Objective Fenebrutinib (GDC‐0853) is a noncovalent, oral, and highly selective inhibitor of Bruton’s tyrosine kinase (BTK). The efficacy, safety, and pharmacodynamics of fenebrutinib in systemic lupus erythematosus (SLE) were assessed in this phase II, multicenter, randomized, placebo‐controlled study. Methods Patients who had moderately to severely active SLE while receiving background standard therapy were randomized to receive placebo, fenebrutinib 150 mg once daily, or fenebrutinib 200 mg twice daily. Glucocorticoid taper was recommended from weeks 0 to 12 and from weeks 24 to 36. The primary end point was the SLE Responder Index 4 (SRI‐4) response at week 48. Results Patients (n = 260) were enrolled from 44 sites in 12 countries, with the majority from Latin America, the US, and Western Europe. The SRI‐4 response rates at week 48 were 51% for fenebrutinib 150 mg once daily (P = 0.37 versus placebo), 52% for fenebrutinib 200 mg twice daily (P = 0.34 versus placebo), and 44% for placebo. British Isles Lupus Assessment Group–based Combined Lupus Assessment response rates at week 48 were 53% for fenebrutinib 150 mg once daily (P = 0.086 versus placebo), 42% for fenebrutinib 200 mg twice daily (P = 0.879 versus placebo), and 41% for placebo. Safety results were similar across all arms, although serious adverse events were more frequent with fenebrutinib 200 mg twice daily. By week 48, patients treated with fenebrutinib had reduced levels of a BTK‐dependent plasmablast RNA signature, anti–double‐stranded DNA autoantibodies, total IgG, and IgM, as well as increased complement C4 levels, all relative to placebo. Conclusion While fenebrutinib had an acceptable safety profile, the primary end point, SRI‐4 response, was not met despite evidence of strong pathway inhibition.
Background:Fenebrutinib (GDC-0853, FEN) is an oral, non-covalent, and selective inhibitor of Bruton’s tyrosine kinase (BTK) in clinical development for autoimmune diseases.Objectives:This was a randomized, placebo-controlled, multi-center study to evaluate the efficacy, safety, and pharmacodynamic effects of FEN in patients with moderate-to-severe systemic lupus erythematosus (SLE) activity.Methods:Patients who met SLICC or revised ACR SLE criteria, had ≥1 serologic marker of SLE, SLEDAI ≥8, and were on ≥1 standard of care (SOC) therapy were included; patients with renal or CNS involvement, or exposure to B cell depleting or calcineurin inhibitor therapy were excluded. Patients were randomized to placebo (PBO), FEN 150 mg QD, or FEN 200 mg BID, for 48 weeks. A corticosteroid taper was recommended, with burst and taper permitted from Week 0 (W0) to W12 and W24 to W36. The primary endpoint was SRI-4 at W48. Post hoc subgroup analyses were conducted based on patient baseline disease characteristics.Results:This study enrolled 260 patients, with the majority recruited in Latin America, USA, and Western Europe. At W48, the SRI-4 response rates for FEN 150 mg QD and FEN 200 mg BID were 51% (95% CI: -8.5, 21.2; p value 0.37) and 52% (95% CI: -7.3, 22.4; p value 0.34), respectively, compared to 44% for PBO (Table 1). Post-hoc analysis showed larger responses in subgroups of patients with higher baseline disease activity (Table 1). Safety results were similar between FEN and PBO arms, although more serious adverse events were observed in the FEN 200 mg BID arm. Study discontinuations were balanced across the 3 arms (24-26%). FEN treatment significantly reduced levels of CD19+ B cells, anti-dsDNA autoantibodies, IgG, and a BTK-dependent RNA signature highly expressed in plasmablasts by W48 compared to PBO; C4 levels modestly improved with FEN vs. PBO (Table 2).Table 1.SRI-4 Response (%) at W48 in Primary Analysis and in Post-hoc Patient SubgroupsPBOFEN 150 mg QDFEN 200 mg BIDSRI-4 Response (%) at W4844n=8451n=8752n=88SRI-4 Response (%) in Baseline Subgroups At least 1 BILAG A48n=4254n=3959n=46 At least 1 BILAG A and SLEDAI increased DNA binding37n=1953n=1765n=26 SLEDAI arthritis with at least 4 swollen joints39n=5750n=5457n=54 SLEDAI arthritis with at least 4 tender joints39n=7153n=7059n=69 CLASI >=1021n=1436n=1131n=16Table 2.Key Biomarker ResultsPBOFEN 150 mg QDFEN 200 mg BIDMedian (%) Change from Baseline at W48 Plasmablast signature-19.7%n=52-54.3%*n=53-51.7%*n=57 CD19+B cells (cells/µl)-0.50n=38-57.0*n=49-57.5*n=48 Anti-dsDNA#(IU/ml)+6.9n=31-38.3*n=36-75.7*n=33 Total IgG (g/L)-0.20n=65-1.25*n=64-1.56*n=64 C3 (g/L)-0.02n=65+0.01n=67-0.01n=66 C4 (g/L)0.00n=65+0.02*n=67+0.01*n=66#Patients who were positive at baseline (>30 IU/mL)*Denotes significant vs. PBO; Kruskal-Wallis false-discovery rate controlled two sided (p-value ≤0.05)Conclusion:The primary endpoint of SRI-4 for FEN was not met despite evidence of strong BTK target and pathway inhibition. FEN had an acceptable safety profile. Several disease activity subgroups were suggestive of a greater treatment effect on SRI-4 compared to PBODisclosure of Interests:David Isenberg Consultant of: Study Investigator and Consultant to Genentech, Richard Furie Grant/research support from: AstraZeneca, Biogen, Consultant of: AstraZeneca, Biogen, Nicholas S. Jones Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Pascal Guibord Shareholder of: Roche, Employee of: Roche, Joshua Galanter Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Chin Lee Shareholder of: Genentech/Roche and Eli Lilly, Employee of: Genentech/Roche, Anna McGregor Employee of: Genentech/Roche, Balazs Toth Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Julie Rae Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Olivia Hwang Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Armend Lokku Shareholder of: Roche, Employee of: Roche, Pedro Miranda Consultant of: Study Investigator for Genentech, Viviane de Souza Consultant of: Study investigator for Genentech, Juan Jaller-Raad Consultant of: Study investigator for Genentech, Anna Maura Fernandes Consultant of: Study investigator for Genentech, Rodrigo Garcia Salinas Consultant of: Study investigator for Genentech, Leslie Chinn Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Michael J. Townsend Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Alyssa Morimoto Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Katie Tuckwell Shareholder of: Genentech/Roche, Employee of: Genentech/Roche
Background:Above 60 years, prevalence rates of neuropsychiatric disorders double with every 5.1 years of age (from 0.7% at 60-65 years to 23.6% for those aged 85 or older). As aged people are dramatically increasing in Portugal, a Country under a serious financial crisis, it is important to understand whether health services are being used appropriately.Objectives:to characterize the use of health services among the elderly, as part of the implementation of the 10/66-Dementia Research Group Population-based Research Protocol in Portugal.Methods:A cross-sectional survey was implemented of all residents aged 65 or more in a semi-rural area in Southern Portugal. Core evaluation included a cognitive module and the Geriatric Mental State-AGECAT (GDS). A structured questionnaire assessed the use of services, including health care providers (public, private), inpatient episodes, medication and costs.Results:703 participants were evaluated. Almost half of the participants (48,9%) were in contact with public primary care facilities, but only 22,5% had a contact with a hospital service. In both settings, nurses and other non-doctor professionals were rarely involved (6,4%) as principal care providers. 11,8% had at least one contact with a private doctor. Inpatient episodes in the last 3 months were very infrequent (3%). The National Health Service covered most costs.Conclusions:Previous research strongly suggests that health services are not provided equitably to people with mental disorders, namely the elderly. Reliable and cross-culturally comparable information about patterns of care may guide the implementation of adequate management in this area in Portugal.
Introduction:The healthcare needs of the elderly are seldom assessed in practice. Research in clinical populations with neuropsychiatric disorders generally unravels high levels of unmet needs. Although there are Portuguese studies in needs assessment, explorations of community or social services’ scenarios have been scarce.Objectives and aims:By gathering data from health and social services research, and from an epidemiological survey in the same region, we aimed to better characterize the unmet needs of Portuguese elderly.Methods:We report on studies with old age people in Seixal, near Lisbon: 1) the Camberwell Assessment of Need for the Elderly was used for auditing a non-profit organization, with day-centre and home support services (n=95), and in a survey of family carers of dementia outpatients (n=116); 2) the 10/66 DRG community prevalence study (n=670) used comprehensive assessments to provide psychiatric diagnoses, data on health and psychosocial needs, and the use of services.Results:In the social service audit, unmet needs were mainly related to food, company, physical health and daytime activities. Domiciliary care users had more unmet needs than day centre users (p<0.001). Informal caregivers of dementia patients reported information and psychological distress needs. Finally, these 10/66 DRG study partial results highlighted a high prevalence of depression (20.4%; 95%CI 17.4-23.7) and huge health services’ utilization needs.Conclusions:Systematic assessments of needs for care generally unravel high proportions of health and psychosocial problems lacking adequate interventions, in clinical and community populations. This may provide a more consistent basis for health services planning.
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