n/m 64/150 73/145 80/140 71/130 Apremilast 20 mg BID Apremilast 30 mg BID mg BID, n/m 61/150 69/144 73/128 64/ mg BID, n/m 52/145 60/138 61/121 61/116 Apremilast 20 mg BID Apremilast 30 mg BID PALACE 2 PALACE mg BID, n/m 48/161 63/146 60/124 65/ mg BID, n/m 69/154 63/145 82/131 80/ % 54.6% 52.9% 52.6% 63.0% 56.0% n/m=number of responders/number of patients with sufficient data for evaluation. Study Week

67 Response (%) Fostamatinib SyK Inhibitor Oral disodium salt - prodrug of the active compound tamatinib which is an inhibitor of the enzyme spleen tyrosine kinase (Syk). Phase II study of rheumatoid arthritis patients failing to respond to a biologic agent showed little efficacy. O O H N N O H N N N N F O O Na + P O Na + O O On June 4, 2013, Astra Zeneca announced discontinuation of future development. O CAL-101 BCR CO-79 Antigen Induced Signaling Fostamatinub PCI AVL Placebo Fostamatinib N= 73 N= 152 ACR 20 ACR 50 ACR 70 DAS < 2.6 Genovese MC. Arthritis Rheum :337