Continuous improvement through differential trajectories of individual minimal disease activity criteria with guselkumab in active psoriatic arthritis: post hoc analysis of a phase 3, randomized, double-blind, placebo-controlled study

Background To explore the trajectory of, and factors contributing to, achievement of individual criteria of minimal disease activity (MDA) in patients with active psoriatic arthritis (PsA) treated with guselkumab. Methods The Phase 3, randomized, placebo-controlled DISCOVER-2 study enrolled adults (N = 739) with active PsA despite standard therapies who were biologic/Janus kinase inhibitor-naive. Patients were randomized 1:1:1 to guselkumab 100 mg every 4 weeks; guselkumab 100 mg at week 0, week 4, then every 8 weeks; or placebo. In this post hoc analysis, patients randomized to guselkumab were included and pooled (N = 493). Longitudinal trajectories of achieving each MDA criterion through week 100 were derived using non-responder imputation. Time to achieve each criterion was estimated with Kaplan-Meier analysis. Multivariate regression for time to achieve each criterion (Cox regression) and achievement at week 100 (logistic regression) was used to identify contributing factors. Results Continuous improvement across all MDA domains was shown over time. ~70% of patients achieved near remission in swollen joint count (SJC), Psoriasis Area and Severity Index (PASI), and enthesitis through week 100. Median times to achieve individual criteria differed significantly (p Conclusions Substantial proportions of guselkumab-treated patients achieved individual MDA criteria, each showing continuous improvement through week 100, although with distinct trajectories. Median times to achieve physician-assessed MDA criteria were significantly faster compared with patient-driven criteria. Identification of modifiable factors affecting the time to achieve patient-reported criteria has the potential to optimize the achievement and sustainability of MDA in the clinic via a multidisciplinary approach to managing PsA, involving both medical and lifestyle interventions. Trial registration number NCT03158285. Trial registration date May 16, 2017

Generic orphan drug substitution: a critical analysis of global practices and Saudi Arabia’s perspective

In an era of cost pressure, substituting generic drugs represents one of the main cost-containment strategies of healthcare systems. Despite the obvious financial benefits, in a minority of cases, substitution may require caution or even be contraindicated. In most jurisdictions, to obtain approval, the bioequivalence of generic products with the brand-name equivalent needs to be shown via bioavailability studies in healthy subjects. Rare diseases, defined as medical conditions with a low prevalence, are a group of heterogenous diseases that are typically severe, disabling, progressive, degenerative, and life-threatening or chronically debilitating, and disproportionally affect the very young and elderly. Despite these unique features of rare diseases, generic bioequivalence studies are typically carried out with single doses and exclude children or the elderly. Furthermore, the excipients and manufacturing processes for generic/biosimilar products can differ from the brand products which may affect the shelf-life of the product, its appearance, smell, taste, bioavailability, safety and potency. This may result in approval of generics/biosimilars which are not bioequivalent/comparable in their target population or that meet bioequivalence but not therapeutic equivalence criteria. Another concern relates to the interchangeability of generics and biosimilars which cannot be guaranteed due to the phenomenon of biocreep. This review summarizes potential concerns with generic substitution of orphan drugs and discusses potentially problematic cases including narrow therapeutic index drugs or critical conditions where therapeutic failure could lead to serious complications or even death. Finally, we put forward the need for refining regulatory frameworks, with emphasis on Saudi Arabia, for generic substitution and recent efforts toward this direction

Guselkumab provides durable improvement across psoriatic arthritis disease domains: post hoc analysis of a phase 3, randomised, double-blind, placebo-controlled study

Objective Evaluate long-term guselkumab effectiveness across Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-recognised domains/related conditions of psoriatic arthritis (PsA). Methods Post hoc analyses used data from DISCOVER-2 (NCT03158285) biologic/Janus-kinase inhibitor-naïve participants with active PsA (≥5 swollen/≥5 tender joints, C-reactive protein ≥0.6 mg/dL), randomised (1:1:1) to guselkumab every 4 or 8 weeks (Q4W/Q8W) or placebo with crossover to guselkumab. Outcomes aligned with key GRAPPA-recognised domains of overall disease activity, peripheral arthritis, axial disease, enthesitis/dactylitis and skin psoriasis (nail psoriasis was not evaluated). PsA-related conditions (inflammatory bowel disease (IBD)/uveitis) were assessed via adverse events through W112. Least squares mean changes from baseline through W100 in continuous outcomes employed repeated measures mixed-effects models adjusting for baseline scores. Binary measure response rates were determined with non-responder imputation for missing data. Results 442/493 (90%) of guselkumab-randomised patients completed treatment through W100. Following early reductions in disease activity with guselkumab, durable improvements were observed across key PsA domains (swollen/tender joints, psoriasis, spinal pain, enthesitis/dactylitis) through W100. Response rates of therapeutically relevant targets generally increased through W100 with guselkumab Q4W/Q8W: Disease Activity Index for PsA low disease activity (LDA) 62%/59%, enthesitis resolution 61%/70%, dactylitis resolution 72%/83%, 100% improvement in Psoriasis Area and Severity Index 59%/53%, Psoriatic Arthritis Disease Activity Score LDA 51%/49% and minimal disease activity 38%/40%. Through W112, no cases of IBD developed among guselkumab-randomised patients and one case of uveitis was reported. Conclusion In biologic-naïve patients with active PsA, guselkumab provided early and durable improvements in key GRAPPA-recognised domains through 2 years, with substantial proportions achieving important treatment targets

Clinical Study A Randomized Trial Assessing the Effectiveness of Ezetimibe in South Asian Canadians with Coronary Artery Disease or Diabetes: The INFINITY Study

Background. There is a paucity of data regarding the effectiveness and safety of lipid-lowering treatments among South-Asian patients. Methods. Sixty-four South-Asian Canadians with coronary artery disease or diabetes and persistent hypercholesterolemia on statin therapy, were randomized to ezetimibe 10 mg/day co-administered with statin therapy (EZE + Statin) or doubling their current statin dose (STAT 2 ). Primary outcome was the proportion of patients achieving target LDL-C (<2.0 mmol/L) after 6 weeks. Secondary outcomes included the change in lipid profile and the incidence of treatment-emergent adverse events through 12 weeks. Exploratory markers for vascular inflammation were assessed at baseline and 12 weeks. Results. At 6 weeks, the primary outcome was significantly higher among the EZE + Statin patients (68% versus 36%; P = 0.031) with an OR (95% CI) of 3.97 (1.19, 13.18) upon accounting for baseline LDL-C and adjusting for age. At 12 weeks, 76% of EZE + Statin patients achieved target LDL-C compared to 48% (P = 0.047) of the STAT 2 patients (adjusted OR (95% CI) = 3.31 (1.01,10.89)). No significant between-group differences in exploratory markers were observed with the exception of CRP. Conclusions. Patients receiving ezetimibe and statin were more likely to achieve target LDL-C after 6 and 12 weeks compared to patients doubling their statin dose. Ezetimibe/statin combination therapy was well tolerated among this cohort of South-Asian Canadians, without safety concerns

Carga económica de la varicela en niños en Perú, entre 2011 y 2016

Objective: The purpose of this study was to evaluate the clinical and economic burden associated with varicella in Peru. Methods: This was a multicenter, retrospective chart review study of patients aged 1-14 years with a varicella diagnosis between 2011 and 2016. Healthcare resource utilization (HCRU) associated with varicella, unit costs, and work loss were used to estimate direct and indirect costs, presented in USD (). The cost and HCRU data was combined with estimates of varicella disease burden to estimate the overall annual costs of management of varicella in Peru. Results: A total of 179 children with varicella (101 outpatients, 78 inpatients) were included. Among outpatients, 5.9% experienced ≥1 complication, compared with 96.2% of inpatients. HCRU estimates included use of over-the-counter (OTC) medications (72.3% vs. 89.7% of outpatient and inpatients, respectively), prescription medications (30.7% vs. 94.9%), tests/procedures (0.0% vs. 80.8%). Among outpatients, direct and indirect costs per case were 36 and $62, respectively; among inpatients, respective costs were$548 and 222. The total annual cost associated with varicella was estimated at 13 907 146. Conclusion: Varicella is associated with substantial clinical complications and high HCRU in Peru, supporting the need for implementation of a routine childhood varicella vaccination plan.Objetivo: Describir las complicaciones mas frecuentes y la carga económica asociada con la varicela en el Perú. Material y métodos: Estudio multicéntrico de revisión de historias clínicas de pacientes de 1 a 14 años con diagnóstico de varicela entre 2011 y 2016. El uso de recursos de atención médica (URAM) asociados con la varicela, los costos unitarios y la pérdida de trabajo se utilizaron para estimar los costos directos e indirectos, presentados en USD (). Los datos de costos y URAM se combinaron con estimaciones de carga de enfermedad para calcular el costo total anual de la varicela en el Perú. Resultados: Se incluyeron un total de 179 niños con varicela (101  ambulatorios, 78  hospitalizados). Entre los pacientes ambulatorios, el 5,9 % presentó una o más complicaciones, en comparación con 96,2 % de pacientes hospitalizados. El URAM incluyó el uso de medicamentos de venta libre (72,3 % frente a 89,7 % de pacientes ambulatorios y hospitalizados, respectivamente), medicamentos con receta (30,7 % frente a 94,9 %) y análisis y procedimientos (0,0 % frente a 80,8 %). Los costos directos e indirectos por caso ambulatorio fueron 36 y $62 respectivamente y por caso hospitalizado fueron$548 y $222. El costo anual total asociado con la varicela se estimó en$13 907 146. Conclusión: La varicela está asociada con complicaciones clínicas importantes y elevado URAM en Perú, lo que respalda la necesidad de implementación de un plan de vacunación universal

Transient dsDNA breaks during pre-replication complex assembly

Initiation of DNA replication involves the ordered assembly of the multi-protein pre-replicative complex (pre-RC) during G1 phase. Previously, DNA topoisomerase II (topo II) was shown to associate with the DNA replication origin located in the lamin B2 gene locus in a cell-cycle-modulated manner. Here we report that activation of both the early-firing lamin B2 and the late-firing hOrs8 human replication origins involves DNA topo II-dependent, transient, site-specific dsDNA-break formation. Topo IIβ in complex with the DNA repair protein Ku associates in vivo and in vitro with the pre-RC region, introducing dsDNA breaks in a biphasic manner, during early and mid-G1 phase. Inhibition of topo II activity interferes with the pre-RC assembly resulting in prolonged G1 phase. The data mechanistically link DNA topo IIβ-dependent dsDNA breaks and the components of the DNA repair machinery with the initiation of DNA replication and suggest an important role for DNA topology in origin activation

Durable control of psoriatic arthritis with guselkumab across domains and patient characteristics: post hoc analysis of a phase 3 study

Objectives: Evaluate patterns of stringent disease control with 2 years of guselkumab across key disease-identified domains and patient-reported outcomes (PROs) in subgroups of patients with psoriatic arthritis (PsA) defined by baseline characteristics. Method: This post hoc analysis of DISCOVER-2 (Clinicaltrials.gov NCT03158285) evaluated biologic-naïve PsA patients (≥ 5 swollen/ ≥ 5 tender joints, C-reactive protein [CRP] ≥ 0.6 mg/dL) randomized to guselkumab every 4 weeks (Q4W); guselkumab at Weeks 0 and 4, then Q8W; or placebo with crossover to guselkumab Q4W at Week 24. Achievement of American College of Rheumatology 50/70% improvement (ACR50/70), Investigator’s Global Assessment (IGA) 0, dactylitis/enthesitis resolution, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue response (≥ 4-point improvement), HAQ-Disability Index (HAQ-DI) response (≥ 0.35-point improvement), PsA Disease Activity Score (PASDAS) low disease activity (LDA), and minimal disease activity (MDA) was assessed at Weeks 24, 52, and 100 in subgroups defined by sex and baseline medication use, body mass index, PsA duration, swollen/tender joints, CRP, and psoriasis severity/extent. Patients with missing categorical response data were considered nonresponders. Results: 442/493 (90%) guselkumab-randomized patients completed treatment through Week 100. Significant multi-domain efficacy of guselkumab versus placebo was shown across adequately sized patient subgroups. A pattern of continuous improvement was observed across key PsA domains and PROs within patient subgroups: 65%–85% of guselkumab-randomized patients had enthesitis/dactylitis resolution, 50%–70% achieved complete skin clearance, 60%–80% reported meaningful improvements in function/fatigue, 40%–65% achieved PASDAS LDA, and 35%–50% achieved MDA at Week 100. Conclusion: Patients with active PsA receiving guselkumab demonstrated durable achievement of stringent endpoints associated with disease control across key PsA domains and PROs, regardless of baseline characteristics. Key Points • Among biologic-naïve patients with highly active psoriatic arthritis (PsA), efficacy of guselkumab across stringent disease endpoints and patient-reported outcomes (PROs) at Week 24 was consistent regardless of baseline demographics and disease characteristics. • Within guselkumab-randomized PsA patient subgroups, major improvements in joint disease activity, complete skin clearance, dactylitis/enthesitis resolution, clinically meaningful improvements in PROs, and achievement of low overall disease activity were maintained through Week 100. • Durable stringent endpoint achievement indicating disease control was observed with guselkumab, regardless of baseline patient or disease characteristics. Graphical Abstract