Efficacy and safety of Sandoz biosimilar rituximab for active rheumatoid arthritis: 52-week results from the randomized controlled ASSIST-RA trial.

OBJECTIVES: This report provides data for the extent of B cell depletion and recovery, efficacy, safety and immunogenicity of Sandoz rituximab (SDZ-RTX; GP2013; Rixathon®) compared with reference rituximab (Ref-RTX) up to week 52 of the ASSIST-RA study. METHODS: Patients were randomized to SDZ-RTX or Ref-RTX in combination with methotrexate according to the RTX label. The primary endpoint was analysed at week 24. Responders (28-joint DAS [DAS28] decrease from baseline >1.2) at week 24 with residual disease activity (DAS28 ≥2.6) were eligible for a second treatment course between week 24 and 52. Endpoints after week 24 included change from baseline in peripheral B cells, DAS28, ACR 20% response rate (ACR20), Clinical and Simplified Disease Activity Indexes (CDAI, SDAI) and HAQ disability index (HAQ-DI). Safety and immunogenicity were assessed by the incidence of adverse events and antidrug antibodies. RESULTS: Primary and secondary endpoints up to week 24 were met. Overall, 260/312 randomized patients completed treatment up to week 52. SDZ-RTX resulted in B cell concentrations over time similar to Ref-RTX. The efficacy of SDZ-RTX was similar to Ref-RTX up to week 52, as measured by DAS28, ACR20/50/70, CDAI, SDAI and HAQ-DI. Safety of SDZ-RTX was similar to Ref-RTX regarding frequency, type and severity of adverse events, which were consistent with the known Ref-RTX safety profile. The incidence of antidrug antibodies was low and transient similarly across treatment groups. CONCLUSION: SDZ-RTX demonstrated similar B cell concentrations over time, efficacy, safety and immunogenicity to Ref-RTX over 52 weeks of the ASSIST-RA study.

A randomised, double-blind trial to demonstrate bioequivalence of GP2013 and reference rituximab combined with methotrexate in patients with active rheumatoid arthritis.

OBJECTIVES: The aim of this report is to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) equivalence as well as similar efficacy, safety and immunogenicity between GP2013, a biosimilar rituximab, and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate response or intolerance to tumour necrosis factor inhibitor (TNFi) treatment. METHODS: In this multinational, randomised, double-blind, parallel-group study, 312 patients with active disease despite prior TNFi therapy were randomised to receive GP2013 or either the EU (RTX-EU) or the US (RTX-US) reference product, along with methotrexate (MTX) and folic acid. The primary endpoint was the area under the serum concentration-time curve from study drug infusion to infinity (AUC0-inf). Additional PK and PD parameters, along with efficacy, immunogenicity and safety outcomes were also assessed up to week 24. RESULTS: The 90% CI of the geometric mean ratio of the AUCs were within the bioequivalence limits of 80% to 125% for all three comparisons; GP2013 versus RTX-EU: 1.106 (90% CI 1.010 to 1.210); GP2013 versus RTX-US: 1.012 (90% CI 0.925 to 1.108); and RTX-EU versus RTX-US: 1.093 (90% CI 0.989 to 1.208). Three-way PD equivalence of B cell depletion was also demonstrated. Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX. CONCLUSIONS: Three-way PK/PD equivalence of GP2013, RTX-EU and RTX-US was demonstrated. Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX. TRIAL REGISTRATION NUMBER: NCT01274182; Results.

Multilingual cross-cultural adaptation of the patient-rated wrist evaluation (PRWE) into Czech, French, Hungarian, Italian, Portuguese (Brazil), Russian and Ukrainian.

The use of patient-reported outcome questionnaires is recommended in studies of the orthopaedic field. Reliable, validated tools are necessary to ensure the comparability of results across different studies, centers, and countries. The patient-rated wrist evaluation (PRWE) is a widely accepted and commonly used outcome measure in the self-evaluation after distal radius fractures. The cross-cultural adaptation of PRWE was performed according to international guidelines, following prescribed six stages: translation, synthesis, back-translation, expert committee review, pre-testing, and submission of documentation. PRWE versions were achieved without any substantive difficulty in all seven languages. Cross-cultural adaptation aims "to attain semantic, idiomatic, experiential and conceptual equivalence between the source and target questionnaires". The present paper provides such adaptation of the PRWE in seven different languages, making this tool available for an additional nearly half a billion potential users.

First-in-Human Study of the Safety, Pharmacokinetics, and Pharmacodynamics of MHV370, a Dual Inhibitor of Toll-Like Receptors 7 and 8, in Healthy Adults.

BACKGROUND AND OBJECTIVE: MHV370, a dual antagonist of human Toll-like receptors (TLR) 7 and 8, suppresses cytokines and interferon-stimulated genes in vitro and in vivo, and  has demonstrated efficacy in murine models of lupus. This first-in-human study aimed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of MHV370 in healthy adults, as well as the effects of food consumption on a single dose of MHV370. METHODS: This was a phase 1, randomised, placebo-controlled study conducted in three parts. In part A, participants received (3:1) a single ascending dose (SAD) of 1, 3, 10, 20, 40, 80, 160, 320, 640 and 1000 mg MHV370 or placebo. In part B, participants received (3:1) multiple ascending doses (MAD) of 25, 50, 100, 200 and 400 mg MHV370 twice daily (b.i.d) or placebo for 14 days. In part C, participants received an open-label single dose of 200 mg MHV370 under fasted or fed conditions. Safety, pharmacokinetic and pharmacodynamic parameters were evaluated. RESULTS: MHV370 was well tolerated, and no safety signal was observed in the study. No dose-limiting adverse events occurred across the dose range evaluated. Plasma concentrations of MHV370 increased with dose (mean [SD] maximum plasma concentrations ranged from 0.97 [0.48] to 1670 [861.0] ng/mL for SAD of 3-1000 mg, 29.5 [7.98] to 759 [325.0] ng/mL for MAD of 25-400 mg b.i.d. on day 1). The intake of food did not have a relevant impact on the pharmacokinetics of MHV370. Pharmacodynamic data indicated time- and dose-dependent inhibition of TLR7-mediated CD69 expression on B cells (100% inhibition at 24 h post-dose starting from SAD 160 mg and MAD 50 mg b.i.d.) and TLR8-mediated TNF release after ex vivo stimulation (>90% inhibition at 24 h post-dose starting from SAD 320 mg and MAD 100 mg b.i.d.). CONCLUSION: The safety, pharmacokinetic and pharmacodynamic data support the further development of MHV370 in systemic autoimmune diseases driven by the overactivation of TLR7 and TLR8.

Preclinical characterization of the Toll-like receptor 7/8 antagonist MHV370 for lupus therapy.

Genetic and in vivo evidence suggests that aberrant recognition of RNA-containing autoantigens by Toll-like receptors (TLRs) 7 and 8 drives autoimmune diseases. Here we report on the preclinical characterization of MHV370, a selective oral TLR7/8 inhibitor. In vitro, MHV370 inhibits TLR7/8-dependent production of cytokines in human and mouse cells, notably interferon-α, a clinically validated driver of autoimmune diseases. Moreover, MHV370 abrogates B cell, plasmacytoid dendritic cell, monocyte, and neutrophil responses downstream of TLR7/8. In vivo, prophylactic or therapeutic administration of MHV370 blocks secretion of TLR7 responses, including cytokine secretion, B cell activation, and gene expression of, e.g., interferon-stimulated genes. In the NZB/W F1 mouse model of lupus, MHV370 halts disease. Unlike hydroxychloroquine, MHV370 potently blocks interferon responses triggered by specific immune complexes from systemic lupus erythematosus patient sera, suggesting differentiation from clinical standard of care. These data support advancement of MHV370 to an ongoing phase 2 clinical trial.

Parameters for defining efficacy in fracture healing.

Complications of the bone-healing process, especially in elderly, osteoporotic patients, are cause of important medical and economical burden. At the same time, there is no clinical study today to have shown the efficacy of a pharmacological treatment to enhance fracture repair. The author analyzes the potential criteria that could be used for the evaluation of treatment efficacy to enhance fracture healing in the frame of a clinical study.

Structural changes in the lengthened rabbit muscle.

This study evaluated the histological changes in muscle tissue after limb lengthening in skeletally mature and immature rabbits and assessed the most vulnerable level of striated muscle. Twenty-three male domestic white rabbits, divided into six groups, were operated on and different lengthening protocols were used in the mature and immature rabbits. The histopathological changes were analysed by a semi-quantitative method according to the scoring system of Lee et al. (Acta Orthop Scand 64(6):688-692, 1993). After the evaluation of the five main degenerative parameters (muscle atrophy, muscle nuclei internalisation, degeneration of the muscle fibre, perimysial and endomysial fibrosis, haematomas), it is evident that the adults lengthened at a rate of 1.6 mm/day showed more degenerative changes than those lengthened at 0.8 mm/day. The adult 1.6 mm/day lengthened group presented significantly higher damage in the muscle and lower regenerative signs compared with the young 1.6 mm/day lengthened group, according to the summarised degenerative scores.

Osteochondritis (Calvé's disease) of a vertebral body--a rare form of vertebra plana.

In 1925, Calvé described vertebra plana as an aseptic necrosis of bone involving a single vertebral body of the spinal column. This theory was set aside in 1954 by Compere, who concluded that vertebra plana is caused by eosinophilic granuloma and not by osteochondritis as suggested by Calvé. It has been well documented in literature that many factors other than eosinophilic granuloma can cause vertebra plana-like destruction of the vertebral body. However, the definition of the terms was not clear, and there was no consensus on whether to call these cases vertebra plana or not. Some authors did, some did not. Anyhow, no publication so far has reported on osteochondritis as a rare cause of vertebra plana. The case of a 12-year-old girl, presented here by the authors, suggests this explanation. Some important conclusions can be drawn from this regarding the nomenclature, the diagnosis, and the therapy.

The incidence of avascular necrosis of the healthy, contralateral femoral head at the end of the use of Pavlik harness in unilateral hip dysplasia.

We examined the incidence of avascular necrosis (AVN) of the healthy femoral head in unilateral hip dysplasia at the end of the use of the Pavlik harness. The evaluation of AVN was done with the help of standardised roentgenograms. Between 1974 and 1982, 1,064 dysplastic hips (869 children) were treated with the Pavlik harness at the Orthopaedic Department of Semmelweis University. Of these, 674 children who had unilateral hip dysplasia were chosen for this study. In the period of our investigation, ultrasonography was not yet used routinely, so in some cases the hip was mistakenly diagnosed as dysplastic. The average patient age was 3.2 months, and the average length of treatment was 4.9 months. We found no correlation between the appearance of AVN in the healthy hips at the end of treatment with the Pavlik harness and the age of the child at the start of treatment. On the other hand, there was a strong significant correlation between the appearance of AVN and the length of treatment.