Donanemab (LY3002813) Phase 1b Study in Alzheimer's Disease: Rapid and Sustained Reduction of Brain Amyloid Measured by Florbetapir F18 Imaging.

BACKGROUND: Donanemab (LY3002813) is an IgG1 antibody directed at an N­terminal pyroglutamate of amyloid beta epitope that is present only in brain amyloid plaques. OBJECTIVES: To assess effects of donanemab on brain amyloid plaque load after single and multiple intravenous doses, as well as pharmacokinetics, safety/tolerability, and immunogenicity. DESIGN: Phase 1b, investigator- and patient-blind, randomized, placebo-controlled study. SETTING: Patients recruited at clinical research sites in the United States and Japan. PARTICIPANTS: 61 amyloid plaque-positive patients with mild cognitive impairment due to Alzheimer's disease and mild-to-moderate Alzheimer's disease dementia. INTERVENTION: Six cohorts were dosed with donanemab: single dose 10-, 20- or 40- mg/kg (N = 18), multiple doses of 10-mg/kg every 2 weeks for 24 weeks (N = 10), and 10- or 20-mg/kg every 4 weeks for 72 weeks (N=18) or placebo (N = 15). MEASUREMENTS: Brain amyloid plaque load, using florbetapir positron emission tomography, was assessed up to 72 weeks. Safety was evaluated by occurrence of adverse events, magnetic resonance imaging, electrocardiogram, vital signs, laboratory testing, neurological monitoring, and immunogenicity. RESULTS: Treatment with donanemab resulted in rapid reduction of amyloid, even after a single dose. By 24 weeks, amyloid positron emission tomography mean changes from baseline for single donanemab doses in Centiloids were: -16.5 (standard error 11.22) 10-mg/kg intravenous; 40.0 (standard error 11.23) 20 mg/kg intravenous; and -49.6 (standard error 15.10) 40-mg/kg intravenous. Mean reduction of amyloid plaque in multiple dose cohorts by 24 weeks in Centiloids were: 55.8 (standard error 9.51) 10-mg/kg every 2 weeks; -50.2 (standard error 10.54) 10-mg/kg every 4 weeks; and -58.4 (standard error 9.66) 20-mg/kg every 4 weeks. Amyloid on average remained below baseline levels up to 72 weeks after a single dose of donanemab. Repeated dosing resulted in continued florbetapir positron emission tomography reductions over time compared to single dosing with 6 out of 28 patients attaining complete amyloid clearance within 24 weeks. Within these, 5 out of 10 patients in the 20 mg/kg every 4 weeks cohort attained complete amyloid clearance within 36 weeks. When dosing with donanemab was stopped after 24 weeks of repeat dosing in the 10 mg every 2 weeks cohort, florbetapir positron emission tomography reductions were sustained up to 72 weeks. For the single dose cohorts on day 1, dose proportional increases in donanemab pharmacokinetics were observed from 10 to 40 mg/kg. Dose proportional increases in pharmacokinetics were also observed at steady state with the multiple dose cohorts. Donanemab clearance was comparable across the dose levels. Mean donanemab elimination-half-life following 20 mg/kg single dose was 9.3 days with range of 5.6 to 16.2 days. Greater than 90% of patients had positive treatment-emergent antidrug antibodies with donanemab. However, overall, the treatment-emergent antidrug antibodies did not have a significant impact on pharmacokinetics. Donanemab was generally well tolerated. Amongst the 46 participants treated with donanemab, the following amyloid-related imaging abnormalities, common to the drug class, were observed: 12 vasogenic cerebral edema events (12 [19.7%] patients), 10 cerebral microhemorrhage events (6 [13.0%] patients), and 2 superficial siderosis events (2 [4.3%] patients). CONCLUSIONS: Single and multiple doses of donanemab demonstrated a rapid, robust, and sustained reduction up to 72 weeks in brain amyloid plaque despite treatment-emergent antidrug antibodies detected in most patients. Amyloid-related imaging abnormalities were the most common treatment-emergent event.

Dramatic impact of morbid obesity on child lung development.

OBJECTIVE: To assess the respiratory function and sleep characteristics of obese adults and children. METHODS: All patients with non-syndromic, severe obesity (BMI ≥3 z-scores for children and ≥40.00kg/m2 for adults), referred for pulmonary function tests at Lille University Hospital, were retrospectively included. RESULTS: A total of 69 children (mean±SD BMI 36.8±6.7 and mean BMI z-score 4.7±1.0) and 70 adults were included (mean BMI 45.7±6.2). Metabolic syndrome was diagnosed in 13 children (26%) and 40 adults (80%). Reduced lung volumes were observed in 34 children (50.0%) and 16 adults (24.0%) and both the mean functional residual capacity (FRC) and the mean residual volume (RV) were lower in children than in adults (FRC: -1.7±2.1 z-score in children vs. -1.0±1.1 in adults, P=0.026; and RV: -0.8±1.2 z-score in children vs. -0.1±1.1 in adults, P=0.002). The prevalence of severe obstructive sleep apnea syndrome was greater in adults (40.7% vs. 18.8%, P=0.007). Children had a higher average oxygen saturation (median of 96.0% [91.0-98.0] vs. 93.0% [76.0-97.0] in adults, P<0.0001). CONCLUSION: Obesity has consequences for lung volumes in children; however, a longitudinal study is needed to determine the impact on pulmonary expansion and growth.

A Phase 2 Study of Galunisertib (TGF-ß1 Receptor Type I Inhibitor) and Sorafenib in Patients With Advanced Hepatocellular Carcinoma.

INTRODUCTION: Inhibition of tumor growth factor-ß (TGF-ß) receptor type I potentiated the activity of sorafenib in preclinical models of hepatocellular carcinoma (HCC). Galunisertib is a small-molecule selective inhibitor of TGF-ß1 receptor type I, which demonstrated activity in a phase 2 trial as second-line HCC treatment. METHODS: The combination of galunisertib and sorafenib (400 mg BID) was tested in patients with advanced HCC and Child-Pugh A liver function without prior systemic therapy. Galunisertib dose was administered 80 or 150 mg b.i.d. orally for 14 days every 28 days in safety lead-in cohorts; in the expansion cohort, all patients received galunisertib 150 mg b.i.d. Objectives included time-to-tumor progression, changes in circulating alpha fetoprotein and TGF-ß1, safety, overall survival (OS), response rate, and pharmacokinetics (PK). RESULTS: Patients (n = 47) were enrolled from 5 non-Asian countries; 3 and 44 patients received the 80 mg and 150 mg b.i.d. doses of galunisertib, respectively. The pharmacokinetics and safety profiles were consistent with monotherapy of each drug. For the 150 mg b.i.d. galunisertib cohort, the median time-to-tumor progression was 4.1 months; the median OS was 18.8 months. A partial response was seen in 2 patients, stable disease in 21, and progressive disease in 13. TGF-ß1 responders (decrease of >20% from baseline) vs nonresponders had longer OS (22.8 vs 12.0 months, P = 0.038). DISCUSSION: The combination of galunisertib and sorafenib showed acceptable safety and a prolonged OS outcome.

Whole body physiologically based modelling of ß-blockers in the rat: events in tissues and plasma following an i.v. bolus dose.

BACKGROUND AND PURPOSE: Whole body physiologically based pharmacokinetic (PBPK) models have been increasingly applied in drug development to describe kinetic events of therapeutic agents in animals and humans. The advantage of such modelling is the ability to incorporate vast amounts of physiological information, such as organ blood flow and volume, to ensure that the model is as close to reality as possible. EXPERIMENTAL APPROACH: Previous PBPK model development of enantiomers of a series of seven racemic ß-blockers, namely, acebutolol, betaxolol, bisoprolol, metoprolol, oxprenolol, pindolol and propranolol, together with S-timolol in rat was based on tissue and blood concentration data at steady state. Compounds were administered in several cassettes with the composition mix and blood and tissue sampling times determined using a D-optimal design. KEY RESULTS: Closed-loop PBPK models were developed initially based on the application of open loop forcing function models to individual tissues and compounds. For the majority of compounds and tissues, distribution kinetics was adequately characterized by perfusion rate-limited models. For some compounds in the testes and gut, a permeability rate-limited distribution model was required to best fit the data. Parameter estimates of the tissue-to-blood partition coefficient through fitting of individual enantiomers and of racemic pair were generally in agreement and also concur with those from previous steady-state experiments. CONCLUSIONS AND IMPLICATIONS: PBPK modelling is a very powerful tool to aid drug discovery and development of therapeutic agents in animals and humans. However, careful consideration of the assumptions made during the modelling exercise is essential.

Marker of coxsackievirus-B4 infection in saliva of patients with type 1 diabetes.

BACKGROUND: Coxsackieviruses B (CV-B) are enteroviruses that have been reported to play a role in the pathogenesis of type 1 diabetes. Enteroviral RNA was detected in the gut mucosa of patients. The mucosal immunity is an interconnected network; therefore, the response to enteroviruses possibly present in the gastrointestinal mucosa can be reflected by specific antibodies in the saliva. In the present study, the anti-CV-B neutralizing activity of saliva samples from patients with type 1 diabetes was investigated. METHODS: Saliva samples were collected from patients and controls of 3 countries, and plasma was obtained from some of them. The anti-CV-B activity of clinical samples was determined by neutralization of the cytopathic effect induced by challenging viruses in vitro and expressed as titre value. RESULTS: Overall prevalence and levels of anti-CV-B4 activity of saliva were higher in patients (n = 181) than in controls (n = 135; P = .0002; titre values ≥ 16: odds ratio = 4.22 95% CI: 1.90-9.38 P = .0002). It has been shown that IgA1 played a role in this activity. There was no correlation between the saliva and the plasma anti-CV-B4 neutralizing activity. The neutralizing activity of saliva against CV-B1, CV-B2, CV-B3, and CV-B5 existed rarely, if at all. Increased levels of anti-CV-B4 activity were observed all along a 4 year follow-up period in patients but not in matched controls (P = .01). CONCLUSION: There is an anti-CV-B4 activity in saliva of patients with type 1 diabetes that may be a useful marker to study the role of CV-B in the pathogenesis of the disease.

[Inhaled corticosteroids and growth: should we be worried?]. / Corticoïdes inhalés et croissance : faut-il s'inquiéter ?

Inhaled corticosteroids (ICSs) are the cornerstone and the first stage of asthma treatment. The objective of this study was to synthesize data on the potential effects of ICSs on growth in children. Studies on the short-term impact of ICSs on growth evaluated by knemometry cannot be extrapolated to the medium or long term and therefore have no utility in real life for a given person. In the medium term, the various ICSs given at the usual doses cause a small reduction in growth after 6 months of treatment. This slowdown occurs at the beginning of treatment, especially in younger children, and the growth velocity corrects itself later but without catching up. In the long term, the prolonged use of ICSs seems to induce a small reduction in the final size in adulthood (close to 1cm) occurring in the first 2 years of treatment without worsening over time. The impact of gender, age at onset of treatment, different ICSs, modes of inhalation, and severity of asthma should also be studied further. The benefit of ICSs in asthma treatment is greater than the risk of side effects, including on growth. The majority of the therapeutic effect is obtained for small to moderate doses of ICSs. Regular adjustment of ICS dose for optimal asthma control should also reduce ICS dose and the impact on growth.

A review of mixed-effects models of tumor growth and effects of anticancer drug treatment used in population analysis.

Population modeling of tumor size dynamics has recently emerged as an important tool in pharmacometric research. A series of new mixed-effects models have been reported recently, and we present herein a synthetic view of models with published mathematical equations aimed at describing the dynamics of tumor size in cancer patients following anticancer drug treatment. This selection of models will constitute the basis for the Drug Disease Model Resources (DDMoRe) repository for models on oncology.

White paper: landscape on technical and conceptual requirements and competence framework in drug/disease modeling and simulation.

Pharmaceutical sciences experts and regulators acknowledge that pharmaceutical development as well as drug usage requires more than scientific advancements to cope with current attrition rates/therapeutic failures. Drug disease modeling and simulation (DDM&S) creates a paradigm to enable an integrated and higher-level understanding of drugs, (diseased)systems, and their interactions (systems pharmacology) through mathematical/statistical models (pharmacometrics)(1)-hence facilitating decision making during drug development and therapeutic usage of medicines. To identify gaps and challenges in DDM&S, an inventory of skills and competencies currently available in academia, industry, and clinical practice was obtained through survey. The survey outcomes revealed benefits, weaknesses, and hurdles for the implementation of DDM&S. In addition, the survey indicated that no consensus exists about the knowledge, skills, and attributes required to perform DDM&S activities effectively. Hence, a landscape of technical and conceptual requirements for DDM&S was identified and serves as a basis for developing a framework of competencies to guide future education and training in DDM&S.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e40; doi:10.1038/psp.2013.16; advance online publication 1 May 2013.

Population pharmacokinetic/pharmacodynamic models for duloxetine in the treatment of diabetic peripheral neuropathic pain.

BACKGROUND: Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor approved for the treatment of diabetic peripheral neuropathic pain (DPNP). The current analyses aimed to identify and evaluate the effect of any significant covariates on DPNP treatment response, via the development of a continuous descriptive Pharmacokinetics/Pharmacodynamics (PK/PD) model for pain score reduction and a proportional odds PK/PD model describing the proportion of patients achieving pain relief. METHODS: A total of 1139 patients received placebo, 20, 60 or 120 mg duloxetine daily for 12 weeks. The primary efficacy measure was 24-h pain scores collected on the 11-point categorical numerical rating scale averaged over a week. PK/PD models were fitted using non-linear mixed-effects models. RESULTS: Baseline pain severity was found to be an important factor in both PK/PD models. Larger drops in pain scores were observed for patients with more severe pain. The proportional odds PK/PD model used an a priori definition for adequate pain relief, which was a decrease in two points from baseline. Simulations showed that approximately 70% of patients in the highest dose groups would obtain pain relief at week 12, although placebo response was relatively high at 40%. The proportion of patients who obtained pain relief was slightly lower in those with mild pain compared to those with more severe pain. CONCLUSIONS: Patients with more severe pain at study entry had larger treatment responses and were more likely to achieve clinically meaningful pain relief with similar amounts of drug, compared to patients with milder pain.

[Asthma and obesity in childhood: what is the link?]. / Asthme et obésité : quelle relation chez l'enfant ?

According to the definition (body mass index>97 degrees percentile), overweight and obesity concern 15% of French children. The parallel trends in the increase in asthma and obesity may indicate a potential link between these two conditions. The purpose of this study was to review the epidemiological data indicating a relationship between asthma and obesity, to evaluate the consequences of obesity on asthma and to assess the mechanisms of this association. We conclude with the implications for treatment strategies.