11/11/2012. Disclosures. Systemic Juvenile Idiopathic Arthritis Growth Defect. Chronic Inflammation and Stunted Growth

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1 // Catch-up Growth During Tocilizumab Therapy for Systemic Juvenile Idiopathic Arthritis: -Year Data From a Phase 3 Clinical Trial Fabrizio De Benedetti, Nicolino Ruperto, Graciela Espada, Valeria Gerloni, Berit Flato, Gerd Horneff, Barry Myones, 3 Karen Onel, 3 James Frane, Andrew Kenwright, 5 Terri H. Lipman, Kamal N. Bharucha, Alberto Martini, Daniel Lovell 3 IRCCS Ospedale Pediatrico Bambino Gesú, Rome, Italy; Paediatric Rheumatology International Trials Organisation, Genoa, Italy; 3 Pediatric Rheumatology Collaborative Study Group, Cincinnati, Ohio; Statisitical Consultant to Genentech, South San Francisco, California; 5 Roche, Welwyn Garden City, United Kingdom; University of Pennsylvania School of Nursing, Philadelphia, Pennsylvania Disclosures F. De Benedetti: Abbott, BMS, Novartis, Novimmune, Pfizer, Roche Pharmaceuticals, SOBI N. Ruperto: Abbott, ACRAF, BMS, Centocor, Novartis, Pfizer, Roche Pharmaceuticals, Xoma G. Horneff: Abbott, Chugai, Novartis, Pfizer, Roche Pharmaceuticals K. Onel: Merck, Roche Pharmaceuticals J. Frane: Consultant to Genentech and to Ipsen Biopharmaceuticals A. Kenwright: Roche Pharmaceuticals K. N. Bharucha: Genentech A. Martini: Abbott, ACRAF, BMS, Centocor, Novartis, Pfizer, Roche Pharmaceuticals, Xoma D. Lovell: Abbott, Amgen, Arthritis and Rheumatism, Astra-Zeneca, BMS, Centocor, Forest Research, Genentech, Hoffmann-La Roche, National Institutes of Health, Novartis, Pfizer, Regeneron, UCB, Wyeth, Xoma G. Espada, V. Gerloni, B. Flato, B. Myones, T. H. Lipman: Nothing to disclose Systemic Juvenile Idiopathic Arthritis Growth Defect Chronic Inflammation and Stunted Growth general arrest of development when the disease begins before second dentition G.F. Still (97) sjia: occurs during periods of disease activity Crohn s disease: growth defect before onset of intestinal symptoms and related to the inflammatory activity of the disease Cystic fibrosis: growth defect related to frequency and severity of pulmonary infections A factor(s) produced during the inflammatory response affects linear growth Portrait of George Frederick Still (from the painting by Gerald Kelly) 3 sjia, systemic juvenile idiopathic arthritis. Chronic Inflammation and Stunted Growth Impact of High Levels of IL- on the Growing Skeleton: Lessons From IL- Transgenic Mice sjia: occurs during periods of disease activity Crohn s disease: growth defect before onset of intestinal symptoms and related to the inflammatory activity of the disease Cystic fibrosis: growth defect related to frequency and severity of pulmonary infections Low levels of IGF-I secondary to increased IGFBP-3 proteolysis Impaired development and ossification of epiphysis Impaired mineralization apposition rate Increased osteoclast and increased osteoblast activity A factor(s) produced during the inflammatory response affects linear growth IL-TG Impaired Growth Systemic Osteoporosis IL-TG Interleukin IGF, insulin-like growth factor; IGFBP, IGF-binding protein; IL-, interleukin. De Benedetti F et al. J Clin Invest 997;99:3-5.; Endocrinology ;:-; Arthritis Rheum 5;5:7-93. sjia, systemic juvenile idiopathic arthritis. 5

2 Height SD Score Height SD Score Screening and Randomization // Aim TENDER Study Design To evaluate in patients with sjia treated with in the TENDER study: Growth rates Changes in IGF-I levels Changes in soluble markers of osteoclast and osteoblast activities Relationship with disease activity and with corticosteroid dose Double-blind Period (Part ) or mg/kg Placebo Open-label Period (Parts and 3) or mg/kg every weeks for 9 weeks (subsequent 3-year extension added) Weeks Day 3, tocilizumab. 7 Escape with rescue therapy TENDER Baseline Growth Characteristics N = 3 Male Patient mg/kg Female/male, n 53/5, mean ± SD. ±.5 Tanner stage <, n (%) (3) Duration of sjia, yr, mean ± SD. ±. Height SD score (WHO), mean ± SD. ±.9 BMI SD score (WHO), mean ± SD. ±. 9 BMI, body mass index; SD, standard deviation; WHO, World Health Organization. Baseline = start of tocilizumab. Excluding patients who received somatropin. Baseline Height SD Score Was Negatively Correlated With sjia Duration Pretreatment Height Velocity versus Baseline Age 5 r =.9, p = r =.3, p <. 7 sjia Duration, yr Females Males r = Pearson correlation. Patients with height measured between 9 and months before baseline. For each gender, the curve represents the expected height velocity based on WHO norms for height

3 Height SD Score IGF- SD Score // Height Velocity versus Baseline Age Majority of females (n = ; 5%) and males (n = 3; 73%) experienced above-normal height velocities. Females Males For each gender, the curve represents the expected height velocity based on WHO norms for height 3 TENDER Baseline Growth Characteristics BMI, body mass index; SD, standard deviation; WHO, World Health Organization. Baseline = start of tocilizumab. Excluding patients who received somatropin. N = 3 Female/male, n 53/5, mean ± SD. ±.5 Tanner stage <, n (%) (3) Duration of sjia, yr, mean ± SD. ±. Height SD score (WHO), mean ± SD. ±.9 BMI SD score (WHO), mean ± SD. ±. Height Velocity and Height SD Score IGF-I Levels (SD Scores) 5 Pre-Tx Year Year Baseline Year Year dashed lines mean normal expected height velocities Pre-Tx, n = 3; Baseline, n = ; Year, n = ; Year, n = 7. Patients with year of who had Tanner stage < at baseline. () Comparisons made between pre-tx and year and year using paired t-tests; all p <.. 5 dashed line at : expected change in height SD score for normal is * Pre-Tx Year Year Pre-Tx, n = 7; Year, n = ; Year, n = 5. Paired t-test p : Pre-Tx, <.. Year,.3. Year,.9. Paired t-test p Pre-Tx: (*) Year,.7. () Year,.5. Osteocalcin/C-Telopeptide of Type Collagen (OC/CTX-) Ratio Osteocalcin/C-Telopeptide of Type Collagen (OC/CTX-) Ratio Osteoclast (CTX) Osteoblast (osteocalcin) Osteoclast (CTX) Osteoblast (osteocalcin) Osteocalcin CTX- OC/CTX- Ratio Baseline 35 ±.5 ±.3 5 ± 7 Year 95 ± *.5 ±.5* ± * 7 *p <. baseline. Patients with both baseline and year OC and CTX- and Tanner < at baseline: n =. 3

4 // versus JADAS-7 at Year Spearman Rank Correlation =. p = JADAS-7 JADAS-7, juvenile arthritis disease activity score in 7 joints. 9 Height Velocity Oral Corticosteroids and JADAS-7 Pre-Tx/Baseline - Months - Months Height Velocity, cm/yr 3. ±. (33). ± 3.5 () 7. ± 3.3 Prednisone-Equivalent Corticosteroid Dose, mg/kg.3 ±. (). ±.3 a (). ±. a a Average dose in the indicated period of time. JADAS-7: b At baseline, median = 3.; c At month, median = 3.; d At month, median =.5. JADAS-7. ±.3 b (). ± 9. c (). ±.7 d Multiple Regression for Regressor variables considered Gender Tanner stage at baseline BMI SD score at baseline Height SD score at baseline Age at baseline Duration of s-jia JADAS-7 at month Mean corticosteroid dose Multiple Regression for Regressor variables not statistically significant (p >.5): Gender, Tanner stage at baseline, BMI SD score at baseline, Duration of sjia, JADAS-7 at month Regressor variables statistically significant (p.) Patients with Tanner stage < at baseline: n =. Patients with Tanner stage < at baseline: n =. Individual contribution of a regressor to R is the difference in R with and without the regressor in question. Because of collinearity, the individual contributions to R do not sum to the total R. Multiple Regression for Conclusions Regressor variables not statistically significant (p >.5): Gender, Tanner stage at baseline, BMI SD score at baseline, Duration of sjia, JADAS-7 at month Regressor variables statistically significant (p.) Contribution to R, % Regression Coefficient Baseline height SD score 7.39 Baseline age, yr 35. Mean corticosteroid dose during first months of, mg/kg Total R, % 5 Patients with Tanner stage < at baseline: n =. Individual contribution of a regressor to R is the difference in R with and without the regressor in question. Because of collinearity, the individual contributions to R do not sum to the total R. 3 Height was markedly reduced at study entry Height SD scores were significantly correlated with disease duration treatment was associated with catch-up growth treatment was associated with beneficial effects on the growth hormone axis (increase in IGF- levels) on bone metabolism (improved osteoblast and osteoclast activities) Height velocity during treatment is related to disease activity, CS dose, and age at baseline

5 // Argentina Cuttica Espada Garay Australia Allen Chaitow Murray Belgium Joos Wouters Brazil Silva Xavier Canada Roth Schneider Czech Republic Dolezalova Germany Horneff Huppertz Minden Greece Mantzourani Siammopoulou Vougiouka Italy Cortis Gerloni Martini Zulian Mexico Burgos Maldonado Netherlands Norway Poland Slovakia Wulffraat Flato Zuber Rovensky Spain Calvo Garcia Consuegra UK Baildam Woo USA Principal Investigators 3 centers Brown Chalom Jerath Kimura Lovell Myones O'Neill Onel Spalding Zemel Extra Slides Height Velocity and Height SD Score baseline WHO Normal Mean WHO Pre- 3. ±. (33). <.. ±. () Height SD Score Previous Year <. Pre-Tx - Months 3. ±. (33). ± 3. () Paired t-test - Months Year Year.7 ±.5 () 7. ±.9 (7) 5.5. <. 5. <. <. Patients with year of who had Tanner stage < at baseline. Baseline height velocity measured during period prior to baseline. Comparisons made using paired t-tests. Height velocities for year and year measured over at least 9 months..9 ±.9 (). ±. (7) <. <. <. <. 7 - Months - Months - Months Patients with Tanner stage < at baseline only. Height velocity measured over 5 to 7 months. 7. ± 3.. ± 3. (75) 7. ±.3 (55)... JADAS-7 Was Significantly Correlated With Height Velocity Osteocalcin/C-Telopeptide of Type Collagen (OC/CTX-) Ratio Spearman Rank Correlation With Year Height Velocity for Spearman Rank Correlation OC CTX- OC/CTX- Ratio Baseline 3. ±...57 Baseline 35 ±.5 ±.3 5 ± 7 Year 5. ±..3. Year 95 ± *.5 ±.5* ± * Year minus baseline 9. ± Year minus baseline ±. ±.5 ± 3 Paired t-test p value <. <.. Patients with both baseline and year JADAS-7 and Tanner stage < at baseline: n =. 9 *p <. baseline. Patients with both baseline and year OC and CTX- and Tanner < at baseline: n =. 3 5

6 Height/Length, cm Height/Length, cm JADAS-7 Pred. Dose, mg/kg JADAS-7 Pred. Dose, mg/kg Height/Length, cm JADAS-7 Pred. Dose, mg/kg // IGF- SD Scores Male Patient Treated With mg/kg Paired t-test for Difference from Baseline Year Year Year minus baseline Year minus baseline.9 ±.7 (7) <..3 ±. ().3. ±.3 (5).93. ±.5 (53).7. ±.9 ().5 Patients with year of who had Tanner stage < at baseline. 3 3 Female Patient Placebo -> mg/kg Female Patient Placebo -> mg/kg Start Dx Dx Start Female Patient mg/kg Dx Start