11/5/2011. Disclosures. Key References. JAK Inhibitors. Tofacitinib(CP ): Phase 2 Studies

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1 Disclosures KINASE INHIBITORS IN RA Michael E. Weinblatt, M.D. Dr. Weinblatt has been a consultant to the following companies involved in the JAK and SYK pathways in RA Pfizer Vertex Astellas Rigel Astra-Zeneca Portolo Key References Kremer JM et al. the safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis. Arthriis Rheum 2009; 60: Fleischmann R et al. Phase 2B dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to DMARDs. Arthritis Rheum Sep 27. doi: /art [Epub ahead of print] Weinblatt ME et al.. An oral spleen tyrosine kinase ( Syk) inhibitor for rheumatoid arthritis. N.Engl.J.Med. 2010; 363: Genovese MC, et al. An oral syk kinase inhibitor in the treatment of rheumatoid arthritis: A 3 month randomized placebo controlled Phase 2 study in patients with active RA who had failed biologic agents. Arthritis Rheum 2011; 63: Autoimmunity Reviews 9 (2009) JAK Inhibitors Critical for signal transduction for multiple interleukins Important for lymphocyte activation, function and proliferation There are 4 identified JAKs 1,2,3,and Tyk 2 Studies in transplant, myelofibrosis, RA, psoraisis, IBD Positive results in animal models of arthritis Positive Phase 2 and 3 studies in RA Several JAK inhibitors in development Tofacitinib(CP ): Phase 2 Studies Transplant in combination with Cell Cept RA Monotherapy- Dose ranging studies Combo with MTX-Dose ranging studies 1

2 patients with ACR response Patients () 11/5/2011 JAK INHIBITOR: Monotherapy Arthritis Rheum 60:1895,2009 JAK INHIBITOR ORAL MOLECULE CP690,550- Tofacitinib BIW DOSING 6WK STUDY LFT AND HEMATOLOGIC SIGNAL Placebo, n=65 5 mg, n=61 15 mg, n=69 30 mg, n=69 JAK INHIBITOR IN RA: Combination with MTX ACR LATE BREAKER 2008 Study- 24 wk RCT, active RA on background mtx 509 pts international study Jak inhibitor- CP690,550 (Tofacitinib) 1, 3,5,10,15 mg bid or 20 mg qd or placebo Wk 12 responses-acr pla, cp responses Wk 24 RESPONSES 35 pla, cp responses Aes- dose dependent increase in ldl, elevated lfts JAK INHIBITOR IN RA: PHASE 2 Monotherapy Eular wk RCT of 5 doses of Tofacitinib (1,3,5,10,15 mg) bid vs Placebo vs Adalimumab 40 mg q2wks 384 pts with Disease Duration > 7 yrs At wk12- ACR 20 Tofacitinib 5,10, 15 mg 61-72, Monotherapy ADA 40 Placebo 24 AEs ---lab changes 6 patients experienced > 50 increase in serum creatinine levels 6 patients (2.2) experienced severe anemia Proportion of tofacitinib patients in 5, 10, 15 mg dose groups with LDL <130 mg/dl at baseline that increased to >130 mg/dl during the study were 29, 36, and 37, respectively DAS28-4 (ESR) Remission at Week 24* Placebo 1 mg 3 mg 5 mg 10 mg 15 mg *Nonresponder imputation. Tofacitinib: Phase 3 Studies Tofacitinib Phase 3 Study: Monotherapy ACR 2010 Monotherapy study Combination with DMARDs Structural damage study TNF failures Combination with MTX with anti-tnf anchor 24 wk RCT of 2 doses of tofacitinib ( 5,10 mg) bid vs Placebo Monotherapy Phase 3 Study At 12 wks placebo- blindly advanced to tofacitinib 3 co-primary endpts- ACR 20, change from baseline in HAQ, DAS (esr) remission 611 pts, disease duration >8 yrs, most (85), had received MTX in past, 15 prior anti-tnf At wk12- ACR 20 HAQ Das remission Placebo mg bid 60 * -0.5* 6 10 mg bid 66 * -0.6* 9.6 * p < AE s increase in LDL Confirms the results of the Phase 2 monotherapy study 2

3 Tofacitinib Phase 3 Study: DMARDs EULAR 2011 Tofacitinib plus Atorvastatin Eular wk RCT of 2 doses of tofacitinib ( 5,10 mg) bid vs placebo plus DMARDS- Phase 3 Study At 12 wks non responder placebo- blindly advanced to tofacitinib Primary endpts- ACR 20, DAS (esr) remission -month 6 change from baseline in HAQ- mo3 792 pts, disease duration >8 yrs, DAS >6.1 At wk24- ACR 20 Das remission HAQ ( 3 mo) Placebo mg bid 53 * * 10 mg bid 58 * 15* -0.56* * p < AE s 4 deaths ( 5 mg- traumatic brain, RA, 10 mg chf, resp failure 4 opportunistic infections ( TB china, thailand, Crypto- australia, zoster finland) lab abnormalities- neutropenia, increased creatinine and lipids Background: Total cholesterol and LDL increased up to 25 in tofacitinib studies. No drug interactions between Tofa and atorvastatin Objective: Evaluate safety and LDL with atorvastatin plus tofa Design: 6 wk open run in of Tofa 10 mg bid and then 6 wk DB of tofa plus atorvastatin 10 mg vs tofa plus placebo Endpoint: Percent change in LDL from wk 6( start of DB) to wk 12 Demographics: 86 white, 43 Asian population, LDL 135 mg/dl Results: 35 reduction of LDL in the atorvastatin group to mean of 80. Total cholesterol, Apo B and triglycerides also decreased. No safety signal with the combination Tofacitinib Abstracts ACR 718. Tofa plus MTX in TNF failures- 6 mo study, 399 pts wk 12 5 mg 10 mg PBO ACR 20 42* 48* 24 ACR 50 27* 28* Structural 24 mo study- 797 pts 5,10 mg bid vs PBO +MTX wk 24 5 mg 10 mg PBO ACR 20 52* 62* 25 TSS change * 0.47 Erosion score Tofa vs PBO vs Adalimumab + MTX- 12 mo study, 717 pt wk 24 5 mg 10 mg ADA PBO ACR 20 52* 53* 47* 28 ACR * 35* INCBO 28050: JAK INHIBITOR ACR wk RCT of 3 doses of INCP ( 4,7,10 mg) QD vs Placebo Study 127 pts, 30 failed biologics At wk12- INCB ACR , placebo ACR- 32 AE s increase in LDL VK-509 in RA: Phase 2 Study ACR 2011 LB JAK inhibitors VK based on in vitro data more selective for inhibition of JAK-3, also observed in vivo with a dose dependent inhibition of a JAK-3 dependent biomarker 12 wk RCT of 4 doses of monotherapy VK 509 (25,50,100,150 mg) bid vs placebo. No background MTX. Study performed in USA and Europe At 12 wk VK 509 (163) ACR 20 ACR 50 ACR mg mg 61 * 32* mg 65 * 38* 18* 150 mg 66* 49* 22* * p <0.01 Placebo ( 41) Adverse events- infections, nausea, headaches, ALT and increase in LDL. No declines in Hb or neutrophils Positive Phase 2 Studies Psoriasis Ulcerative Colitis Negative Phase 2 study Crohn s Disease 3

4 Tofacitinib : Long term studies Eular 2011 Long term extension study of Tofa 5 or 10 mg bid- rollovers from monotherapy and como studies with MTX Baseline 1070 pts year pts year pts Withdrawals (AE) Infections Monotherapy (648) MTX +Tofa (422) TB reported in 2 pts one on the combo, one on mono 2 mo after stopping tofa 7 pts on MTX stopped due to labs- 3 lfts, 1 anemia, 1 pancyto and 1 leukopenia, 1 pt on mono stopped due to lfts Tofacitinib: Long term ACR #407 Pts from Phase 2/3 studies who entered Long term extension 3227 pts with a total duration of 3118 pt years Mean duration of therapy 349, maximum 1456 days Serious infection events IR 3.01 (2.45,3.68) Laboratory Decreased Hb (>2 g/dl or Hb<8) 2.5 ALT >3x 1.7 Neutropenia ( WBC < 1.5) -0.5 Creatinine increase >33-12 Tofacitinib: All cause mortality and infection ACR 2011 #409 JAK Inhibitors AE profile Tofa All doses 3030 Placebo 681 Adalimumab 204 LTE 3227 Deaths 12 (0.4) 1 (0.15) 1 ( 0.49) 20 ( 0.62) Exposure Incidence rate 0.57 (.3,1.01).49 (0.7, 3.5) 0.6 (.08, 3.9) Serious Infections (0.4, 0.99) Pts ( n) 61 (2.0) 3 (0.4) 3 (1.5) 93 (2.9) Exposure pt y Incidence rate 2.9 (2.2,3.7) 1.5 (.48,4.6) 1.68 (0.5,5.2) 2.99 (2.45,3.67) Infections Opportunistic infections Zoster Lipid abnormalities Neutropenia Anemia Increase serum creatinine clinical significance? LFTs JAK Inhibitors Questions about JAK Inhibitors JAK inhibitors work as monotherapy or in combination with MTX in RA Works quickly Narrow therapeutic dose window AEs relate to biological activity Lipid elevations, hematological Extensive Phase 3 program in RA Studies in psoriasis, psa, transplantation Is there a differential response between monotherapy and combination with mtx? If so what is the mechanism? If there a difference in response and toxicity between Tofa 5 and 10mg? What happens if the dose is reduced from 10 to 5 or increased from 5 to 10? What about lab toxicities- is this class or drug specific Anemia- who develops this Creatinine- what does this mean? Lipids is the increase pathogenic- What about long term infection and malignancy risk? What about reproductive issues (female/male)? Where will it be positioned and where will it be used? Will more selective JAK inhibitors be as effective and offer a toxicity advantage 4

5 Spleen Tyrosine Kinase ( Syk) Cytoplasmic tyrosine kinase Found in a variety of cells including mast cells, macrophages, neutrophils and B cells. Syk plays a key role in signaling downstream of the B cell receptor Important mediator of immunoreceptor signalling in mast cells, macrophages, neutrophils and B cells Distal to Syk are a series of MAP kinases Syk expression detected in RA synovium as compared to OA Syk activation important in TNF induced cytokine and MMP production in RA synoviocytes Blocks TNF activation of JNK with reduced expression of JNK regulated genes IL-6 and MMP-3 ( RA fibroblast synoviocytes) Positive results in standard models of arthritis and SLE in rodents Initial positive results in pts with ITP Positive studies in RA in combination with MTX Syk Inhibitor R788 (Fostamatinib Disodium) R788 is a pro-drug of R406, a moderately selective splenic tyrosine kinase (Syk) inhibitor, also inhibits other kinases including jak and vegf Pharmacology- rapid oral absorption, terminal half life of hrs, steady state achieved in 3-4 days R 788 Program TASKi 1 Phase 2b R ,100, 150 mg bid, vs Placebo 12 wk RCT add on study to mtx TASKi 2 Phase 2b R mg bid, 150 mg qd vs Placebo 24 wk add on study to mtx TASKi 3 Phase 2b R mg bid vs placebo 24 wk add on study to mtx Biologic failure study Substudy with MRI SYK INHIBITOR IN RA Arthritis Rheum 58:3309,2008 Study- 12 wk rct, active RA on MTX 189 pts study USA and Mexico R , 100, 150 mg bid vs placebo Wk 12 responses-acr 20 Pla mg mg mg 72 Aes- dose dependent- diarrhea, increase bp, elevated lfts, neutropenia Response Rates at 12 Weeks ACR 20 Responder Rate by Time over Treatment ACR Response Rates Placebo N () N = 47 R788 50mg bid N () N = 46 R mg bid N () N = 49 R mg bid N () N = 47 ACR (38) 15 (32) 32 (65)* 34 (72) ACR 50 9 (19) 8 (17) 24 (49) 27 (57) ACR 70 2 (4) 1 (2) 16 (33) 19 (40) DAS28 <2.6 3 (8) 6 (16) 11 (26) 19 (49) * p=0.008 p=0.002 p<0.001 p=

6 ACR20 response rate ( of patients) Patients 11/5/2011 Change from Baseline in IL-6 (pg/ml) and MMP-3 (ng/nl) over the 12-Week Course of Study IL-6 MMP-3 SYK INHIBITOR IN RA NEJM 2010; 363: WK RCT, Active RA on background mtx, phase 2 study. Prior biologic rx was allowed in no more than 30 of population 457 PTS, international study R mg bid, 150 mg qd vs placebo Wk 24 responses-acr 20 Pla 35, R100 mg bid 67, R150 mg qd 57 Clinical effect by wk1 Aes- diarrhea increase in bp, elevated lfts, neutropenia ACR20 Responses Week 1 Response Rates at Month 6 of Patients Achieving ACR20 at Week 1 N=53 (36) N=34 (23)* ACR 20 ACR 50 ACR 70 DAS-28<2.6 * * N=21 (14) Plb 150mg 100mg qd bid Plb 150mg 100mg qd bid Plb 150mg 100mg qd bid Plb 150mg 100mg qd bid ACR 20 ACR 50 ACR 70 DAS28 Treatment (N) <2.6, Placebo mg qd * 14 21* *p=0.04, p<0.001(compared to placebo) 100 mg bid P < 0.001, * P <0.01 (compared to placebo) ACR20 Responses at Month 6 by Region and Prior Biologic Use FosD ACR20 response over time by baseline MTX dose mg mg mg Consistent responses across all geographic areas 65 Treatment Assigned United States (n=109) Latin America (n=223) Eastern Europe (n=124) Prior Biologic Therapy (n=67) No Prior Biologic Therapy (n=389) Placebo R mg qd 50 (p=0.012) 66 (p<0.001) 50 (p=0.425) 46 (p=0.021) 59 (p<0.001) R mg bid 56 (p=0.003) 69 (p<0.001) 74 (p=0.004) 43 (p<0.037) 71 (p<0.001) Difference in R mg bid-placebo ACR20 response Week PLACEBO R MG PO QD R MG PO BID 6

7 Patients 11/5/2011 DAS28-CRP over Time Effect of Dose Reduction Patient Reported Outcome Measures ACR PLACEBO DAS28-CRP R MG QD R MG BID Dose reduction to 100 mg qd No dose reduction Fostamatinib 100 mg bid was associated with statistically significant improvements in HRQoL outcomes. Significant improvements in Pt VAS, Pain, HAQ DI, SF 36 physical domain and Fatigue There were significantly more patients showing clinically meaningful improvements in physical functioning and other aspects of physical health status (notably in physical health-related role activities, bodily pain, general health, and vitality) fostamatinib 100mg bid compared with placebo Improvements in pain, disease activity, and physical functioning were detected as early as 1 week from start of treatment BASELINE M 1 M 2 M 3 M 4 M 5 M 6 M 1 BASELINE Base M1 M2 M3 M4 M5 M6 Base M1 M2 M3 M4 M5 M6 R788 efficacy maintained despite dose reduction M 2 M 3 M 4 M 5 M 6 M 1 BASELINE M 2 M 3 M 4 M 5 M 6 Treatment-Emergent Adverse Events Most Common (>5) Blood Pressure Changes Mean Blood Pressure - mmhg Placebo R mg qd R mg bid Placebo R mg qd R mg bid Baseline (systolic/ diastolic) 125/76 125/77 125/77 Urinary Tract Infections Upper Respiratory Infection Total # patients Change from Baseline to Month 1 All patients (systolic/ diastolic) -2.0/ / /+3.1 Diarrhea Change from Baseline to Month 6 (LOCF) All patients (systolic/ diastolic) -1.8 / / /+1.4 Nausea Headache Total patients initiated or changed anti-hypertensives 11 (7) 27 (18) 35 (23) # pts with history of HTN or baseline 73 (48) 84 (55) 71 (47) Change from Baseline to Month 1 HTN patients (systolic/ diastolic) Change from Baseline to Month 6 (LOCF) HTN patients (systolic/ diastolic) -4.1/ / / / / /+0.9 Hypertension responsive to standard therapies Syk inhibitor: Phase 2 study in pts with hx of prior biologics Arthritis Rheum 2011; 63: Objective Assess efficacy of R mg PO bid as compared to placebo over 3 months in patients with active RA who had failed biologic therapies Study Design 3 month, randomized, placebo control, parallel dose clinical trial Primary Efficacy Measure ACR20 at Month 3 (withdrawals prior to study conclusion were calculated as non-responders) Secondary Change in radiologic/ structural response at 3 months by MRI (modified RAMRIS) ACR20, ACR50, ACR70, ACRn over the course of the study DAS28-CRP and DAS28-ESR over time 219 patients randomized (2:1 Active: Control) R mg bid (146 patients) Placebo bid (73 patients) ACR Response R788 Month 3 Treatment (N) ACR 20 ACR 50 ACR 70 DAS-28 Plcbo 100mg bid Plcbo 100mg bid Plcbo 100mg bid Plcbo 100mg bid ACR 20 ACR 50 ACR 70 DAS28 <2.6, Placebo p= 0.84 p= 0.09 p= 0.37 p= mg bid 6 7

8 Fostamatinib : Long term studies ACR 2011 # 2594 Long term study of Fosta 150 mg or 100 mg bid plus MTX or DMARDs 803 pts with 1038 pts of fosta exposure ( mean exposure 1.3 yrs) Most common Aes diarrhea ( 27) and HBP ( 22) SIEs 3.4 including pneumonia and UTI Deaths 6 4 due to CV or cerebral vascular events and 2 due to infections ( 1 was in the placebo group) Arthritis Rheum 63: 337,2011 Fostamatinib AE profile Infections Diarrhea Neutropenia LFTs HBP Fostamatinib: Studies PHASE III MTX IR DMARD IR SINGLE ANTI-TNF FAILURE THREE ARM STUDIES PLACEBO INDUCTION DOSING WITH 100 MG BID 100 MG BID 150 MG QD PHASE II AMBULATORY BP STUDY MONOTHERAPY SYK INHIBITORS IN RA An inhibitor of the spleen tyrosine kinase pathway has demonstrated efficacy in Phase 2 studies The drug worked quickly achieving response as early as one week in combination with MTX One phase 2 study in pts who failed prior biologics was not positive- this may have been due to study design and patient selection Toxicity included diarrhea and hypertension these AEs were responsive to dose reduction and/or anti-bp meds Phase 3 studies are in progress Questions about SYK Does Fostamatinib work as monotherapy? Does Fostamatinib work in TNF failures? Can you lower dose and maintain response What about toxicities? What about long term infection, HBP and malignancy risk? What is the etiology of the HBP VEGF inhibition? Is the mechanism of action due to Syk inhibition or other kinase inhibition Where will it be positioned and where will it be used? Will more selective Syk inhibitors be as effective and offer a toxicity advantage 8