Effects of BI 655064, an antagonistic anti-CD40 antibody, on clinical and biomarker variables in patients with active rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase IIa study.

OBJECTIVE: To evaluate the safety, efficacy and therapeutic mechanism of BI 655064, an antagonistic anti-CD40 monoclonal antibody, in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX-IR). METHODS: In total, 67 patients were randomised to receive weekly subcutaneous doses of 120 mg BI 655064 (n=44) or placebo (n=23) for 12 weeks. The primary endpoint was the proportion of patients who achieved 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Safety was assessed in patients who received at least one dose of study drug. RESULTS: At week 12, the primary endpoint was not met, with 68.2% of patients treated with BI 655064 achieving an ACR20 vs 45.5% with placebo (p=0.064); using Bayesian analysis, the posterior probability of seeing a difference greater than 35% was 42.9%. BI 655064 was associated with greater changes in CD40-CD40L pathway-related markers, including reductions in inflammatory and bone resorption markers (interleukin-6, matrix metalloproteinase-3, receptor activator of nuclear factor-κB ligand), concentration of autoantibodies (immunoglobulin [Ig]G rheumatoid factor [RF], IgM RF, IgA RF) and CD95+ activated B-cell subsets. No serious adverse events (AEs) related to BI 655064 treatment or thromboembolic events occurred; reported AEs were mainly of mild intensity. CONCLUSION: Although blockade of the CD40-CD40L pathway with BI 655064 in MTX-IR patients with RA resulted in marked changes in clinical and biological parameters, including reductions in activated B-cells, autoantibody production and inflammatory and bone resorption markers, with a favourable safety profile, clinical efficacy was not demonstrated in this small phase IIa study. TRIAL REGISTRATION NUMBER: NCT01751776.

Efficacy and Safety of Candidate Biosimilar CT-P43 Versus Originator Ustekinumab in Moderate to Severe Plaque Psoriasis: 28-Week Results of a Randomised, Active-Controlled, Double-Blind, Phase III Study.

BACKGROUND: CT-P43 is a candidate ustekinumab biosimilar in clinical development. OBJECTIVES: This paper aims to demonstrate equivalent efficacy of CT-P43 to originator ustekinumab in adults with moderate to severe plaque psoriasis. METHODS: This double-blind, phase III trial randomised patients (1:1) to receive subcutaneous CT-P43 or originator ustekinumab (45/90 mg for patients with baseline body weight ≤ 100 kg/> 100 kg) at week 0 and week 4 in Treatment Period I. Prior to week 16 dosing in Treatment Period II, patients receiving originator ustekinumab were re-randomised (1:1) to continue originator ustekinumab or switch to CT-P43; patients initially randomised to CT-P43 continued receiving CT-P43 (at weeks 16, 28 and 40). The primary endpoint of the trial was mean per cent improvement from baseline in Psoriasis Area Severity Index (PASI) score at week 12. Equivalence was concluded if confidence intervals (CIs) for the estimate of treatment difference were within pre-defined equivalence margins: ± 10% [90% CI; modified intent-to-treat set; Food and Drug Administration (FDA) approach] or ± 15% [95% CI; full analysis set for patients only receiving 45 mg doses in Treatment Period I; European Medicines Agency (EMA) approach]. Additional efficacy, pharmacokinetic, safety and immunogenicity endpoints were evaluated through week 52. Results to week 28 are reported here. RESULTS: In Treatment Period I, 509 patients were randomised (CT-P43: N = 256; originator ustekinumab: N = 253). The mean per cent improvement in PASI score at week12 was 77.93% and 75.89% for CT-P43 and originator ustekinumab, respectively (FDA approach); per the EMA approach, corresponding values were 78.26% and 77.33%. Estimated treatment differences were 2.05 (90% CI -0.23, 4.32) and 0.94 (95% CI -2.29, 4.16); equivalence was achieved for both sets of assumptions. Further efficacy parameters and pharmacokinetic, safety and immunogenicity outcomes were comparable between treatment groups, including after switching from originator ustekinumab to CT-P43. CONCLUSIONS: CT-P43 demonstrated equivalent efficacy to originator ustekinumab in patients with moderate to severe plaque psoriasis, with comparable pharmacokinetic, safety and immunogenicity profiles. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04673786; date of registration: 17 December, 2020.

The application of FRAX® to determine intervention thresholds in osteoporosis treatment in Poland.

INTRODUCTION: FRAX®, an assessment algorithm for estimating fracture probability, has been widely used for the evaluation of osteoporosis since 2008. Its clinical use requires that osteoporotic fracture probability is established at which treatment can be recommended. OBJECTIVES: The aim of the present study was to explore possible treatment thresholds for Poland. PATIENTS AND METHODS: The FRAX-based probabilities were calculated in 1608 unselected postmenopausal women from Bialystok using the British model (version 3.1). Intervention thresholds were set at fracture probability equal to women with a bone mass density (BMD) T-score of -2.5 standard deviation (criterion A), equal to women with a prior fracture using a fixed threshold irrespective of age (criterion B), or an age-dependent threshold (criterion C). Additionally, we assumed that all women with a prior fracture would be eligible for treatment plus those with a fracture probability equal to women with a prior fracture using a fixed threshold (criterion D). RESULTS: Mean 10-year probability of a major osteoporotic fracture was 10.9% when BMD was not included in the FRAX calculation and 11.6% with BMD included. In women with a prior fragility fracture, the respective probabilities were 18.0% and 17.4%. For criterion A, 39% women aged 50 years or more would be eligible for treatment, for criterion D--35%, and for criteria B and C--16%. For criteria B and C, women with higher risk would be eligible for treatment compared with criteria A and D. Assuming a relative fracture risk reduction of 30%, the number needed to treat (NNT) to prevent a major fracture was lower for criteria B and C (NNT = 13 and 14, respectively) than for criteria A and D (NNT = 18). CONCLUSIONS: The use of intervention thresholds based on the probabilities equal to women with a prior fracture is most efficient. The use of an age-specific threshold may be more clinically appropriate than a fixed probability threshold for all ages.

The characteristics of osteoporotic fractures in the region of Bialystok (BOS-2). The application of the WHO algorithm, FRAX®BMI and FRAX®BMD assessment tools to determine patients for intervention.

BACKGROUND: The 2007 WHO guidelines for the treatment of osteoporosis require that we know the population risk of an osteoporotic fracture for each country to classify patients requiring treatment. MATERIAL AND METHODS: Studies have been carried out among a random cohort of 1,608 women over the age of 40 to assess a ten-year absolute risk of main osteoporotic fractures (AR-10 m.o.fx.) and hip fractures (AR-10 h.fx.) by using FRAX®BMI and FRAX®BMD based on the epidemiology of fractures in England. RESULTS: Both methods gave similar results in assessing the probability of fracture, showing the increase of AR-10 m.o.fx. in subsequent life decades to rise from 5% in the fifth decade to 25% in the ninth, mean result 11%, and AR-10 h.fx. to rise over the same period from 0.5% to 13%, mean result 3%. The number of fractures increases up to the seventh and eighth decades, and decreases according to the number of patients in the age group. The commonest fracture risks reported, other than old age and low BMI, were a prior fracture, a family history of hip fracture and smoking. CONCLUSIONS: Comparative analysis of examined parameters of FRAX between people with and without fractures showed considerable differences only in age and AR-10 m.o.fx. This doubled in people with previous fractures (ca. 18% vs. 9%) and AR-10 h.fx. (ca. 5% vs. 2.5%). The "middle" area between the average population risks (AR-10 m.o.fx. 11% and AR-10 h.fx. 3%) and the risks in patients with fractures (AR-10 m.o.fx. 18% and AR-10 h.fx. 9%) could work as an indicator: below those values the risk is low and no treatment is required; above those values, the risk is high, and intervention is necessary; the middle area implies a BMD examination and reassessment of the fracture risk.