Pharmacokinetics, Safety, and Tolerability of Tezepelumab (AMG 157) in Healthy and Atopic Dermatitis Adult Subjects.
Clin Pharmacol Ther. 2019 Feb 19;:
Authors: Parnes JR, Sullivan JT, Chen L, Dias C
Tezepelumab (AMG 157) is a monoclonal antibody that targets thymic stromal lymphopoietin (TSLP) and has shown benefits in treating asthma. We assessed the safety, tolerability, and pharmacokinetics of single- and multiple-ascending doses in two randomized, double-blind, placebo-controlled Phase 1 studies. Healthy and atopic dermatitis subjects were enrolled in the single-dose study, and healthy subjects in the multiple-dose study. Tezepelumab showed linear pharmacokinetics in both healthy and atopic dermatitis subjects. The half-life after a subcutaneous or intravenous administration ranged from 19.9 to 25.7 days. After multiple doses, the mean area under the curve accumulation ratio was 1.82, 1.64, and 1.59 for the 35 mg, 105 mg, and 210 mg monthly subcutaneous doses, respectively. The mean Cmax accumulation ratio was 1.59, 2.84, and 6.74 for the 210 mg dose given every 28, 14, and 7 days, respectively. Tezepelumab was well tolerated in both studies with no evidence of immunogenicity. This article is protected by copyright. All rights reserved.
PMID: 30779339 [PubMed - as supplied by publisher]
Asthma with multiple allergic comorbidities is associated with complete response to omalizumab.
Clin Exp Allergy. 2019 Feb 18;:
Authors: Sesé L, Schneider M, Bourgoin M, Saint-Pierre P, Lambert N, Guiddir T, Couderc R, Amat F, Just J
Patients with severe asthma constitute a heterogeneous population, and different phenotypes have been identified both in adults and children. Severe asthma affects 4.5% of children with current asthma. Several studies have shown that omalizumab, a humanized anti-IgE monoclonal antibody, is effective in exacerbations and asthma control, and well tolerated in children with severe allergic asthma. However, as biotherapy response varies among patients, it is important to clearly define which children will benefit the most from treatment. This article is protected by copyright. All rights reserved.
PMID: 30779241 [PubMed - as supplied by publisher]
Clinical Efficacy, Safety and Tolerability of a New Subcutaneous Immunoglobulin 16.5% (Octanorm [Cutaquig®]) in the Treatment of Patients With Primary Immunodeficiencies.
Front Immunol. 2019;10:40
Authors: Kobayashi RH, Gupta S, Melamed I, Mandujano JF, Kobayashi AL, Ritchie B, Geng B, Atkinson TP, Rehman S, Turpel-Kantor E, Litzman J
Introduction: Subcutaneously administered immunoglobulin (SCIG) is increasingly used to treat patients with primary immunodeficiencies (PIDs). Octanorm (marketed as cutaquig® in USA and Canada) is a new 16.5% solution of human SCIG, manufactured by a process based on that of the intravenous preparation (IVIG) octagam®. Objectives: To investigate the efficacy, safety and tolerability of octanorm in a prospective, open-label, single-arm phase 3 study involving adult and pediatric patients with PIDs (NCT01888484; clinicaltrials.gov/ct2/show/NCT01888484). Methods: Patients who were previously treated with IVIG received a total of 64 weekly SCIG infusions, including 12 weekly infusions during the wash-in/wash-out period, followed by 52 weekly infusions during the evaluation period. Results: A total of 61 patients aged 2-73 years received 3,497 infusions of octanorm. The mean dose per patient was 0.175 g/kg/infusion. The mean calculated dose conversion factor from the patients' previous IVIG dose for octanorm was 1.37. No serious bacterial infections developed during the study. The rate of other infections per person-year during the primary observation period was 3.43 (upper 95% CI 4.57). All but one non-bacterial infection were mild or moderate in intensity. IgG trough levels were constant during the course of the study. Eleven patients (18.0%) experienced 14 mild or moderate systemic adverse events (AEs) related to octanorm. The rate of related AEs per infusion was 0.004. In 76.7% of infusions, no infusion site reactions were observed and only two (0.3%) reactions were deemed severe. The incidence of site reactions decreased with successive infusions. Conclusion: The new 16.5% SCIG octanorm was shown to be efficacious in preventing infections in PIDs, and was well tolerated.
PMID: 30778345 [PubMed - in process]
The role of oral magnesium supplements for the management of stable bronchial asthma: a systematic review and meta-analysis.
NPJ Prim Care Respir Med. 2019 Feb 18;29(1):4
Authors: Abuabat F, AlAlwan A, Masuadi E, Murad MH, Jahdali HA, Ferwana MS
Asthma is a chronic lung disease characterized by airway inflammation and hyper-responsiveness of airway smooth muscles. There is growing evidence that magnesium may have a role in managing asthma through its dual effect as an anti-inflammatory and bronchodilating agent. To assess the efficacy of oral magnesium supplements in chronic asthmatic patients. In addition to searching through Clinicaltrials.gov/ and references for oral magnesium supplement studies, we performed a database search in Medline, CINAHL, CENTRAL, and Embase. We contacted the authors of the included trials to ask for additional information. We included randomized controlled trials that compared oral magnesium supplements versus placebo, in addition to standard asthma treatment in mild-moderate asthmatic adults and children (older than 6 years). Two reviewers independently performed the study selection, data abstraction, and the assessment of the risk of bias. Eight trials at moderate risk of bias enrolling a total of 917 patients were included. Oral magnesium improved FEV1 at week 8 (5.69 (L/min); 95% CI: 1.92, 9.46; I2: 45%). There was no significant improvement in FEV1 at other follow up periods. There was no significant change in FVC, Methacholine challenge test, the frequency of bronchodilator use, or symptoms score. There were no data on mortality or quality of life. Oral magnesium supplements may lead to improvement in FEV1 that was only demonstrated at eight weeks; but no effect on any other outcome. Until future evidence emerges, oral magnesium cannot be recommended as adjuvants to standard treatment for mild to moderate asthmatic individuals.
PMID: 30778086 [PubMed - in process]
Efficacy and safety of AZD7594, an inhaled non-steroidal selective glucocorticoid receptor modulator, in patients with asthma: a phase 2a randomized, double blind, placebo-controlled crossover trial.
Respir Res. 2019 Feb 18;20(1):37
Authors: Brown MN, Fuhr R, Beier J, Su HL, Chen Y, Forsman H, Hamrén UW, Jackson H, Aggarwal A
BACKGROUND: Inhaled corticosteroids reduce inflammation in asthma but chronic use may cause adverse effects. AZD7594, an inhaled non-steroidal selective glucocorticoid receptor modulator, has the potential of an improved risk-benefit profile. We investigated the safety and efficacy of AZD7594 in asthma.
METHODS: This phase 2a multi-center, randomized, double-blind, placebo-controlled crossover study enrolled adults with asthma aged 18 to 75 years. Patients were treated with budesonide 200 μg twice daily for 2-3 3 weeks (run in part one). If controlled, as demonstrated by an asthma control questionnaire-5 score of < 1.5, patients entered a three-week run-in (part two) where they received a short acting bronchodilator alone. Thereafter, patients with a fractional exhaled nitric oxide (FENO) ≥25 ppb and pre-dose FEV1 40 to 90% predicted were randomized to one of nine treatment sequences. Each patient received placebo and two of three dose levels of AZD7594 (58, 250, 800 μg) once daily via inhalation, in 14-day treatment periods, separated by three-week washout periods. The primary endpoint was the change from baseline in morning trough FEV1 versus placebo on day 15. Secondary endpoints included measures of airway inflammation and asthma control.
RESULTS: Fifty-four patients were randomized and received at least 1 dose of treatment, 48 patients completed the study. Overall 52 patients received placebo, 34 received AZD7594 58 μg, 34 received AZD7594 250 μg, and 34 received AZD7594 800 μg. AZD7594 800 μg demonstrated a significant improvement in Day 15 morning trough FEV1versus placebo (LS means difference 0.148 L 95% CI 0.035-0.261, p = 0.011), with a dose-dependent response seen in the 250 μg (0.076 L -0·036-0·188, p = 0.183) and 58 μg (0·027 L -0·086-0·140, p = 0.683). All secondary endpoints showed statistically significant improvement at the 800 μg dose. All doses demonstrated a significant reduction in FENO at day 15 p < 0.01. No statistically significant difference in plasma cortisol level was observed between AZD7594 and placebo at any dose. AZD7594 was considered safe and well tolerated.
CONCLUSIONS: Two-week treatment with AZD7594 demonstrated a favorable risk-benefit profile in patients with mild to moderate asthma. Further clinical studies are needed to fully characterize AZD7594.
TRIAL REGISTRATION: ClinicalTrials.gov number NCT02479412 .
PMID: 30777086 [PubMed - in process]