NZ Respiratory & Sleep Institute

Alpha-1 antitrypsin deficiency (AATD) is characterized by low alpha-1 antitrypsin (AAT) levels, predisposing individuals to lung disease. The standard of care, plasma-derived AAT (pdAAT), is delivered as weekly infusions to maintain serum AAT concentrations ≥11µM (≈50% of those in healthy individuals). INBRX-101, a recombinant human AAT-Fc fusion protein, was designed to have a longer half-life and achieve higher AAT levels than pdAAT. In this phase 1 dose-escalation study (N=31), adults with AATD received 1 dose (part 1) or 3 doses (part 2) of 10 (part 1), 40, 80, or 120mg/kg INBRX-101 every 3 weeks (Q3W) via intravenous infusion. The primary endpoint was safety and tolerability. Secondary endpoints were pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of INBRX-101. INBRX-101 was well tolerated. Most treatment-emergent adverse events were grade ≤2. In part 2 (n=18; each dose, n=6), dose-related increases in serum functional AAT (fAAT) were observed; mean fAAT levels remained above the 21 µM target for up to 4 weeks after the final dose in the 120-mg/kg cohort. Antidrug antibodies had no meaningful impact on PK or PD. INBRX-101 was detected in pulmonary epithelial lining fluid (PELF) from all patients assessed (n=11), and PELF fAAT increased after dosing. PK/PD modeling projected steady-state serum fAAT ≥21µM at 120 mg/kg Q3W (average concentration ≈43µM; trough concentration ≈28µM) and Q4W (≈34µM; ≈21µM). The favorable safety profile and ability to maintain serum fAAT levels >21µM with extended-interval dosing, support a phase 2 trial evaluating Q3W and Q4W dosing of INBRX-101.

Editorial

An immobility reflex may be induced in fish by a vigorous flow of water through the branchial chamber. The reflex was observed in 22 species representing bony and cartilaginous fishes from diverse habitats, and was invariably characterised by loss of caudal muscle tone and limp posture. The immobilised state may be maintained for many hours, and revival is instantaneous. The critical flow rate for induction increases with increasing body size in the snapper, Pagrus auratus, and heart rate falls below the resting rate. In addition, haematological parameters, and plasma lactate after 6 h were typical of resting fish. Although the mechanism is unclear, and the selective advantage for the fish unknown, pressure-sensitive receptors in the branchial chamber are likely to be involved. Application in live fish transport, and recovery from handling and exercise stressors is suggested.

Abstract Summary information is presented on faults that have been evident in papers that have been refereed statistically since 1983. Most problems that are identified when papers are refereed, whether by a biological or by a statistical referee, turn on the quality and interpretation of the data. A common fault is inadequate explanation of the experimental design. Other faults were: inappropriate use of correlations; failure to make coarse checks on statistical assumptions; the confusion of different strata of variation; and use of individual significance tests where a trend or response surface analysis was required.

Existing classifications of Tenebrionidae are reviewed briefly. The inclusion of the families Alleculidae, Lagriidae, and Nilionidae in Tenebrionidae is confirmed. The splitting off from this complex of a family, Tentyriidae, by Doyen is discussed and rejected. Various taxa which had been included in Tenebrionidae are excluded, amongst which Syrphetodes, Brouniphylax, Exohadrus, Arthopus, Cotulades, Docalis, and Latometus (=Elascus) have not previously been formally excluded. A new family, Archeocrypticidae, is established and defined briefly for Archeocrypticus, Sivacrypticus, and Enneboeus. Data from matrices based on adult and larval characters comparing Tenebrionidae with most other families of Tenebrionoidea (=Heteromera) are presented for derived characters in common, and for overall similarity. The families most closely related to Tenebrionidae according to these data are Zopheridae, Chalcodryidae, Merycidae, Archeocrypticidae, Synchroidae, Colydiidae, and Monommatidae; none is very close to Tenebr...