ACR Congress Review 2019

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At 6 months post-switch, patients switched to adalimumab achieved 69%, 37%, 16% improvements in ACR20/50/70 responses, and 40% and 21% achieved DAS28-CRP≤3.2 and ≤2.6. Patients switched to upadacitinib achieved 81%, 56%, 32% improvements in ACR20/50/70, and 56% and 35% achieved DAS28-CRP≤3.2 and ≤2.6 at 6 months. Mean changes from the original baseline in HAQ-DI were -0.58 and -0.73 for patients switching to adalimumab and upadacitinib, respectively. The proportions of patients with infection and serious infection through 6 months post-switching appeared consistent with those observed for adalimumab and upadacitinib during comparable periods. The authors concluded that patients with initial non-response to either upadacitinib or adalimumab can benefit from switching to the other therapy [2907*]. Effects of upadacitinib on reverse cholesterol transport Charles-Schoeman and colleagues presented findings on the effect of upadacitinib treatment on cholesterol efflux capacity (CEC) and the association of CEC with changes in inflammation and serum lipids using data from a subset of patients in the BALANCE II and SELECT-NEXT studies. In both studies, changes in global and ABCA1-dependent CEC, and to a lesser extent non-ABCA1-dependent CEC, were significantly higher in the upadacitinib-treated group compared with the placebo group. Thus, upadacitinib treatment was associated with significant improvement in CEC. This effect was observed even among those demonstrating minimal clinical response (but not in those treated with placebo). The effect seemed to be primarily driven by ABCA1-dependent cholesterol efflux and is strongly correlated with a rise in HDL cholesterol as well as reduction in systemic inflammation as measured by change in CRP levels [510]. Normalisation of key pathobiological pathways in upadacitinib-treated patients A poster on the mode of action of upadacitinib in patients with RA was presented by Sornasse et al. The authors used a proteomic approach to evaluate a set of plasma proteins associated with inflammation in randomly selected plasma samples from patients in the SELECT-NEXT and SELECT-BEYOND studies (placebo, n=167; upadacitinib 15 mg QD, n=200). Consistent with its selectivity for JAK1, upadacitinib was found to operate via inhibition of multiple JAK1-dependent upstream pathways that result in the normalisation of key functional downstream effects associated with the pathobiology of RA, including T cell and myeloid cell-related pathways. It was also noted that non-JAK signalling pathways were also normalised, suggesting functional integration of JAK1 with parallel pathogenic signalling in RA effector cells [522*]. Upadacitinib MOA assessed by genome-wide RNA expression Lent and colleagues presented a poster on upadacitinib mechanism of action as assessed by genome-wide RNA expression. Whole blood samples were analysed from a subset of patients from the SELECT-NEXT study (upadacitinib 15 mg QD, n=99; placebo, n=100). Analysis of the top 100 most affected transcripts by upadacitinib at Week 2, Week 4, and Week 12 identified modest but highly significant modulation of a set of genes known to be differentially expressed in RA peripheral blood. mRNA associated with B and T lymphocytes were increased, while mRNA associated with neutrophils and monocytes were decreased, likely reflecting (at least in part) changes in leukocyte recirculation. Pathway analysis demonstrated a broad inhibitory effect by upadacitinib on cytokines associated with the pathobiology of RA, on intracellular signalling, and on toll-like receptor-pathways. Similarly, pathways related to both innate and adaptive immune activation, leukocyte movement, phagocytic cell activity, and leukocyte adhesion were predicted based on mRNA modulation, to be inhibited by upadacitinib. Reciprocally, pathways associated with the numbers of B, T, and haematopoietic cells were predicted to be activated by upadacitinib. In summary, upadacitinib normalizes key pathobiological pathways in RA consistent with its clinical effect [545*]. *Chairman’s Pick
Upadacitinib in axial spondylarthritis Ismail and colleagues presented a sub-analysis of the SELECT-AXIS I study to explore the relationship between upadacitinib exposures and several ankylosing spondylitis (AS) efficacy endpoints and safety parameters to support dose selection for future studies. Upadacitinib plasma exposures in patients with AS were also compared with those in RA. A total of 187 patients were included (upadacitinib 15 mg QD, n=93; placebo, n=94). Patients in the active treatment arm had statistically significant higher response rates for ASAS 40, ASAS 20, and ASAS PR compared to those in the placebo arm. However, within the single active treatment arm there were no clear exposure-response relationships between increasing upadacitinib average concentrations and the probability of achieving the evaluated efficacy outcomes, suggesting the achievement of a plateau in response. With increasing upadacitinib exposure, there was an increase in the percentage of subjects experiencing decreases of haemoglobin of ≥ 1 g/dL from baseline, and no upadacitinib exposure-dependent increases in percentage of subjects experiencing lymphopenia or infection were observed. Upadacitinib plasma concentrations and pharmacokinetic parameters (drug clearance and volume of distribution) in patients with AS were similar to those previously observed in subjects with RA in the SELECT-BEYOND and SELECT-NEXT studies. Overall, the results of this analysis support selection of the upadacitinib 15 mg QD dose for further evaluation in future AS/axial SpA studies [1492]. BTK inhibitors Fenebrutinib in RA – Phase 2 results Cohen and colleagues presented findings from a fenebrutinib Phase 2 study, which enrolled patients with moderate-to-severe active RA with an inadequate response to either MTX (Cohort 1) or TNF inhibitors (Cohort 2). Results were presented for cohort 2 TNF-IR patients, who were randomised to fenebrutinib 200 mg (n=48) or placebo (n=50); the majority of patients (98% and 90%, respectively) completed the 12-week study. ACR20/50/70 responses in were greater for fenebrutinib versus placebo (58/25/15% versus 24/12/4%) and generally increased over time, with a plateau of ACR50 after Week 8 for all patients. At Week 12, DAS28-CRP decreased by -1.43 and -2.26 from baseline in the placebo and fenebrutinib arms, respectively. More patients in the placebo arm (45%) than in the fenebrutinib arm (22%) reported at least one AE, and no serious AEs were reported. One case of herpes zoster and two grade 3 chemistry abnormalities (low phosphorous, high uric acid) were reported in the fenebrutinib arm. There were no clinically significant changes in haematology or immunoglobulin parameters. No Grade 4 or 5 abnormalities were reported. No deaths or malignancies were reported. In summary, fenebrutinib demonstrated higher efficacy rates across disease activity measures versus placebo at Week 12 in the TNF-IR population and the safety profile was acceptable [929*]. New agents PF-06650833 in RA: Phase 2b results Danto and colleagues presented Phase 2b study results for PF-06650833, a highly selective, small molecule, reversible IRAK4 inhibitor in development for RA treatment. Patients with moderately to severely active ACPA-positive RA and an inadequate response to methotrexate were randomised to 12 weeks’ dosing with PF-06650833 20 mg, 60 mg, 200 mg, 400 mg modified-release tablets QD, tofacitinib 5 mg BID, or placebo. Overall, 269 patients were randomised and treated (PF-06650833, n=187; tofacitinib, n=43; placebo, n=39). Mean change from baseline in Week 12 SDAI was significantly higher in the PF-06650833 arms versus placebo (P≤0.005) and in the 200 mg and 400 mg groups (sensitivity analysis; P
Page 1 and 2: Enhancing knowledge of the clinical
Page 3 and 4: Highlights from ACR 2019 During the
Page 5 and 6: In summary, individually, high base
Page 7 and 8: treatment with MTX. A total of 1629
Page 9: Individual and composite measures o
Page 13 and 14: Safety, efficacy and PROs with a to
Page 15 and 16: Impact of BMI on tofacitinib safety
Page 17 and 18: Patient-reported outcomes with JAK
Page 19 and 20: Update on JAK inhibitor safety data
Page 21 and 22: In the first presentation, the anal
Page 23 and 24: References Bergman M, Tanaka Y, Cit
Page 25 and 26: Kremer J, Van den Bosch F, Rubbert-

ACR Congress Review 2019

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