Background: Guselkumab, a fully human monoclonal antibody targeting the interleukin (IL)-23p19 subunit, is approved to treat adults with active psoriatic arthritis (PsA). In the Phase 3 DISCOVER-2... Show moreBackground: Guselkumab, a fully human monoclonal antibody targeting the interleukin (IL)-23p19 subunit, is approved to treat adults with active psoriatic arthritis (PsA). In the Phase 3 DISCOVER-2 trial of 739 bilogico-naive patients with active PsA, guselkumab 100 mg resulted in less radiographic progression, assessed via change from baseline in PsA-modified van der Heijde-Sharp (vdH-S) score, compared with placebo at week (W) 24 when given at W0, W4, and then every 4 weeks (Q4W) or Q8W. The least squares mean differences from placebo were-0.66 for guselkumab Q4W (p=0.011) and-0.43 for guselkumab Q8W (p=0.072). Reports suggest baseline C-reactive protein (CRP) and joint erosions are strongly prognostic of poor outcomes, especially radiographic progression, in PsA patients. We designed a trial (APEX) to further assess the effect of guselkumab on radiographic progression in patients with active PsA and risk factors for radiographic progression. Methods: Patients are eligible for APEX if they have had PsA for >= 6 months and active disease (> 3 swollen and >= 3 tender joints, CRP > 0.3 mg/dL) despite prior therapy with conventional synthetic disease-modifying antirheu-matic drugs, apremilast, and/or nonsteroidal anti-inflammatory drugs, with >= 2 joints with erosions on baseline radiographs (hands and feet). The primary and major secondary endpoints are the proportion of patients achieving >= 20% improvement in American College of Rheumatology response criteria (ACR20) response at W24 and change from baseline at W24 in PsA-modified vdH-S score, respectively. Sample sizes of 350/250/350 for guselkumab Q8W/ guselkumab Q4W/placebo are expected to provide > 99% power to detect significant differences in W24 ACR20 response rates for each guselkumab group vs placebo, as well as >= 90% (Q4W vs placebo) and >= 80% (Q8W vs placebo) power to detect a significant difference in PsA-modified vdH-S score change at W24. A Cochran-Mantel-Haen-szel test and analysis of covariance will compare treatment efficacy for the primary and major secondary endpoints, respectively. Discussion: DISCOVER-2 findings informed the design of APEX, a Phase 3b study intended to further evaluate the impact of guselkumab in patients with active PsA and known risk factors for radiographic progression. Show less
Ritchlin, C.T.; Coates, L.C.; Mease, P.J.; Heijde, D. van der; Song, J.; Jiang, Y.S.; ... ; Rahman, P. 2023
BackgroundGuselkumab, a fully human monoclonal antibody targeting the interleukin (IL)-23p19 subunit, is approved to treat adults with active psoriatic arthritis (PsA). In the Phase 3 DISCOVER-2... Show moreBackgroundGuselkumab, a fully human monoclonal antibody targeting the interleukin (IL)-23p19 subunit, is approved to treat adults with active psoriatic arthritis (PsA). In the Phase 3 DISCOVER-2 trial of 739 bilogico-naïve patients with active PsA, guselkumab 100 mg resulted in less radiographic progression, assessed via change from baseline in PsA-modified van der Heijde-Sharp (vdH-S) score, compared with placebo at week (W) 24 when given at W0, W4, and then every 4 weeks (Q4W) or Q8W. The least squares mean differences from placebo were -0.66 for guselkumab Q4W (p=0.011) and -0.43 for guselkumab Q8W (p=0.072). Reports suggest baseline C-reactive protein (CRP) and joint erosions are strongly prognostic of poor outcomes, especially radiographic progression, in PsA patients. We designed a trial (APEX) to further assess the effect of guselkumab on radiographic progression in patients with active PsA and risk factors for radiographic progression.MethodsPatients are eligible for APEX if they have had PsA for ≥6 months and active disease (≥3 swollen and ≥3 tender joints, CRP ≥0.3 mg/dL) despite prior therapy with conventional synthetic disease-modifying antirheumatic drugs, apremilast, and/or nonsteroidal anti-inflammatory drugs, with ≥2 joints with erosions on baseline radiographs (hands and feet). The primary and major secondary endpoints are the proportion of patients achieving ≥20% improvement in American College of Rheumatology response criteria (ACR20) response at W24 and change from baseline at W24 in PsA-modified vdH-S score, respectively. Sample sizes of 350/250/350 for guselkumab Q8W/guselkumab Q4W/placebo are expected to provide >99% power to detect significant differences in W24 ACR20 response rates for each guselkumab group vs placebo, as well as ≥90% (Q4W vs placebo) and ≥80% (Q8W vs placebo) power to detect a significant difference in PsA-modified vdH-S score change at W24. A Cochran-Mantel-Haenszel test and analysis of covariance will compare treatment efficacy for the primary and major secondary endpoints, respectively.DiscussionDISCOVER-2 findings informed the design of APEX, a Phase 3b study intended to further evaluate the impact of guselkumab in patients with active PsA and known risk factors for radiographic progression. Show less
Little experimental evidence of multiple generations of inbreeding depression is available for marine invertebrates. Here, we report that two generations of inbreeding significantly reduced larval... Show moreLittle experimental evidence of multiple generations of inbreeding depression is available for marine invertebrates. Here, we report that two generations of inbreeding significantly reduced larval growth and metamorphosis, but did not significantly impact fertilization and hatching in the sea urchin Strongylocentrotus intermedius. A higher inbreeding coefficient had significantly more negative impacts on some traits of S. intermedius larvae (for example, larval length) but not all. Maternal effects of inbreeding depression probably appear in the eight-arm stage and metamorphosis of S. intermedius. The present study provides convincing evidence of inbreeding depression on larval growth and metamorphosis in S. intermedius and highlights the importance of avoiding multiple generations of inbreeding in sea urchin aquaculture.statement of relevance:Multiple inbreeding dramatically impacts aquaculture of marine species. Here, we investigated effects of second generation of inbreeding on fertilization, hatching, larval growth and metamorphosis in sea urchins. The present study provides the convincing evidence on the inbreeding depression of larval growth and metamorphosis in sea urchins and highlights the importance of avoiding multiple generation of inbreeding in sea urchin aquaculture. Show less
Haan, T. de; Benson, B.; Bleem, L.; Allen, S.; Applegate, D.; Ashby, M.; ... ; Zenteno, A. 2016
