How To Test For A Clinical Trial On Mxx

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1 Efficacy and Safety of Baricitinib in Japanese Patients with Rheumatoid Arthritis at 12 Weeks Tsukasa Matsubara, MD, PhD Tsukasa Matsubara 1, Douglas Schlichting 2, Kahaku Emoto 3, Mika Tsujimoto 3, William Macias 2 1 Matsubara Mayflower Hospital, Hyogo, Japan; 2 Eli Lilly and Company; 3 Eli Lilly Japan K.K. Funded by Eli Lilly Japan K.K.

2 Author Disclosure Dr. Matsubara has received research grants from Nippon Kayaku, Pfizer Japan, Bristol-Myers Squibb, Otsuka Pharmaceutical, Quintiles Transnational Japan, Janssen Pharmaceutical, Astellas Pharma, Takeda Chemical Industries, Eli Lilly Japan, Mitsubishi Tanabe Pharma, AstraZeneca, Eisai, Santen Pharmaceutical, Daiichi Sankyo and speaking fees from Pfizer Japan and Janssen Pharmaceutical. Dr. Emoto is an employee and stockholder of Eli Lilly Japan K.K. 2

3 JAK-STAT Pathway Family of 4 tyrosine kinases 1 JAK1, JAK2, JAK3, and TYK2 Mediate signal transduction for variety of cytokines involved in inflammatory conditions IL-6 JAK1/JAK2 or JAK1/TYK2 IL- JAK2/TYK2 IL-12 JAK2/TYK2 INF- JAK1/JAK2 INF- / JAK1/TYK2 Figure from O Shea, O Shea et al. Immunity 2012;36(4):

4 Baricitinib (LY ) Oral, reversible inhibitor of JAK1 and JAK2 In-vitro potency (IC 50 ) JAK1 and JAK2 ~ 2-5 nm TYK2 ~ 53 nm JAK3 ~ 560 nm Pharmacokinetic parameters t max ~ 1.5 hrs Terminal t ½ between 10 (healthy subjects) and 14.9 hrs (RA patients) 4

5 Study Design Key Inclusion Criteria 6 swollen and 6 tender joints based on 66/68 joint count Regular use of MTX for 12 weeks and a stable dose of MTX (6 to 16 mg/week) for 8 weeks ACR functional class I, II, or III CRP >0.5mg/dL or ESR >28 mm/hr Key Exclusion Criteria Use of DMARDs (other than MTX and/or sulfasalazine 3000 mg/day) in the 8 weeks prior to randomization Prior biologic DMARD therapy AND discontinuation due to insufficient efficacy egfr <50 ml/min Serum AST or ALT >3x ULN or total bilirubin 1.5x ULN 0 Week Patients and Investigators remained blinded during Part B Part A (12 weeks) Double-Blind Placebo QD (N=49) Baricitinib 1 mg QD Baricitinib 2 mg QD Baricitinib 4 mg QD Baricitinib 8 mg QD R 12 Weeks Primary Endpoint Part B (52 weeks) Single-Blind Baricitinib 4 mg QD Baricitinib 8 mg QD Baricitinib 4 mg QD Baricitinib 8 mg QD to 4 mg QD Follow-Up 64 Weeks 68 Weeks Combined 4-mg and 8-mg dose groups vs. placebo in ACR20 response Secondary Endpoint ACR20/50/70 response, DAS28-CRP response Safety and tolerability Patient-reported outcomes (HAQ-DI) R = Patients assigned to placebo or Baricitinib 1 mg or 2 mg once-daily (QD) will be re-randomized to either 4 mg or 8 mg QD at Week 12. Patients assigned to Baricitinib 8 mg QD at Week 12 switched to 4 mg QD. 5

6 Patient Disposition Screened (N=199) Randomized (N=145) Placebo (N=49) 1 mg QD 2 mg QD 4 mg QD 8 mg QD Discontinuation n = 1 Adverse Event Discontinuation n = 1 Adverse Event Discontinuation n = 1 Subject withdrawal Placebo (N=48) 1 mg QD (N=) 2 mg QD 4 mg QD (N=) 8 mg QD Completed 12 Weeks of Treatment 6

7 Baseline Characteristics Parameter Placebo (N=49) 1 mg QD 2 mg QD Baricitinib 4 mg QD 8 mg QD Combined (N=96) Age (years), mean Gender (% female) Duration of RA (years), mean CCP (% positive) Rheumatoid Factor (% positive) MTX dose (mg/week) [mean] Tender joint count (68) [mean] Swollen joint count (66) [mean] DAS28-CRP (mean) HAQ-DI (mean)

8 Primary Endpoint: ACR20 for Combined 4-mg and 8-mg (NRI) Dose Groups vs. Placebo ACR20 Percent (%) Patients ACR20 Response Rate n (%) Baseline DAS28-CRP mean Placebo (N=49) Combined 4 mg and 8 mg (N=48) 15 (31%) 37 (77%) P<0.001 (adjusted for baseline DAS28-CRP) Placebo (N=49) Baricitinib 4 mg and 8 mg QD combined (N=48) The primary analysis used a 1-sided, 0.05-level test from a logistic regression model that included treatment group as a fixed factor and baseline DAS28 as a continuous covariate. N=number of patients; n=number of patients in subgroup; NRI=non-responder imputation 8

9 ACR Responses at Week 12 ACR20 ACR50 ACR70 Percent (%) Patients a 83 a 67 a 88 a 8 33 a 46 a 54 a 54 a 0 13 a Placebo QD 1 mg QD 2 mg QD 4 mg QD 8 mg QD 29 a 29 a 21 a ACR20/50/70 calculated via NRI. a p<0.05 vs. Placebo with a 1-sided Fisher's exact test. 9

10 DAS28-CRP Responses at Week 12 DAS28-CRP <3.2 DAS28-CRP < Percent (%) Patients a a 63a a a 0 DAS28-CRP calculated by LOCF. a p<0.05 vs. Placebo with a 1-sided Fisher's exact test. Placebo QD 1 mg QD 2 mg QD 4 mg QD 8 mg QD LOCF = last-observation-carried-forward 10

11 SDAI Remission at Week 12 SDAI 11.0 SDAI Percent (%) Patients a 58 a 54 a 67 a a SDAI calculated by LOCF. a p<0.05 vs. Placebo with a 1-sided Fisher's exact test. Placebo QD 1 mg QD 2 mg QD 4 mg QD 8 mg QD 11

12 HAQ-DI Remission at Week 12 HAQ-DI MCID, change HAQ-DI Remission, 0.5 Percent (%) Patients a 58a 75 a 71 a a 0 HAQ-DI MCID calculated by LOCF. a p<0.05 vs. Placebo with a 1-sided Fisher's exact test. Placebo QD 1 mg QD 2 mg QD 4 mg QD 8 mg QD 12

13 Change in ACR Core Components LSMean change from baseline LSMean change from baseline Week Physician's Global Assessment of Disease Activity Tender Joint Count (68) -6-8 Placebo 1 mg 2 mg 4 mg 8 mg Placebo 1 mg 2 mg mg 8 mg p<0.05 p<0.01 p<0.001 Week LSMean change from baseline LSMean change from baseline Swollen Joint Count (66) -6 Placebo 1 mg -8 2 mg 4 mg 8 mg Week Patient's Global Assessment of Disease Activity Placebo 1 mg 2 mg mg 8 mg Week

14 Change in ACR Core Components (Cont.) LSMean change from baseline LSMean change from baseline Patient's Assessment of Pain -25 Placebo mg 2 mg 4 mg 8 mg Placebo 1 mg 2 mg 4 mg 8 mg Week hscrp (mg/l) Week p<0.05 p<0.01 p<0.001 LSMean change from baseline LSMean change from baseline Placebo 1 mg 2 mg 4 mg 8 mg HAQ-DI -0.4 Placebo 1 mg mg 4 mg 8 mg Week ESR (mm/h) Week

15 Safety Overview at Week 12 2 subjects discontinued Part A due to adverse event (AE) Pollakiuria in 1 patient in placebo group Herpes simplex in 1 patient in 1-mg group 2 serious adverse events (SAEs) were reported 1 case of cholecystitis in placebo group 1 case of pancreatitis in 2-mg group 15

16 Safety Overview at Week 12 Baricitinib N (%) Placebo (N=49) 1 mg QD 2 mg QD 4 mg QD 8 mg QD TEAEs 26 (53) 11 (46) 11 (46) 13 (54) 18 (75) TEAEs related to study drug 14 (29) 6 (25) 5 (21) 11 (46) 15 (63) TEAEs related to infections (sorted by the SOC, Infections and infestations ) 11 (22) 6 (25) 4 (17) 6 (25) 5 (21) N=number of patients 16

17 Selected Laboratory Data at Week 12: Change from Baseline Median (Min, Max) n Placebo Baricitinib n 1 mg QD n 2 mg QD n 4 mg QD n 8 mg QD Hemoglobin (mmol/l) (-1.18, 1.06) (-0.94, 2.54) (-1.42, 0.93) (-1.30, 0.50) (-1.12, 1.06) Neutrophil count (10 9 /L) (-2.44, 4.76) (-2.94, 1.71) (-6.66, 1.36) (-6.98, 2.14) (-5.28, 1.22) Creatinine ( mol/l) (-13, 10) 4.0 (-3, 11) (-5, 13) 5.0 (-2, 17) 5.0 (-5, ) HDL cholesterol (mmol/l) (-0.59, 0.36) (-0.37, 0.49) (-0.88, 0.83) (-0.62, 0.85) (-0.39, 0.70) LDL cholesterol (mmol/l) (-0.72, 0.70) (-0.54, 0.78) (-1.19, 1.68) (-0.44, 1.17) (-2., 1.32) Median (Min, Max) are shown due to a skewed distribution. n=number of patients in subgroup 17

18 Summary Patients receiving baricitinib 2, 4, and 8 mg showed numerically similar improvement as measured by ACR20/50/70, DAS28-CRP remission, and SDAI remission Patients receiving baricitinib 4 mg and 8 mg showed apparent improvement in HAQ-DI compared to placebo. Similar safety profiles across placebo, 1-, 2-, and 4-mg groups were evident More TEAEs and laboratory abnormalities observed in the 8-mg group 18

19 Investigation Sites National Nagasaki Medical Center National Sagamihara Medical Center Shinko Hospital Hokkaido Medical Center for Rheumatic Diseases Matsubara Mayflower Hospital National Tokyo Medical Center National Hospital Organization Osaka Minami Medical Center National Hospital Organization Kyushu Medical Center Sasebo Chuo Hospital Honjo Rheumatism Clinic Uchida Clinic Hiroshima Rheumatology Clinic Hiroshima Red Cross/Atom Bomb Hospital Nagasaki Medical Hospital of Rhematology Oribe Clinic Rheumatism and Medicine Kawasaki Municipal Kawasaki Hospital PS Clinic Taga General Hospital Higashi-Hiroshima Memorial Hospital Izumihara Rheumatism Internal Medicine Clinic Shono Rheumatism Clinic Red Cross Okayama Hospital National Chiba-East Hospital Matsubara Clinic Hikarichuo Clinic 19

20 Acknowledgement The authors wish to acknowledge Victoria Crotzer, PhD and Julie Sherman from Eli Lilly and Company for editorial and process support of this presentation. 20

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22 Backup slides

23 Study JADN 1 st study of baricitinib in Japanese patients with RA with an inadequate response to MTX Safety and efficacy of baricitinib intended to inform benefit-risk relationship and Phase 3 dose selection Study conducted in 2 parts (Parts A and B) Part A (Weeks 0 to 12): Completed and is basis for this presentation Part B (Weeks 12 to 52): Completed JADN study number: NCT

24 Objectives Primary Endpoint Combined 4-mg and 8-mg dose groups vs. placebo in ACR20 response at Week 12 Major Secondary Endpoints ACR20/50/70 response at Week 12 DAS28-CRP response at Week 12 Safety and tolerability Patient-reported outcomes (HAQ-DI) at Week 12 24

25 Eligibility Criteria Key Inclusion Criteria 6 swollen and 6 tender joints based on 66/68 joint count Regular use of MTX for 12 weeks and a stable dose of MTX (6 to 16 mg/week) for 8 weeks ACR functional class I, II, or III CRP >0.5mg/dL or ESR >28 mm/hr Key Exclusion Criteria Use of DMARDs (other than MTX and/or sulfasalazine 3000 mg/day) in the 8 weeks prior to randomization Prior biologic DMARD therapy AND discontinuation due to insufficient efficacy egfr <50 ml/min Serum AST or ALT >3x ULN or total bilirubin 1.5x ULN 25

26 Other Laboratory Measures at Week 12 Median Placebo (N=49) 1 mg QD 2 mg QD Baricitinib 4 mg QD 8 mg QD Anti-CCP (U/mL) Baseline (n) 98.0 (48) 72.9 (24) (24) (24) (24) Week 12 Absolute Change from Baseline (%; n) Rheumatoid Factor (ku/l) -0.9 (-6.2; 47) -0.6 (-1.9; ) Median is shown due to a skewed distribution. p<0.05 p<0.01 p< (-.6; 24) (-28.3; ) (-36.1; ) Baseline (n) 37.5 (48) 32.5 (24) 27.0 (24) 66.5 (24) 51.5 (24) Week 12 Absolute Change from Baseline (%; n) N=number of patients; n=number of patients in subgroup 0.0 (0.0; 47) -5.0 (-11.2; ) -3.5 (-.5; 24) -9.0 (-29.6; ) (-38.2; ) 26

27 Selected Bone Markers at Week 12 Median Placebo (N=49) 1 mg QD 2 mg QD Baricitinib 4 mg QD 8 mg QD Osteocalcin ( g/l) Baseline (n) 17.8 (48) 19.3 (24) 19.5 (24) 17.5 (24) 16.1 (24) Week 12 Absolute Change from Baseline (%; n) 1.0 (5.9; 47) 0.0 (0.0; ) -0.1 (-0.3; 24) -1.5 (-8.7; ) -1.3 (-9.8; ) P1NP (ng/ml) Baseline (n) 38.4 (48) 42.2 (24) 40.1 (24) 45.5 (24) 43.6 (24) Week 12 Absolute Change from Baseline (%; n) -0.9 (-2.5; 47) 0.4 (2.1; ) Median is shown due to a skewed distribution. p<0.05 p<0.01 p<0.001 N=number of patients; n=number of patients in subgroup; P1NP=Procollagen Type 1 N-Propeptide (-9.3; 24) -8.6 (-.1; ) -4.6 (-10.6; ) 27