A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-α monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients.

OBJECTIVE: To assess the pharmacodynamic effects of sifalimumab, an investigational anti-IFN-α monoclonal antibody, in the blood and muscle of adult dermatomyositis and polymyositis patients by measuring neutralisation of a type I IFN gene signature (IFNGS) following drug exposure. METHODS: A phase 1b randomised, double-blinded, placebo controlled, dose-escalation, multicentre clinical trial was conducted to evaluate sifalimumab in dermatomyositis or polymyositis patients. Blood and muscle biopsies were procured before and after sifalimumab administration. Selected proteins were measured in patient serum with a multiplex assay, in the muscle using immunohistochemistry, and transcripts were profiled with microarray and quantitative reverse transcriptase PCR assays. A 13-gene IFNGS was used to measure the pharmacological effect of sifalimumab. RESULTS: The IFNGS was suppressed by a median of 53-66% across three time points (days 28, 56 and 98) in blood (p=0.019) and 47% at day 98 in muscle specimens post-sifalimumab administration. Both IFN-inducible transcripts and proteins were prevalently suppressed following sifalimumab administration. Patients with 15% or greater improvement from baseline manual muscle testing scores showed greater neutralisation of the IFNGS than patients with less than 15% improvement in both blood and muscle. Pathway/functional analysis of transcripts suppressed by sifalimumab showed that leucocyte infiltration, antigen presentation and immunoglobulin categories were most suppressed by sifalimumab and highly correlated with IFNGS neutralisation in muscle. CONCLUSIONS: Sifalimumab suppressed the IFNGS in blood and muscle tissue in myositis patients, consistent with this molecule's mechanism of action with a positive correlative trend between target neutralisation and clinical improvement. These observations will require confirmation in a larger trial powered to evaluate efficacy.

Safety profile and clinical activity of sifalimumab, a fully human anti-interferon α monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-blind randomised study.

BACKGROUND: Type I interferons (IFNs) appear to play a central role in disease pathogenesis in systemic lupus erythematosus (SLE), making them potential therapeutic targets. METHODS: Safety profile, pharmacokinetics, immunogenicity, pharmacodynamics and clinical activity of sifalimumab, an anti-IFNα monoclonal antibody, were assessed in a phase I, multicentre, randomised, double-blind, dose-escalation study with an open-label extension in adults with moderately active SLE. SUBJECTS: received one intravenous dose of sifalimumab (n=33 blinded phase, 0.3, 1, 3, 10 or 30 mg/kg; n=17 open-label, 1, 3, 10 or 30 mg/kg) or placebo (n=17). Each phase lasted 84 days. RESULTS: Adverse events (AEs) were similar between groups; about 97% of AEs were grade 1 or 2. All grade 3 and 4 AEs and all serious AEs (2 placebo, 1 sifalimumab) were deemed unrelated to the study drug. No increase in viral infections or reactivation was observed. Sifalimumab caused dose-dependent inhibition of type I IFN-induced mRNAs (type I IFN signature) in whole blood and corresponding changes in related proteins in affected skin. Exploratory analyses showed consistent trends toward improvement in disease activity in sifalimumab-treated versus placebo-treated subjects. A lower proportion of sifalimumab-treated subjects required new or increased immunosuppressive treatments (12% vs 41%; p=0.03) and had fewer Systemic Lupus Erythematosus Disease Activity Index flares (3% vs 29%; p=0.014). CONCLUSIONS: Sifalimumab had a safety profile that supports further clinical development. This trial demonstrated that overexpression of type I IFN signature in SLE is at least partly driven by IFNα, and exploratory analyses suggest that IFNα inhibition may be associated with clinical benefit in SLE. Trial registration number NCT00299819.

Safety profile and clinical activity of multiple subcutaneous doses of MEDI-528, a humanized anti-interleukin-9 monoclonal antibody, in two randomized phase 2a studies in subjects with asthma.

BACKGROUND: Interleukin-9 (IL-9)-targeted therapies may offer a novel approach for treating asthmatics. Two randomized placebo-controlled studies were conducted to assess the safety profile and potential efficacy of multiple subcutaneous doses of MEDI-528, a humanized anti-IL-9 monoclonal antibody, in asthmatics. METHODS: Study 1: adults (18-65 years) with mild asthma received MEDI-528 (0.3, 1, 3 mg/kg) or placebo subcutaneously twice weekly for 4 weeks. Study 2: adults (18-50 years) with stable, mild to moderate asthma and exercise-induced bronchoconstriction received 50 mg MEDI-528 or placebo subcutaneously twice weekly for 4 weeks. Adverse events (AEs), pharmacokinetics (PK), immunogenicity, asthma control (including asthma exacerbations), and exercise challenge test were evaluated in study 1, study 2, or both. RESULTS: In study 1 (N = 36), MEDI-528 showed linear serum PK; no anti-MEDI-528 antibodies were detected. Asthma control: 1/27 MEDI-528-treated subjects had 1 asthma exacerbation, and 2/9 placebo-treated subjects had a total of 4 asthma exacerbations (one considered a serious AE). In study 2, MEDI-528 (n = 7) elicited a trend in the reduction in mean maximum decrease in FEV1 post-exercise compared to placebo (n = 2) (-6.49% MEDI-528 vs -12.60% placebo; -1.40% vs -20.10%; -5.04% vs -15.20% at study days 28, 56, and 150, respectively). Study 2 was halted prematurely due to a serious AE in an asymptomatic MEDI-528-treated subject who had an abnormal brain magnetic resonance imaging that was found to be an artifact on further evaluation. CONCLUSIONS: In these studies, MEDI-528 showed an acceptable safety profile and findings suggestive of clinical activity that support continued study in subjects with mild to moderate asthma.

A randomized, double-blind, placebo-controlled, phase I study of MEDI-545, an anti-interferon-alfa monoclonal antibody, in subjects with chronic psoriasis.

BACKGROUND: Interferon-alfa (IFN-alpha) has been implicated in the pathogenesis of psoriasis. OBJECTIVE: To evaluate the safety profile of MEDI-545, a fully human anti-IFN-alpha monoclonal antibody and to explore its effect on the involvement of type I IFN-alpha activity in the maintenance of established plaque psoriasis. METHODS: We conducted an 18-week, randomized, double-blind, placebo-controlled, dose-escalating study in 36 subjects with chronic plaque psoriasis. Subjects received one intravenous dose of MEDI-545 (0.3-30.0 mg/kg) or placebo. Study outcomes were safety profile, pharmacokinetics, immunogenicity, and clinical effects. RESULTS: There was no difference in adverse events between MEDI-545 and placebo. Two serious adverse events were reported; one drug-related hypotensive infusion reaction occurred in one subject in the 30.0 mg/kg MEDI-545 dose group, causing discontinuation of study drug in that subject and study dismissal of the other subjects in the same cohort; and a myocardial infarction occurred in one subject in the 10 mg/kg MEDI-545 dose group, which was considered to be unrelated to treatment. MEDI-545 was nonimmunogenic, had a half-life of 21 days, showed no significant inhibition of the type I IFN gene signature, and had no clinical activity. LIMITATIONS: The study addressed only IFN-alpha and chronic psoriatic lesions. CONCLUSION: The safety profile of MEDI-545 supports further clinical development. IFN-alpha does not appear to be significantly involved in the maintenance of established plaque psoriasis.

Ribaxamase, an Orally Administered ß-Lactamase, Diminishes Changes to Acquired Antimicrobial Resistance of the Gut Resistome in Patients Treated with Ceftriaxone.

INTRODUCTION: Intravenous (IV) ß-lactam antibiotics, excreted through bile into the gastrointestinal (GI) tract, may disrupt the gut microbiome by eliminating the colonization resistance from beneficial bacteria. This increases the risk for Clostridium difficile infection (CDI) and can promote antimicrobial resistance by selecting resistant organisms and eliminating competition by non-resistant organisms. Ribaxamase is an orally administered ß-lactamase for use with IV ß-lactam antibiotics (penicillins and cephalosporins) and is intended to degrade excess antibiotics in the upper GI before they can disrupt the gut microbiome and alter the resistome. METHODS: Longitudinal fecal samples (349) were collected from patients who participated in a previous Phase 2b clinical study with ribaxamase for prevention of CDI. In that previous study, patients were treated with ceftriaxone for a lower respiratory tract infection and received concurrent ribaxamase or placebo. Extracted fecal DNA from the samples was subjected to whole-genome shotgun sequencing and analyzed for the presence of antimicrobial resistance (AMR) genes by alignment of sequences against the Comprehensive Antibiotic Resistance Database. A qPCR assay was also used to confirm some of the results. RESULTS: Database alignment identified ~1300 acquired AMR genes and gene variants, including those encoding ß-lactamases and vancomycin resistance which were significantly increased in placebo vs ribaxamase-treated patients following antibiotic exposure. qPCR corroborated the presence of these genes and supported both new acquisition and expansion of existing gene pools based on no detectable copy number or a low copy number in pre-antibiotic samples which increased post-antibiotics. Additional statistical analyses demonstrated significant correlations between changes in the gut resistome and clinical study parameters including study drug assignment and ß-lactamase and vancomycin resistance gene frequency. DISCUSSION: These findings demonstrated that ribaxamase reduced changes to the gut resistome subsequent to ceftriaxone administration and may help limit the emergence of AMR.

Use of ribaxamase (SYN-004), a ß-lactamase, to prevent Clostridium difficile infection in ß-lactam-treated patients: a double-blind, phase 2b, randomised placebo-controlled trial.

BACKGROUND: Infections with Clostridium difficile are a health threat, yet no products are currently licensed for prevention of primary C difficile infections. Intravenous ß-lactam antibiotics are considered to confer a high risk of C difficile infection because of their biliary excretion into the gastrointestinal tract and disruption of the gut microbiome. ribaxamase (SYN-004) is an orally administered ß-lactamase that was designed to be given with intravenous ß-lactam antibiotics to degrade excess antibiotics in the upper gastrointestinal tract before they disrupt the gut microbiome and lead to C difficile infection. We therefore aimed to determine whether administration of ribaxamase could prevent C difficile infection in patients being treated with intravenous ceftriaxone for a lower respiratory tract infection, thereby supporting continued clinical development. METHODS: In this parallel-group, double-blind, multicentre, phase 2b, randomised placebo-controlled trial, we recruited patients who had been admitted to a hospital with a lower respiratory tract infection with a pneumonia index score of 90-130 and who were expected to be treated with ceftriaxone for at least 5 days. Patients were recruited from 54 clinical sites in the USA, Canada, Bulgaria, Hungary, Poland, Romania, and Serbia. We randomly assigned patients older than 50 years to groups (1:1) in blocks of four by use of an interactive web portal; these groups were assigned to receive either 150 mg ribaxamase or placebo four times per day during, and for 72 h after, treatment with ceftriaxone. All patients, clinical investigators, study staff, and sponsor personnel were masked to the study drug assignments. The primary endpoint was the incidence of C difficile infection, as diagnosed by the local laboratory, in patients who received at least one treatment dose, and this outcome was assessed during treatment and for 4 weeks after treatment. This study is registered with ClinicalTrials.gov, number NCT02563106. FINDINGS: Between Nov 16, 2015, and Nov 10, 2016, we screened 433 patients for inclusion in the study. Of these patients, 20 (5%) patients were excluded from the study (16 [4%] patients did not meet inclusion criteria; four [1%] patients because of dosing restrictions). We enrolled and randomly assigned 413 patients to groups, of whom 207 patients were assigned to receive ceftriaxone plus ribaxamase and 206 patients were assigned to receive ceftriaxone plus placebo. However, one (<1%) patient in the ribaxamase group withdrew consent and was not treated with ribaxamase. During the study and within the 4 weeks after antibiotic treatment, two (1·0%) patients in the ribaxamase group and seven (3·4%) patients in the placebo group were diagnosed with an infection with C difficile (risk reduction 2·4%, 95% CI -0·6 to 5·9; one-sided p=0·045). Adverse events were similar between groups but more deaths were reported in the ribaxamase group (11 deaths vs five deaths in the placebo group). This disparity was due to the higher incidence of deaths attributed to cardiac-associated causes in the ribaxamase group (six deaths vs one death in the placebo group). INTERPRETATION: In patients treated with intravenous ceftriaxone for lower respiratory tract infections, oral ribaxamase reduced the incidence of C difficile infections compared with placebo. The imbalance in deaths between the groups appeared to be related to the underlying health of the patients. Ribaxamase has the potential to prevent C difficile infection in patients treated with intravenous ß-lactam antibiotics, and our findings support continued clinical development of ribaxamase to prevent C difficile infection. FUNDING: Synthetic Biologics.

Erratum: Selection of a cut-off for high- and low-methane producers using a spot-methane breath test: results from a large north American dataset of hydrogen, methane and carbon dioxide measurements in breath.

[This corrects the article DOI: 10.1093/gastro/gow048.][This corrects the article DOI: 10.1093/gastro/gow048.].

Selection of a cut-off for high- and low-methane producers using a spot-methane breath test: results from a large north American dataset of hydrogen, methane and carbon dioxide measurements in breath.

BACKGROUND: Levels of breath methane, together with breath hydrogen, are determined by means of repeated collections of both, following ingestion of a carbohydrate substrate, at 15-20 minutes intervals, until 10 samples have been obtained. The frequent sampling is required to capture a rise of hydrogen emissions, which typically occur later in the test: in contrast, methane levels are typically elevated at baseline. If methane emissions represent the principal objective of the test, a spot methane test (i.e. a single-time-point sample taken after an overnight fast without administration of substrate) may be sufficient. METHODS: We analysed 10-sample lactulose breath test data from 11 674 consecutive unique subjects who submitted samples to Commonwealth Laboratories (Salem, MA, USA) from sites in all of the states of the USA over a one-year period. The North American Consensus (NAC) guidelines criteria for breath testing served as a reference standard. RESULTS: The overall prevalence of methane-positive subjects (by NAC criteria) was 20.4%, based on corrected methane results, and 18.9% based on raw data. In our USA dataset, the optimal cut-off level to maximize sensitivity and specificity was ≥4 ppm CH4, 94.5% [confidential interval (CI): 93.5-95.4%] and 95.0% (CI: 94.6-95.5%), respectively. The use of a correction factor (CF) (5% CO2 as numerator) led to reclassifications CH4-high to CH4-low in 0.7 % and CH4-low to CH4-high in 2.1%. CONCLUSIONS: A cut-off value for methane at baseline of either ≥4 ppm, as in our USA dataset, or ≥ 5 ppm, as described in a single institution study, are both highly accurate in identifying subjects at baseline that would be diagnosed as 'methane-positive' in a 10-sample lactulose breath test for small intestinal bacterial overgrowth.

Age-conditional probabilities of developing cancer.

We propose an estimator of the probability of developing a disease in a given age range, conditional on never having developed the disease prior to the beginning of the age range. Our estimator improves the one described by Wun, Merrill and Feuer ( Lifetime Data Analysis 1998; 4, 169-186) that is currently used by the U.S. National Cancer Institute for the SEER Cancer Statistics Review. Both estimators use cross-sectional disease rates and provide an interpretation of these rates in terms of the age-conditional probability of developing disease in a hypothetical cohort. The difficulty of this problem is that rates are not available per person-years alive and disease free, but only per person-years alive. Wun et al. used ad hoc methods to handle this problem which did not properly account for competing risks, did not provide a measure of variability, and only allowed age ranges using prespecified 5-year age intervals. Here we solve the problem under a unified competing risks framework, which allows the calculation of the age-conditional probabilities for any age range. We generalize gamma confidence intervals to apply to our new statistic. Although our new method provides estimates which are numerically similar to that of Wun et al., this paper provides a comprehensive theoretical basis for estimation and inference about the age-conditional probability of developing a disease.