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Background The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived “alarmin.” Astegolimab, a human IgG2 mAb, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (type 2-high), but limited options are available for patients with low blood eosinophils (type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics. Objectives This study evaluated astegolimab efficacy and safety in patients with severe asthma. Methods This double-blind, placebo-controlled, dose-ranging study (ZENYATTA [A Study to Assess the Efficacy and Safety of MSTT1041A in Participants With Uncontrolled Severe Asthma]) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg doses of astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at week 54. Enrollment caps ensured ∼30 patients who were eosinophil-high (≥300 cells/μL) and ∼95 patients who were eosinophil-low ( Results Overall, adjusted AER reductions relative to placebo were 43% (P = .005), 22% (P = .18), and 37% (P = .01) for 490-mg, 210-mg, and 70-mg doses of astegolimab, respectively. Adjusted AER reductions for patients who were eosinophil-low were comparable to reductions in the overall population: 54% (P = .002), 14% (P = .48), and 35% (P = .05) for 490-mg, 210-mg, and 70-mg doses of astegolimab. Adverse events were similar in astegolimab- and placebo-treated groups. Conclusions Astegolimab reduced AER in a broad population of patients, including those who were eosinophil-low, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated.

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease. Although anti-fibrotic treatments, such as pirfenidone, are available that reduce the rate of disease progression, these medications have limitations in tolerability, and IPF patients still have poor prognoses. GDC-3280, an orally available small molecule that was designed to improve upon pirfenidone's activity, has anti-fibrotic activity in animal models. This first-in-human, phase 1 trial evaluated GDC-3280 to determine its safety, tolerability, and pharmacokinetics (PK). METHODS Single and multiple ascending-doses of GDC-3280 were administered to healthy volunteers in two parts. Part A consisted of 6 treatment groups, each receiving a single, oral dose of GDC-3280 (25-1600 mg) or placebo in the fasted state. Part A also assessed the effect of food and coadministration of a proton pump inhibitor (rabeprazole) on the tolerability and PK of single doses of 400- and 800-mg GDC-3280. Part B consisted of 3 treatment groups who received either 200- or 275-mg GDC-3280 twice daily or 525-mg once daily after a low-fat meal for 7 days. The trial monitored treatment-emergent adverse events (TEAEs) and assessed the pharmacokinetics of GDC-3280 in blood and urine samples. RESULTS Fifty-six subjects (42 GDC-3280, 14 placebo) in Part A and 24 subjects (18 GDC-3280, 6 placebo) in Part B received treatment. No deaths, serious adverse events, or dose-limiting adverse events occurred, and no subjects withdrew due to a TEAE. In both Parts A and B, most TEAEs were mild. The most frequent TEAEs in Part A were headache and nausea. TEAEs occurred more often when GDC-3280 was administered with food. Pretreatment and coadministration with rabeprazole had no effect on GDC-3280 tolerability. In Part B, the most frequent TEAEs were nausea, dizziness, nasal congestion, and cough. Transient, treatment-related increases in serum creatinine occurred at doses greater than 400 mg in Part A (12%-18% from baseline) and after multiple doses in each group in Part B (20%-34% from baseline). GDC-3280 was generally readily absorbed with a median tmax < 4.0 h following single- or repeat-dose oral administration. In Part A, less-than-dose-proportional increases in systemic exposure occurred, and in Part B, dose-proportional increases occurred within the dose range tested. At doses of 200 mg or lower, more than 50%-70% of orally administered doses were recovered in urine as unchanged GDC-3280 when subjects received a single dose of GDC-3280, suggesting renal excretion is one of the major routes of elimination. Administration of single doses of 400- and 800-mg GDC-3280 after a meal caused statistically significant increases in exposure due to increased rates of absorption compared to the fasted state. Pretreatment and coadministration of rabeprazole dosing led to decreases in exposure compared to GDC-3280 alone, indicating a weak drug-drug interaction. Following repeat dose administration, steady-state plasma concentrations of GDC-3280 were achieved within 2 days with an apparent terminal half-life (t1/2) between 5 and 6 h. CONCLUSIONS Single and multiple doses of GDC-3280 were generally well tolerated, with acceptable safety and pharmacokinetic profiles that support twice-daily, oral administration with food in future clinical trials.

Background Inhibition of interleukin (IL)-13, a Type 2 inflammatory mediator in asthma, improves lung function and reduces exacerbations; however, more effective therapies are needed. A subset of asthma patients also exhibits elevated IL-17, which is associated with greater disease severity, neutrophilic inflammation, and steroid resistance. BITS7201A is a novel, humanized bispecific antibody that binds and neutralizes both IL-13 and IL-17. Methods Safety, pharmacokinetics, and immunogenicity of BITS7201A were evaluated in a phase 1 study. Part A was a single ascending-dose design with 5 cohorts: 30-, 90-, and 300-mg subcutaneous (SC), and 300- and 750-mg intravenous (IV). Part B was a multiple ascending-dose design with 3 cohorts: 150-, 300-, and 600-mg SC every 4 weeks × 3 doses. Both parts enrolled approximately 8 healthy volunteers into each cohort (6 active: 2 placebo). Part B included an additional cohort of patients with mild asthma (600-mg SC). Results Forty-one subjects (31 active, 10 placebo) and 26 subjects (20 active, 6 placebo) were enrolled into Parts A and B, respectively. The cohort with mild asthma patients was terminated after enrollment of a single patient. No deaths, serious adverse events, or dose-limiting adverse events occurred. In Part A, 12 active (39%) and 5 placebo subjects (50%), and in Part B, 6 active (30%) and 3 placebo subjects (50%) experienced at least 1 treatment-emergent adverse event (TEAE). The most common AEs were fatigue (n = 3) and influenza-like illness (n = 2). One injection-site reaction was reported. Two subjects with elevated blood eosinophil counts at baseline had transient elevations in blood eosinophils (≥Grade 2, > 1500 cells/μL). In Parts A and B, 16 of 30 (53%) and 16 of 17 (94%) active subjects, respectively, tested positive for anti-drug antibodies (ADAs). No anaphylaxis or hypersensitivity events occurred. BITS7201A exhibited single- and multiple-dose pharmacokinetic characteristics consistent with an IgG monoclonal antibody; exposure generally increased dose-proportionally. Postdose elevations of the serum pharmacodynamic biomarkers, IL-17AA and IL-17FF, occurred, confirming target engagement. Conclusions BITS7201A was well tolerated, but was associated with a high incidence of ADA formation. Trial registration ClinicalTrials.gov, NCT02748642; registered April 6, 2016 (retrospectively registered).

Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adults after renal, cardiac, and liver transplantation. This study investigated the safety, tolerability, and pharmacokinetics of MMF suspension in pediatric renal allograft recipients. One hundred renal allograft recipients were enrolled into three age groups (33 patients, 3 months to

We compared a coronary risk profile (developed by the Framingham Study) based on age, sex, cigarette smoking, glucose intolerance, left ventricular hypertrophy, systolic blood pressure and serum cholesterol to angiographically determined severity of coronary-artery disease in 158 consecutive patients undergoing cardiac catheterization. A profile of 1.0 indicated average relative risk. Risk profiles for 105 patients with angiographically documented coronary-artery disease was 1.52 whereas it was 1.08 for the group without coronary disease (P