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Pharmacokinetics and safety of capmatinib with food in patients with MET-dysregulated advanced solid tumors
No full textAbstract
Purpose: In GEOMETRY mono-1, the potent and selective MET inhibitor capmatinib had considerable activity in METex14-mutated metastatic non–small cell lung cancer at a dose of 400 mg twice daily (bid). The current recommended dose is 400 mg bid in tablet formulation, with or without food. Herein, we report the pharmacokinetics (PK), safety, and tolerability of capmatinib 300 and 400 mg bid given with food in MET-dysregulated advanced solid tumors.
Methods: This multicenter, open-label, phase 1 study enrolled adult patients with MET-dysregulated advanced solid tumors. In the dose-escalation phase, capmatinib tablets were orally administered at a dose of 300 mg bid with food; if tolerated, the dose-escalation cohort of 400 mg bid was to be opened to enrollment. In the expansion phase, patients were to be enrolled at the higher of the tolerated doses. Tablets were taken within 30 minutes of an unrestricted meal type, except on cycle 1 day 1 (C1D1) and C1D7, when they were given with a high-fat meal. The primary objectives were to determine the higher of the tolerated study doses and assess PK, with a secondary objective of safety.
Findings: Overall, 35 patients (300 mg bid, n=8; 400 mg bid, n=27) with MET-dysregulated advanced solid tumors were enrolled; all patients had received prior antineoplastic therapy and the most common primary site was lung (45.7%). Among PK-evaluable patients, the median time to peak plasma concentration (Tmax) for capmatinib after administration with a high-fat meal (on C1D1/C1D7) was 4.0‒5.6 hours across doses. At steady state (C1D7), capmatinib accumulation was low across dose levels (geometric mean of accumulation ratios 1.29–1.69), with an increase in exposure from 300 to 400 mg bid (AUClast geometric mean 8660 vs 16800 ng*h/mL; Cmax geometric mean 1550 vs 3050 ng/mL). There were no occurrences of dose-limiting toxicity. All patients experienced at least one adverse event (AE) and treatment-related AEs occurred in 28 patients (80%; 300 mg bid, n=6; 400 mg bid, n=22), the most frequent of which were fatigue (37.1%) and nausea (34.3%).
Implications: Capmatinib tablet formulation at a dose of up to 400 mg bid with food is well tolerated in patients with MET-dysregulated advanced solid tumors, with safety observations consistent with the existing profile under fasted conditions. These findings support the capmatinib dosing recommendation of 400 mg bid with or without food
Prostaglandin D2 metabolites activate asthmatic patient-derived type 2 innate lymphoid cells and eosinophils via the DP2 receptor.
No full textProstaglandin D2 (PGD2) signaling via prostaglandin D2 receptor 2 (DP2) contributes to atopic and non-atopic asthma. Inhibiting DP2 has shown therapeutic benefit in certain subsets of asthma patients, improving eosinophilic airway inflammation. PGD2 metabolites prolong the inflammatory response in asthmatic patients via DP2 signaling. The role of PGD2 metabolites on eosinophil and ILC2 activity is not fully understood.Eosinophils and ILC2s were isolated from peripheral blood of atopic asthmatic patients. Eosinophil shape change, ILC2 migration and IL-5/IL-13 cytokine secretion were measured after stimulation with seven PGD2 metabolites in presence or absence of the selective DP2 antagonist fevipiprant.Selected metabolites induced eosinophil shape change with similar nanomolar potencies except for 9α,11β-PGF2. Maximal values in forward scatter of eosinophils were comparable between metabolites. ILC2s migrated dose-dependently in the presence of selected metabolites except for 9α,11β-PGF2 with EC50 values ranging from 17.4 to 91.7 nM. Compared to PGD2, the absolute cell migration was enhanced in the presence of Δ12-PGD2, 15-deoxy-Δ12,14-PGD2, PGJ2, Δ12-PGJ2 and 15-deoxy-Δ12,14-PGJ2. ILC2 cytokine production was dose dependent as well but with an average sixfold reduced potency compared to cell migration (IL-5 range 108.1 to 526.9 nM, IL-13 range: 125.2 to 788.3 nM). Compared to PGD2, the absolute cytokine secretion was reduced in the presence of most metabolites. Fevipiprant dose-dependently inhibited eosinophil shape change, ILC2 migration and ILC2 cytokine secretion with (sub)-nanomolar potencies.Prostaglandin D2 metabolites initiate ILC2 migration and IL-5 and IL-13 cytokine secretion in a DP2 dependent manner. Our data indicate that metabolites may be important for in vivo eosinophil activation and ILC2 migration and to a lesser extent for ILC2 cytokine secretion
Siponimod (BAF312) penetrates, distributes, and acts in the central nervous system: Preclinical insights.
No full textSiponimod (BAF312), a selective S1P1/S1P5 agonist, reduces disability progression in secondary progressive MS. Recent observations suggest it could act via S1P1/S1P5-dependent anti-inflammatory and pro-myelination effects on CNS-resident cells.Generate preclinical evidence confirming siponimod's CNS penetration and activity.Siponimod's CNS penetration and distribution was explored in rodents and non-human primates (NHPs) using: Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS), quantitative whole-body autoradiography (QWBA) using 14C-radiolabeled siponimod or non-invasive single-photon emission CT (SPECT) with a validated 123I-radiolabeled siponimod analog. Functional CNS activity was investigated by S1P1 receptor quantification in brain homogenates.In mice/rats, siponimod treatments achieved dose-dependent efficacy and dose-proportional increase in drug blood levels, with mean brain/blood drug-exposure ratio (Brain/BloodDER) of 6-7. Efficacy in rat brain tissues was revealed by a dose-dependent reduction in brain S1P1 levels. QWBA distribution analysis in rats indicated that [14C]siponimod related radioactivity could readily penetrate CNS, with particularly high uptakes in white matter of cerebellum, corpus callosum, and medulla oblongata versus lower exposures in other areas such as olfactory bulb. SPECT monitoring in NHPs revealed CNS distribution with a brain/bloodDER of ∼6, as in rodents.Findings demonstrate siponimod's CNS penetration and distribution across species, with high translational potential to human
TRAWLING: a Transcriptome Reference Aware of spLIciNG events
No full textAlternative splicing is critical for human gene expression regulation and plays an important role in multiple human diseases. In this context, RNA sequencing has emerged as powerful approach to detect alternative splicing events.
In parallel, fast alignment-free methods have emerged as a viable alternative to quantify gene and transcript level abundance from RNAseq data. However, the ability to detect differential splicing events is dependent on the annotation of the transcript reference provided by the user.
Here, we introduce a new reference transcriptome aware of splicing events, TRAWLING, which simplifies the detection of aberrant splicing events in a fast and simple way. In addition, we evaluate the performances and the benefits of aligning transcriptome data to TRAWLING using three different RNA sequencing datasets: whole transcriptome sequencing, single cell RNA sequencing and Digital RNA with pertUrbation of Genes.
Collectively, our comprehensive evaluation underlines the value of using TRAWLING in transcriptomic data analysis
The CRL4 DCAF1 cullin‐RING ubiquitin ligase is activated following a switch in oligomerization state
No full textThe cullin-4-based RING-type (CRL4) family of E3 ubiquitin ligases functions together with dedicated substrate receptors. Out of the ˜29 CRL4 substrate receptors reported, the DDB1- and CUL4-associated factor 1 (DCAF1) is essential for cellular survival and growth, and its deregulation has been implicated in tumorigenesis. We carried out biochemical and structural studies to examine the structure and mechanism of the CRL4DCAF1 ligase. In the 8.4 Å cryo-EM map of CRL4DCAF1 , four CUL4-RBX1-DDB1-DCAF1 protomers are organized into two dimeric sub-assemblies. In this arrangement, the WD40 domain of DCAF1 mediates binding with the cullin C-terminal domain (CTD) and the RBX1 subunit of a neighboring CRL4DCAF1 protomer. This renders RBX1, the catalytic subunit of the ligase, inaccessible to the E2 ubiquitin-conjugating enzymes. Upon CRL4DCAF1 activation by neddylation, the interaction between the cullin CTD and the neighboring DCAF1 protomer is broken, and the complex assumes an active dimeric conformation. Accordingly, a tetramerization-deficient CRL4DCAF1 mutant has higher ubiquitin ligase activity compared to the wild-type. This study identifies a novel mechanism by which unneddylated and substrate-free CUL4 ligases can be maintained in an inactive state
High Density Bioprocessing of Human Pluripotent Stem Cells by Metabolic Control and in Silico Modeling
No full textno abstrac
Chemo-proteomics exploration of HDAC degradability by small molecule degraders.
No full textTargeted protein degradation refers to the use of small molecules that recruit a ubiquitin ligase to a target protein for ubiquitination and subsequent proteasome-dependent degradation. While degraders have been developed for many targets, key questions regarding degrader development and the consequences of acute pharmacological degradation remain, specifically for targets that exist in obligate multi-protein complexes. Here, we synthesize a pan-histone deacetylase (HDAC) degrader library for the chemo-proteomic exploration of acute degradation of a key class of chromatin-modifying enzymes. Using chemo-proteomics, we not only map the degradability of the zinc-dependent HDAC family identifying leads for targeting HDACs 1-8 and 10 but also explore important aspects of degrading epigenetic enzymes. We discover cell line-driven target specificity and that HDAC degradation often results in collateral loss of HDAC-containing repressive complexes. These findings potentially offer a new mechanism toward controlling chromatin structure, and our resource will facilitate accelerated degrader design and development for HDACs
Bimagrumab, an Activin Type II Receptor Antagonist, for the Treatment of Obesity and Type 2 Diabetes: A Randomized ClinicalTrial
No full textIMPORTANCE
Antibody blockade of the activin type II receptor (ActRII) signaling pathway stimulates skeletal muscle growth. Previous clinical studies suggest that ActRII inhibition with the human monoclonal antibody bimagrumab also promotes excess adipose tissue loss and improves insulin resistance.
OBJECTIVE
This multicenter randomized study determined the efficacy and safety of bimagrumab on body
composition and glycemic control in adults with overweight and obesity and who had type 2 diabetes.
DESIGN
This was a double-blind, placebo-controlled 48-week phase 2 study.
SETTING
Nine sites in the United States and United Kingdom participated in the study from February 2017 through May 2019.
PARTICIPANTS
Adults (n=75) with body mass index 28–40 kg/m2 64 who had type 2 diabetes and glycated hemoglobin levels 6.5%–10.0%.
INTERVENTION
Participants were randomized to intravenous bimagrumab or placebo every 4 weeks for 48 weeks. All patients received diet and exercise counseling.
MAIN OUTCOME MEASURES
The primary endpoint was least squares mean change from baseline (80% CI) to Week 48 in total body fat mass. Key secondary and exploratory endpoints included changes in lean mass, waist circumference, glycated hemoglobin, and body weight from baseline to Week 48.
RESULTS
At Week 48, 77.3% of patients completed the study. Total body fat mass decreased by 21% in
bimagrumab-treated patients vs 0.5% in those treated with placebo (P<0.001). Secondary endpoints for bimagrumab vs placebo included a lean mass increase of 3.6% vs a decrease of 0.8% (P<0.001); waist circumference decrease of 9.00 cm vs increase of 0.45 cm (P<0.001); glycated hemoglobin reduction of 0.76 percentage points vs 0.04 percentage points (P=0.005); and weight reduction of 6.5% vs 0.8% (P<0.001). Bimagrumab was safe and well-tolerated.
CONCLUSIONS AND RELEVANCE
ActRII blockade with bimagrumab led to marked loss of total body fat, gain in lean mass, and metabolic improvements over 48 weeks in patients with overweight and obesity who had type 2 diabetes. ActRII pathway inhibition provides a novel approach for the pharmacologic management of excess adiposity and accompanying metabolic disturbances.
TRIAL REGISTRATION
Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT03005288
An IMiD-inducible degron provides reversible regulation for chimeric antigen receptor expression and activity
No full textThe recent development of successful CAR (chimeric antigen receptor) T cell therapies has been accompanied by a need to better control potentially fatal toxicities that can arise from adverse immune reactions. Here we present a ligand-controlled CAR system, based on the IKZF3 ZF2 β-hairpin IMiD-inducible degron, which allows for the reversible control of expression levels of type I membrane proteins, including CARs. Testing this system in an established mouse xenotransplantation model for acute lymphoblastic leukemia, we validate the ability of the CAR19-degron to target and kill CD19-positive cells displaying complete control/clearance of the tumor. We also demonstrate that the activity of CAR19-degron can be regulated in vivo when dosing a US Food and Drug Administration-approved drug, lenalidomide