A Phase 2 Trial of Peresolimab for Adults with Rheumatoid Arthritis.

BACKGROUND: Peresolimab is a humanized IgG1 monoclonal antibody designed to stimulate the endogenous programmed cell death protein 1 (PD-1) inhibitory pathway. Stimulation of this pathway would be a novel approach to the treatment of patients with autoimmune or autoinflammatory diseases. METHODS: In this phase 2a, double-blind, randomized, placebo-controlled trial, we assigned, in a 2:1:1 ratio, adult patients with moderate-to-severe rheumatoid arthritis who had had an inadequate response to, a loss of response to, or unacceptable side effects with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) or to biologic or targeted synthetic DMARDs to receive 700 mg of peresolimab, 300 mg of peresolimab, or placebo intravenously once every 4 weeks. The primary outcome was the change from baseline to week 12 in the Disease Activity Score for 28 joints based on the C-reactive protein level (DAS28-CRP). The DAS28-CRP ranges from 0 to 9.4, with higher scores indicating more severe disease. The primary comparison was between the 700-mg group and the placebo group. Secondary outcomes included the percentages of patients with American College of Rheumatology 20 (ACR20), ACR50, and ACR70 responses - defined as improvements from baseline of 20%, 50%, and 70% or more, respectively, in the numbers of tender and swollen joints and in at least three of five important domains - at week 12. RESULTS: At week 12, the change from baseline in the DAS28-CRP was significantly greater in the 700-mg peresolimab group than in the placebo group (least-squares mean change [±SE], -2.09±0.18 vs. -0.99±0.26; difference in change, -1.09 [95% confidence interval, -1.73 to -0.46]; P<0.001). The results of the analyses of secondary outcomes favored the 700-mg dose over placebo with respect to the ACR20 response but not with respect to the ACR50 and ACR70 responses. Adverse events were similar in the peresolimab and placebo groups. CONCLUSIONS: Peresolimab showed efficacy in a phase 2a trial in patients with rheumatoid arthritis. These results provide evidence that stimulation of the PD-1 receptor has potential efficacy in the treatment of rheumatoid arthritis. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT04634253.).

Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis.

BACKGROUND: We assessed the efficacy and safety of brodalumab, a human monoclonal antibody against interleukin-17 receptor A (IL17RA), in a phase 2, randomized, double-blind, placebo-controlled study involving patients with psoriatic arthritis. METHODS: We randomly assigned patients with active psoriatic arthritis to receive brodalumab (140 or 280 mg subcutaneously) or placebo on day 1 and at weeks 1, 2, 4, 6, 8, and 10. At week 12, patients who had not discontinued their participation in the study were offered open-label brodalumab (280 mg) every 2 weeks. The primary end point was 20% improvement in American College of Rheumatology response criteria (ACR 20) at week 12. RESULTS: Of the 168 patients who underwent randomization (57 in the brodalumab 140-mg group, 56 in the brodalumab 280-mg group, and 55 in the placebo group), 159 completed the double-blind phase and 134 completed 40 weeks of the open-label extension. At week 12, the brodalumab 140-mg and 280-mg groups had higher rates of ACR 20 than the placebo group (37% [P=0.03] and 39% [P=0.02], respectively, vs. 18%); they also had higher rates of 50% improvement (ACR 50) (14% [P=0.05] and 14% [P=0.05] vs. 4%). Rates of 70% improvement were not significantly higher in the brodalumab groups. Similar degrees of improvement were noted among patients who had received previous biologic therapy and those who had not received such therapy. At week 24, ACR 20 response rates in the brodalumab 140-mg and 280-mg groups were 51% and 64%, respectively, as compared with 44% among patients who switched from placebo to open-label brodalumab; responses were sustained through week 52. At week 12, serious adverse events had occurred in 3% of patients in the brodalumab groups and in 2% of those in the placebo group. CONCLUSIONS: Brodalumab significantly improved response rates among patients with psoriatic arthritis. Larger studies of longer duration are necessary to assess adverse events. (Funded by Amgen; ClinicalTrials.gov number, NCT01516957 .).

Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study.

BACKGROUND: Baricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor. METHODS: In this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3. RESULTS: More patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein. CONCLUSIONS: In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage. TRIAL REGISTRATION NUMBER: NCT01721057; Results.

A phase I pharmacokinetics trial comparing PF-05280586 (a potential biosimilar) and rituximab in patients with active rheumatoid arthritis.

AIMS: Pharmacokinetic (PK) similarity was assessed among PF-05280586 (a proposed biosimilar) vs. rituximab sourced from the European Union (rituximab-EU) and the United States (rituximab-US). Pharmacodynamics (PD), overall safety and immunogenicity were also evaluated. METHODS: Patients with active rheumatoid arthritis on a background of methotrexate and inadequate response to one or more tumour necrosis factor antagonist therapies were randomized to intravenous PF-05280586, rituximab-EU or rituximab-US 1000 mg doses on study days 1 and 15. RESULTS: A total of 220 patients were randomized to receive study treatment as assigned. Of these, 198 met per-protocol population criteria for inclusion in the PK data analysis. PF-05280586, rituximab-EU and rituximab-US exhibited similar PK profiles following administration of assigned study drug on days 1 and 15. The 90% confidence intervals of test-to-reference ratios for Cmax , AUCT , AUC0-∞ and AUC2-week were within the bioequivalence margin of 80.00-125.00% for comparisons of PF-05280586 with rituximab-EU, PF-05280586 with rituximab-US, and rituximab-EU with rituximab-US. All treatments resulted in a rapid and profound reduction in CD19+ B cells and sustained profound B cell suppression up to week 25. The incidence of antidrug antibody (ADA) response (n = 7, 10 and 9 for PF-05280586, rituximab-EU and rituximab-US, respectively), time to ADA emergence and ADA titres were similar across treatments. None of the ADA-positive samples was positive for neutralizing activity. No clinically meaningful differences in adverse events were identified. CONCLUSIONS: The study demonstrated PK similarity among PF-05280586, rituximab-EU and rituximab-US. In addition, all treatments showed comparable CD19+ B cell depletion PD responses, as well as safety and immunogenicity profiles.

Do COX-2 inhibitors provide additional pain relief and anti-inflammatory effects in patients with rheumatoid arthritis who are on biological disease-modifying anti-rheumatic drugs and/or corticosteroids? Post-hoc analyses from a randomized clinical trial with etoricoxib.

BACKGROUND: Our objective was to evaluate the effect of background biological disease-modifying anti-rheumatic drugs (bDMARDs) and/or corticosteroids (CS) on response to nonsteroidal anti-inflammatory drugs (NSAIDs) in rheumatoid arthritis (RA) patients. METHODS: The following efficacy endpoints were evaluated using time-weighted change from baseline in a 12-week, randomized controlled clinical trial with etoricoxib: Patient Global Assessment of Pain, Swollen Joint Count, Tender Joint Count, Health Assessment Questionnaire. The following three treatment groups were evaluated: placebo, pooled etoricoxib 10/30/60 mg, and etoricoxib 90 mg. Screening values, values post flare, as well as changes after treatment were analyzed. RESULTS: Of the 1014 patients screened, 761 were randomized; 50% were on no background bDMARDs and/or CS therapy, 23% used bDMARDs, 34% used CS, and 8% used both bDMARDs and CS. It was demonstrated that RA patients on bDMARDs or CS had similar pain levels at screening as patients without this co-medication. They experienced flare upon NSAID withdrawal and demonstrated dose-dependent pain improvement with etoricoxib. CONCLUSION: These results support that RA patients receiving bDMARDs or CS may still require the use of concomitant analgesics to treat pain. Clinicians should continue to monitor and treat pain even after initiating a bDMARD and/or CS. TRIAL REGISTRATION: [clinicaltrials.gov; NCT00264147].

Safety of infusing rituximab at a more rapid rate in patients with rheumatoid arthritis: results from the RATE-RA study.

BACKGROUND: As recommended in the current prescribing information, rituximab infusions in patients with rheumatoid arthritis (RA) take 4.25 hours for the first infusion and 3.25 hours for subsequent infusions, which is a burden on patients and the health care system. We therefore evaluated the safety of infusing rituximab at a faster rate for an infusion period of 2 hours in patients with RA. METHODS: Patients with an inadequate response to anti-TNF who were rituximab-naive or -experienced received 2 courses of rituximab: Infusion 1 (Day 1) was administered over the standard 4.25 hours, and Infusions 2 (Day 15), 3 (Day 168) and 4 (Day 182) were administered over a faster 2-hour period. The primary endpoint was incidence of infusion-related reactions (IRRs) associated with Infusion 2. RESULTS: Of the 351 patients enrolled, 87% and 13% were rituximab-naive and -experienced, respectively. The incidence (95% CI) of IRRs associated with Infusion 1 was 16.2% (12.5%, 20.5%) and consistent with weighted historical incidence of 20.7% (19.4%, 22.1%). The incidence (95% CI) of IRRs associated with Infusions 2, 3, and 4 compared with respective weighted historical incidences at the standard infusion rate was 6.5% (4.1%, 9.7%) vs 8.1% (7.2%, 9.1%); 5.9% (3.5%, 9.3%) vs 11.5% (10.3%, 12.8%); and 0.7 (0.1%, 2.6%) vs 5.0% (4.2%, 6.0%), respectively. All IRRs were grade 1 or 2, except for 3 grade 3 IRRs associated with Infusion 1 and 2 grade 3 IRRs associated with Infusion 2. Four patients experienced a total of 5 grade 3 IRRs; 3 of these patients continued on to received subsequent infusions at the faster rate. There were no serious IRRs. CONCLUSION: This study demonstrated that rituximab can be administered at the faster infusion rate at the second and subsequent infusions without increasing the rate or severity of IRRs.

Risk of Venous Thromboembolism With Tofacitinib Versus Tumor Necrosis Factor Inhibitors in Cardiovascular Risk-Enriched Rheumatoid Arthritis Patients.

OBJECTIVE: The ORAL Surveillance trial found a dose-dependent increase in venous thromboembolism (VTE) and pulmonary embolism (PE) events with tofacitinib versus tumor necrosis factor inhibitors (TNFi). We aimed to assess VTE incidence over time and explore risk factors of VTE, including disease activity, in ORAL Surveillance. METHODS: Patients with rheumatoid arthritis (RA) aged 50 years or older with at least one additional cardiovascular risk factor received tofacitinib 5 or 10 mg twice daily (BID) or TNFi. Post hoc, cumulative probabilities and incidence rates (patients with first events/100 patient-years) by 6-month intervals were estimated for adjudicated VTE, deep vein thrombosis, and PE. Cox regression models identified risk factors. Clinical Disease Activity Index leading up to the event was explored in patients with VTE. RESULTS: Cumulative probabilities for VTE and PE were higher with tofacitinib 10 mg BID, but not 5 mg BID, versus TNFi. Incidence rates were consistent across 6-month intervals within treatments. Across treatments, risk factors for VTE included prior VTE, body mass index greater than or equal to 35 kg/m2, older age, and history of chronic lung disease. At the time of the event, most patients with VTE had active disease as defined by Clinical Disease Activity Index. CONCLUSION: Incidences of VTE and PE were higher with tofacitinib (10 > 5 mg BID) versus TNFi and were generally consistent over time. Across treatments, VTE risk factors were aligned with previous studies in the general RA population. These data highlight the importance of assessing VTE risk factors, including age, body mass index, and VTE history, when considering initiation of tofacitinib or TNFi in patients with active RA.

Tabalumab, an anti-BAFF monoclonal antibody, in patients with active rheumatoid arthritis with an inadequate response to TNF inhibitors.

OBJECTIVE: To evaluate the efficacy and safety of tabalumab, a monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with active rheumatoid arthritis (RA) who showed inadequate response to tumour necrosis factor (TNF) inhibitors. METHODS: Patients on stable methotrexate and with inadequate response to one or more TNF inhibitors were randomised to placebo (n=35), 30 mg tabalumab (n=35) or 80 mg tabalumab (n=30) given intravenously at 0, 3 and 6 weeks. The primary outcome was the proportion of patients achieving an American College of Rheumatology 50% response (ACR50) at week 16 (all tabalumab-treated patients vs placebo). RESULTS: At week 16, no significant differences were observed in the combined tabalumab group versus placebo in ACR50 (12.7% vs 2.9%, p=0.101) or ACR20 response rates (27.0% vs 17.1%, p=0.198). However, significant differences between the combined tabalumab group and placebo were observed at earlier time points for ACR20, ACR50 and Disease Activity Score in 28 joints (DAS28)-C-reactive protein (CRP) reduction. Treatment-emergent adverse events (AEs) were similar with 30 mg tabalumab (65.7%), 80 mg tabalumab (76.7%) and placebo (71.4%), although certain events occurred more often with tabalumab than placebo (eg, infection, anaemia and gastrointestinal events). Serious AEs occurred in two (6.7%) patients receiving 80 mg tabalumab and three (8.6%) receiving placebo, with one serious infection in the placebo group. Initial increases in total and mature B cells were followed by progressive decreases, despite declines in serum tabalumab. CONCLUSIONS: At week 16, the primary end point was not achieved, but an indication of efficacy was observed at earlier time points. Safety findings for tabalumab were consistent with other biological RA therapies. CLINICAL TRIAL REGISTRATION NUMBER: NCT00689728.

Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized controlled trial.

OBJECTIVE: To assess the safety of rituximab in combination with a tumor necrosis factor (TNF) inhibitor and methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: Adult patients with active RA (≥ 5 swollen and ≥ 5 tender joints) receiving a stable dose of MTX (10-25 mg/week) and stable dose of TNF inhibitor (etanercept or adalimumab) for ≥ 12 weeks were randomized 2:1 to receive one course of rituximab or placebo, given intravenously at a dose of 2 × 500 mg. The primary end point was the proportion of patients developing ≥ 1 serious infection through week 24. RESULTS: Fifty-one patients were treated with either rituximab or placebo in combination with background MTX and a TNF inhibitor. Baseline characteristics were generally balanced between groups, except for corticosteroid usage (36% in the rituximab arm versus 17% in the placebo arm). A serious infection (pneumonia) was observed in 1 patient (3%) in the rituximab group after 14.4 patient-years of exposure (6.95 events per 100 patient-years, 95% confidence interval 0.98-49.35), compared with none in the placebo group at week 24. Infections were reported in 18 patients (55%) and 11 patients (61%) in the rituximab and placebo groups, respectively. Grade 3 infections were reported in 3 patients (9%) receiving rituximab and in none of the patients receiving placebo. No grade 4 infections were observed, nor were there any opportunistic, fungal, or tuberculosis infections. Serious adverse events (SAEs) were reported in 2 rituximab-treated patients (pneumonia and coronary artery occlusion), whereas there were no SAEs reported in placebo-treated patients. At week 24, the percentage of patients achieving an American College of Rheumatology 20% (ACR20) improvement response was 30% in the rituximab group compared with 17% in the placebo group, and ACR50 responses were achieved by 12% and 6% of patients, respectively. CONCLUSION: The preliminary safety profile of rituximab in combination with a TNF inhibitor and MTX was consistent with the safety profile of rituximab in combination with MTX in other RA trials without a TNF inhibitor, with no new safety signals observed. SAEs were numerically more frequent in the rituximab group, and there was no clear evidence of an efficacy advantage in patients receiving rituximab in combination with a TNF inhibitor and MTX.

Preventive care: vaccines matter.

A database of information about more than 30,000 patients verified improved morbidity and mortality due to vaccines and preventive health care in prospective trials.

Safety and Efficacy of Filgotinib: Up to 4-year Results From an Open-label Extension Study of Phase II Rheumatoid Arthritis Programs.

OBJECTIVE: The long-term safety and efficacy of filgotinib (from phase II studies), with or without methotrexate (MTX), for the treatment of patients with rheumatoid arthritis was assessed in DARWIN 3, a long-term, open-label extension study (ClinicalTrials.gov: NCT02065700). METHODS: Eligible patients completing the 24-week DARWIN 1 (filgotinib + MTX) and DARWIN 2 (filgotinib monotherapy) studies entered DARWIN 3, where they received filgotinib 200 mg/day, except for 15 men who received filgotinib 100 mg/day. Safety analyses were performed using the safety analysis set and the exposure-adjusted incidence rate (EAIR) of treatment-emergent adverse events (TEAEs) was calculated. Efficacy was assessed from baseline in the parent studies. RESULTS: Of 790 patients completing the phase II parent studies, 739 enrolled in the study. Through April 2019, 59.5% of patients had received ≥ 4 years of the study drug. Mean (SD) exposure to filgotinib was 3.55 (1.57) years in the filgotinib + MTX group and 3.38 (1.59) years in the filgotinib monotherapy group. EAIR per 100 patient-years of exposure for TEAEs was 24.6 in the filgotinib + MTX group and 25.8 in the filgotinib monotherapy group, and for serious TEAEs, the EAIR was 3.1 and 4.3, respectively. American College of Rheumatology 20/50/70 responses among patients remaining in the study could be maintained through 4 years, with 89.3%/69.6%/49.1% of the filgotinib + MTX group and 91.8%/69.4%/44.4% of the monotherapy group maintaining ACR20/50/70 responses, respectively, based on observed data. CONCLUSION: Filgotinib was well tolerated with a 4-year safety profile comparable to that of the parent trials, both in patients receiving combination therapy with MTX or as monotherapy.

Improved GI tolerability with monthly ibandronate in women previously using weekly bisphosphonates.

OBJECTIVE: This subanalysis of CURRENT, an open-label, 6-month, multicenter study, assesses changes in gastrointestinal (GI) tolerability with once-monthly oral ibandronate in women who switched from once-weekly bisphosphonates and had reported GI symptoms with their previous weekly bisphosphonate regimen. METHODS: Postmenopausal women currently taking a weekly bisphosphonate switched to 150 mg monthly ibandronate. At the start of the treatment phase and after 6 months of therapy, all participants completed the Osteoporosis Patient Satisfaction Questionnaire (OPSAT-Q), a validated instrument consisting of four domains: convenience, satisfaction, quality of life, and side effects. This subanalysis assessed GI tolerability in those women who reported GI symptoms at baseline in the side effects domain of OPSAT-Q and change in satisfaction in those who had reported stomach upset within 48 hours of taking their previous bisphosphonate at screening. RESULTS: Of women who reported GI symptoms at baseline, >60% reported an improvement in heartburn or acid reflux after switching to monthly ibandronate. Further, >70% reported improvements in stomach upset (excluding heartburn or acid reflux). Of those women who reported stomach upset within 48 hours of taking their previous weekly bisphosphonate at screening (n = 89), >80% reported improved overall satisfaction compared with baseline. Monthly ibandronate was generally well tolerated. CONCLUSION: A majority of women who experienced GI tolerability issues with weekly bisphosphonates reported improvements in GI symptoms after transitioning from a weekly bisphosphonate to monthly ibandronate for 6 months.

FKB327, an adalimumab biosimilar, versus the reference product: results of a randomized, Phase III, double-blind study, and its open-label extension.

OBJECTIVE: To compare the efficacy, serum drug concentrations, immunogenicity, and safety of FKB327 with the adalimumab reference product (RP) in combination with methotrexate in patients with moderate-to-severe, active rheumatoid arthritis (RA). METHODS: Patients were randomized 1:1 in a double-blind study (NCT02260791), received 40 mg of FKB327 or RP by subcutaneous injection every other week for 24 weeks (Period I), then re-randomized 2:1, remaining on the same study drug or switching to the other up to week 54 in an open-label extension (Period II, NCT02405780). Efficacy was evaluated using American College of Rheumatology (ACR20) response rate difference at week 24 with equivalence margins of ± 13% and - 12% to + 15% using 95% and 90% confidence intervals (CIs), respectively. Efficacy, serum drug concentrations, immunogenicity, and safety were compared at week 54. RESULTS: A total of 730 patients were randomized in Period I (n = 367 FKB327, n = 363 RP), and 645 transitioned to Period II (n = 216 FKB327-FKB327, n = 108 FKB327-RP, n = 108 RP-FKB327, n = 213 RP-RP). At week 24, ACR20 response rates were 74.1% with FKB327 versus 75.7% with RP. 95% and 90% CI of the response rate difference were - 7.9 to 4.7% and - 7.3 to 3.6%, respectively, meeting predefined equivalence margins. The ACR20 response rate remained over 70% of patients to week 54 with all treatment sequences. In Period I, mean trough serum drug concentrations were slightly higher for patients receiving FKB327 than those receiving RP. Mean concentrations were stable over time and reflected steady state in Period II. The proportions of patients with samples positive for neutralizing antidrug antibodies (ADAs) were comparable (57.7% with FKB327 vs. 55.5% with RP) at week 24, and no consistent difference in ADA were seen between continuous and switched treatments in Period II. Efficacy was slightly reduced in the small proportion of patients with high ADA titers in all treatment groups. No clinically significant differences were observed in the incidence of commonly reported treatment-emergent adverse events between the treatments across Periods I and II. CONCLUSION: FKB327 was equivalent to RP in clinical efficacy and demonstrated comparable safety and immunogenicity in patients with moderate-to-severe RA. No effect of switching between FKB327 and RP was observed. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02260791, Registered 29 July 2014. ClinicalTrials.gov, NCT02405780, Registered 17 July 2015.

Two-Year Safety and Effectiveness of Peficitinib in Moderate-To-Severe Rheumatoid Arthritis: A Phase IIb, Open-Label Extension Study.

INTRODUCTION: Peficitinib is a novel orally bioavailable, once-daily Janus kinase (JAK) inhibitor approved in Japan for the treatment of rheumatoid arthritis (RA). This 2-year extension study of two global phase IIb trials investigated the long-term safety and effectiveness of peficitinib. METHODS: All eligible patients with moderate-to-severe RA including patients in the placebo group who participated in one of two global phase IIb trials ('with methotrexate' or 'without methotrexate') were included in this 2-year open-label extension study and were converted to peficitinib 100 mg once daily. The primary objective was to evaluate an additional 2 years of safety by assessing treatment-emergent adverse events (AEs) and clinical laboratory evaluations for 105 weeks. Evaluation of an additional 2 years of effectiveness using American College of Rheumatology (ACR) 20/50/70 responses was the exploratory objective. RESULTS: Overall, 611 patients were enrolled in the extension study: 319 (52.2%) patients completed the study and 292 (48%) discontinued treatment, including for withdrawal of patient consent (n = 96), failure to achieve low disease activity (n = 62), and AE not including death (n = 41). AEs were reported in 463 (76%) patients. The most common AEs (per 100 patient-years) were upper respiratory tract infections (9.9) and urinary tract infections (7.2). Serious AEs were reported in 80 (13%) patients, with incidences per 100 patient-years of serious infections 2.7, herpes zoster 1.5 (including one herpes zoster ophthalmic), and malignancies 0.6 (most frequently basal cell carcinoma). At week 105, 269 (44%) patients demonstrated an ACR20 response relative to their respective phase IIb trial baselines. CONCLUSION: Among 319 patients who completed this 2-year extension of two global phase IIb studies, peficitinib 100 mg once daily demonstrated a stable safety profile and sustained effectiveness in patients with moderate-to-severe RA. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01711814. Registered 19 October 2012. FUNDING: Astellas Pharma Global Development, Inc.

Biosimilars Have Arrived: Rituximab.

A biosimilar is a biologic product that is highly similar to a licensed biologic ("originator") such that there are no clinically meaningful differences in safety, purity, or potency between the biosimilar and the originator. As patent protection and data exclusivity for the biologic rituximab expire, several potential biosimilars to rituximab are in development, which could soon lead to the availability of numerous rituximab biosimilars. Biosimilars are evaluated using thorough and rigorous analyses of the potential biosimilar versus the originator biological to confirm similar structure, function, and clinical efficacy as well as safety. Approval of a biosimilar is based upon the totality of the evidence demonstrating similarity to the originator. An understanding of the process of the interchangeable designation of a biosimilar is important in the context of patient outcomes. We conducted an analysis of the properties and benefits of rituximab in the treatment of inflammatory diseases, the development and approval of biosimilars, and the potential benefits of rituximab biosimilars. PubMed and ClinicalTrials.gov databases were searched for "biosimilar" and "rituximab" and regulatory and pharmaceutical company web pages were screened regarding biosimilars in development and specific guidelines developed for the approval of biosimilars. The results indicate that, at present, six rituximab biosimilar candidates are undergoing comparative clinical development, and two were recently approved in the European Union. Our analysis indicates rituximab biosimilars are expected to have a continuing role in treating inflammatory conditions such as rheumatoid arthritis.

Baricitinib in Patients with Rheumatoid Arthritis and an Inadequate Response to Conventional Disease-Modifying Antirheumatic Drugs in United States and Rest of World: A Subset Analysis.

INTRODUCTION: This article evaluates the efficacy and safety of baricitinib 4 mg versus placebo in United States including Puerto Rico (US) and rest of the world (ROW) subpopulations using data pooled from RA-BEAM and RA-BUILD, which enrolled patients with moderate-to-severe adult-onset rheumatoid arthritis (RA). METHODS: In RA-BEAM, patients with an inadequate response (IR) to methotrexate, at least one X-ray erosion, and high sensitivity C-reactive protein (hsCRP) ≥ 6 mg/L were randomized to placebo or orally administered baricitinib 4 mg daily or subcutaneously administered adalimumab 40 mg every other week. In RA-BUILD, patients with an IR to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD) and with hsCRP ≥ 3.6 mg/L were randomized to placebo or baricitinib 2 or 4 mg daily. Patients in both trials were biologic naive. In this post hoc analysis, data from both studies were pooled (714 baricitinib 4 mg-treated, 716 placebo-treated patients). RESULTS: Overall, 188 US and 1242 ROW patients were included. Subgroups differed in baseline characteristics including race, weight, age, time since RA diagnosis, current corticosteroid use, and previous csDMARD use. At weeks 12 and 24, baricitinib-treated patients had larger responses compared to placebo-treated patients for multiple efficacy outcomes: American College of Rheumatology 20/50/70 response, low disease activity, remission, Disease Activity Score 28-C-reactive protein, and Health Assessment Questionnaire-Disability Index. Overall, similar efficacy was observed in US and ROW subgroups with no notable safety differences between subgroups at weeks 12 or 24. CONCLUSION: Baricitinib 4 mg was efficacious compared to placebo in US and ROW subpopulations. Safety was similar between subgroups. FUNDING: Eli Lilly & Company and Incyte Corporation. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT01721057; NCT01710358.

Effects of baricitinib on radiographic progression of structural joint damage at 1 year in patients with rheumatoid arthritis and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs.

BACKGROUND: Baricitinib was efficacious in a 24-week phase III study in patients with rheumatoid arthritis (RA) and an inadequate response to conventional synthetic disease-modifying anti rheumatic drugs (DMARDs) (csDMARDs) (RA-BUILD). OBJECTIVES: To evaluate radiographic progression of structural joint damage in RA-BUILD patients over 48 weeks of baricitinib treatment in the long-term extension study, RA-BEYOND. METHODS: In RA-BUILD, patients were randomised to placebo, baricitinib 2 mg or 4 mg once daily, with rescue possible from week 16. Patients completing RA-BUILD and entering RA-BEYOND continued to receive the baricitinib dose received at the end of RA-BUILD. Patients receiving placebo were switched to baricitinib 4 mg in RA-BEYOND. Joint damage was measured using the van der Heijde modified total Sharp score. To account for missing scores and scores obtained after rescue, switch or discontinuation of study drug, data were analysed using (1) linear extrapolation (LE) and (2) observed/last observation carried forward (LOCF). The observed/LOCF method used all available observed data, including after rescue or switch, with patients analysed according to original treatment assignment. RESULTS: Using LE, radiographic progression at 24 and 48 weeks was statistically significantly lower for both baricitinib 2 or 4 mg compared with placebo. Only baricitinib 4 mg demonstrated statistically significant inhibition of progressive radiographic joint damage compared with patients initially randomised to placebo using observed/LOCF at week 48. CONCLUSIONS: Once daily oral baricitinib inhibited radiographic progression of structural joint damage in patients with an inadequate response or intolerance to csDMARDs over 48 weeks. The most robust benefit was seen for the 4 mg dose.

A mode of error: Immunoglobulin binding protein (a subset of anti-citrullinated proteins) can cause false positive tuberculosis test results in rheumatoid arthritis.

Citrullinated Immunoglobulin Binding Protein (BiP) is a newly described autoimmune target in rheumatoid arthritis (RA), one of many cyclic citrullinated peptides(CCP or ACPA). BiP is over-expressed in RA patients causing T cell expansion and increased interferon levels during incubation for the QuantiFERON-Gold tuberculosis test (QFT-G TB). The QFT-G TB has never been validated where interferon is increased by underlying disease, as for example RA. Of ACPA-positive RA patients (n = 126), we found a 13% false-positive TB test rate by QFT-G TB. Despite subsequent biologic therapy for 3 years of all 126 RA patients, none showed evidence of TB without INH. Most of the false-positive RA patients after treatment with biologic therapy reverted to a negative QFT-G test. False TB tests correlated with ACPA level (p < 0.02). Three healthy women without arthritis or TB exposure had negative QFT-G TB. In vitro, all three tested positive every time for TB correlating to the dose of BiP or anti-BiP added, at 2 ug/ml, 5 ug/ml, 10 ug/ml, and 20 ug/ml. BiP naturally found in the majority of ACPA-positive RA patients can result in a false positive QFT-G TB. Subsequent undertreatment of RA, if biologic therapy is withheld, and overtreatment of presumed latent TB may harm patients.

Peficitinib, a JAK Inhibitor, in Combination With Limited Conventional Synthetic Disease-Modifying Antirheumatic Drugs in the Treatment of Moderate-to-Severe Rheumatoid Arthritis.

OBJECTIVE: To evaluate the efficacy and safety of orally administered once-daily peficitinib in combination with limited conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with moderate-to-severe rheumatoid arthritis (RA). METHODS: In this randomized, double-blind, phase IIb trial, patients with RA (n = 289) were treated with peficitinib 25 mg, 50 mg, 100 mg, or 150 mg or matching placebo once daily for 12 weeks. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 12. RESULTS: ACR20 response rates at week 12 were 22.0%, 36.8%, 48.3% (P < 0.05), 56.3% (P < 0.01), and 29.4% in the peficitinib 25 mg, 50 mg, 100 mg, 150 mg, and placebo groups, respectively. Patients in the peficitinib 100 mg and 150 mg groups achieved a rapid and statistically significant ACR20 response compared with those in the placebo group (P < 0.05), reaching statistical significance by week 2. Overall, the incidence of adverse events (AEs) was similar between patients receiving peficitinib and those receiving placebo. The most common AEs were upper respiratory tract infection (5% [n = 15]), nausea (4% [n = 12]), and urinary tract infection (4% [n = 10]). There was 1 case of herpes zoster in the placebo group, and 1 serious infection (limb abscess) in the peficitinib 25 mg group. There were no incidences of grade 2 or higher neutropenia or lymphopenia. CONCLUSION: In patients with moderate-to-severe RA, orally administered once-daily peficitinib in combination with limited csDMARDs resulted in a dose-dependent ACR20 response rate over 12 weeks with satisfactory tolerability.