ACR Congress Review 2019

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corticosteroids, and different classes of DMARDs on filgotinib efficacy as measured by ACR20 and DAS28(CRP). Of the 448 patients randomised and treated at baseline, 80.4% were female with a mean age of 56 years and a mean RA duration of 12.4 years. Benefits were observed for filgotinib across subgroups. Notably, there was an absence of impact of disease duration, seropositivity, disease activity and concurrent medication use, on the effectiveness of filgotinib [504]. Genovese et al. evaluated the efficacy of filgotinib in FINCH2 based on number and mechanism of action (MOA) of prior biologics. Prior bDMARD exposure, including the total number and MOA, was well balanced amongst the 3 treatment arms. Compared with placebo, filgotinib demonstrated improved clinical outcomes in bDMARD refractory patients. The efficacy observed with filgotinib was maintained with no significant effects based on the number and MOA of prior bDMARD use, including in patients with prior exposure to IL-6 inhibitors [517]. A third analysis of FINCH2, which investigated the extent of anaemia, thrombocytopenia and leukopenia, was also presented by Genovese and colleagues. Overall, haemoglobin levels, platelet, lymphocyte and neutrophil counts remained consistent throughout the study. At baseline, 28.8%, 0.9%, 2.2% and 5.8% patients had mild-moderate low levels of haemoglobin, platelet, neutrophil and lymphocyte, respectively, and 1.1% had severely low levels of lymphocytes. Of the patients with mild-moderate haemoglobin levels at baseline, 13.1% with filgotinib 200 mg, 9.5% with filgotinib 100 mg, and 7.6% with placebo achieved normal haemoglobin at Week 24. All patients with baseline mild-moderate low platelets and neutrophils had normal levels at Week 24, except for one patient with mild neutropenia receiving filgotinib 100 mg. Of the patients with normal platelet and neutrophil levels at baseline, >94% maintained normal levels at Week 24 in all treatment groups. The authors summarised that most patients with normal haemoglobin, platelet, lymphocyte and neutrophil levels at baseline maintained them over 24 weeks of filgotinib treatment. Overall, the results suggest that filgotinib does not increase the incidence of anaemia, thrombocytopenia or leukopenia in patients who entered the study with active RA despite prior biologic therapies [2875]. Modulation of disease-associated cytokines with filgotinib Taylor and colleagues presented three analyses of disease-associated cytokines in the FINCH2 study. Cytokine profiles were compared with those of 50 demographically matched healthy volunteers in a transcriptomic and proteomic study of serum samples from 449 patients. Among 28 cytokines evaluated in baseline RA serum, 18 were significantly different from healthy volunteers. Of these, CXCL13, CCL2, CCL3, CCL4, IL-18 and osteocalcin reversed toward healthy volunteer phenotype after filgotinib treatment, whereas only IL-18 reached healthy volunteer levels in placebo-treated patients. The baseline transcriptional profile of RA patients was enriched with pathways implicated in RA pathology, including inflammatory responses and IFN, IL-6, TNFα signalling. Reversal of transcriptional profiles was broadly dose- and time-dependent, with fewer genes differentially expressed from healthy volunteers after 12 weeks of filgotinib versus placebo. In summary, differences in the peripheral molecular profile were observed between bDMARD-experienced RA patients and healthy volunteers. While an overall trend toward the non-diseased molecular profile was observed following filgotinib, only a subset of cytokines and pathways were statistically indistinguishable from healthy volunteers after 12 weeks [45]. Data from a longitudinal study of cytokines in blood and urine samples from FINCH2 RA patients were also presented. Comparing filgotinib 100 mg to placebo, high baseline serum levels of CCL3, CXCL10, IL-5, IL-6, IL-18, MMP3, SAA and VCAM1 were individually associated with improved ACR response or reduction in RA activity (DAS28-CRP) at Week 12. High baseline serum CRP, CXCL13 and VEGFA levels were also associated with improved response to filgotinib 200 mg. In placebo-treated patients, a low sICAM1/CXCL13 ratio led to a lower ACR50 response rate than those with a high ratio. In contrast, in filgotinib-treated patients, a low sICAM1/CXCL13 ratio led to an improved ACR50 response. *Chairman’s Pick
In summary, individually, high baseline levels of key inflammatory serum cytokines, as well as the presence of a low sICAM1/CXCL13 ratio, were each indicative of positive outcomes in bDMARD-IR RA patients treated with filgotinib [46*]. Finally, Taylor and colleagues presented results of an RNA sequencing study that examined the value of baseline gene expression for predicting therapeutic response to filgotinib in patients from FINCH2. Baseline Rodriguez-Carrio IFN signature score showed no significant association with Week 12 clinical response (P>0.05 for all comparisons). In contrast, the baseline FINCH2-derived composite IFN-based signature was significantly associated with an increase of DAS28-CRP after 12 weeks (P=0.0026), independent of treatment. The composite IFN-based signature score was significantly associated with a filgotinib-specific improvement in DAS28-CRP (100 mg, P=0.0045; 200 mg, P=0.0005) and ACR-N responses (100 mg, P=0.036) after 12 weeks. The authors concluded that IFN signalling alone is not sufficient to predict response to MTX in a bDMARD experienced population. However, an expanded FINCH2-derived composite IFN signature demonstrated a treatment-specific significant association at Week 12 [2012]. Effect of filgotinib on cholesteryl ester transfer protein levels in RA patients Di Paolo and colleagues presented findings on the in vitro profiles of JAKis as evaluated using human cell-based assays and pharmacokinetic-pharmacodynamic models. Filgotinib 100 and 200 mg resulted in lower calculated cellular inhibition than the other JAKis at clinical exposures. Notably, filgotinib 100 mg and 200 mg were calculated to reduce cholesteryl ester transfer protein (CETP) expression by 17.3% and 27.4%, respectively. Baricitinib, tofacitinib, and upadacitinib did not alter CETP levels. These results provide a potential mechanistic link to the observed reduction of CETP concentration and activity following filgotinib treatment, and the associated observed reduction in LDL:HDL in RA patients [59*]. Peficitinib Interim results of peficitinib a long-term open-label extension study Takeuchi and colleagues presented the interim results of a long-term open-label extension study of peficitinib (NCT01638013) conducted in Japan, Korea and Taiwan. Patients who had previously completed Phase 2b or Phase 3 studies (RAJ1/3/4) received oral peficitinib (50, 100 or 150 mg) once daily. Starting dose was 100 mg (RAJ3/4) or 50 mg (RAJ1). Doses could be increased to 150 mg/day or reduced (from 100 mg/day or 150 mg/day) to 50 mg/day according to clinical response and safety assessment, as judged by the investigator. A total of 843 patients received peficitinib (RAJ1, n=201; RAJ3, n=225; RAJ4, n=417) with a mean treatment exposure of 22.7 months. During long-term treatment, ACR20 responses were maintained from baseline for patients receiving maximum doses of 100/150 mg/day and were improved then maintained in patients receiving maximum doses of 50 mg/day. ACR components and DAS28-CRP also demonstrated continuous improvements from the baselines of preceding studies. TEAEs were reported in 89.8% of patients and were primarily grade 1/2 in severity; the most common were nasopharyngitis, RA and herpes zoster. Rates of AEs of special interest (serious infections, herpes zoster-related disease and malignancies) were greater for patients from RAJ3/4 than RAJ1. There was no evidence to support a trend towards increasing incidence rate/100 patient years with treatment duration. One death during and one death after the study were considered probably and possibly related to study drug, respectively. The authors concluded that no additional safety concerns were observed with longer term administration of peficitinib in RA patients, and efficacy was maintained for the study duration [508]. *Chairman’s Pick
Page 1 and 2: Enhancing knowledge of the clinical
Page 3: Highlights from ACR 2019 During the
Page 7 and 8: treatment with MTX. A total of 1629
Page 9 and 10: Individual and composite measures o
Page 11 and 12: Upadacitinib in axial spondylarthri
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-

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