Annual Rheumatology & Therapeutics Review for Organizations & Societies

Annual Rheumatology & Therapeutics Review for Organizations & Societies Small Molecule Inhibitors in Rheumatology

The Concept of Intracellular Signaling Pathways

Cytokine, Immune complex, Antigen…

TNF Transduction Transcription Nucleus eg, STAT, MAPK DNA P Anti-TNF P P eg, STAT, NF-kB eg, JAK, SYK, BtK Ligand Binding mRNA

microRNA Translation Cell Membrane Release/ Secretion Effector Protein Expressed

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. 2011. Key Concept: Cascading Events

P P Kinase Kinase P Kinase Kinase P Kinase Kinase P Activated Transcription Factors 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

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 TK TKL of a negatively charged phosphate group to STE proteins CMGC – Regulates protein function in both normal CK1 and disease states – Over 500 kinome genes have been identified AGC

CAMK 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

Targets

• SYK • JAK • BTK • PDE4 • P13K

Pertinent Presumed Pathways in RA

NFKB signaling SYK (& BTK) P13K cascade signaling signaling cascade cascade MAPK JAK signaling signaling cascade Lipid cascade messengers P13k P13k Syk P13K P13k BTK JAK Second JAK Kinases messengers IKK STAT Kinases STAT ERK NFKB JNK STAT p38 STAT

Gene Transcription Cytoplasm

Nucleus JAKs

Cytokine

Cytokine receptor

SOCS JAK JAK PTP

Ub Proteasome JAK

STAT STAT Υ P Υ P PTP STAT Υ

STAT P Υ P1AS P PTP STAT Υ Nucleus Transcription Tofacitinib A JAK1/JAK3 Inhibitor

• Tofacitinib is a reversible competitor 1,2 H of the ATP binding site of JAK with a N N chemical structure related to ATP3 4 • Half-life of approximately 3 hours N • Originally developed as a JAK3 N inhibitor, tofacitinib was found to inhibit O JAK3 and JAK1 with functional specificity N CN over JAK22,4 N • Tofacitinib has demonstrated rapid clinical improvement in patients with RA for whom treatment with csDMARDs or TNFi have failed5,6 • Tofacitinib became the first JAK inhibitor to gain FDA approval7 in November 2012 and Swissmedic approval8 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;51:8012-8018; 2. Meyer DM, et al. J Inflamm (London). 2010;7:41; 3. ATP Compound Summary, PubChem http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5957. Accessed November 23, 2013; 4. Xeljanz SmPC, www.swissmedicinfo.ch; 5. van Vollenhoven RF, et al. N Engl J Med. 2012;367:508-519; 6. Burmester G, et al. Lancet. 2013;381:451-460; 7. Drugs@FDA, Xeljanz®, http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=XELJANZ [last visited August 2014]; 8. Swissmedic Journal 07/2013, 08/2013:586. Cytokine Receptor Activation and JAK Pathway Signaling

• Cytokines bind to cell surface Cytokine receptors leading to receptor polymerization and activation of associated JAKs.1 The JAK family

includes JAK1, JAK2, JAK JAK

JAK3, and TYK21-3 P P P P P

• Activated JAKs phosphorylate the P

STAT STAT

cytokine receptors. These Phosphate group

receptors then dock (bind) STATs1

STAT STAT • Activated JAKS then phosphorylate the docked STATs. The now activated STATs dimerize and move to the nucleus to activate Gene transcription/ Cytokine production new gene transcription1,3

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):900-911; 2. O’Sullivan LA, et al. Mol Immunol. 2007;44:2497-2506; 3. O’Shea JJ, et al. N Engl J Med. 2013;368:161-170. Jakinibs Inhibit JAK Pathway Signaling

Cytokine

• Cytokine binding to its cell Jakinib surface receptor leads to receptor polymerization1 • Jakinibs inhibit the autophosphorylation and JAK JAK

activation of JAKs2

• JAKs cannot phosphorylate the

cytokine receptors. Therefore, STAT the receptors cannot dock STAT STATs2 • Because the STATs cannot dock, they are not phosphorylated or activated. Gene transcription Gene transcription/ and cytokine production is Cytokine production thereby inhibited2

JAK = Janus kinase; STAT = signal transducer and activator of transcription 1. Shuai K, Liu B. Nat Rev Immunol. 2003;3(11):900-911; 2. Jiang JK, et al. J Med Chem. 2008;51(24):8012-8018; Tofacitinib Clinical Pharmacology

Summary of PK Parameters of Tofacitinib in Human Subjects

Parameter Mean (SD)

Oral administration: absolute bioavailability (%)2,3 74

1,2,3 † Rapid absorption: Tmax (h) 0.5 - 1 Volume of distribution (L)3 87 (16) Protein binding to albumin in clinical dose range (%)1,3 40 Metabolism and elimination1,3 Hepatic 70%, Renal 30%

1,2,3 Rapid elimination: Terminal phase t½ (h) 3.3 (0.5) Clearance (L/h)2 24.8 Clearance pathways2 ~53% CYP3A4, ~17% CYP2C19, ~30% renal

No major circulating or active metabolites2 <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;24:513-526; 2. Dowty ME, et al. Drug Metab Dispos 2014;42:759–773; 3. Xeljanz® SmPC, www.swissmedicinfo.ch Tofacitinib Clinical Development Program 5 Randomized Studies in DMARD-IR

• Tofacitinib efficacy and safety evaluated in treatment settings representative of clinical practice Combination Therapy Monotherapy

TNF - inhibitors TNF - inhibitors MTX - inadequate MTX - inadequate inadequate responders inadequate responders responders (MTX-IR) responders (MTX-IR) (TNFi-IR) and other DMARDs (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 2013. 1. Mariette X, et al. Arthritis Rheum. 2013;65 (suppl 10):S340, abstract 802 2. Wollenhaupt J, et al. Arthritis Rheum. 2013a;65(suppl 10):S993, abstract 2328. A Broad Range of Patient Types Was Studied in the Tofacitinib Phase 3 Confirmatory Studies

Patients Distinguishing Patient Type Treatment Study Duration Study Enrolled Feature

Tofacitinib 5 or 10 ORAL Solo1 DMARD-IR 610 Monotherapy 6 months mg BID Tofacitinib 5 or 10 Background mg BID + ORAL Sync2 DMARD-IR 792 12 months DMARDs* nonbiologic DMARD(s)

Tofacitinib 5 or 10 ORAL Step3 TNFi-IR 399 TNFi-IR 6 months mg BID + MTX

ORAL Active control† Tofacitinib 5 or 10 MTX-IR 717 12 months Standard†,4 (adalimumab) mg BID + MTX

Tofacitinib 5 or 10 ORAL Scan5 MTX-IR 797 Radiographic data 24 months mg BID + MTX

*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;367:495-507; 2. Kremer J, et al. Ann Intern Med. 2013;159:253-261; 3. Burmester G, et al. Lancet. 2013;381:451-460; 4. van Vollenhoven R, et al. N Engl J Med. 2012;367:508-519; 5. van der Heijde D, et al. Arthritis Rheum. 2013;65(3):559-570; ORAL Standard: Tofacitinib or Adalimumab in Treating Adult Patients With RA After an Inadequate Response to MTX ORAL Standard Study Design

Tofacitinib 5 mg BID + MTX

Tofacitinib 10 mg BID +MTX

Inadequate Placebo + MTX responders Tofacitinib 5 mg BID + MTX to MTX Randomization N=717 Placebo + MTX Tofacitinib 10 mg BID + MTX

4:4:1:1:4 4:4:1:1:4 Adalimumab 40 mg Q2W + MTX

Baseline Month 6 Month 12 Study End Co-primary efficacy endpoints This study was not designed for  ACR20 (month 6) non-inferiority/superiority comparisons  HAQ-DI change from baseline (month 3) between tofacitinib and adalimumab.  DAS28-4 (ESR) <2.6 (month 6)

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;367:508-519. . ORAL Standard Patient Demographics

Characteristic1 Placebo  Tofacitinib Tofacitinib Adalimumab

5 mg BID 10 mg BID 5 mg BID 10 mg BID 40 mg Q2W N=56 N=52 N=204 N=201 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) 55.5 51.9 53.0 52.9 52.5 Mean disease 6.9 9.0 7.6 7.4 8.1 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 1. 1. van Vollenhoven RF, et al. N Engl J Med. 2012;367:508-519; 2. Arthritis Advisory Committee Meeting presentation deck. Tofacitinib. May 9, 2012. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/ucm304198.htm. ORAL Standard Baseline Disease Characteristics

Characteristic Placebo  Tofacitinib Tofacitinib Adalimumab

5 mg BID 10 mg BID 5 mg BID 10 mg BID 40 mg Q2W N=56 N=52 N=204 N=201 N=204 Mean tender joints 26.6 28.1 28.5 26.1 26.7 (68) Mean swollen joints 16.9 16.4 16.7 15.8 16.4 (66) ESR (mm/h) 52.7 42.9 48.6 49.9 48.5 CRP (mg/L) 20.3 11.6 14.9 17.3 17.5

Positive for RF (%) 71.4 60.8 66.8 66.2 68.2

Positive for anti-CCP 76.4 62.0 71.3 64.0 74.8 antibodies (%)

Mean DAS28 4(ESR) 6.6 6.3 6.6 6.5 6.4

Mean DAS28-3(CRP) 5.6 5.3 5.4 5.4 5.3

Mean HAQ-DI score 1.5 1.4 1.5 1.5 1.5

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;367:508-519. ORAL Standard Prior DMARD Use Other Than MTX

Placebo  Tofacitinib Tofacitinib

5 mg BID 10 mg BID 5 mg BID N=56 N=52 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 30 (53.6%) 29 (55.8%) 109 (53.4%) including MTX)

• 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;367:508-519. ORAL Standard ACR20 Primary Endpoint With and Without Advancement Penalty

ACR20 (NRI) at month 6 With Advancement Penalty† Without Advancement Penalty†† 80 80 62.8 60.7 58.3 51.5 52.6 ** ** 47.2 60 60 123/196

** 119/196 116/199 101/196 103/196 94/199

40 28.3 40 Patients (%) Patients 30/106 20 20

0 0 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;367:508-519. ORAL Standard HAQ-DI Primary Endpoint

HAQ-DI (month 3)

-0.1

-0.2 MCID = -0.22

Baseline -0.3 -0.24

-0.4

-0.5 -0.49 ** -0.6 -0.55 ** -0.61

-0.7 ** LSM change from from change LSM -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;367:508-519. ORAL Standard Mean Change From Baseline in HAQ-DI

1 3 6 9 12

-0.2

baseline)

DI DI -

-0.4

from from HAQ

(change (change -0.6

-0.8 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;367:508-519. ORAL Standard DAS28-4(ESR) <2.6 Primary Endpoint

DAS28-4 (ESR) <2.6 (Month 6) With Advancement Penalty† Without Advancement Penalty††

16 16

14 ** 14 13.1

12.5 2.6 2.6 23/176 12 22/176 12

10 10

ESR) < ESR) < ESR) patients (%) patients

patients (%) patients 8 * 8 7.3 4 4 (

4 4 ( * 6.7

- - 6) 6) 6) 6) 6.2 6.2 13/178 6 12/178 6 11/177 11/177

4 4

DAS28 DAS28

month month month

( ( 2 1.1 2 1/92 0 0

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;367:508-519. ORAL Standard Treatment-Emergent AEs and Discontinuations Due to AEs Months 0 to 3 and 3 to 6

Tofacitinib Tofacitinib Adalimumab Placebo 5 mg BID 10 mg BID 40 mg Q2W N=108 N=204 N=201 N=204 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)

Placebo Placebo tofacitinib tofacitinib Placebo Months 3-6 (n (%)) 5mg BID 10mg BID N=59 N=28 N=21

AEs 67 (32.8) 62 (30.8) 7 (25.0) 9 (42.9) 16 (27.1)

Serious AEs 10 (4.9) 7 (3.5) 0 0 2 (3.4)

Serious IEs 2 (1.0) 1 (0.5) 0 0 0

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;367:508-519. ORAL Solo: Efficacy and Safety of 2 Doses of Tofacitinib Monotherapy in Patients With Active RA responders to ≥1 DMARD(s) Fleischmann R, etFleischmann al. N HAQ disease = modifyingDMARD

Inadequate Study Design ORAL Solo - DI=Health Assessment Assessment DI=HealthQuestionnaireIndex; Disability DAS=diseaseerythrocytescore; =activityESRsedimentation rate • • • Co N=610 DAS28 HAQ ACR20 response (NRI) - primary efficacy endpointsefficacy primary

- DI change from baseline from change DI - Engl 4(ESR)<2.6

J Med. J 2012;367:495 antirheumatic Baseline Randomization

drug; BID=twice daily; ACR=American College of of Collegedaily; Rheumatology;drug; BID=twice ACR=American NRI=non

- 507. Placebo Placebo

Tofacitinib Tofacitinib (Month

3 ) 10 mg BID 5 mg BID

Month 3 (Monotherapy) Tofacitinib 5 mg BID(Mono) Tofacitinib 10 mg BID (Mono) (Monotherapy)

- responder imputation; responder

study Month 6

end

ORAL Solo ACR20

ACR20 (NRI)

100 100

80 80 *** 69.3 71.1 65.7

*** 59.8 58.3 60 60 56.7

40 40 Patients (%) Patients 26.7

20 20

0 0 1 Month 3 (Primary) Month 62 32/120 144/241 159/242 35/60 34/60 167/241 172/242

Placebo Tofacitinib 5 mg BID Tofacitinib 10 mg BID Placebo  5 mg Tofacitinib BID Placebo  Tofacitinib 10 mg BID

***p<0.0001 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;367:495-507.; 2. Fleischmann R., et al. Presentation ACR 2010, Abstract #4352 ORAL Solo HAQ-DI

Month 3 (Primary)1 Month 62 0.0

-0.2

-0.19 MCID = -0.22

DI - -0.4 -0.43 -0.50 -0.6 *** -0.57 -0.59 -0.62 *** -0.67 Changein HAQ -0.8

-1.0 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<0.0001 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;367:495-507; 2. Fleischmann R., et al. Presentation ACR 2010, Abstract #4352 ORAL Solo DAS28-4 (ESR)

DAS28-4(ESR) <2.6 (NRI) 35

20 15.3 15 14.2 9.8 Patients (%) Patients 10 8.7 6.9 5.6 4.4 5

0 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;367:495-507. ORAL Solo ACR Scores

ACR20 (NRI) Tofacitinib 5 mg BID 100

Tofacitinib 10 mg BID 80 Placebo Placebo 5 mg BID *** *** 60 *** Placebo 10 mg BID *** *** *** 40 *** All patients randomized to placebo

Patients (%) Patients 20 *** for 3 months were blindly advanced to tofacitinib at Month 3 0 0 1 2 3 4 5 6 ACR50 (NRI) ACR70 (NRI)

100 100

80 80 60 60 40 *** *** 40 *** ****

Patients (%) Patients *** 20 ** *** (%) Patients 20 *** *** ** ** 0 0 * 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Month 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<0.0001 vs placebo Fleischmann R, et al. N Engl J Med. 2012;367:495-507. . ORAL Solo: Treatment-Emergent AEs and Discontinuations Due to AEs Months 0 to 3 and 3 to 6

Tofacitinib Tofacitinib10 mg BID Placebo Months 0-3, n (%) 5 mg BID N=245 N=122 N=243 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) Placebo Placebo Tofacitinib Tofacitinib Tofacitinib Tofacitinib Months 3-6, n (%) 5 mg BID 10 mg BID 5mg BID 10mg BID N=243 N=245 N=61 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;367:495-507. ORAL Scan: Efficacy and Safety of 2 Doses of Tofacitinib in Patients With Active RA on Background MTX ORAL Scan Study Design

Tofacitinib 5 mg BID + MTX Inadequate responders Tofacitinib 10 mg BID +MTX to MTX N=797 Placebo + MTX Tofacitinib 10 mg BID + MTX

Randomization 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;65:559-570. ORAL Scan ACR20 Primary Endpoint

ACR20 (NRI, Month 6) 80

70 *** 61.8 60 *** 51.5 50 Placebo + MTX

40 Tofacitinib 5 mg BID + MTX Tofacitinib 10 mg BID + MTX 30 25.3

ACR20 response, Patients (%) Patients response, ACR20 10

0 n= 39/154 159/309 191/309

***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;65:559-570. ORAL Scan HAQ-DI and DAS28-4(ESR)<2.6 Primary Endpoints

HAQ-DI Improvement DAS28-4(ESR)<2.6 (Month 3) (NRI, Month 6)

0 20 *** 146 16.0 16 -0.2 MCID 257 -0.17 = -0.22 12

From Baseline From -0.4 † 294 8 7.2 -0.48

Patients (%) Patients 265 -0.6 *** 300 -0.62 4 1.6 *** LSM change change LSM -0.8 0 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;65:559-570. Efficacy of Tofacitinib as Monotherapy and Combination Therapy Demonstrated Statistically Significant ACR Response Rates ORAL Solo1 ORAL Scan2 ORAL Standard3 3-Month Primary Endpoint 6-Month Primary Endpoint 6-Month Primary Endpoint (MTX-IR; bkgrd MTX) 70 *** (DMARD-IR) (MTX-IR; bkgrd MTX) 65.7 *** *** 61.8 59.8 60 *** *** *** 52.6

(%) (%) 71.0 51.5

† ** 50 *** 47.2 43.7 *** *** 40 36.8 36.7 *** *** 34.7 *** 32.4 31.1 * 28.3 30 26.7 27.6 25.3 *** *** *** 22.3 *** 21.9 20.3 19.9 20 * *** 15.4 14.6 12.5 Patient Response Rates PatientResponse 12.3 8.4 9.1 10 5.8 1.3 1.9 0 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 Placebo Tofacitinib 5 mg twice daily Tofacitinib 10 mg twice daily Adalimumab 40 mg Q2W • Without background DMARDs • Monotherapy • Monotherapy • Plus background MTX (Solo) (Solo) (Solo) (Standard) • Plus background MTX • Plus background MTX • Plus background MTX (Scan and Standard) (Scan and Standard) (Scan and Standard)

*p<0.01; **p<0.001; ***p<0.0001 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;367:495-507; 2. van der Heijde D, et al. Arthritis Rheum. 2013;65:559-570; 3. van Vollenhoven RF, et al. N Engl J Med. 2012;367:508-519. 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 Safety Summary for Tofacitinib 5 mg versus 10 mg BID

Risk Ration (95% Cl) Incidence Rate 10 mg /5 mg (events/100 PY) Endpoint Comparison 5 mg 10 mg All Cause Mortality P3ALL 0.79 0.553 0.439 LTE 0.49 0.367 0.178

Serious Infection P3ALL 0.92 3.217 2.97 LTE 1.74 2.332 4.058

Malignancy (excl. NMSC) P3ALL 1.59 0.553 0.879 LTE 1.17 1.065 1.248

NMSC P3ALL 1.66 0.332 0.55 LTE 2.43 0.368 0.894

Lung Cancer P3ALL 0.33 0.332 0.11 LTE 3.23 0.147 0.475 MACE 0.443 0.659 P3ALL 1.49 LTE 1.66 0.18 0.298

GI Perforation P3ALL NA 0 0.22 LTE 1.21 0.147 0.178 Herpes Zoster P3ALL 4.391 4.231 0.96 LTE 1.16 4.089 4.736

P3ALL 0.01 0.10 1.00 10.00 100.00 LTE Data as of 29SEP2011 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 203214). Presentation [Accessed December 2012] http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM304200.pdf Safety Conclusions

• Safety profile of tofacitinib – Well described, based on nearly 13,000 patient years of exposure1 – Similar to existing immunomodulatory therapies for rheumatoid arthritis (RA), with specific differences as described2 – 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 802 2. FDA Advisory Committee Meeting, 9 May 2012 (NDA 203214). Presentation [Accessed August 2014] http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM304200.pdf Apremilast There Are 11 Distinct Families of PDEs

cAMP cGMP PKA, CaMK PDE1A, B,C Ca/CaM Ca/CaM cGMP cGMP PDR2A

PKA, PKB PDE3A,B Membrane-associated domain insert

ERK2 PDE4A,B,C,D Targeting domain cGMP PDE5A GAF GAF A B PDE6A,B,C GAF GAF A B PDE7A,B Targeting domain PDE8A,B PAS domain PDE9A REC PDE10A GAF GAF PDE11A A B GAF GAF A B

PDE = phosphodiesterase. Lugnier C. Pharmacol Ther. 2006;109:366-398. PDE4 Is the Predominant PDE in Immune Cells In Vitro

PDE4 Activity in Monocytes and DCs1

80 PDE1 PDE3 PDE4 PDE total– PDE 1/3/4

, 60

PDE4 is the y

v i

Predominant t 50

c A

PDE in inflammatory 40 E

Cells based on an in D

P 30

Vitro analysis1,2 l

a t

o 20 T 10 0 Monocyte Immature Mature DC Mature DC DC (LPS) (LPS/IFN-ϒ)

DC = dendritic cells; LPS = lipopolysaccharide; IFN = interferon; PDE = phosphodiesterase. 1. Heystek HC, et al. Int Immunol. 2003;15:827-835. 2. Gottlieb AB, et al. J Drugs Dermatol. 2013;12:888-897. 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;26:2016-2029. 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;26:2016-2029. Apremilast Mechanism of Action

Schafer PH, et al. Biochem Pharmacol. 2012;83:1583-1590. Apremilast Regulates the Production of Pro- and Anti-Inflammatory Cytokines In Vitro

100

n IC50 (μM)

i t

) 75 l

c GM-CSF 7.8

r t

d IL-12p70 0.12

o r o 50 P 0.11

C TNF-α

i IFN-γ 0.013

% o

( 25

y C

0.0001 0.001 0.01 0.1 1 10 Effect of apremilast Apremilast (μM) on cytokine and

175 Chemokine production

IL-10

n 150

o i

t IL-6

)

o u

r IL-8 t

d 125

o r

o IL-1β

e RANTES o

n 100

(

t y

C 75

0.0001 0.001 0.01 0.1 10 Apremilast 30 mg BID Apremilast (μM) human plasma mean Cmax= (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;159:842-855. 2. Schafer P. Biochem Pharmacol. 2012;83:1583-1590. Apremilast Limits Cytokine Production by Human T Cells In Vitro

IC50 (μM)

) 100 RANTES 4.1

M E

n IL-2 2.4

c IFN-γ 1.3 n

u 75

d e

o GM-CSF 1.0

e TNF-α 0.93

o r

n 50

i k

n IL-13 0.28

C IL-10 0.19 o

25 %

( IL-17 0.09 IL-5 0.03 0 0.001 0.01 0.1 1 [apremilast] (μM)

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;26:2016-2029. Apremilast Shows Selectivity for Suppressing Innate Immune Responses In Vitro

) TLR4-Stimulated PBMC TLR9-Stimulated pDC

l )

l 100

r r t IC (μM)

50 t

n o

100 apremilast o

C 0.029

C 75

f o

lenalidomide

0.014 o

% 75

( %

pomalidomide 0.0027 (

n 50

t i t

c 50 IC50(μM)

d d

o 25 apremilast 0.62

r r

P 25

P lenalidomide

>10

- α

F N

N 0 0

T I 1 1 1 1 1 1 0 1 1 1 1 1 1 0 0 0 0 0 . 1 0 0 0 0 . 1 0 0 0 . 0 0 0 .0 . 0 0 0 . 0 0 0 0 0 0 . 0 .0 . . 0 0 0 0 [Compound] (μM) [Compound] (μM)

B-Cell Stimulation T-Cell Stimulation

) l

o 2000

)

l n

o 125 1000

f o 175

100 o

f 150

(

75 n 125

(

i t

n 100

i u

t 50

IC (μM) d 75

c 50

o u apremilast >10 r

d 50

P apremilast IC50=2.4 μM

o 25

r 2

pomalidomide 0.063 - 25 pomalidomide

P EC50=0.0084 μM

L I

G 0 0

g I 1 1 1 1 1 1 0 0.001 0.01 0.1 1 10 0 0 0 .0 . 1 0 0 .0 0 0 0 .0 0 .0 0 [Compound] (μM) 0 [Compound] (μM) TLR = toll-like receptor; PBMC = peripheral blood mononuclear cells; pDC = plasmacytoid dendritic cells. Schafer PH, et al. Cell Signal. 2014;26:2016-2029. 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;26:2016-2029. Schafer P. Biochem Pharmacol. 2012;83:1583-1590. PALACE 1 Biomarker Subset Demographics

Baseline Demographic and Clinical Characteristics of Biomarker Substudy Patients (N=150)

Apremilast Placebo 20 mg BID 30 mg BID n=51 n=51 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/m2 30.7 (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 58.0 (20.4) 59.4 (18.9) 57.9 (17.4) (0-100 mm visual analog scale), mean (SD) 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]. Change in Biomarkers at Weeks 4 and 16

Week 4 (Data as Observed) Week 16 (LOCF)

§ 100 Placebo

) 100

Apremilast 20 mg BID Placebo

) E

Apremilast 30 mg BID M Apremilast 20 mg BID

S E

80 ± S Apremilast 30 mg BID

e (

e a

40 s

B a

e 20 F

t 0

C 0

r P

-20 e -20 P

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=0.0527.

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]. Apremilast Induced Changes in Plasma Biomarkers in Psoriatic Arthritis (PALACE 1) at Week 16

Association Between ACR20 Response and Biomarker Change at Week 16

Multivariate Univariate Analysis 1* Analysis 2§

Placebo Apremilast 20 mg BID Apremilast 30 mg BID Interaction n=51 n=51 n=48 Odds Ratio Odds Ratio Odds Ratio Biomarker‡ (2-Sided 95% P Value (2-Sided 95% P Value (2-Sided 95% P Value P Value CI) CI) CI) 0.0995 1.006 0.978 TNF-α (pg/mL) NS 0.0205 0.0166 0.0024 (0.986, 1.003) (1.001, 1.011) (0.960, 0.996) 1.000 0.997 0.994 IL-8 (pg/mL) NS NS NS NS (0.990, 1.010) (0.985, 1.008) (0.984, 1.004) 0.998 1.002 0.989 IL-6 (pg/mL) NS NS NS NS (0.992, 1.004) (0.991, 1.013) (0.977, 1.002) 0.996 1.001 0.992 Ferritin (ng/mL) NS NS NS NS (0.974, 1.019) (0.984, 1.018) (0.969, 1.016) 1.012 0.996 1.007 vWF (μg/mL) NS 0.0253 NS 0.0387 (0.985, 1.040) (0.938, 0.996) (0.992, 1.022) *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≥0.05. 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]. Change in Biomarkers at Week 24

Week 24 (LOCF)

100 Placebo )

M Apremilast 20 mg BID E

S Apremilast 30 mg BID

± 80

M (

s a

B 40

e 20

t 0

r e

P -20

TNF-α IL-8 MIP-1β MCP-1 IL-6 Ferritin vWF *P<0.05 vs. placebo (rank ANCOVA 2-sided P value). 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. Mean Percent Change in Biomarkers at Week 40

400 Apremilast 20 mg BID )

M Apremilast 30 mg BID

S ±

n 300

(

e n

i 200

m 100

h C

r e

P -20

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]. 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 long- term 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]. 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 fibroblasts1 • CD3+ T cell numbers were significantly lower in PsA than in RA1 • Synovial tissue in PsA is also characterized by the expression of pro-inflammatory cytokines including2,3: ‒ 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;65:1551-1557. 2. Fitzgerald O, Winchester R. Arthritis Res Ther. 2009;11:214. 3. van Baarsen LGM, et al. Ann Rheum Dis. 2011;70(Suppl 2):A79. Apremilast Inhibits Osteoclastogenesis In Vitro

150

Dex + Vit.D

100

0 / y y l 1 1 0 0 0 0 x l l ro . 1 1 1 3 (% of Control) of (% e n n t 0 .D o o n R L D it R P R N F o D x o A P O E L V t. e C P A R L U TRAP5+ Cell Count Cell TRAP5+ N o i D A A S Human osteoclast N V resorbing bone *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. 21012;64:10(Suppl)S17 [abstract 45]. Adams M, Schafer PH. ACR 2012 [poster]. PDE4 Expression Is Elevated in Psoriatic Skin

Schafer P, et al. AAD 2013 [e-poster 6634]. Table 1: Dosage Titration Schedule

Day 6 Day 1 Day 2 Day 3 Day 4 Day 5 & 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 Table 3: Proportion of Patients with ACR Responses in Studies PsA-1, PsA-2 and PsA-3

PsA 1 PsA 2 PsA 3

Otezla 30 Otezla 30 Otezla 30 Placebo ± mg twice Placebo ± mg twice Placebo ± mg twice DMARDs daily ± DMARDs daily ± DMARDs daily ± Na DMARDs DMARDs DMARDs N=168 N=159 N=169 N=168 N=162 N=167 ACR 20 19% 38% 19% 32%b 18% 41%b Week 16 ACR 50 6% 16% 5% 11% 8% 15% Week 16 Reference ID: 3475511

ACR 70 1% 4% 1% 1% 2% 4% Week 16 aN is number of randomized and treated patients b Statistically significantly different from placebo (p<0.05) 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 Day 6 to Day 112 Day 1 to 5 Day 6 to Day 112 Preferred Term (N=495) (N=490) (N=497) (N=493) N(%)c n(%) N(%) n(%)

Diarrheaa 6 (1.2) 8 (1.6) 46 (9.3) 38 (7.7)

Nauseaa 7 (1.4) 15 (3.1) 37 (7.4) 44 (8.9)

Headachea 9 (1.8) 11 (2.2) 24 (4.8) 29 (5.9)

Upper respiratory tract 3 (0.6) 9 (1.8) 3 (0.6) 19 (3.9) infectiona

Vomitinga 2 (0.4) 2 (0.4) 4 (0.8) 16 (3.2)

Nasopharyngitisa 1 (0.2) 8 (1.6) 1 (0.2) 13 (2.6)

Abdominal pain uppera 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. 5.1 Depression 5.2 Weight Decrease 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) During the controlled period of the studies, weight decrease between 5-10% of of patients treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) body weight was reported in 10% (49/497) of patients treated with OTEZLA’s 30 treated with placebo. During the clinical trials, 0.3% (4/1441) of patients treated with OTEZLA mg twice daily compared to 3.3% (16/495) treated with placebo [see Adverse discontinued Reactions (6.1)]. Patients treated with OTEZLA should have their weight treatment due to depression or depressed mood compared with none in placebo treated patients (0.495). monitored regularly. If unexplained or clinically significant weight loss occurs, Depression was reported as serious in 0.2% (3/1441) of patients exposed to OTEZLA, compared to weight loss should be evaluated, and discontinuation of OTEZLA should be none in placebo treated patients (0/495). Instances of suicidal ideation and behavior have been observed considered. 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 5.3 Drug Interactions OTEZLA treated patients. Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior in a reduction of systemic exposure of apremilat, which may result in a loss of prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. efficacy of OTEZLA. Therefore, the use of cytochrome P450 enzyme inducers Patients, their caregivers,and families should be advised of the need to be alert for the emergence or (e.g. rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact recommended [ see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur. Apremilast PSA 3 Infliximab RESPOND

100 100% 90 90%

80 80%

70 70% 60 60%

50 50% MTX 40 40% MTX + INF 30 30% Apremilast 20 20% 30 BID 10 10%

0 0% ACR 20 ACR 50 ACR 70 ACR20 ACR50 ACR70 ACR20 Response Over 52 Weeks PALACE 1, 2, and 3

Patients Receiving Apremilast From Baseline (Data as Observed) 80 Apremilast 20 mg BID PALACE 1 60 63.0% Apremilast 30 mg BID 54.6%

20 0 0 10 16 20 24 30 40 50 52 20 mg BID, n/m 51/158 59/145 75/129 75/119

30 mg BID, n/m 64/150 73/145 80/140 71/130

80 Apremilast 20 mg BID PALACE 2 60 Apremilast 30 mg BID 52.9% 40 52.6% 20 0 0 10 16 20 24 30 40 50 52

20 mg BID, n/m 61/150 69/144 73/128 64/121

30 mg BID, n/m 52/145 60/138 61/121 61/116 80 Apremilast 20 mg BID PALACE 3 60 Apremilast 30 mg BID 63.0% 40 56.0% 20 Patients Achieving ACR20 Response (%) Response ACR20 Achieving Patients 0 0 10 16 20 24 30 40 50 52

20 mg BID, n/m 48/161 63/146 60/124 65/116

30 mg BID, n/m 69/154 63/145 82/131 80/127 n/m=number of responders/number of patients with sufficient data for evaluation. Study Week Fostamatinib – SyK Inhibitor

• Oral disodium salt - prodrug of the active ONa+ compound tamatinib which is an inhibitor of O P + the enzyme spleen tyrosine kinase (Syk). O Na O

H H • Phase II study of rheumatoid arthritis patients O N NNN N O failing to respond to a biologic agent showed N little efficacy. O F O O • On June 4, 2013, Astra Zeneca announced discontinuation of future development.

Antigen Induced Signaling 80 ACR 20

BCR ) 60 ACR

% Placebo Fostamatinib (

50 e s 37 38

Fostamatinub n 40 ACR

o p

s 70

e 22 R 20 12 DAS < CO-79 10 9 12 5 2.6 CAL-101 PCI-32765 AVL-292 0 N= 73 N= 152

Genovese MC. Arthritis Rheum 2011 63:337