Integrated safety analysis of filgotinib in patients with moderate-to-severe rheumatoid arthritis over a treatment duration of up to 8.3 years.

OBJECTIVES: To update the long-term safety profile of filgotinib, a Janus kinase-1 preferential inhibitor, in patients with moderate-to-severe rheumatoid arthritis. METHODS: Data from seven trials were integrated (NCT01888874, NCT01894516, NCT02889796, NCT02873936, NCT02886728, NCT02065700 and NCT03025308). Patients received once-daily filgotinib 100 mg or 200 mg. Exposure-adjusted incidence rates (EAIRs)/100 patient-years of exposure (PYE) were calculated for treatment-emergent adverse events (TEAEs). Post hoc analyses assessed patients aged <65 and ≥65 years. RESULTS: Patients (N=3691) received filgotinib for a median (maximum) of 3.8 (8.3) years (12 541 PYE). Rates of TEAEs of interest: serious infections, malignancies, major adverse cardiovascular events (MACE) and venous thromboembolism were stable over time and comparable between doses. In the overall population, numerically lower EAIR (95% CI)/100 PYE of herpes zoster was observed for filgotinib 100 mg versus 200 mg (1.1 (0.8 to 1.5) vs 1.5 (1.2 to 1.8)). Incidence of serious infections, herpes zoster, MACE, malignancies and all-cause mortality was higher in patients aged ≥65 versus <65 years. In patients aged ≥65 years, EAIRs (95% CI)/100 PYE for non-melanoma skin cancer (NMSC) (0.4 (0.1 to 1.1) vs 1.4 (0.8 to 2.2)), malignancies excluding NMSC (1.0 (0.5 to 1.9) vs 2.0 (1.3 to 2.9)) and all-cause mortality (1.3 (0.7 to 2.2) vs 1.6 (1.0 to 2.5)) were numerically lower for filgotinib 100 mg versus 200 mg. CONCLUSIONS: In the overall population, TEAEs of interest were stable over time and similar between filgotinib 100 mg and 200 mg dose groups, except for herpes zoster. A dose-dependent relationship between malignancies and all-cause mortality was suggested in patients ≥65 years old.

Effect of Filgotinib on Body Mass Index (BMI) and Effect of Baseline BMI on the Efficacy and Safety of Filgotinib in Rheumatoid Arthritis.

INTRODUCTION: This post hoc analysis of the phase 3 rheumatoid arthritis (RA) filgotinib clinical trial program assessed the effect of filgotinib on body mass index (BMI) in patients with RA and the impact of BMI on the efficacy and safety of filgotinib. METHODS: FINCH 1-3 were randomized, double-blind, active- or placebo-controlled phase 3 trials of filgotinib 100 and 200 mg in patients with RA (N = 3452). BMI assessments included the mean change from baseline in BMI and the proportion of patients whose BMI increased by incremental thresholds. Efficacy measures included American College of Rheumatology (ACR) 20/50/70 response and low disease activity/remission according to Disease Activity Score 28 using C-reactive protein. The exposure-adjusted incident rate (EAIR) of adverse events (AEs) was assessed by baseline BMI, using integrated data from the FINCH 1-4 and the phase 2 DARWIN 1-3 studies (total filgotinib exposure = 8085 patient-years). RESULTS: Mean change from baseline in BMI over time was similar across treatment arms. In most patients, BMI increased by ≤ 1 or 2 kg/m2 at both weeks 12 and 24, regardless of treatment group or baseline BMI; few patients had increases of ≥ 4 kg/m2. For most efficacy measures, filgotinib 200 mg was more efficacious than filgotinib 100 mg or active comparators or placebo across BMI subgroups. For the higher filgotinib dose, the EAIR of serious treatment-emergent AEs, venous thrombotic and embolic events, and major adverse cardiovascular events increased with increasing BMI. CONCLUSIONS: Filgotinib did not lead to substantial changes in BMI, and BMI did not appear to affect the efficacy of filgotinib. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02889796, NCT02873936, NCT02886728, NCT03025308, NCT01888874, NCT01894516, NCT02065700.

Some rheumatoid arthritis treatments cause patients to gain weight or are less effective in patients with obesity than in patients without obesity. Also, obesity can make rheumatoid arthritis worse. Filgotinib is a rheumatoid arthritis treatment that was evaluated in seven randomized clinical studies (FINCH 1­4 and DARWIN 1­3). We investigated whether filgotinib causes changes in weight and whether body mass index (BMI) affects the efficacy or safety of filgotinib. We analyzed how the BMI of patients who participated in FINCH 1, 2, or 3 changed over time. Most patients had a small increase in BMI (around 1­2 kg/m²) after 24 weeks of filgotinib treatment. This change in BMI was not affected by patients' BMI at baseline. Baseline BMI did not impact the efficacy of filgotinib, which was assessed using standard measures of disease activity. Filgotinib was more effective than other rheumatoid arthritis treatments and placebo in all patients, regardless of BMI subgroup. Using safety data from all seven clinical studies (FINCH 1­4 and DARWIN 1­3), we found that some adverse events occurred more often in patients with obesity (a BMI of ≥ 30 kg/m²) than in those without obesity. The increased adverse events included venous thrombotic and embolic events and major adverse cardiovascular events, for which obesity is a known risk factor. These results show that filgotinib did not substantially change BMI (which increased by around 1­2 kg/m² in most patients), and that baseline BMI did not affect the efficacy of filgotinib.

Prevention of Radiographic Progression in Higher-Risk Patients with Rheumatoid Arthritis Using Filgotinib in Phase III Studies: Narrative Review of Post Hoc Analyses.

Filgotinib is an oral preferential Janus kinase 1 inhibitor that demonstrated significant reductions in radiographic progression, with an acceptable tolerability and safety profile, vs placebo in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX-IR; FINCH 1) and vs MTX in MTX-naïve patients with RA (FINCH 3). International treatment guidelines identify multiple poor prognostic factors (PPFs) associated with worse disease outcomes among patients with RA. However, questions remain both about the clinical utility of considering PPFs and about which PPFs should drive treatment decisions. Additionally, the role of radiographic findings in clinical practice continues to be discussed and to evolve. This review examines radiographic results from post hoc analyses of phase 3 trials of filgotinib that examined subgroups with 4 PPFs or with baseline estimated rapid radiographic progression (e-RRP). In MTX groups, there were trends toward greater progression among patients with 4 PPFs or e-RRP, suggesting these subgroups may comprise a higher-risk population. Results show general consistency for the efficacy of filgotinib 200 mg plus MTX vs placebo plus MTX/MTX monotherapy on radiographic assessments, including change from baseline in modified total Sharp score and proportions without radiographic progression, even among MTX-IR or MTX-naïve patients with 4 PPFs or e-RRP who may be at higher risk of bone damage. Multivariate analysis identified multiple factors associated with baseline e-RRP status. This summary of the current understanding of benefits associated with filgotinib on radiographic progression and the relevance of baseline factors to these benefits may help inform treatment decisions for patients facing high risk of radiographic progression.

Effects of filgotinib on semen parameters and sex hormones in male patients with inflammatory diseases: results from the phase 2, randomised, double-blind, placebo-controlled MANTA and MANTA-RAy studies.

OBJECTIVES: The phase 2 MANTA and MANTA-RAy studies aimed to determine if the oral Janus kinase 1 preferential inhibitor filgotinib affects semen parameters and sex hormones in men with inflammatory diseases. METHODS: MANTA (NCT03201445) and MANTA-RAy (NCT03926195) included men (21-65 years) with active inflammatory bowel disease (IBD) and rheumatic diseases (rheumatoid arthritis, spondyloarthritis or psoriatic arthritis), respectively. Eligible participants had semen parameters in the normal range per the WHO definition. In each study, participants were randomised 1:1 to receive once-daily, double-blind filgotinib 200 mg or placebo for 13 weeks for pooled analysis of the primary endpoint (proportion of participants with a ≥50% decrease from baseline in sperm concentration at week 13). Participants who met the primary endpoint were monitored over an additional 52 weeks for 'reversibility'. Secondary endpoints included change from baseline to week 13 in: sperm concentration, total motility, normal morphology, total count and ejaculate volume. Sex hormones (luteinising hormone, follicle stimulating hormone, inhibin B and total testosterone) and reversibility were exploratory endpoints. RESULTS: Across both studies, 631 patients were screened, and 248 were randomised to filgotinib 200 mg or placebo. Baseline demographics and characteristics were similar within indications between treatment groups. Numerically similar proportions of filgotinib-treated versus placebo-treated patients met the primary endpoint (8/120 (6.7%) vs 10/120 (8.3%)), Δ-1.7% (95% CI -9.3% to 5.8%)). There were no clinically relevant changes from baseline to week 13 in semen parameters or sex hormones, or patterns of reversibility between treatment groups. Filgotinib was well tolerated, with no new safety events. CONCLUSIONS: Results suggest that once daily filgotinib 200 mg for 13 weeks has no measurable impact on semen parameters or sex hormones in men with active IBD or inflammatory rheumatic diseases.

Antibiotic resistance profiling and valorization of food waste streams to starter culture biomass and exopolysaccharides through fed-batch fermentations.

The present study evaluated antibiotic resistance (ABR) in bacteria isolated from different food wastes viz., meat slaughterhouses, dairy and restaurants. About 120 strains isolated from the food waste were subjected to ABR screening. More than 50% of all the strains were resistant to Vancomycin, Neomycin and Methicilin, which belong to third-generation antibiotics. Two lactic acid bacteria (LAB) free of ABR were chosen to be used as starter cultures in media formulated from food waste. Food waste combination (FWC-4) was found to be on par with the nutrient broth in biomass production. The non-ABR LAB strains showed excellent probiotic properties, and in the fed-batch fermentation process, adding a nitrogen source (soya protein) enhanced the microbial biomass (3.7 g/l). Additionally, exopolysaccharide production was found to be 2.3 g/l. This study highlights the ABR incidence in food waste medium and its economic advantage for starter culture biomass production. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-022-01222-9.

Benefit of Filgotinib, a JAK1 Preferential Inhibitor, in Rheumatoid Arthritis Patients with Previous Rapid Radiographic Progression: Post Hoc Analysis of Two Trials.

INTRODUCTION: We conducted a post hoc analysis of efficacy and safety of filgotinib stratified by estimated radiographic progression rate before baseline (BL) in patients with rheumatoid arthritis (RA) who had inadequate response to methotrexate (MTX; FINCH 1; NCT02889796) or were naïve to it (FINCH 3; NCT02886728). METHODS: Radiographic progression rate was BL-Modified Total Sharp Score (mTSS) divided by RA duration (BL mTSS/year); estimated rapid radiographic progression (e-RRP) was BL change in mTSS/year ≥ 5; and estimated nonrapid radiographic progression (e-NRRP) was BL mTSS/year < 5. Efficacy and safety were compared between subgroups. All p-values are nominal. RESULTS: In FINCH 1 and FINCH 3, 558/1755 (31.8%) and 787/1249 (63.0%) patients, respectively, had BL e-RRP. BL characteristics were generally similar between subgroups within each trial. At week (W) 24, in FINCH 1, proportions achieving a Disease Activity Score 28 for rheumatoid arthritis with C-reactive protein < 2.6 were significantly greater with filgotinib 200 (FIL200) and 100 mg (FIL100) versus placebo among e-RRP and e-NRRP subgroups. In each study, proportions of FIL-treated patients achieving Clinical Disease Activity Index ≤ 2.8 and Simple Disease Activity Index ≤ 3.3 were similar between subgroups. In FINCH 3, disease activity measures were at least numerically improved among patients receiving FIL versus MTX monotherapy. At W24, mTSS changes from BL (CFB) were greater among patients with e-RRP in FINCH 1 and FINCH 3 versus e-NRRP (0.81 versus 0.19, p = 0.001; 0.67 versus 0.25, p = 0.31, respectively). At W52, in FINCH 1, mTSS CFBs were smaller among e-RRP patients treated with FIL200 (0.40; p < 0.001) and FIL100 (0.77; p = 0.024) versus adalimumab (ADA; 1.46). In FINCH 3 at W52, mTSS CFBs were significantly smaller with FIL200 versus MTX among e-RRP patients. Rates of treatment-emergent adverse events (AEs) were comparable between subgroups and across treatment arms. CONCLUSIONS: Patients with previous e-RRP who received standard care tended to progress radiographically. FIL200 demonstrated persistent, consistent benefit for disease activity control among e-RRP and e-NRRP subgroups, and AE profiles were similar between subgroups. Although filgotinib efficacy was somewhat reduced among patients with e-RRP, filgotinib treatment slowed radiographic progression in both subgroups. TRIAL REGISTRATION: Clinicaltrials.gov NCT02889796, NCT02886728.

Miniaturized head-mounted microscope for whole-cortex mesoscale imaging in freely behaving mice.

The advent of genetically encoded calcium indicators, along with surgical preparations such as thinned skulls or refractive-index-matched skulls, has enabled mesoscale cortical activity imaging in head-fixed mice. However, neural activity during unrestrained behavior substantially differs from neural activity in head-fixed animals. For whole-cortex imaging in freely behaving mice, we present the 'mini-mScope', a widefield, miniaturized, head-mounted fluorescence microscope that is compatible with transparent polymer skull preparations. With a field of view of 8 × 10 mm2 and weighing less than 4 g, the mini-mScope can image most of the mouse dorsal cortex with resolutions ranging from 39 to 56 µm. We used the mini-mScope to record mesoscale calcium activity across the dorsal cortex during sensory-evoked stimuli, open field behaviors, social interactions and transitions from wakefulness to sleep.

Identification of transforming growth factor-beta-regulated microRNAs and the microRNA-targetomes in primary lung fibroblasts.

BACKGROUND: Lung fibroblasts are involved in extracellular matrix homeostasis, which is mainly regulated by transforming growth factor-beta (TGF-ß), and are therefore crucial in lung tissue repair and remodeling. Abnormal repair and remodeling has been observed in lung diseases like COPD. As miRNA levels can be influenced by TGF-ß, we hypothesized that TGF-ß influences miRNA expression in lung fibroblasts, thereby affecting their function. MATERIALS AND METHODS: We investigated TGF-ß1-induced miRNA expression changes in 9 control primary parenchymal lung fibroblasts using miRNA arrays. TGF-ß1-induced miRNA expression changes were validated and replicated in an independent set of lung fibroblasts composted of 10 controls and 15 COPD patients using qRT-PCR. Ago2-immunoprecipitation followed by mRNA expression profiling was used to identify the miRNA-targetomes of unstimulated and TGF-ß1-stimulated primary lung fibroblasts (n = 2). The genes affected by TGF-ß1-modulated miRNAs were identified by comparing the miRNA targetomes of unstimulated and TGF-ß1-stimulated fibroblasts. RESULTS: Twenty-nine miRNAs were significantly differentially expressed after TGF-ß1 stimulation (FDR<0.05). The TGF-ß1-induced miR-455-3p and miR-21-3p expression changes were validated and replicated, with in addition, lower miR-455-3p levels in COPD (p<0.05). We identified 964 and 945 genes in the miRNA-targetomes of unstimulated and TGF-ß1-stimulated lung fibroblasts, respectively. The TGF-ß and Wnt pathways were significantly enriched among the Ago2-IP enriched and predicted targets of miR-455-3p and miR-21-3p. The miR-455-3p target genes HN1, NGF, STRADB, DLD and ANO3 and the miR-21-3p target genes HHEX, CHORDC1 and ZBTB49 were consistently more enriched after TGF-ß1 stimulation. CONCLUSION: Two miRNAs, miR-455-3p and miR-21-3p, were induced by TGF-ß1 in lung fibroblasts. The significant Ago2-IP enrichment of targets of these miRNAs related to the TGF-ß and/or Wnt pathways (NGF, DLD, HHEX) in TGF-ß1-stimulated fibroblasts suggest a role for these miRNAs in lung diseases by affecting lung fibroblast function.

Theoretical analysis of noncanonical base pairing interactions in RNA molecules.

Noncanonical base pairs in RNA have strong structural and functional implications but are currently not considered for secondary structure predictions. We present results of comparative ab initio studies of stabilities and interaction energies for the three standard and 24 selected unusual RNA base pairs reported in the literature. Hydrogen added models of isolated base pairs, with heavy atoms frozen in their 'away from equilibrium' geometries, built from coordinates extracted from NDB, were geometry optimized using HF/6-31G** basis set, both before and after unfreezing the heavy atoms. Interaction energies, including BSSE and deformation energy corrections, were calculated, compared with respective single point MP2 energies, and correlated with occurrence frequencies and with types and geometries of hydrogen bonding interactions. Systems having two or more N-H...O/N hydrogen bonds had reasonable interaction energies which correlated well with respective occurrence frequencies and highlighted the possibility of some of them playing important roles in improved secondary structure prediction methods. Several of the remaining base pairs with one N-H...O/N and/or one C-H...O/N interactions respectively, had poor interaction energies and negligible occurrences. High geometry variations on optimization of some of these were suggestive of their conformational switch like characteristics.

Randomized comparison of Vasoseal and Angioseal closure devices in patients undergoing coronary angiography and angioplasty.

AngioSeal (AS) and VasoSeal (VS) are collagen-based arterial closure devices utilized to achieve earlier hemostasis and ambulation in diagnostic and interventional percutaneous procedures. To our knowledge, there has been no randomized studies comparing these two devices as approved for use in the United States. One hundred fifty-seven patients were randomized to receive either the 8 Fr AS (n = 79) or VS (n = 78) closure device. Data on 95 patients who had coronary angiography (49 AS, 46 VS) and 55 patients who underwent angioplasty (28 AS, 27 VS) were completed. Heparin was not administered during the coronary angiogram procedure. The activated clotting time was kept at approximately 300 sec during angioplasty. Patients on coumadin or GP IIb/IIIa platelet inhibitors were not included in this study. The time unit interval to achieve hemostasis in this study was based on the time the AS tension spring was left over the common femoral artery following collagen deployment as per the manufacturer's instructions (20 min). Time to hemostasis, time to ambulation, and major and minor complications were prospectively recorded. Two-tailed t-test and chi-square analysis were performed on continuous and dichotomous variables, respectively. For the angiogram-only subgroup, time (min) to hemostasis (20.51 +/- 4.36 vs. 18.59 +/- 11.77; P = 0.30) and ambulation (145.71 +/- 124 vs. 109.89 +/- 60.37; P = 0.075) were not statistically different for the AS and VS, respectively. Similarly, for the angioplasty subgroup, time (min) to hemostasis (24.23 +/- 12.70 vs. 19.57 +/- 2.27; P = 0.077) and ambulation (607.32 +/- 344.22 vs. 486.48 +/- 200.37; P = 0.12) were not statistically different for both AS and VS, respectively. Furthermore, there were no statistical differences in deployment failure, major, minor, or total complication rates between the two devices. In the absence of GP IIb/IIIa inhibitors, VS and the 8 Fr AS devices have statistically similar time to hemostasis and ambulation as well as device failures and complication rates following coronary angiography and angioplasty.