IL-6 Targeting. Arthur Kavanaugh: Disclosures. Abbott Amgen Astra-Zeneca Biogen-Idec BMS Celgene Centocor Genentech TREG Consultants LLC

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1 IL-6 Targeting Arthur Kavanaugh, MD Professor of Medicine Division of Rheumatology, Allergy, and Immunology Director, Center for Innovative Therapy University of California San Diego La Jolla, CA Arthur Kavanaugh: Disclosures Abbott Amgen Astra-Zeneca Biogen-Idec BMS Celgene Centocor Genentech TREG Consultants LLC ITN LCTC MedImmune NIH Roche Sanofi-Aventis Teva UCB

2 Ann Rheum Dis 213;72:583-9 & Ann Rheum Dis 213;72:583-9 &

3 Mean change in HAQ score Mean CRP levels (mg/dl) 3. OPTION: Tocilizumab induces rapid normalisation of CRP levels Placebo + MTX TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX * ULN= Time (weeks) ULN = Upper limit of normal OPTION: Rapid and sustained improvement in HAQ score with tocilizumab Placebo + MTX TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX Time (weeks) MCID= MCID = Minimal clinically important difference

4 CDAI Patients (%) RADIATE - Clinical responses to tocilizumab in RA patients post TNF-i failure p<.1 p<.1 5.% 3.4% 28.8% 16.8% 1.1% 3.8% Placebo + MTX TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX p<.1 P= % 5.% 1.3% ACR2 ACR5 ACR7 Tocilizumab: efficacy assessed by measures without an acute-phase component Tocilizumab 8 mg/kg Tocilizumab 4 mg/kg Placebo ** * ** weeks *p<.1; p<.5; **p<.1 Smolen J & Aletaha D. Arthritis Rheum 211; 63:43 52.

5 Helix-II (cartilage) media change (%) Change from baseline (%) Mean change from baseline LITHE - Primary endpoint: X-Rays at Week 14 Change from baseline in Total Sharp-Genant score (TSS) (Linear extrapolation Post-rescue and post-w/d data excluded) p<.1 p< % 81% A B C Placebo + MTX TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX p<.1 p<.1 p< p< A B C A B C A B C TSS Erosion score JSN score n= LITHE: effects on bone and cartilage Median percentage change in serum osteocalcin Placebo + MTX (n=256) TCZ 4 mg/kg + MTX (n=241) TCZ 8 mg/kg + MTX (n=244) Rescue patients Placebo + MTX (n=256) Time (weeks) TCZ 4 mg/kg + MTX (n=241) Time (weeks) TCZ 8 mg/kg + MTX (n=244) Garnero P, et al. EULAR 29. Poster SAT19

6 Mean change from BL Patients (%) TCZ (ACTSTAR subanalysis): Effects of dose escalation in combination with nonbiologic DMARDs 363 pts initiating TCZ 4 mg/kg continued their current synthetic DMARD. Patients who did not achieve 2% improvement in TJC and SJC at Week 8 increased TCZ dose to 8 mg/kg After Week 8, TCZ dose escalation to 8 mg/kg per physician discretion 68 patients increased to 8 mg/kg after Week 8; 142 patients increased to 8 mg/kg at Week 8 and 152 patients received only 4 mg/kg Increase to 8 mg/kg at Week 8 24 Increase to 8 mg/kg after >Week 8 24 ACR Mean DAS28 BL to Wk % 12.% 3.5% % 36.8% 11.8% Patients who escalated TCZ dose from 4 mg/kg to 8 mg/kg after or at Week 8 were observed to have improvements in DAS28 and ACR core components following dose escalation Weinblatt M, et al. Arthritis Care & Res 213. TCZ with and without MTX (ACT-RAY): 1-yr clinical and radiographic effects Multicenter, DBRCT (1:1), 52 weeks; active RA; 1 erosion; MTX-IR; TCZ 8 mg/kg + MTX vs TCZ 8 mg/kg + PBO 1 EP DAS28 <2.6 at Week 24 After Week 24, both groups continued on Rx if DAS 28<3.2; if DAS 3.2 OL DMARDs added Change in DAS28 Weeks TCZ + MTX (n=277) TCZ + PBO (n=276) DAS28 <2.6 (remission) DAS (LDAS) P=.3 NS NS P=.3 Week 24: NS Week 52: NS Week TCZ monotherapy similar to TCZ + MTX;? Subset do better with combo Dougados M, et al. ACR 212, Washington DC, #255

7 TCZ with and without MTX in RA (ACT-RAY): 1-yr clinical and radiographic effects Multicenter, DBRCT (1:1), 52 weeks MTX-IR IV TCZ 8 mg/kg q4w + MTX vs IV TCZ 8 mg/kg q4w + PBO 1 EP DAS28 <2.6 at Week 24 After Week 24, open label DMARDs allowed if DAS28 >3.2 ACR 2/5/7/9 responses remain similar between groups to year 1 Clinical parameter TCZ + MTX (n=277) Wk 24 TCZ + PBO (n=276) P-value DAS28 <2.6), % DAS28 3.2, % gtss, mean from BL * Pts w/o radiographic progression, % TCZ + MTX (n=277) Wk 52 TCZ + PBO (n=276) P-value * TCZ monotherapy mostly equivalent to TCZ + MTX? Dougados M, et al. EULAR 212, Berlin, #THU93 Early reductions in synovitis & osteitis with TCZ are maintained through week 52: ACT-RAY MRI substudy RA pts (n=63) on stable MTX randomized to MTX or PBO + TCZ 8mg/kg IV every 4 weeks Decreases in synovitis & osteitis at week 12 sustained at week 52 No significant change in mean erosions over 52 weeks No patients developed new regions of synovitis *P<.5 vs BL * * * * Early reduction of SYN & OST by MRI w/ TCZ maintained through 1 y Troum O, et al. EULAR 211, London, # SAT282

8 Mean DAS28 ADACTA: Ph4, Multicenter, Randomized, Double-blind Study of TCZ vs ADA in RA Treated (N = 326) Randomised Drug Treatment TCZ 8 mg/kg IV Q4 weeks + SC Placebo Q2 weeks ADA 4 mg SC Q2 weeks + IV Placebo Q4 weeks Safety Follow-up 1:1 randomization Superiority Trial Design. Week 16+: Escape Week 24 (primary endpoint): ΔDAS28 Week 32 Patients: RA 6 months; DAS28 >5.1; SJC 6, TJC 8 (66/68 joint count); ESR >28 mm/h or CRP 1. mg/dl; MTX intolerant. No prior biologics. Criteria for escape: <2% improvement from baseline in SJC and TJC at week 16 or later; Escape therapy: Weekly SC (ADA/placebo) injections; study medication remained blinded Gabay C, Kavanaugh A, et al. Lancet 213 (Epub 3/13) 15 TCZ vs ADA monotherapy: ADACTA 326 RA pts; DAS28 >5.1; MTX intolerant/inappropriate; 1º DAS28 24 weeks Safety comparable; SAE, SIE, typical TCZ AE DAS28 P<.1 ADA 4 mg + placebo (IV) (n=162) TCZ 8 mg/kg + placebo (SC) (n=163) P<.1 BL Week In biologic-naïve MTX-IR RA patients, TCZ monotherapy achieved higher responses than ADA monotherapy Gabay C, Kavanaugh A, et al. Lancet 213 (Epub 3/13)

9 Responders (%) Absolute mean CDAI TCZ vs ADA monotherapy in RA patients: 24-week ADACTA study Mean CDAI score over time BL Weeks HAQ (<1.5 vs 1.5) No. previous DMARDs ( 5) Anti-CCP +ve (no vs yes) Age (5-65 vs <5 y) Age (5-65 vs >65 y) CRP (.3 to <1 vs <.3) CRP (.3 to <1 vs 1 to <3) CRP (.3 to <1 vs 3 to <1) CRP (.3 to <1 vs 1) BMI (kg/m 2 ) ( 3 vs ) BMI (kg/m 2 ) ( 3 vs <25) Duration of RA (<2 vs 2 y) Sex (F vs M) HGB (HGB <LLN vs HGB LLN) RF +ve (no vs yes) Potential BL predictors of any Rx response ADA (n=162) TCZ (n=163) Not possible to predict potentially differential response to treatment with TCZ vs ADA monotherapy in RA Gabay C, Kavanaugh A, et al. Lancet 213 (Epub 3/13) TCZ SC vs IV (SUMMACTA, MUSASHI) in patients with moderate to severe RA 2-y Phase 3 RCT, 24-wk DB period; 72-wk OL active controlled, non-inferiority trial (SUMMACTA) 1 95% CI;12% non-inferiority margin 1 EP: ACR2 at Wk 24 MUSASHI: SC vs IV 2 No decrease in effectiveness when pts switched to SC in 12 mos OLE 1 patient developed Ab in OLE ACR2 1 TCZ SC comparable efficacy and safety to TCZ IV with similar safety 1. Burmester GR, et al. ACR 212, Washington DC, # Ogata A, et al. ACR 212, Washington DC, #1295

10 Responders (%) Mean change in mtss Adj mean change* in HAQ score Patients (%) TCZ SC (BREVACTA): TCZ SC + DMARD vs PBO + DMARD in DMARD-IR 24-wk DBRCT TCZ SC 162 mg q2w or PBO SC q2w, + DMARDs Safety as expected TCZ SC + DMARDs (n=437) PBO SC + DMARDs (n=219) 2 EP: mtss from BL at Wk 24 P=.149 (ITT) Patients achieving an ACR2 (1 EP) /5/7 responses P<.1 P<.1 P<.1 TCZ SC + DMARDs (n=348) HAQ-DI PBO SC + DMARDs (n=124) TCZ SC + DMARDs (n=391) PBO SC + DMARDs (n=186) TCZ SC q2w + DMARD effective Kivitz A, et al. ACR 212, Washington DC, #L8 P=.54 TCZ (ARTIS): Clinical experience for RA in the Swedish biologics register All 522 pts on TCZ 8 mg/kg Drug survival: 1-y 63%; 2-y 5% Predicators of continued therapy High CRP (multivariate HR for D/C.8 per SD; 95% CI:.69,.91) Low HAQ Few previous biologics Non- predictors of continued therapy Concomitant MTX Age Disease duration Baseline DAS28 *Good/moderate 39 patients with f/u DAS28 data at months High CRP and low baseline HAQ predict continued therapy with TCZ Forsblad-d Elia H, et al. ACR 212, Washington DC, #463

11 GREAT PERFORMANCE! LUXURY - FUN TO DRIVE! Price does not include taxes/title/destination charges and other charges. Some restrictions may apply. Actual mileage may vary. Discount not applicable for trade ins. Offer expires midnight May 1, 211. May not be combined with any other promotion. Performance, luxury and fun while driving are not guaranteed. Roles of IL-6 Relevant to Autoimmune Diseases Hepatocytes Induction of auto-antibodies (e.g. RF) Hyper -globulinemia Production of acute phase proteins (CRP) and hepcidin B cells Thrombocytosis Maturation of megakaryocytes Activation of Endothelium / adhesion molecules Activation of Synoviocytes IL-6 Activation of osteoclasts Bone resorption T cell activation Activation of monocytes / macrophages

12 Potential Safety Issues With IL-6 Inhibitors Target Related General Immunomodulatory Infections / serious infections / opportunistic GI perforations / diverticulitis Malignancies IL-6 Specific (?) Transaminase elevation Leukopenia / Neutropenia Increased lipids Thrombocytopenia Agent Related Administration reactions Immunogenicity Tocilizumab Safety Study (ACT-STAR) 24-week, OL, IIIb study; 1 outcome SAEs over 24 wks. 886 USA RA pts, 65-92% past biologic Rx (no wash out) DMARD or DMARD + Bio IR at BL TCZ 4 mg/kg + DMARD TCZ 8 mg/kg + DMARD Biologic-IR alone at BL TCZ 8 mg/kg monotherapy 3 GI perforations: 1 Crohn's, 2 diverticulitis (subsequently diagnosed) 21% on statins at BL, 11% added statins during the study 42% TCZ 4/DMARD maintain to Month 6; 4 8 ACR2 1.4% wk 8 3.3% wk 24. Similar response +/- past biologic % Patients TCZ 4/8 TCZ 8 +DMARD +DMARD n=364 n=381 TCZ 8 n=138 SAE SAE D/C Deaths (n) 2 SIE PMNs (Gr 3) ALT: 1.5 3x ULN >3x ULN LDL-C 13 (<13 at BL) No difference in SAE, SIE or efficacy between TCZ 4 or 8 as DMARD COMBO & TCZ 8 as MONO; dose escalation 4 8 can capture efficacy Weinblatt ME, et al. Arthritis Care & Research 213;65: Copyright 211, TREG Consultants, LLC

13 TCZ: Long-term safety 4,9 pts 5 PBO-controlled trials, clinical pharmacology study, and LTE Pooled data from initial TCZ exposure to April 1, 211 Mean treatment duration 3.7 years ( 5.8), 14,994 pt/ys Event rate/1 pt-ys (95% CI) over 12-mo period 12 mo (3,471 pt-ys) mo (3,28 pt-ys) mo (2,766 pt-ys) >36 mo (5,729 pt-ys) Overall 14,994 pt-ys SAEs 16.1 (14.7, 17.4) 14.2 (12.9, 15.7) 15.7 (14.2, 17.2) (12.5, 14.5) 14.6 (14, 15.3) SIEs 4.6 (4., 5.4) 3.9 (3.3, 4.7) 5.4 (4.6, 6.3) 4.2 (3.7, 4.7) 4.5 (4.1, 4.8) MI SAEs.29 (.14,.53).17 (.5,.39).29 (.12,.57).26 (.15,.43).25 (.18,.35) Stroke SAEs.43 (.24,.71).26 (.11,.52).29 (.12,.57).28 (.16,.45).31 (.23,.42) GI perforations.2 (.8,.42).13 (.4,.34).29 (.12,.57).19 (.1,.34).2 (.13,.28) Stable safety events over time Genovese MC, et al. ACR 212, Washington DC, #164 TCZ: Humoral immune response to vaccines (pneumococcal and tetanus toxoid) in >1 TNFi failures 1 RA (n=74) assigned (2:1) to TCZ 8 mg/kg IV q4w + MTX or MTX BL serology collected 3 wks after 1 st infusion, just before 23VPPV and TTV. Antipneumococcal and antitetanus Ab titers evaluated at Wk 8 (data evaluated in 61 pts) 1 EP: Proportion of pts with positive response (2-fold or >1 mg/l increase in serum Ab titers) to 6 of 12 23VPPV serotypes 2 EP: Proportion with positive response (4-fold or.2 mg/l increase in serum Ab titers) to TTV (secondary) at Wk 8 (5 wks post vaccination) TCZ-treated pts treated able to mount immune response to 23VPPV and TTV Patients >5 years less responsive to 23VPPV, but degree of attenuation observed similar in pts treated with TCZ + MTX or MTX alone Concomitant treatment with oral corticosteroids did not appear to attenuate responsiveness to 23VPPV in either treatment group Trivalent A/H1N1, A/H3N2, B-1 in pts treated with MTX/IFX/ETN/ADA/TCZ/ABA? Difference among biologics 2 1. Bingham C, et al. ACR 212, Washington DC, # Hayashi M, et al. ACR 212, Washington DC, #2465

14 IL-6 Inhibitors: Safety Research Agenda More post-marketing safety data (pharmacovigilance) Sequelae (changes in PMNs, LFTs, cholesterol,?) Optimal monitoring Screening/stratification of patients to optimize safety Concomitant medications, dosage effects on safety Effects on vaccination Delineating mechanisms of action (e.g. IL-17, etc) Safety in other autoimmune diseases Use in combination with other biologic agents TCZ in systemic JIA: 2-year data from TENDER 112 patients age 2 17 with sjia for 6 months randomized 2:1 to TCZ (8 mg/kg n=75) or placebo (n=37) qow for 12 weeks in part 1 All patients received open-label TCZ in part 2 up to 14 weeks with no change in safety Week 12 Week 52 Week 14 Week 14 PBO (n=37) TCZ (n=75) TCZ (n=16) TCZ (n=65) JIA ACR7, n (%) JIA ACR9, n (%) 3 (8) 53 (71) 2 (5) 28 (37) 92 (87) 57 (88) 67 (63) 46 (71) Active joint (mean ±SD) 9.5 ± ± ± ± 3.6 No active joints, n (%) 2 (5) 12 (16) 5 (47) 36 (55) TENDER 2-y results demonstrated continued maintenance of efficacy and no change in the safety profile with long-term TCZ Rx De Benedetti F, et al. EULAR 212, Berlin, #FRI328

15 IL-6 Inhibitors in Development Site 3 Site 1 gp13 :: IL-6 :: gp8 gp13 IL-6 gp8 Boulanger MJ et.al., Science. 23 3(5628): anti-il-6 Anti-IL-6R BMS (ALD518; mab) Sarilumab (SAR15319/REGN88) Sirukumab (CNTO136) ALX-1 (nanobody) Olokizumab (CDP638) ail-6 mab BMS in MTX-IR Asialylated mab to IL-6 NOT IL-6R 8, 16, 32 mg vs PBO, IV+MTX q 8 wks 1 T ½ = 3 days SC vs IV dosing: 2 Bioavailability of ALD518 6% for SC vs IV dosing Rapid, sustained reductions in serum CRP all doses, IV or SC Phase III with SC dosing Positive proof of concept at Week Responders (%) 1 EP: Week 12 ACR and LDAS ACR 2 ACR 5 ACR 7 LDAS *P<.5 27 * 71 * * * * * * PBO (n=33) 8mg (n=32) 16mg (n=34) 32mg (n=28) 5 * Mease, et al. ACR 21, Atlanta, #2168; 2. Shakib, et al. Ibid, #1124

16 Geometric mean plasma CRP (mg/l), log scale Tolerability and pharmacodynamic effect of single IV/SC doses of olokizumab (OLO) (anti-il-6 mab) in RA Objective: Characterize PK/PD relationship between OLO and CRP level after 1 IV or SC dose RDBPC Phase 1 (42 pts on MTX) RA, DAS28(CRP) <5.1 IV:.1 or 1 mg/kg or PBO SC: 1 or 3 mg/kg or PBO Results: OLO <3 mg/kg markedly suppressed CRP Dose dependent in complement Geometric mean CRP concentration (per protocol pharmacodynamic population) IV OLO.1 mg/kg (n=6) IV OLO 1 mg/kg (n=7) Combined PBO (n=1) SC OLO 1 mg/kg (n=8) SC OLO 3 mg/kg (n=9) Time to assessment relative to dosing (days) Fleischmann R, et al. ACR 212, Washington DC, #1339

17 Rheumatology Winter Clinical Symposium February 12-15, 214 Wailea Marriott IL-6 Targeting in 213 Arthur Kavanaugh, MD Professor of Medicine Division of Rheumatology, Allergy, and Immunology Director, Center for Innovative Therapy University of California San Diego La Jolla, California