Distribution, habitats, phenology and conservation of New Caledonian Odonata.

Compared to other archipelagos of the Pacific, the New Caledonian Odonata fauna is rich and diverse with 56 valid species or subspecies (23 endemics, 41%) from eight families (four Zygoptera: Argiolestidae, Coenagrionidae, Isostictidae, Lestidae, and four Anisoptera: Aeshnidae, Corduliidae, Synthemistidae, Libellulidae) and 31 genera (including four endemics, 13%). In Zygoptera, we record 19 species including 12 endemics (63%), and among Anisoptera, we record 37 species or subspecies, including 11 endemics (30%). We removed five species from the list that had been erroneously recorded as occurring in New Caledonia: Tramea carolina (Linnaeus, 1763), Austroargiolestes icteromelas (Selys-Longchamps, 1862), Ischnura torresiana Tillyard, 1913, Xiphiagrion cyanomelas Selys-Longchamps, 1876 and Hemicordulia oceanica Selys-Longchamps, 1871. The occurrence of Tramea limbata (Desjardins, 1835) appears also doubtful, but we were unable to clarify to which taxon this record referred hence we excluded it from our update. From a biogeographic perspective, the New Caledonian fauna has mostly Australian affinities with some connections with southeast Asia and the Pacific region. We provide for each species, whenever information was available, a distribution map with a brief review of its known ecology, behaviour and phenology. We also evaluated each species' conservation status, in light of known threats (range restriction, scarcity and human activity including altered water flow). We consider seventeen species (30%) endangered. The most immediate threats concern water pollution including alteration to the flow of water courses caused by mining, deforestation and fires. Invasive species, such as alien fish, may be predators of concern for odonata larva, although this has not yet been proven in New Caledonia.

Population pharmacokinetic analysis of danvatirsen supporting flat dosing switch.

Danvatirsen is a Generation 2.5 antisense oligonucleotide under clinical development. Population PK modelling was conducted using data from 3 available danvatirsen Phase I/II studies in oncology patients to investigate the impact of flat dosing on exposure compared to ideal body weight-based dosing. A total of 126 patients who received danvatirsen doses ranging from 1 to 4 mg/kg as monotherapy or in combination with durvalumab, most at 3 mg/kg (n = 70), was used in the danvatirsen population PK analysis. A 2-compartment model with linear elimination described the data well. Covariate analysis revealed ideal body weight was not a significant covariate on the PK of danvatirsen; nor was age, sex or race. The model-based simulation suggested that steady state weekly AUC and Cmax were very similar between 3 mg/kg and 200 mg flat dosing (geometric mean of AUC: 62.5 vs. 63.4 mg h/L and Cmax: 26.2 vs. 26.5 mg/L for two dose groups) with slightly less overall between-subject variability in the flat dosing regimen. The switch to flat dosing was approved by multiple regulatory agencies, including FDA, EMA, PMDA and ANSM. Several ongoing studies have been evaluating flat dosing. Interim analysis from an ongoing study (D5660C00016, NCT03421353) has shown the observed steady state concentration from 200 mg flat dose is in agreement with the model predictions. The population PK model could be further utilized in subsequent exposure-response efficacy and safety modelling.

STAT3 antisense oligonucleotide AZD9150 in a subset of patients with heavily pretreated lymphoma: results of a phase 1b trial.

BACKGROUND: The Janus kinase (JAK) and signal transduction and activation of transcription (STAT) signaling pathway is an attractive target in multiple cancers. Activation of the JAK-STAT pathway is important in both tumorigenesis and activation of immune responses. In diffuse large B-cell lymphoma (DLBCL), the transcription factor STAT3 has been associated with aggressive disease phenotype and worse overall survival. While multiple therapies inhibit upstream signaling, there has been limited success in selectively targeting STAT3 in patients. Antisense oligonucleotides (ASOs) represent a compelling therapeutic approach to target difficult to drug proteins such as STAT3 through of mRNA targeting. We report the evaluation of a next generation STAT3 ASO (AZD9150) in a non-Hodgkin's lymphoma population, primarily consisting of patients with DLBCL. METHODS: Patients with relapsed or treatment refractory lymphoma were enrolled in this expansion cohort. AZD9150 was administered at 2 mg/kg and the 3 mg/kg (MTD determined by escalation cohort) dose levels with initial loading doses in the first week on days 1, 3, and 5 followed by weekly dosing. Patients were eligible to remain on therapy until unacceptable toxicity or progression. Blood was collected pre- and post-treatment for analysis of peripheral immune cells. RESULTS: Thirty patients were enrolled, 10 at 2 mg/kg and 20 at 3 mg/kg dose levels. Twenty-seven patients had DLBCL. AZD9150 was safe and well tolerated at both doses. Common drug-related adverse events included transaminitis, fatigue, and thrombocytopenia. The 3 mg/kg dose level is the recommended phase 2 dose. All responses were seen among DLBCL patients, including 2 complete responses with median duration of response 10.7 months and 2 partial responses. Peripheral blood cell analysis of three patients without a clinical response to therapy revealed a relative increase in proportion of macrophages, CD4+, and CD8+ T cells; this trend did not reach statistical significance. CONCLUSIONS: AZD9150 was well tolerated and demonstrated efficacy in a subset of heavily pretreated patients with DLBCL. Studies in combination with checkpoint immunotherapies are ongoing. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT01563302 . First submitted 2/13/2012.