Charles Ludivico

Baricitinib in Patients with Refractory Rheumatoid Arthritis

BACKGROUND In phase 2 studies, baricitinib, an oral Janus kinase 1 and 2 inhibitor, reduced disease activity in patients with rheumatoid arthritis who had not previously received treatment with biologic disease-modifying antirheumatic drugs (DMARDs). METHODS In this phase 3 study involving 527 patients with an inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both, we randomly assigned the patients in a 1:1:1 ratio to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. End points, tested hierarchically at week 12 to control type 1 error, were the American College of Rheumatology 20% (ACR20) response (primary end point), the Health Assessment Questionnaire-Disability Index (HAQ-DI) score, the 28-joint Disease Activity Score based on C-reactive protein level (DAS28-CRP), and a Simplified Disease Activity Index (SDAI) score of 3.3 or less (on a scale of 0.1 to 86.0, with a score of 3.3 or less indicating remission). Comparisons with placebo were made first with the 4-mg dose of baricitinib and then with the 2-mg dose. RESULTS Significantly more patients receiving baricitinib at the 4-mg dose than those receiving placebo had an ACR20 response at week 12 (55% vs. 27%, P<0.001). Differences between the higher-dose baricitinib group and the placebo group were also significant for the HAQ-DI score and the DAS28-CRP but not for an SDAI score of 3.3 or less. Adverse-event rates through 24 weeks were higher for patients receiving the 2-mg dose of baricitinib and those receiving the 4-mg dose than for patients receiving placebo (71% and 77%, respectively, vs. 64%), including infections (44% and 40%, vs. 31%). The rates of serious adverse events were 4%, 10%, and 7% in the three groups, respectively. Two nonmelanoma skin cancers and two major adverse cardiovascular events, including a fatal stroke, occurred in the higher-dose group. Baricitinib was associated with a small reduction in neutrophil levels and increases in serum creatinine and low-density lipoprotein cholesterol levels. CONCLUSIONS In patients with rheumatoid arthritis and an inadequate response to biologic DMARDs, baricitinib at a daily dose of 4 mg was associated with clinical improvement at 12 weeks. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01721044.).

A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study)

Objectives This study compared the efficacy and safety of subcutaneous (SC) versus intravenous (IV) formulations of tocilizumab in patients with rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs (DMARD). Methods Patients (n=1262) were randomly assigned to receive tocilizumab-SC 162 mg weekly+placebo-IV every 4 weeks or tocilizumab-IV 8 mg/kg every 4 weeks+placebo-SC weekly in combination with traditional DMARD. The primary outcome was to demonstrate the non-inferiority of tocilizumab-SC to tocilizumab-IV with regard to the proportion of patients in each group achieving an American College of Rheumatology (ACR) 20 response at week 24 using a 12% non-inferiority margin (NIM). Secondary outcomes were disease activity score using 28 joints (DAS28), ACR responses, health assessment questionnaire scores and safety assessments. Results At week 24, 69.4% (95% CI 65.5 to 73.2) of tocilizumab-SC-treated patients versus 73.4% (95% CI 69.6 to 77.1) of tocilizumab-IV-treated patients achieved an ACR20 response (weighted difference between groups −4.0%, 95% CI −9.2 to 1.2); the 12% NIM was met. ACR50/70 responses, DAS28 and physical function improvements were comparable between the tocilizumab-SC and tocilizumab-IV groups. The safety profiles of tocilizumab-SC and tocilizumab-IV were similar, and the most common adverse event was infection. Injection-site reactions (ISR) occurred more frequently in the tocilizumab-SC group than in the tocilizumab-IV (placebo-SC) group. No anaphylaxis was reported over the 24 weeks. Conclusions Tocilizumab-SC 162 mg weekly demonstrated comparable efficacy to tocilizumab-IV 8 mg/kg. The safety profile of tocilizumab-SC is consistent with the known and well-established safety profile of tocilizumab-IV, with the exception of a higher incidence of ISR, which were more common with tocilizumab-SC administration.

Evaluation of abatacept administered subcutaneously in adults with active rheumatoid arthritis: impact of withdrawal and reintroduction on immunogenicity, efficacy and safety (phase Iiib ALLOW study)

Objectives To assess the effect of a temporary interruption in subcutaneous (SC) abatacept on immunogenicity, safety and efficacy in patients with active rheumatoid arthritis despite methotrexate in a phase III trial. Methods Following a 12-week open-label introduction (period I; intravenous abatacept loading dose and weekly fixed-dose SC abatacept 125 mg), patients were randomised 2:1 to double-blind SC placebo or SC abatacept for 12 weeks (period II). At the end of period II, patients receiving SC abatacept continued treatment and patients on placebo were reintroduced to SC abatacept (12-week open-label period III). The co-primary end points were ELISA-detected immunogenicity rate and safety at the end of period II. Efficacy was also monitored. Results Of 167 patients entering period I, 72% qualified for period II; during periods II and III, three patients discontinued treatment. Mean (SD) disease duration was 6.6 (6.5) years and Disease Activity Score 28 was 4.8 (0.8). The primary end point was met, with a non-significant increase in immunogenicity upon withdrawal (7/73 placebo vs 0/38 abatacept in period II; p=0.119) which was reversed upon reintroduction of SC abatacept (2/73 vs 1/38, end period III). Safety was comparable regardless of withdrawal, with no unexpected events upon reintroduction. Two patients experienced reactions at the SC injection site. On withdrawal, patients experienced slight worsening in efficacy which improved following reintroduction. Conclusions Overall immunogenicity to SC abatacept is low, consistent with intravenous abatacept, and is not significantly affected by a 3-month interruption and reintroduction. This stop–start schedule was well tolerated, with little impact on safety and efficacy. These are important considerations for the clinical use of SC abatacept. ClinicalTrials gov Identifier NCT00533897

Immunogenicity, Safety, and Efficacy of Abatacept Administered Subcutaneously With or Without Background Methotrexate in Patients With Rheumatoid Arthritis: Results From a Phase III, International, Multicenter, Parallel‐Arm, Open‐Label Study

To evaluate the impact of concomitant methotrexate (MTX) on subcutaneous (SC) abatacept immunogenicity, and to assess safety and efficacy.

Efficacy and safety of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional DMARDs in patients with RA at week 97 (SUMMACTA)

Objectives To evaluate the long-term efficacy and safety of subcutaneous (SC) tocilizumab (TCZ) versus intravenous (IV) TCZ, including switching formulations, in patients with rheumatoid arthritis (RA) and inadequate response to disease-modifying antirheumatic drugs (DMARDs). Methods Patients (n=1262) were randomised 1:1 to receive TCZ-SC 162 mg weekly (qw)+placebo-IV every four weeks (q4w) or TCZ-IV 8 mg/kg q4w+placebo-SC qw in combination with DMARD(s). After a 24-week double-blind period, patients receiving TCZ-SC were re-randomised 11:1 to TCZ-SC (n=521) or TCZ-IV (TCZ-SC–IV, n=48), and patients receiving TCZ-IV were re-randomised 2:1 to TCZ-IV (n=372) or TCZ-SC (TCZ-IV–SC; n=186). Maintenance of clinical responses and safety through week 97 were assessed. Results The proportions of patients who achieved American College of Rheumatology (ACR)20/50/70 responses, Disease Activity Score in 28 joints remission and improvement from baseline in Health Assessment Questionnaire Disability Index ≥0.3 were sustained through week 97 and comparable across arms. TCZ-SC had a comparable safety profile to TCZ-IV through week 97, except that injection site reactions (ISRs) were more common with TCZ-SC. Safety profiles in patients who switched were similar to those in patients who received continuous TCZ-SC or TCZ-IV treatment. The proportion of patients who developed anti-TCZ antibodies remained low across treatment arms. No association between anti-TCZ antibody development and clinical response or adverse events was observed. Conclusions The long-term efficacy and safety of TCZ-SC was maintained and comparable to that of TCZ-IV, except for ISRs. Profiles in patients who switched formulations were comparable to those in patients who received TCZ-IV or TCZ-SC. TCZ-SC provides additional treatment options for patients with RA. Trial registration number NCT01194414.

OP0029 Baricitinib, An Oral Janus Kinase (JAK)1/JAK2 Inhibitor, in Patients with Active Rheumatoid Arthritis (RA) and an Inadequate Response to TNF Inhibitors: Results of the Phase 3 RA-Beacon Study

Background In ph 2 studies, baricitinib (bari) improved disease activity with an acceptable safety profile in patients (pts) with active RA naïve to biologic DMARDs (bDMARDs).1,2 Objectives To report results from a ph 3 study of bari in pts with active RA and an inadequate response or intolerance to ≥1 TNF inhibitor (TNFi). Methods Pts with active RA (TJC & SJC ≥6, hsCRP ≥3mg/L) on conventional DMARDs (cDMARDs) were randomized 1:1:1 to placebo (PBO) or bari (2 or 4 mg) QD for 24 wks. All bDMARDs were discontinued ≥28d prior to treatment. Primary endpoint was ACR20 response at Wk 12 for bari 4 mg vs. PBO. Results Of 527 randomized pts, 57% had received ≥2 bDMARDs and 38% had received ≥1 non-TNFi bDMARD. Fewer pts discontinued treatment prior to Wk 24 on bari 2 or 4 mg vs. PBO (10%, 11%, 18%, respectively). ACR20 response at Wk 12 was higher with bari 4 mg vs. PBO (55% vs. 27%, p≤0.001). Improvements in ACR20, ACR50, ACR70, DAS28, CDAI, SDAI, and HAQ-DI were seen (Table), many as early as Wk 1. Treatment benefit was sustained through Wk 24 for the 4 mg dose. More TEAEs occurred in pts receiving bari 2 or 4 mg compared to PBO (71%, 77%, 64%, respectively) including infections (44%, 40%, 31%, respectively). SAE rates through 24 wks were similar among pts receiving bari 2 or 4 mg or PBO (4%, 10%, and 7%, respectively) including serious infections (2%, 3%, and 3%, respectively). There were no opportunistic infections, TB, or GI perforations. Two non-melanoma skin cancers and 2 major adverse cardiovascular events, including 1 death (stroke), were seen with bari 4 mg. Lab findings were consistent with ph 2 studies. Abnormalities leading to discontinuation were infrequent. Wk 12 Wk 24 PBO 2 mg QD 4 mg QD PBO 2 mg QD 4 mg QD (N=176) (N=174) (N=177) (N=176) (N=174) (N=177) ACR20 27 49*** 55*** 27 45*** 46*** ACR50 8 20** 28*** 13 23* 29*** ACR70 2 13*** 11** 3 13*** 17*** DAS28-hsCRP ≤3.2 9 24*** 32*** 11 20* 33*** DAS28-hsCRP <2.6 4 11** 16*** 6 11 22*** DAS28-ESR ≤3.2 4 13** 12** 7 12 17** DAS28-ESR <2.6 1 6** 6* 3 5 9* CDAI ≤10 11 24** 28*** 15 23 31*** CDAI ≤2.8 2 3 6 3 5 9* SDAI ≤11 9 22*** 28*** 14 22* 31*** SDAI ≤3.3 2 2 5 2 5 9** HAQ-DI MCID ≥0.22 43 59** 67*** 30 50*** 53*** Data are % patients achieving response (NRI);* p≤0.05,** p≤0.01,*** p≤0.001 vs. PBO. Conclusions In pts with active RA on cDMARDs and an inadequate response to bDMARDs, once daily oral bari was associated with rapid and sustained clinical improvements through 24 wks, with an acceptable safety and tolerability profile. The largest benefit was seen with the 4 mg dose. Additional ph 3 studies in bDMARD-naive pts are ongoing. References Keystone et al. Ann Rheum Dis 2015;24:333-340 Tanaka et al. Arthritis Rheum 2013;65(S10):S765 Disclosure of Interest M. Genovese Grant/research support from: Abbvie, Astellas, Eli Lilly & Company, Galapagos, Pfizer, Vertex, Consultant for: Abbvie, Astellas, Eli Lilly & Company, Galapagos, Pfizer, Vertex, J. Kremer Grant/research support from: Abbvie, Amgen, BMS, Genentech, Eli Lilly & Company, Pfizer, UCB, Consultant for: Eli Lilly & Company, Employee of: Corrona, O. Zamani Grant/research support from: Eli Lilly & Company, C. Ludivico Grant/research support from: Eli Lilly & Company, M. Krogulec Grant/research support from: Eli Lilly & Company, L. Xie Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, S. Beattie Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, A. Koch Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, T. Cardillo Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, T. Rooney Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, W. Macias Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, D. Schlichting Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, J. Smolen Grant/research support from: Abbvie, Janssen, MSD, Pfizer, Roche, UCB, Consultant for: Abbvie, Amgen, Astra-Zeneca, Astro, Celgene, Glaxo, Janssen, Eli Lilly & Company, Medimmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB

SAT0105 Summacta: A Randomized, Double-Blind, Parallel Group Study of the Safety and Efficacy Of Tocilizumab SC Versus Tocilizumab IV, in Combination with Traditional Dmards in Patients With Moderate to Severe Ra

Background The efficacy and safety profile of intravenous (IV) tocilizumab (TCZ) has been well established in patients (pts) with rheumatoid arthritis (RA). The aim of a subcutaneous (SC) TCZ dosing regimen is to provide the convenience of patient home use and self-administration. In the BREVACTA study, the primary endpoint was met by demonstrating superiority of TCZ SC 162 mg q2w over placebo for ACR20 response at 24 weeks (ACR 2012). Objectives The objective of SUMMACTA study was to compare the efficacy and safety of TCZ SC and TCZ IV regimens in pts with adult RA who had an inadequate response to DMARDs (up to 20% may have failed one or more anti-TNF agents). Methods SUMMACTA is a 2-year, Phase 3 trial, which is a randomized, active controlled, parallel group study that includes a 24-week double-blind (DB) period, followed by a 72-week open-label phase. During the DB period, pts received TCZ SC 162 mg qw + placebo IV q4w or TCZ IV 8mg/kg q4w + placebo SC qw, in combination with traditional DMARDs. The primary endpoint was the proportion of patients achieving an ACR20 response at Week 24. The hypothesis of non-inferiority of TCZ SC with respect to TCZ IV regarding ACR20 response was tested by means of the 95% confidence interval (CI) and with a 12% non-inferiority margin (NIM). Additional clinical efficacy, immunogenicity and safety assessments were evaluated as secondary outcomes. Pts were stratified at baseline by body weight and region. Results A total of 1262 pts were enrolled globally. All patients’ baseline characteristics were well balanced between TCZ SC and TCZ IV groups, including age, RA disease duration and DAS 28-ESR. At Week 24, 69.4% (95% CI: 65.5, 73.2) of TCZ SC-treated pts achieved an ACR20 response versus 73.4% (95% CI: 69.6, 77.1) of TCZ IV-treated pts. The weighted difference between groups was -4.0% [95% CI: -9.2, 1.2]) and a 12% NIM was met. ACR50/70 responses, disease activity and physical function improvements were also comparable between the TCZ SC and TCZ IV groups. Up to Week 24, the proportions of pts with at least one adverse event (AE) or serious AE were 76.2% and 4.6%, respectively, in the TCZ SC group compared with 77.0% and 5.2%, respectively, in the TCZ IV group. The most common AE in both groups was infection. Injection site reactions occurred more frequently in the TCZSC group than the TCZ IV group (10.1% vs 2.4%, respectively); but none required dose interruption or study withdrawal. No anaphylaxis was reported over the 24-week period. Conclusions TCZ SC 162mg qw demonstrated efficacy and safety profile comparable to TCZ IV 8mg/kg q4w. The TCZ-SC formulation could provide an additional, more convenient administration option and opportunity for home injection for patients with RA. Disclosure of Interest G. Burmester Grant/research support from: Roche, Abbott, Pfizer, UCB, BMS, MSD, Consultant for: Roche, Chugai, Pfizer, UBC, BMS, Speakers bureau: Roche, Pfizer, MSD, BMS, Abbott, A. Rubbert-Roth Grant/research support from: Roche, Pfizer, Consultant for: Roche, Chugai, Pfizer, MSD, Abbott, UCB, Speakers bureau: Roche, UCB, A. Cantagrel Grant/research support from: UCB, Pfizer, Consultant for: BMS, Chugai, Roche, UCB, Abbott, Pfizer, S. Hall: None Declared, P. Leszczynski Consultant for: Roche, D. Feldman: None Declared, M. Rangaraj Grant/research support from: Roche, G. Roane: None Declared, C. Ludivico Grant/research support from: Roche, BMS, Pfizer, Human Genome Science, Lilly, Sanofi-Aventis, Speakers bureau: BMS, E. Mysler Grant/research support from: Roche, Consultant for: Roche, Speakers bureau: Roche, L. Rowell Employee of: Roche, I. Vranic Employee of: Roche

Survey of synovial fluid cryoprecipitates.

Synovial fluid cryoproteins from various inflammatory and noninflammatory arthritides were examined for the presence of immunoglobulin, fibrinogen, antiglobulin activity, and third component of complement and correlated with the synovial fluid leucocyte count. The majority of rheumatoid synovial fluid cryoproteins contained either IgG-IgM complexes or IgG alone. Contrary to previous reports, many synovial fluid cryoproteins from psoriasis, Reiters syndrome, nonspecific acute polyarthritis, gout, and gonococcal arthritis also contained IgG and occasionally IgG-IgM complexes. Noninflammatory synovial fluids were less likely to contain any immunoglobulin. The highest concentration of cryoprotein was found in Reiters syndrome. There was a significant (P < 0.05) correlation between the presence of immunoglobulin and the concentration of the synovial fluid cryoprotein with the synovial fluid leucocyte count. Since synovial fluid cryoproteins containing immunoglobulin are present in the synovial fluids of many diverse rheumatic diseases not postulated to be immune complex mediated, they may be a nonspecific phenomenon related to the degree of inflammation.