November 2020

Safety Profile of Upadacitinib in Rheumatoid Arthritis: Integrated Analysis from the SELECT Phase III Clinical Programme

Ann Rheum Dis 2020 DOI:10.1136/annrheumdis-2020-218510

This integrated Phase III safety analysis of UPA showed that UPA had a similar profile to ADA and MTX for serious infections, malignancies, and thromboembolic events. Patients receiving UPA had increased risk of HZ and creatine phosphokinase elevation versus ADA.This integrated Phase III safety analysis of UPA examined >3500 RA patients and 4000 patient-years of exposure. Data were pooled from 3834 patients in SELECT-NEXT, SELECT-BEYOND, SELECT-MONOTHERAPY, SELECT-COMPARE and SELECT-EARLY studie...

Keywords:

Trial of UPA or Abatacept in Rheumatoid Arthritis

N Engl J Med 2020;383:1511–21 DOI: 10.1056/NEJMoa2008250

In patients with refractory RA to bDMARDs, upadacitinib was found to be superior to abatacept in DAS28-CRP change from baseline and the achievement of remission at week 12.612 bDMARD-IR patients were randomised 1:1 to UPA 15 mg QD or ABA, each in combination with stable synthetic DMARDs. At Week 12, patients with <20% decrease in TJC and Swollen joint count (SJC) had background medication adjusted or added. All patients completing Week 24 were eligible to remain in an open-label, long-term exten...

Keywords:

Age-Based (<65 vs ≥65 years) Incidence of Infections and Serious Infections with Tofacitinib Versus Biological DMARDs in Rheumatoid Arthritis Clinical Trials and the US Corrona RA Registry

Ann Rheum Dis 2020; DOI: 10.1136/annrheumdis-2020-218992

Reports from clinical trials and the US Corrona RA registry showed that serious infection event (SIE) incidence was higher in older versus younger patients with RA receiving 10 mg BID of TOF and ADA, however, SIE risk was similar between age groups with TOF 5 mg BID and ADA.Data were collected from Phase II–IV tofacitinib studies, and the US Corrona RA registry. The clinical data set evaluated patients receiving TOF 5 and 10 mg BID versus TNFi (ADA/ETN) in RA patients aged ≥50 years. The EMA rec...

Keywords:

October 2020

Preclinical characterisation of itacitinib, a Novel Selective Inhibitor of JAK1, for the Treatment of Inflammatory Diseases

European Journal of Pharmacology. 2020 Oct 15;885:173505. doi: 10.1016/j.ejphar.2020.173505

Itacitinib is an orally active JAK inhibitor and effectively delayed disease onset, reduced symptom severity, and accelerated recovery of inflammatory diseases in mouse models. Covington M et al demonstrated itacitinib’s high selectivity for JAK 1, its inhibition on IL-2 induced T cell proliferation and JAK/STAT signalling, its ability to also inhibit of the JAK/STAT pathway in response to IL-6 stimulation, and its effect on rat adjuvant induced arthritis model. The study used recombinant enzym...

Keywords:

Efficacy of Baricitinib in Treating Rheumatoid Arthritis: Modulatory Effects on Fibrotic and Inflammatory Biomarkers in a Real-Life Setting

Int Immunopharmacol. 2020 Sep;86:106748.

BARI demonstrated to be a safe immune modulator that reduces the concentrations biomarkers of lung fibrosis and inflammation in RA patients, including a subgroup with interstitial lung involvement. Professor Alessandro and colleagues analysed the effects of baricitinib in a population of RA and RA-ILD patients in a real-life setting, describing any changes in lung function parameters, serum inflammatory biomarkers and fibrotic biomarkers after 6 months of treatment. Fifteen patients were recruit...

Keywords:

Baricitinib, a drug with potential effect to prevent SARS-COV-2 from entering target cells and control cytokine storm induced by COVID-19

Journal of International Immunopharmacology. 2020 Sep;86:106749. doi: 10.1016/j.intimp.2020.106749.

BARI may potentially interrupt the passage of SARS-CoV-2 into the target cells by binding to AAK1 and GAK, which are regulators of the ACE2 receptor regulator identified for its uptake, and could also treat cytokine storm through suppression JAK1/JAK2. Professor Zhang and et al reviewed BARI, as a potential drug to prevent SARS-COV-2 from entering target cells. They also evaluated BARI’s ability to control COVID-19 induced cytokine storm. As a cell surface protein, ACE2 is involved in receptor-m...

Keywords:

Tofacitinib and Baricitinib Are Taken up by Different Uptake Mechanisms Determining the Efficacy of Both Drugs in RA

Int. J. Mol. Sci. 2020; 21:6632 DOI: 10.3390/ijms21186632

Amrhein et al examined the different uptake and expulsion mechanisms of BARI and TOF in cellular assays. Different cellular uptake mechanism for BARI and TOF was observed and showed that BARI’s transport was not dependent on organic cation transporters. Results indicated TOF was exported from RASF in a MATE-1 dependent way. TOF might be exported from healthy cells, thereby not inhibiting JAK pathway in these cellsThe interaction of BARI and TOF with OCTs was investigated using quenching experime...

Keywords:

September 2020

Incidence of venous and arterial thromboembolic events reported in the tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis development programmes and from real-world data

Annals of the Rheumatic Diseases 05 August 2020 2020 Nov;79(11):1400-1413. doi: 10.1136/annrheumdis-2019-216761. Epub 2020 Aug 5.

Concerns surrounding increased rates of PE and cardiovascular associated deaths has led to black box warnings when prescribing JAK inhibitors. As such, ongoing investigations regarding cardiovascular and VTE event risks in JAK inhibitor therapies, both clinical and real-world, are vital. Mease and colleagues consider data from clinical tofacitinib development programmes, and the ongoing real-data study A3921133. Conclusions from data analysis state that those with pre-existing cardiovascular and...

Keywords:

Assessment of the association of baseline anti-CarbV and anti-MCV antibodies with response to treatment and radiographic progression in an RA population treated with either methotrexate or baricitinib: post-hoc analyses from RA-BEGIN

Arthritis Res Ther. 2020;22(1):193

Autoantibodies associated with the onset of RA have gained attention in recent years as prognostic biomarkers. Though not used diagnostically, anti-CarbV (carbamylated vimentin) and anti-MCV (vimentin modified by citrullination) baseline titers are being investigated as predictors of treatment response. In this post-hoc analysis of data from the RA-BEGIN cohort of active RA patients, López-Romero and colleagues consider the potential predictive values of baseline anti-CarbV and anti-MCV titers r...

Keywords:

Infections in Baricitinib Clinical Trials for Patients with Active Rheumatoid Arthritis

Annals of the Rheumatic Diseases, May 2020

Baricitinib, an oral selective JAK1 and JAK2 inhibitor,8 demonstrated significant clinical efficacy in phase 3 RA trials. Pooled data from these trials, including a long-term extension (LTE), inform the safety profile for baricitinib, mainly to evaluate the incidence of infection in patients with active rheumatoid arthritis (RA), with a focus on serious infection, tuberculosis (TB), herpes zoster (HZ) and opportunistic infection (OI). The data collected were from eight double-blind randomised tr...

Keywords: