Efficacy and Safety of ABBV-3373, a Novel Anti-Tumor Necrosis Factor Glucocorticoid Receptor Modulator Antibody-Drug Conjugate, in Adults with Moderate-to-Severe Rheumatoid Arthritis Despite Methotrexate Therapy: A Randomized, Double-Blind, Active-Controlled Proof-of-Concept Phase IIa Trial.

OBJECTIVE: To assess the efficacy and safety of ABBV-3373, a novel antibody-drug conjugate (ADC) composed of the anti-tumor necrosis factor (anti-TNF) monoclonal antibody adalimumab linked to a glucocorticoid receptor modulator (GRM), compared to adalimumab, in patients with rheumatoid arthritis (RA). METHODS: In this randomized, double-blind, active-controlled, proof-of-concept trial (ClinicalTrials.gov identifier: NCT03823391), adults with moderate-to-severe RA receiving background methotrexate were administered intravenously (IV) ABBV-3373 100 mg every other week for 12 weeks, followed by placebo for 12 weeks, or subcutaneous adalimumab 80 mg every other week for 24 weeks. The primary end point was change from baseline in the Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) at week 12, with 2 prespecified primary comparisons of ABBV-3373 versus historical adalimumab (80 mg every other week or equivalent dose) and versus combined in-trial/historical adalimumab. Secondary end points included change from baseline in the Clinical Disease Activity Index, Simplified Disease Activity Index, and DAS28 using erythrocyte sedimentation rate, as well as the proportion of patients achieving a DAS28-CRP of ≤3.2 and the American College of Rheumatology 50% improvement criteria. RESULTS: Forty-eight patients were randomized to receive either ABBV-3373 (n = 31) or adalimumab (n = 17). At week 12, ABBV-3373 demonstrated a reduction in DAS28-CRP compared to historical adalimumab (-2.65 versus -2.13; P = 0.022) and compared to combined in-trial/historical adalimumab (-2.65 versus -2.29; probability 89.9%), with numerically greater improvement than in-trial adalimumab (-2.51). For secondary end points, greater efficacy was observed with ABBV-3373 compared to historical adalimumab; ABBV-3373 was predicted with 79.3-99.5% probability to be more effective than adalimumab based on combined in-trial/historical adalimumab data. Of the ABBV-3373-treated patients who achieved DAS28-CRP ≤3.2 at week 12, 70.6% maintained this response at week 24 despite switching to placebo. Four serious adverse events (SAEs) were reported with ABBV-3373 (noncardiac chest pain, pneumonia, upper respiratory tract infection, and anaphylactic shock) and 2 SAEs with adalimumab (breast abscess and bronchitis). After increasing the duration of IV ABBV-3373 administration from 3 minutes to 15-30 minutes, no similar events of anaphylactic shock were reported. CONCLUSION: Data from this proof-of-concept trial support the continued development of a TNF-GRM ADC for the treatment of RA, with the potential to achieve superior outcomes compared to currently available therapies.

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.

Symptoms and signs of polymositis, systematic lupus erythematosus and antiphospholipid syndrome follow consecutively / Sekwencyjne pojawianie sie objawów zapalenia wielomiesniowego, tocznia rumieniowatego ukladowego i zespolu antyfosfolipidowego.

Polymyositis (PM) and dermatomyositis (DM) are very rare connective tissue disorders which only in exceptional circumstances affect white men. The present paper describes the case of an obese 55-years-old man in whom no muscular-skeletal system symptoms were found during the period of 2 years before the onset of arthritis, and who was treated because of cardiac involvement (pericarditis, PAF), pleuritis, malaise and fever. Only the occurrence of non erosive arthritis decided on the connective tissue disorder as a cause of his complaints. Previously the diagnostics was based on the exclusion of malignant diseases and bacterial and viral infections. The determination of antinuclear antibodies in high titer without any specific, typical of individual disease entities antinuclear antibodies allowed only the diagnose of undifferentiated connective tissue disease. Glucocorticosteroid treatment was initiated, however six months later despite treatment with metyloprednisolone the symptoms and signs associated with PM accompanied by high level of creatinophosphokinase and elevated transaminase were found. The muscle biopsy revealed myositis, but no specific antibodies, especially anti-Jo-1, were detected. It is very interesting that cyclophosphamide + glucocorticoids pulse therapy failed to prevent the development of antiphospholipide syndrome and interstitial pulmonary fibrosis in the PM patient. Overlapping of immunological tissue disorders is a well-known phenomenon, but in the case of fulminating and distinct symptoms and signs the lack of detection of specific antibodies is quite uncommon.