Augmentation therapy with the approved dose of 60 mg/kg weekly intravenous (IV) alpha-1 proteinase inhibitor (alpha1-PI), achieves a trough serum level of 11 μM in individuals with alpha-1 antitrypsin deficiency (AATD), yet this is still below the level observed in healthy individuals. This study assessed the safety and pharmacokinetic profile of weekly infusions of a 120 mg/kg dose of alpha1-PI in 30 adults with AATD. Subjects with symptomatic, genetically determined (genotypes PI*ZZ, PI*Z(null), PI*(null)(null) or PI*(Z)Mmalton) AATD were randomly assigned to weekly infusions of 60 or 120 mg/kg alpha1-PI (Prolastin-C®) for 8 weeks before crossing over to the alternate dose for 8 weeks. Adverse events (AEs) (including exacerbations), vital signs, pulmonary function tests, and laboratory assessments were recorded. Pharmacokinetic measurements included AUC0-7days, Cmax, trough, tmax, and t1/2, based on serum alpha1-PI concentrations. In total for both treatments, 112 AEs were reported, with exacerbation of COPD being the most frequent, consistent with the subjects' diagnoses. Mean steady-state serum alpha1-PI concentrations following 120 mg/kg weekly IV alpha1-PI were higher than with the 60 mg/kg dose and mean trough concentrations were 27.7 versus 17.3 μM, respectively. Dose proportionality was demonstrated for AUC0-7days and Cmax, with low inter-subject variability. The 120 mg/kg alpha1-PI weekly dose was considered to be safe and well tolerated, and provided more favorable physiologic alpha1-PI serum levels than the currently recommended 60 mg/kg dose. The effect of this dosing regimen on slowing and/or preventing emphysema progression in subjects with AATD warrants further investigation.

Since the death of Chief Opechankanough >350 years ago, the myasthenia gravis (MG) community has gained extensive knowledge about MG and how to treat it. This review highlights key milestones in the history of treatment and discusses the current "golden age" of clinical trials. Although originally thought by many clinicians to be a disorder of hysteria and fluctuating weakness without observable cause, MG is one the most understood autoimmune neurologic disorders. However, studying it in clinical trials has been challenging due to the fluctuating nature of the medical condition which impacts MG clinical outcomes. Clinical trials must also account for the possibility of a placebo effect. Because MG is a rare incurable autoimmune disorder, it limits the number of potential patients available to participate in clinical trials. In the last 15 years, however, significant progress has been made with MG randomized clinical trials, resulting in a new drug (eculizumab) for physicians' treatment repertoire and an old technique (thymectomy) confirmed effective for MG. Some of the therapies (eg, thymectomy, corticosteroids, plasma exchange, and intravenous immunoglobulin [IVIg]) have survived the test of time. Others (eg, eculizumab and neonatal Fc receptor inhibitor) are novel and hold promise.

Background Inhaled alpha1-proteinase inhibitor (PI) is known to reduce neutrophil elastase burden in some patients with CF. This phase 2a study was designed to test inhaled Alpha-1 HC, a new aerosolized alpha1-PI formulation, in CF patients. Methods We performed a randomized, double-blind, placebo-controlled study and evaluated the safety of 100 or 200 mg of inhaled Alpha-1 HC once daily for 3 weeks in subjects with CF. Thirty adult subjects were randomized in a 2:1 ratio to receive Alpha-1 HC or placebo. Results Drug delivery was confirmed by a dose-dependent increase in the sputum alpha1-PI. Seven (20.0%) of the 35 adverse events in the 100-mg dose group, 3 (13.0%) of 23 in the 200-mg dose group, and 4 (14.3%) of 28 in the placebo group were drug-related in these subjects. One serious adverse event occurred in 1 subject within each group. Conclusions Alpha-1 HC inhalation was safe and well tolerated.

NCT01983241.