First-in-human trial of the PI3Kß-selective inhibitor SAR260301 in patients with advanced solid tumors.

BACKGROUND: Phosphoinositide 3-kinase (PI3K) ß is the dominant isoform for PI3K activity in many phosphatase and tensin homolog (PTEN)-deficient tumor models. This was a first-in-human study to determine the maximum tolerated dose, safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of SAR260301, a potent PI3Kß-selective inhibitor (clinicaltrials.gov identifier NCT01673737). METHODS: Successive cohorts of patients with advanced solid tumors received increasing doses of oral SAR260301 according to a Bayesian escalation with an overdose-control process based on the occurrence of dose-limiting toxicity in the first 28-day cycle. Adverse events, tumor response, PK, and the effect of food on PK were evaluated. Target engagement was assessed in platelets. Physiologically-based PK modeling was used for exposure predictions. RESULTS: Twenty-one patients received treatment at doses ranging from 100 mg once daily to 440 mg/m2 twice daily. Dose-limiting toxicities included 1 episode of grade 3 pneumonitis (400 mg twice daily) and 1 grade 3 γ-glutamyltransferase increase (600 mg twice daily). The maximum tolerated dose was not reached. The most frequently occurring treatment-related adverse events were nausea, vomiting, and diarrhea (14% each). Pharmacologically active concentrations were reached, but SAR260301 was rapidly cleared, and exposures associated with antitumor activity in preclinical models were not maintained at the highest dose tested. Food further decreased SAR260301 exposure. CONCLUSIONS: SAR260301 had an acceptable safety profile, but exposure sufficient to inhibit the PI3K pathway was unachievable because of rapid clearance, and clinical development was terminated. These results demonstrate the importance of PK and pharmacodynamic assessments in early drug development. Cancer 2018;124:315-24. © 2017 American Cancer Society.

Anti-GPVI Fab SAR264565 effectively blocks GPVI function in ex vivo human platelets under arterial shear in a perfusion chamber.

INTRODUCTION: Glycoprotein VI (GPVI) is the major platelet receptor for collagen-mediated platelet adhesion and activation. SAR264565 is an anti-GPVI-Fab, binds to GPVI with high affinity, and blocks GPVI function in human platelets in vitro. METHODS: The effect of SAR26456 on platelet responsiveness in the blood of 21 healthy male subjects was investigated using Sakariassen's ex vivo thrombogenesis perfusion chamber model on a collagen-coated surface under conditions mimicking arterial flow. Ex vivo effects of SAR264565 (10 and 100 µg/mL) were investigated before administration of aspirin or clopidogrel to study subjects (baseline), after aspirin (2× 300 mg) administration alone, and after combined aspirin (2× 300 mg)/clopidogrel (600 mg) administration. Additional ex vivo and in vitro platelet tests were also performed. RESULTS: Addition of SAR264565 to the perfusion chamber dose-dependently reduced platelet and fibrin deposition, reaching statistical significance at 100 µg/mL (415 ± 67 compared to 137 ± 36 platelets/cm2, [p < 0.01] and fibrin 0.095 ± 0.014 compared to 0.032 ± 0.008 µg/cm2, [p < 0.001]). Aspirin administration caused an additive and dose-dependent reduction of SAR264565-induced platelet and fibrin deposition. Combined aspirin/clopidogrel administration did not lead to additional SAR264565-induced inhibition of platelet or fibrin deposition. CONCLUSION: GPVI antagonism by the anti-GPVI-Fab fragment SAR264565 dose-dependently inhibits platelet adhesion and fibrin formation on a collagen surface under arterial shear. Additive inhibition is observed after prior aspirin administration with no further amplification on top of a combination of aspirin with clopidogrel. Ex vivo antiplatelet tests confirmed a selective inhibiting effect of SAR264565 on collagen-induced platelet activation.

Naturally dissolved arsenic concentrations in the Alpine/Mediterranean Var River watershed (France).

A detailed study on arsenic (As) in rocks and water from the Var River watershed was undertaken aiming at identifying (i) the origin and the distribution of As in this typical Alpine/Mediterranean basin, and (ii) As input into the Mediterranean Sea. Dissolved As concentrations in the Var River range from 0.1 to 4.5 µg⋅L(-1), due to high hydrological variability and the draining through different geological formations. In the upper part of the Var drainage basin, in the Tinée and the Vésubie valleys, high levels of dissolved As concentrations occur (up to 263 µg⋅L(-1)). The two main sources of As in rocks are the Hercynian metamorphic rocks and the Permian argilites. Highly heterogeneous distribution of As in waters draining through metamorphic rocks is probably related to ore deposits containing arsenopyrite. As, U, W and Mo concentrations in water and rocks correspond to the formation of As-rich ore deposits around Argentera granite by hydrothermal fluids deposited at the end of the Hercynian chain formation, which occurred about 300 My ago. In 2009, weekly monitoring was performed on the Var River (15 km upstream of the mouth), highlighting an average dissolved As concentration (<0.45 µm) of 2.7 ± 0.9 µg⋅L(-1), which is significantly higher than the world-average baseline for river water (0.83 µg⋅L(-1)). Taking the average annual discharge (49.4 m(3)⋅s(-1)) into account and the As levels in the dissolved phase and in deposits of the Var River, dissolved As input into the Mediterranean Sea would be 4. 2± 1.4 tons⋅year(-1) which represents 59% of the total As flux. This study also reveals a probable non-conservative As behaviour, i.e., possible transfer between aqueous and solid phases, during the mixing of the Var River with a tributary.

A drug and disease model for lixisenatide, a GLP-1 receptor agonist in type 2 diabetes.

Incretin hormone analogs such as glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as promising new options for the treatment of type 2 diabetes mellitus (T2DM), targeting several of its pathophysiological traits, including reduced insulin sensitivity, inadequate insulin secretion, and loss of ß-cell mass (BCM). This article describes the semi-mechanistic modeling of lixisenatide dose-response over time using fasting plasma glucose (FPG), fasting serum insulin (FSI) and glycated hemoglobin (HbA1c) data from two Phase II and four Phase III clinical trials, for a total of 2470 T2DM patients. Previously published models for FPG, FSI, and BCM as well as HbA1c were adapted and expanded to describe the available data. The model incorporated aspects describing disease progression, standard-of-care, FPG-dependent and -independent HbA1c synthesis, and covariate effects of body size, race, and sex. The final model described lixisenatide effects on ß-cell responsiveness, insulin sensitivity and FPG-independent HbA1c synthesis, was able to describe the observed FPG, FSI, and HbA1c data accurately, and was successful in predicting data from an unseen Phase III clinical study.

Differential sensitivity and kinetics of response of different ex vivo tests monitoring functional variability of platelet response to clopidogrel.

We previously showed that variability of response to clopidogrel is linked to occupancy of the P2Y12 receptor by clopidogrel active-metabolite, and that maximal platelet aggregation intensity (MAI) measured by light transmission aggregometry (LTA) correlates with occupancy. The present study compared a range of ex vivo platelet tests at various levels of P2Y12 occupancy. After screening with clopidogrel 75 mg/day for seven days, subjects were selected to obtain 'low', 'average' and 'high' responders and randomised to clopidogrel (75 mg/day days 1-10; 300 mg day 11), or placebo. Assays were LTA in platelet-rich plasma using 2, 5 and 20 mM ADP, VerifyNow P2Y12, flow cytometric analysis of platelet activation markers and vasodilator-stimulated phosphoprotein (VASP) index, and a thromboelastographic test that is sensitive to clopidogrel. The reference test was P2Y12 receptor occupancy, measured by binding of 33P-2MeS-ADP to platelets. MAI showed the best correlation with P2Y12 occupancy. Similar results were seen with different ADP concentrations and when LTA data were expressed as inhibition of platelet aggregation. A plot of free receptors/cell versus VASP index was biphasic, with poor correlation for low-level P2Y12 occupancy. Sensitivity of the VerifyNow P2Y12 assay decreased at higher clopidogrel responses. Thromboelastography and P-selectin expression had poor correlation with receptor occupancy. In conclusion, LTA data correlate best with P2Y12 occupancy, the gold standard for detecting clopidogrel's effect at the receptor level. Our results highlight a limitation of the VASP index, which appears unable to distinguish low, average and high responders early after clopidogrel initiation when P2Y12 occupancy is still low.