Adolescent boys with constitutional delay of growth and puberty grow faster than patients with organic growth hormone deficiency.

OBJECTIVE: Constitutional delay of growth and puberty (CDGP) is a tempo variant with a good prognosis. Healthy late-maturing adolescents grow slower than postulated by age-related references, and therefore, CDGP is frequently confused with growth hormone deficiency (GHD). For differential diagnosis, height velocity references for CDGP are needed. DESIGN AND PATIENTS: Here, we provide height velocity data for late-maturing boys based on mixed longitudinal and cross-sectional observations in a group of 38 German adolescents with proven CDGP and compare them with cross-sectional observations in a group of 164 adolescents with organic GHD from the National Cooperative Growth Study registry. RESULTS: In the critical age interval from 13.4 to 14.9 years, the growth of prepubertal adolescents with CDGP was faster (mean/median height velocity, 5.2/5.4 cm/years; quartiles, 4.4-6.2 cm/years) than that of prepubertal adolescents with organic GHD (3.5/3.2 cm/years; quartiles, 2.0-4.4 cm/years) in the cross-sectional analysis (p < .0001). Based on our mixed longitudinal and cross-sectional analysis, the height velocity of adolescent boys with CDGP exceeded previous model calculations on average by 1.0 cm. CONCLUSIONS: In conclusion, prepubertal adolescents with CDGP grow faster than patients with organic GHD. Previous model estimates underestimated height velocity of boys with CDGP.

Changes in Manufacturing Processes of Biologic Therapies Can Alter the Immunogenicity Profile of the Product.

Manufacturing process changes may alter the characteristics of a protein therapeutic. In 2009, somatropin (version 1.0), a recombinant human growth hormone therapeutic, underwent a manufacturing update (version 1.1). The immunogenicity of somatropin version 1.1 as a daily subcutaneous injection was evaluated in 2014 in a prospective, open-label, single-arm clinical study of treatment-naive pediatric patients with idiopathic human growth hormone deficiency for 1 year. The primary end point was the proportion of patients who developed antidrug antibodies (ADAs) after treatment. Eighty-two patients were enrolled. The mean (SD) treatment duration was 347 (53) days. The incidence of ADAs was 3.7%. No neutralizing antibodies were observed in the three patients with ADA-positive samples. Two patients (2.6%) had growth attenuation, but they were not ADA positive. The manufacturing changes for somatropin version 1.1 resulted in a similar safety and efficacy profile compared with somatropin version 1.0 and a different immunogenicity profile with a lower incidence of ADAs.

Cardiovascular and cerebrovascular events among patients receiving omalizumab: Results from EXCELS, a prospective cohort study in moderate to severe asthma.

BACKGROUND: EXCELS, a postmarketing observational cohort study, was a commitment to the US Food and Drug Administration to assess the long-term safety of omalizumab in an observational setting, focusing predominantly on malignancies. OBJECTIVE: The aim of this study was to examine a potential association between omalizumab and cardiovascular (CV)/cerebrovascular (CBV) events in EXCELS. METHODS: Patients (≥12 years of age) with moderate to severe allergic asthma and who were being treated with omalizumab (n = 5007) or not (n = 2829) at baseline were followed up for ≤5 years. Analyses included overall CV/CBV events, but focused on the subset of arterial thromboembolic events (ATEs), comprising CV death, myocardial infarction, ischemic stroke, transient ischemic attack, and unstable angina. A prespecified analysis of the end point of ATE was conducted to control for available potential confounders. A blinded independent expert panel adjudicated all events. RESULTS: At baseline, the 2 cohorts had similar demographic characteristics, but severe asthma was more common in the omalizumab versus the non-omalizumab group (50% vs 23%). Omalizumab-treated patients had a higher rate of CV/CBV serious adverse events (13.4 per 1,000 person years [PYs]) than did non-omalizumab-treated patients (8.1 per 1,000 PYs). The ATE rates per 1,000 PYs were 6.66 (101 patients/15,160 PYs) in the omalizumab cohort and 4.64 (46 patients/9,904 PYs) in the non-omalizumab cohort. After control for available confounding factors, the hazard ratio was 1.32 (95% CI, 0.91-1.91). CONCLUSION: This observational study demonstrated a higher incidence rate of CV/CBV events in the omalizumab versus the non-omalizumab cohort. Differences in asthma severity between cohorts likely contributed to this imbalance, but some increase in risk cannot be excluded.

Efficacy and safety of omalizumab in patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on H1 antihistamines: a randomized, placebo-controlled study.

ASTERIA I was a 40-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of subcutaneous omalizumab as add-on therapy for 24 weeks in patients with chronic idiopathic urticaria/spontaneous urticaria (CIU/CSU) who remained symptomatic despite H1 antihistamine treatment at licensed doses. Patients aged 12-75 years with CIU/CSU who remained symptomatic despite treatment with approved doses of H1 antihistamines were randomized (1:1:1:1) in a double-blind manner to subcutaneous omalizumab 75 mg, 150 mg, or 300 mg or placebo every 4 weeks for 24 weeks followed by 16 weeks of follow-up. The primary end point was change from baseline in weekly itch severity score (ISS) at week 12. Among randomized patients (N=319: placebo n=80, omalizumab 75 mg n=78, 150 mg n=80, 300 mg n=81), 262 (82.1%) completed the study. Compared with placebo (n=80), mean weekly ISS was reduced from baseline to week 12 by an additional 2.96 points (95% confidence interval (CI): -4.71 to -1.21; P=0.0010), 2.95 points (95% CI: -4.72 to -1.18; P=0.0012), and 5.80 points (95% CI: -7.49 to -4.10; P<0.0001) in the omalizumab 75-mg (n=77), 150-mg (n=80), and 300-mg groups (n=81), respectively. The omalizumab 300-mg group met all nine secondary end points, including a significant decrease in the duration of time to reach minimally important difference response (⩾5-point decrease) in weekly ISS (P<0.0001) and higher percentages of patients with well-controlled symptoms (urticaria activity score over 7 days (UAS7) ⩽6: 51.9% vs. 11.3%; P<0.0001) and complete response (UAS7=0: 35.8% vs. 8.8%; P<0.0001) versus placebo. During the 24-week treatment period, 2 (2.9%), 3 (3.4%), 0, and 4 (5.0%) patients in the omalizumab 75-mg, 150-mg, 300-mg, and placebo groups, respectively, experienced a serious adverse event. Omalizumab 300 mg administered subcutaneously every 4 weeks reduced weekly ISS and other symptom scores versus placebo in CIU/CSU patients who remained symptomatic despite treatment with approved doses of H1 antihistamines.

Incidence of malignancy in patients with moderate-to-severe asthma treated with or without omalizumab.

BACKGROUND: The Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS) assessed the long-term safety of omalizumab in a clinical practice setting as part of a phase IV US Food and Drug Administration postmarketing commitment. OBJECTIVE: We sought to evaluate long-term safety in omalizumab-treated and nonomalizumab-treated patients. Primary outcome measures focused on assessment of malignancies. METHODS: EXCELS was a prospective observational cohort study in patients (≥12 years of age) with moderate-to-severe allergic asthma. There were 2 cohorts: omalizumab (taking omalizumab at baseline) and nonomalizumab (no history of omalizumab treatment). Primary outcomes included all confirmed, incident, study-emergent primary malignancies (malignancies), including and excluding nonmelanoma skin cancer (NMSC); all malignancies were externally adjudicated. RESULTS: The omalizumab cohort had a higher proportion of patients with severe asthma compared with the nonomalizumab cohort (50.0% vs 23.0%). Median follow-up was approximately 5 years for both cohorts. Crude malignancy rates were similar in the omalizumab and nonomalizumab cohorts, with a rate ratio of 0.84 (95% CI, 0.62-1.13) for all malignancies and 0.98 (95% CI, 0.71-1.36) for all malignancies excluding NMSC. Kaplan-Meier plots of time to first confirmed study-emergent primary malignancy were similar for the 2 treatment cohorts. Cox proportional hazards modeling, adjusting for confounders and risk factors, resulted in a hazard ratio (omalizumab vs nonomalizumab) of 1.09 (95% CI, 0.87-1.38) for all malignancies and 1.15 (95% CI, 0.83-1.59) for all malignancies excluding NMSC. CONCLUSION: Results from EXCELS suggest that omalizumab therapy is not associated with an increased risk of malignancy.

Baseline characteristics of patients enrolled in EXCELS: a cohort study.

BACKGROUND: The Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS) is a unique opportunity to evaluate the prospective, long-term clinical safety and effectiveness of the anti-IgE antibody omalizumab (Xolair) in real-world clinical practice. OBJECTIVES: To describe the study design and study cohorts of EXCELS at baseline and to compare the characteristics of this population with other large asthma cohorts. METHODS: Patients with moderate-to-severe persistent asthma and a positive skin test result or in vitro reactivity to a perennial aeroallergen were eligible for EXCELS. Two cohorts of patients with asthma were enrolled: those treated with omalizumab and those not treated with omalizumab. We analyzed baseline demographic and clinical characteristics, including asthma history and control and allergy history. RESULTS: Large proportions of patients enrolled in EXCELS had historically severe and poorly or not well-controlled asthma at the time of enrollment, objective evidence of airway obstruction, a history of long-term oral corticosteroid use, and/or other allergic disorders. Minor differences were observed between the omalizumab and nonomalizumab cohorts. Our total patient cohort was generally similar to other large cohorts. In a subgroup analysis, patients who had received omalizumab within 7 days before enrollment had more severe asthma and greater degrees of impairment at baseline than nonomalizumab patients. CONCLUSIONS: This study of baseline characteristics in EXCELS offers a unique opportunity to better understand the history of allergic patients with moderate-to-severe asthma in a real-world treatment setting. This analysis of EXCELS baseline data sets the foundation for long-term assessment of the safety and effectiveness of omalizumab.