To evaluate the efficacy and safety of different doses and regimens of filgotinib, an oral Janus kinase 1 inhibitor, as add-on treatment to methotrexate (MTX) in patients with active rheumatoid ...arthritis (RA) and inadequate response to MTX.
In this 24-week phase IIb study, patients with moderate-to-severe active RA receiving a stable dose of MTX were randomised (1:1:1:1:1:1:1) to receive placebo or 50, 100 or 200 mg filgotinib, administered once daily or twice daily. Primary end point was the percentage of patients achieving a week 12 American College of Rheumatology (ACR)20 response.
Overall, 594 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib 100 mg once daily or 200 mg daily (both regimens) achieved an ACR20 response versus placebo. For other key end points at week 12 (ACR50, ACR-N, Disease Activity Score based on 28 joints and C reactive protein value, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index), differences in favour of 100 or 200 mg filgotinib daily were seen versus placebo; responses were maintained or improved through to week 24. Rapid onset of action and dose-dependent responses were observed for most efficacy end points and were associated with an increased haemoglobin concentration. No significant differences between once-daily and twice-daily regimens were seen. Treatment-emergent adverse event rates were similar in placebo and filgotinib groups. Serious infections occurred in one and five patients in the placebo and filgotinib groups, respectively. No tuberculosis or opportunistic infections were reported.
Filgotinib as add-on to MTX improved the signs and symptoms of active RA over 24 weeks and was associated with a rapid onset of action. Filgotinib was generally well tolerated.
NCT01888874.
This article presents the design of clinical trials for the development of biosimilars in the European Union and the United States, with special focus on inflammatory diseases.
All information ...available in PubMed and the Internet relating to the clinical development of biosimilars in inflammatory rheumatic conditions (e.g. rheumatoid arthritis, psoriasis, psoriatic arthritis and ankylosing spondylitis) was collated. The European Medicines Agency (EMA) and US Food and Drug Administration (FDA) websites were screened for guidelines on biosimilars.
More than 10 years ago the EMA began to publish guidelines for the development of biosimilars and several biosimilars have now been approved. In the USA the FDA has published guidance for the nonclinical and clinical development of biosimilars but until early 2015 no biosimilar had been approved.
Clinical trials aim to resolve uncertainties that may remain following nonclinical development regarding the similarity of the proposed biosimilar with the reference product. Pharmacokinetic and pharmacodynamic studies are essential for early clinical development and further phase 3 clinical studies. Factors to be considered in the clinical process include study population, design, endpoints, sample size, duration and analytical methods.
Protein kinase inhibitors represent a novel and promising approach to the treatment of rheumatoid arthritis (RA). By targeting intracellular signaling pathways of cytokine-mediated reactions, these ...substances are able to interfere with critical immune processes that underly the pathology of RA. With tofacitinib, the first Janus kinase (JAK) inhibitor has been approved in the USA, as well as in Switzerland and other countries. Several other substances are currently undergoing phase II or phase III trials.A crucial question that will shape the future of these new drugs is whether they are safe and in particular, whether they are safer than biological therapies. This article provides an overview on current data concerning the efficacy and safety of the most promising substances and discusses the potential future role of intracellular kinase inhibitors.
Objective. People with RA have episodes of worsening disease activity (flares) that prompt them to seek clinical review or medication change. This study explored patients' perspectives of flare that ...prompts them to seek medication review.
Methods. Fourteen focus groups across five countries comprised 67 RA patients. Transcripts were analysed by several researchers and a patient, using inductive thematic analysis.
Results. Patients use flare for five different scenarios, including flare that prompts medical help-seeking, where six themes were identified. In 'Symptoms and early warnings', pain is intense (wanting to die), constant and persistent and considered a key feature. Systemic features predominate, including fatigue, feeling generally ill (flu-like), physical and cognitive shut-down and social withdrawal. Warning signs (prodrome) comprise fatigue and flu-like symptoms. 'Self-management of intensifying symptoms' includes pacing, heat/cold, rest and increasing medication, often without medical advice. Patients 'Define this as uncontrollable flare' when clusters of unprovoked, persistent symptoms halt their ability to run daily life, until prompted into 'Seeking help when symptoms can't be contained'. Underpinning themes are 'Individual context' (e.g. different symptom clusters) and 'Uncertainty' (e.g. when to seek help). Patients report that the current patient global visual analogue scale (VAS) does not capture flare.
Conclusion. Patients use flare for multiple events and seek help for complex clusterings of intense, unprovoked symptoms that defy self-management, not necessarily captured in joint counts or global VAS. Flare terminology and definition have implications for clinical practice and trials, therefore further research should establish a professional/patient consensus.
This 9-month open-label extension of the Circadian Administration of Prednisone in Rheumatoid Arthritis Study (CAPRA 1) investigated the long-term safety and efficacy of prednisone chronotherapy with ...a novel modified-release (MR) prednisone for up to 12 months.
Of 288 patients with rheumatoid arthritis originally randomised to MR or immediate-release (IR) prednisone, 249 continued with prednisone chronotherapy (2-10 mg/day) in the 9-month open-label extension. Duration of morning stiffness of the joints (MS), disease activity scores (DAS28), American College of Rheumatology (ACR20) responses and plasma levels of interleukin 6 (IL-6) were assessed. Safety was analysed from adverse event reports and laboratory investigations.
During the 3-month double-blind phase, patients in the MR group achieved a reduction in MS of 33.1% while no change was observed in the IR group. After 6 months of treatment, MS was reduced in the IR/MR group by 54% and in the MR/MR group by 56%. MS reduction after 12 months was 45% (IR/MR group) and 55% (MR/MR group). Plasma levels of IL-6 declined on MR treatment. DAS28 was reduced from 5.8 to 4.8 (MR/MR group) and 4.9 (IR/MR group), respectively. 37% of the 219 patients who completed the 12-month study achieved improvement according to the ACR20 criteria. Adverse events did not differ from the known profile of low-dose prednisone.
Prednisone chronotherapy with the MR tablet was safe and well tolerated and provided a sustained improvement which resulted in a better benefit to risk ratio of low-dose glucocorticoid treatment for at least 12 months.
Cytokines and associated intracellular signal cascades play a major role in the pathogenesis of autoimmune diseases. Janus kinases (JAK) are part of these intracellular signal transduction processes. ...A relatively new drug group of targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) are JAK inhibitors (JAKi) and are a promising treatment approach for autoimmune diseases.
Hitherto, three JAKis, Tofacitinib, Baricitinib and Upadacitinib, have been approved for treatment of Rheumatoid Arthritis (RA) in the USA, Switzerland and the EU. Filgotinib, another JAKi, also showed promising results in the treatment of RA. Furthermore, tofacitinib received approval for the treatment of ulcerative colitis and psoriatic arthritis. In addition to the JAKis already mentioned, several other JAKis, e.g. filgotinib and peficitinib, are being and were investigated in various studies on indications, such as atopic dermatitis, ankylosing spondylitis and systemic lupus erythematosus.
Being immunosuppressants, JAKis show an elevated incidence of severe infections, comparable to biologics. The increased reactivation of varicella zoster virus is especially noteworthy. Under JAKi treatment cytopenia is also more frequent. Lymphopenia under JAKi treatment is of particular clinical relevance because of its association with an increase in the number of severe infections. Furthermore, an elevated risk of thromboembolic events, particularly pulmonary embolism has been noted. The risks concerning metabolic alterations and the occurrence of malignant neoplasms are comparable to those under treatment with biologics.
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