ImportanceOnce-weekly insulin icodec could provide a simpler dosing alternative to daily basal insulin in people with type 2 diabetes.ObjectiveTo evaluate the efficacy and safety of once-weekly icodec vs once-daily insulin degludec in people with insulin-naive type 2 diabetes.Design, Setting, and ParticipantsRandomized, double-masked, noninferiority, treat-to-target, phase 3a trial conducted from March 2021 to June 2022 at 92 sites in 11 countries in adults with type 2 diabetes treated with any noninsulin glucose-lowering agents with hemoglobin A1c (HbA1c) of 7%-11% (53-97 mmol/mol).InterventionsParticipants were randomly assigned in a 1:1 ratio to receive either once-weekly icodec and once-daily placebo (icodec group; n = 294) or once-daily degludec and once-weekly placebo (degludec group; n = 294).Main Outcomes and MeasuresThe primary end point was change in HbA1c from baseline to week 26 (noninferiority margin, 0.3% percentage points). Secondary end points included change in fasting plasma glucose from baseline to week 26, mean weekly insulin dose during the last 2 weeks of treatment, body weight change from baseline to week 26, and number of level 2 (clinically significant; glucose level <54 mg/dL) and level 3 (severe; requiring external assistance for recovery) hypoglycemic episodes.ResultsAmong 588 randomized participants (mean [SD] age, 58 [10] years; 219 [37%] women), 564 (96%) completed the trial. Mean HbA1c level decreased from 8.6% (observed) to 7.0% (estimated) at 26 weeks in the icodec group and from 8.5% (observed) to 7.2% (estimated) in the degludec group (estimated treatment difference [ETD], −0.2 [95% CI, −0.3 to −0.1] percentage points), confirming noninferiority (P < .001) and superiority (P = .002). There were no significant differences between the icodec and degludec groups for fasting plasma glucose change from baseline to week 26 (ETD, 0 [95% CI, −6 to 5] mg/dL; P = .90), mean weekly insulin dose during the last 2 weeks of treatment, or body weight change from baseline to week 26 (2.8 kg vs 2.3 kg; ETD, 0.46 [95% CI, −0.19 to 1.10] kg; P = .17). Combined level 2 or 3 hypoglycemia rates were numerically higher in the icodec group than the degludec group from week 0 to 31 (0.31 vs 0.15 events per patient-year exposure; P = .11) and statistically higher in the icodec group from week 0 to 26 (0.35 vs 0.12 events per patient-year exposure; P = .01).Conclusions and RelevanceAmong people with insulin-naive type 2 diabetes, once-weekly icodec demonstrated superior HbA1c reduction to once-daily degludec after 26 weeks of treatment, with no difference in weight change and a higher rate of combined level 2 or 3 hypoglycemic events in the context of less than 1 event per patient-year exposure in both groups.Trial RegistrationClinicalTrials.gov Identifier: NCT04795531
Insulin icodec* (icodec) is a novel once-weekly basal insulin analog in development. This post hoc analysis explored hypoglycemia duration using double-blinded CGM (Dexcom G6®) data from 2 phase 2, randomized, open-label, treat-to-target 16-week trials. One trial compared 3 titration algorithms of icodec vs. insulin glargine U100 (IGlar U100) in 205 insulin-naïve patients with T2D (NCT03951805), the other assessed 154 basal insulin-treated patients with T2D switching from any daily basal insulin to icodec with or without a 100% loading dose vs. IGlar U100 (NCT03922750). In line with ATTD guidelines, a hypoglycemic episode was defined as a CGM period of interstitial glucose (IG) <70 mg/dL for at least 15 min, ending when IG ≥70 mg/dL for at least 15 min. In the titration trial, hypoglycemia duration was similar across all arms: median overall hypoglycemic episode duration (IQR) was 35.0 (20.0, 70.0) min for icodec titrations A (SMBG 80-130 mg/dL ±21 U/wk) and B (80-130 mg/dL ±28 U/wk) and for IGlar U100 (80-130 mg/dL ±4 U/day), and 39.0 (24.0, 70.0) min for icodec titration C (70-108 mg/dL ±28 U/wk). The distribution pattern of hypoglycemic episodes by duration was similar across all treatment arms. Results were similar for nocturnal hypoglycemic episodes. Similarly, in the switch trial, the duration of hypoglycemia was similar between arms, irrespective of loading dose use: median overall hypoglycemic episode duration (IQR) was 40.0 (20.0, 75.0) min for icodec with loading dose, 40.0 (25.0, 80.0) min for icodec without loading dose, and 35.0 (20.0, 60.0) min for IGlar U100.The distribution pattern of hypoglycemic episodes by duration was similar across treatment arms. Similar results were seen for the nocturnal period. In conclusion, CGM-derived hypoglycemic episode duration was similar with icodec vs. IGlar U100 in insulin-naïve and insulin-experienced patients with T2D, regardless of titration algorithm or initial loading dose use. *Proposed INN. Disclosure R. J. Silver: Advisory Panel; Self; Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk. M. Asong: Employee; Self; Novo Nordisk A/S. K. Begtrup: None. M. M. Koefoed: Employee; Self; Novo Nordisk. S. R. Heller: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk, Zealand Pharma A/S, Consultant; Self; Zealand Pharma A/S, Other Relationship; Self; Dexcom, Inc., Eli Lilly and Company, MannKind Corporation, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk. J. Rosenstock: Board Member; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Consultant; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Research Support; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Genentech, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Oramed Pharmaceuticals, Inc., Pfizer Inc., REMD Biotherapeutics, Sanofi.
Background The prognosis of patients with brain metastases (BM) is poor despite advances in our understanding of the underlying pathophysiology. The high incidence of thrombotic complications defines tumor progression and the high mortality rate. We, therefore, postulated that von Willebrand factor (VWF) promotes BM via its ability to induce platelet aggregation and thrombosis. Methods We measured the abundance of VWF in the blood and intravascular platelet aggregates of patients with BM, and determined the specific contribution of endothelial and platelet-derived VWF using in vitro models and microfluidics. The relevance for the brain metastatic cascade in vivo was demonstrated in ret transgenic mice, which spontaneously develop BM, and by the intracardiac injection of melanoma cells. Results Higher levels of plasma VWF in patients with BM were associated with enhanced intraluminal VWF fiber formation and platelet aggregation in the metastatic tissue and peritumoral regions. Platelet activation triggered the formation of VWF multimers, promoting platelet aggregation and activation, in turn enhancing tumor invasiveness. The absence of VWF in platelets, or the blocking of platelet activation, abolished platelet aggregation, and reduced tumor cell transmigration. Anticoagulation and platelet inhibition consistently reduced the number of BM in preclinical animal models. Conclusions Our data indicate that platelet-derived VWF is involved in cerebral clot formation and in metastatic growth of melanoma in the brain. Targeting platelet activation with low-molecular-weight heparins represents a promising therapeutic approach to prevent melanoma BM.
FLT3 is a receptor tyrosine kinase (RTK) that is mutated and constitutively active in 30% of patients with acute myeloid leukemia (AML). Notably, mutations in FLT3 serve as poor prognostic indicator in AML patients. Despite its clinical relevance, the mechanisms of FLT3 subcellular trafficking remain poorly understood. Apart from the canonical downstream signaling cascades within the cytoplasm, accumulating data reveal direct nuclear translocation of RTKs. This alternative signaling pathway suggests that upon nuclear entry, RTKs can influence transcription and regulate gene expression. Interestingly, increased nuclear RTK levels have been linked to advanced tumor stages and poor clinical outcome. Whether or not the same phenomenon occurs in oncogenic FLT3 remains to be elucidated. This study focuses on establishing whether FLT3 undergoes nuclear translocation in AML. Moreover, we aim to understand the underlying subcellular trafficking mechanisms involved. First, the intracellular location of FLT3 was investigated in different human AML cell lines, stably transfected murine cell lines, as well as in primary patient samples. Subcellular fractionation protocols were optimized for each cell type and validated using protein markers for different cellular organelles. The cells were fractionated into cytoplasmic and nuclear fractions and analyzed by immunoblotting, immunofluorescent staining, and confocal imaging. Cells expressing FLT3 internal tandem duplication (FLT3-ITD) mutation show predominant cytoplasmic localization of FLT3. Interestingly, a basal level of FLT3-ITD was also detected in the nuclear fraction independent of ligand stimulation. To determine whether the same thing holds true for wild-type FLT3, AML cell lines which express wild-type FLT3 (FLT3-WT) were stimulated with its ligand for different time periods. FLT3-WT receptor was scarcely present in the nucleus under basal conditions. However, upon stimulation, a transient increase in nuclear FLT3 was observed. Using cell surface biotin labeling, we could verify that the detected nuclear FLT3 comes from the cell surface. Our results further show that nuclear FLT3 is phosphorylated to a certain degree, but that receptor activation is not required for nuclear translocation to occur. To investigate the subcellular trafficking mechanisms involved, the cells were treated with various small molecule inhibitors of cellular trafficking. Nuclear FLT3 levels were attenuated upon inhibition of clathrin and importin β, but stabilized by proteasomal inhibition. Modification of proteins by small ubiquitin-like modifier (SUMO) is a post-translational modification mainly observed in nuclear proteins. Since some RTKs require SUMOylation for nuclear entry, we investigated if this was also true for FLT3. Using immunoprecipitation, we could demonstrate that nuclear FLT3 gets SUMOylated by SUMO-1. To determine whether FLT3 SUMOylation is physiologically relevant, detection of endogenous SUMOylated FLT3 was done without overexpression of components of the SUMO machinery. Taken together, the present study demonstrates a previously uncharacterized post-translational modification and intracellular localization of FLT3. These data provide novel insights on the pathogenesis of AML and possibly new clues to improve targeted treatment of the disease. Additional in vitro studies and clinical data are necessary to establish the functional relevance of FLT3 translocation. On-going studies involve chromatin immunoprecipitation followed by sequencing (ChIP-seq) to gain further understanding on the biological function of nuclear FLT3. Ultimately, we will validate its clinical significance by analyzing nuclear FLT3 in AML patient samples and correlating this with patient outcome. Disclosures Ronnstrand: Acrivon Therapeutics: Consultancy.
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