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Current Clinical Trials in SJIA & MAS - Dr. Daniel Lovell

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This talk was given by Dr. Daniel Lovell of Cincinnati Children's Hospital to a group of patient families, at Systemic Juvenile Idiopathic Arthritis (or SJIA) Family Day on July 22nd, 2017.

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Current Clinical Trials in SJIA & MAS - Dr. Daniel Lovell

  1. 1. Current Clinical Trials in SJIA & MAS Daniel J. Lovell, MD, MPH Joseph E. Levinson Professor and Chair in Pediatric Rheumatology Chairman, Pediatric Rheumatology Collaborative Study Group 1
  2. 2. Recent Clinical Trials in SJIA • Recent breakthroughs have been the testing of inflammatory mediators known to have a central role in the SJIA disease process –Interleukin 1- Anakinra (Kineret) and Canakinumab (Ilaris) –Interleukin 6- Tocilizumab (Actemra) • Ilaris and Actemra have been approved by the FDA for the treatment of SJIA 2
  3. 3. Effects of Interleukin 1 3
  4. 4. Fever Joint Inflammation Growth Impairment Interleukin-6 in sJIA Anemia Thrombocytosis J Exp Med 1998 J Clin Invest 1997 Endocrinol 2001 A&R 1991 A&R 1991 Lancet 1995 Blood 1996 J Clin Invest 1994 IL6/soluble IL6R and CRP MAS Osteoporosis A&R 2006
  5. 5. JIA CLINICAL TRIAL METHODS AND DEFINITIONS 5
  6. 6. JIA core set and response criteria JIA core set 1. Physician global assessment of overall disease activity 2. Parent or patient global assessment of overall well-being 3. Functional ability (CHAQ) 4. Number of joints with active arthritis 5. Number of joints with limited range of motion 6. Index of inflammation: ESR or CRP 7. (FEVER for systemic JIA) ACR Criteria: 3/6 core set variables improved ≥ 30% (50%, 70%, 90%, 100%) with no more than 1/6 worsened by >30% (AND NO FEVER) FDA and EMA accepted Giannini, Ruperto et Al. Arthritis Rheum 1997
  7. 7. JIA clinical inactive disease/remission Inactive disease – No joints with active arthritis – No fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to JIA – No active uveitis (to be defined) – Normal ESR or CRP – No disease activity according to MD evaluation – Morning stiffness ≤ 15 minutes Clinical remission – On medication for 6 months and – off medication for 12 months Wallace, Ruperto et al J Rheumatol 2004 Wallace…for CARRA/PRINTO/PRCSG. Arthritis Care Res 2011
  8. 8. BLINDED WITHDRAWAL STUDIES Screen Blinded Follow-Up Placebo Arm Experimental Arm EndOfStudy All subjects receive experimental therapy for several months Responders Randomized Flares go to Open 3-6 mo open Open label extension
  9. 9. S1 S2 S3 S4 S5 S6 S7 S8 S9 0 3 6 9 12 Baseline 1 week 1 month follow-up S1 S2 S3 S4 S5 S6 S7 S8 S9 baseline 1 week 1 month follow-up n.ofactivejoints CRP(mg/dL) A NS P = 0.005 P = 0.005 P = 0.005 P = 0.005 P = 0.005 P = 0.005 B S10 S10 0 2 4 6 8 10 12 14 16 18 20 30 Gattorno et al, Arthritis Rheum 2008 Anti IL-1 (anakinra) and systemic JIA Pascual et al: J Exp Med 2005
  10. 10. Anakinra in systemic JIA: study design Quartier et al. Annals Rheum Dis 2012
  11. 11. Anakinra in systemic JIA (1 month results) Response Anakinra (N=12) Placebo (N=12) P value Mod ACR 30 10 (83%) 3 (25%) 0.004 Mod ACR 50 7 (58%) 0 0.005 Mod ACR 70 5 (42%) 0 0.038 Mod ACR 100 0 0 1 Quartier et al. Annals Rheum Dis 2012
  12. 12. Long-term Efficacy and Safety of Canakinumab in Patients With Active Systemic Juvenile Idiopathic Arthritis (SJIA): Results From a Phase III Extension Study H. I. Brunner1 , N. Ruperto2 , P. Quartier3 , T. Constantin2 , E. Alexeeva2 , I. Kone-Paut4 , K. Marzan2 , N. Wulffraat2 , R. Schneider1 , S. Padeh2 , V. Chasnyk2 , C. Wouters2 , J. B. Kuemmerle-Deschner2 , T. Kallinich2 , B. Lauwerys5 , E. Haddad2 , E. Nasonov2 , M. Trachana2 , O. Vougiouka2 , K. Leon6 , E. Vritzali7 , K. Lheritier7 , A. Martini2 , D. Lovell1 1 PRCSG, Cincinnati, United States; 2 PRINTO-Istituto Gaslini, Genoa, Italy; 3 Necker-Enfants Malades Hospital, Paris; 4 Bicêtre hospital, Paris Sud, France; 5 Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels, Belgium; 6 Novartis Pharmaceuticals Corporation, East Hanover, United States; 7 Novartis Pharma AG, Basel, Switzerland
  13. 13. 13 Patients aged ≥2 to <20 yrs, with active SJIA features (≥2 of the following): 1. Spiking intermittent fever of >38°C for 1 day within 1 week of baseline 2. ≥2 joints with active arthritis 3. CRP levels of >30 mg/L [normal <10 mg/L] 4. Rash, serositis, lymphadenopathy and hepatosplenomegaly were included Methods Eligibility Criteria
  14. 14. 14 Results Demographics and Baseline Disease Characteristics Variable Overall N=123 Age (years), mean (SD) 9.0 (4.5) Female, n (%) 75 (61.0) Predominant race: Caucasian, n (%) 111 (90.2) Fever at entry, n (%) 70 (57.0) Presence of systemic signs after first 6 months of disease, n (%) 95 (77.2) Time from SJIA diagnosis to study entry (years), mean (SD) 2.66 (3.27) Prior use of other biologics, n (%) 32 (26.0) CRP at baseline (mg/L), median (Q1, Q3) 79 (22.0, 170.0) PGA (VAS, mm), median (Q1, Q3) 54.7 (39.0, 70.0) Number of active joints median (Q1, Q3) 5.0 (3.0, 14.0) Number of joints with limitation of motion, median (Q1, Q3) 5.0 (2.0, 12.0) CHAQ score, median (Q1, Q3) 1.37 (0.62, 2.0) JADAS10-CRP, median (Q1, Q3) 22.3 (17.2, 28.0) JADAS27-CRP, median (Q1, Q3) 21.5 (16.8, 28.4) Mean prednisone-equivalent dose (mg/kg/day) (SD) 0.95 (2.3)
  15. 15. 15  Canakinumab treatment provided a rapid response at Day 15. Over 50% of patients had aACR70 responses; 23.5% had aACR100 responses at Day 15  At last assessment, 67% of patients had aACR ≥70 responses and 51% were aACR100 Results Efficacy: aACR Responses in Naïve Patients
  16. 16. 16 Results Efficacy: Clinical remission on medication *At least 6 consecutive months of inactive disease; #at least 12 consecutive months of inactive disease # %of123patients
  17. 17. 17  SAEs were reported in 40 (32.5%) patients  No deaths occurred Results: Rates of Most Common Serious Adverse Events (SAEs) SAEs by preferred term (>2 events) Canakinumab (N= 123; rate /100 pt days) Total SAEs, n (incidence rate/100 Pt days)* 103 (0.15) Juvenile idiopathic arthritis flare 16 (0.02) Macrophage activation syndrome 8 (0.01) Fever 5 (0.01) Pneumonia 3 (<0.01) Lymph node inflammation 3 (<0.01) Lymph node enlargement 3 (<0.01) Hepatitis toxic 2 (<0.01)
  18. 18. 18  Rapid response and sustained therapeutic efficacy were demonstrated in canakinumab-naïve patients with active SJIA • More than 50% of the patients achieved aACR 70 response by Day 15, and the response was sustained until last assessment • At least 50% with inactive disease at the last assessment • Almost 1/3 of the patients were in clinical remission for 1 year  No new safety findings were observed upon long-term use of canakinumab, and the safety profile was consistent with that observed in the pivotal program Conclusions
  19. 19. Efficacy and Safety of Tocilizumab (TCZ) in Patients with Systemic Juvenile Idiopathic Arthritis (sJIA): TENDER 52-Week Data F. De Benedetti, H. Brunner, N. Ruperto, I. Calvo, R. Cuttica, C. Malattia, R. Schneider, P. Woo, C. Wouters, R. Xavier, L. Zemel, S. Wright, A. Kenwright, D. Lovell, A. Martini
  20. 20. TENDER: 12-Week Randomized, Double-blind, Placebo- Controlled, Parallel Group, 2-Arm Study (Part I) with Single Arm Open-label Extension (Parts II and III)—5 Years in Total Open-Label Period (Parts II - III) Tocilizumab 8 or 12 mg/kga every 2 weeks for 92 weeks (subsequent 3- year extension added) Double-Blind Period (Part I) Tocilizumab 8 or 12 mg/kga x 6 Placebo x 6 75 pts 37 pts Screening&Randomization 0 Escape with rescue therapy 2 4 6 8 10 12 Week Day 3 Study Design
  21. 21. TENDER: Key Inclusion Criteria • Diagnosis of sJIA according to ILAR criteria • Age 2–17 years • Persistent disease activity for ≥6 months, with an inadequate response to corticosteroids and NSAIDs due to toxicity or lack of efficacy • ≥5 active joints OR ≥2 active joints with fever >38°C • Maximum dose of oral corticosteroids: 0.5 mg/kg/day of prednisone equivalent • Stable dose of oral corticosteroids, MTX, and/or NSAIDs • No other DMARDs or biologic allowed
  22. 22. TENDER: Efficacy in Double-Blind Phase 24.3 85.3 0 20 40 60 80 100 Placebo (n=37) TCZ (n=75) 61.5% (95% CI: 44.9–78.1)*,† n=9 n=64 JIA ACR30 + Absence of Fever at Week 12 JIA ACR 50/70/90 responses at Week 12 10.8 90.7 8.1 85.3 5.4 70.7 0 20 40 60 80 100 JIA ACR50 JIA ACR70 JIA ACR90 Placebo (n=37) TCZ (n=75) † † † Responders(%) Responders(%)
  23. 23. TENDER: Demographic and Baseline Characteristics N = 112 Age (y), mean (SD) 9.7 (4.6) Disease duration (y), mean (SD) 5.2 (4.1) Number of previous DMARDs, mean (SD) 1.3 (1.2) Number of previous biologics, mean (SD) 1.8 (1.4) Physician VAS, mean (SD) 64.9 (22.3) Parent/patient VAS, mean (SD) 58.7 (24.4) Number of active joints, mean (SD) 19.8 (15.7) Number of joints with LOM, mean (SD) 19.8 (15.6) ESR (mm/hr) mean (SD) 57.6 (34.2) CHAQ, mean (SD) 1.7 (0.9) CRP (mg/l), mean (SD) 166.43 (349.25) Fever (last 7 days), n (%) 48 (43) Background oral corticosteroid dose, (mg/kg/day PDN eq), mean (SD) 0.30 (0.20)
  24. 24. TENDER: JIA ACR Responses + Absence of Fever Over 52 Weeks N = 112* 20 40 60 80 100 0 6 12 18 24 30 36 42 48 54 Time (weeks) Response(%) JIA ACR30 + absence of fever JIA ACR50 + absence of fever JIA ACR70 + absence of fever JIA ACR90 + absence of fever 2 52 0
  25. 25. TENDER: Mean Active Joints and Joints with Limited Motion Over 52 Weeks 112 111 111 110 105 107 105 99n = 0 2 4 6 8 10 12 14 16 18 20 Mean±SEJointCount Active Joints (71 Joints) Joints with Limited Motion (67 Joints) 0 6 12 18 24 30 36 42 48 54 Time (weeks) 2 52
  26. 26. TENDER: Mean Oral Corticosteroid Dose Over 52 Weeks 0.3 0.06 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0 6 12 18 24 30 36 42 48 54 Time (weeks) 112112 112 109 109 109 108 99n = 522 Mean±SEdose(mg/kg/day)
  27. 27. Tocilizumab Cumulative Safety   Week 104 Exposure to TCZ, y 202.03 Rate of SAEs/100PY (n)  23.3 (47) Rate of infections and infestations/100PY (n) 282.1 (570) Rate of serious infection AEs/100PY (n)  10.9 (22) SAEs related (remotely, possibly, probably) to TCZ/100 PY (n) 7.4 (15) Macrophage activation syndrome/100PY (n) 1.5 (3) AEs leading to withdrawal/100PY (n) 3.0 (6)c Deaths/100PY (n)d   1.5 (3)+3 Pneumothorax 1 Sepsis (possibly related) 1 Road Traffic Accident 1
  28. 28. TENDER: Clinical Laboratory Evaluations No. (%) Neutrophils Low (500-1,000 cells/mm3 ) 17 (15.2) Very low (< 500 cells/mm3 ) 2 (1.8) Platelets Low (25,000-50,000 cells/mm3 ) 1 (0.9) Very low (< 25,000 cells/mm3 ) 0 (0)a ALT High (> 5-20 times ULN) 7 (6.3) Very high (> 20 times ULN) 1 (0.9)a
  29. 29. Tocilizumab Conclusions • Year 1 results from this first global phase 3 study demonstrated that tocilizumab was highly effective for the treatment of sJIA – The response to tocilizumab increased over time – Over 50% of the patients were able to discontinue oral corticosteroids by week 52 – 55% in inactive disease status by week 52 • In this population of sJIA patients, tocilizumab exhibited an acceptable safety profile
  30. 30. MAS and IL-1 and IL-6 treatment • Cases of MAS have occurred in both clinical trials even in patients with very well controlled disease • Treatment with either IL-1 or IL-6 does not seem to increase the risk for MAS- the rate is the same or less than in overall SJIA • Causes of MAS are the same as the general population – Infection – Flare of SJIA – No obvious explanation • Manifestations of MAS and response to treatment generally the same as MAS in those not on biologic therapy – With MAS and canakinumab lower ferritin compared to those not on canakinumab – With MAS and tocilizumab less often fever and more severe lab abnormalities compared to those not on tocilizumab 30
  31. 31. Earlier treatment with anti IL-1? …It is possible, but far from proven, that anakinra or other biologic agents may take advantage of a «window of opportunity» in which disease pathophysiology can be altered to avoid chronic arthritis. Testing this hypothesis represents and important scientic priority in pediatric rheumatology PA Nigrovic
  32. 32. What’s next Test effect of earlier treatment with biologics Determine if biologics have effect on joint erosions/narrowing Determine clinical or lab tests that can predict response/steroid discontinuation/clinical remission Determine long term safety and efficacy data Entirely new mechanism of action- JAK kinase inhibition- tofacitinib in SJIA trial starting now in many PR centers
  33. 33. Roles for JAK in Arthritis
  34. 34. Overall Conclusions • Both IL-1 and IL-6 blocking biologics represent huge breakthroughs in the treatment of SJIA especially in those with systemic features • Other companies are developing other IL-1 and IL-6 blocking biologics that will likely have similar results • Frequency and causes of MAS are similar with or without these treatments but manifestations are slightly different • Effect of early onset treatment with either IL-1 or IL-6 is being evaluated • Other types of treatments such as tofacitinib (a pill) will be tested in SJIA very soon 34

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