The chemokine ligand 2 (CCL2) promotes angiogenesis, tumor proliferation, migration, and metastasis. Carlumab is a human IgG1κ monoclonal antibody with high CCL2 binding affinity. Pharmacokinetic/pharmacodynamic data from 21 cancer patients with refractory tumors were analyzed. The PK/PD model characterized the temporal relationships between serum concentrations of carlumab, free CCL2, and the carlumab-CCL2 complex. Dose-dependent increases in total CCL2 concentrations were observed and were consistent with shifting free CCL2. Free CCL2 declined rapidly after the initial carlumab infusion, returned to baseline within 7 days, and increased to levels greater than baseline following subsequent doses. Mean predicted half-lives of carlumab and carlumab-CCL2 complex were approximately 2.4 days and approximately 1 hour for free CCL2. The mean dissociation constant (KD ), 2.4 nM, was substantially higher than predicted by in vitro experiments, and model-based simulation revealed this was the major factor hindering the suppression of free CCL2 at clinically viable doses.

BackgroundTyrosine kinase 2 (Tyk2) is a member of the JAK family that phosphorylates STAT proteins downstream of the IL-12, IL-23 and the Type I interferon receptor. Tyk2 genetic variants have been linked to multiple autoimmune diseases,1 with a deactivating coding variant conferring significant protection against multiple immune-mediated disorders including systemic lupus erythematosus (SLE).2 Selective pharmacologic inhibition of Tyk2 has proven daunting, given the high degree of similarity among JAK catalytic domains. Using a novel approach, we have developed BMS-986165, a highly selective and potent small molecule inhibitor, which blocks receptor-mediated Tyk2 activation by stabilizing the regulatory pseudokinase domain of the protein. Lupus-like disease is strongly inhibited in NZB/W mice treated with BMS-986165. Together, these data establish Tyk2 as a highly promising therapeutic target for SLE.ObjectivesWe report the first evidence of safety, pharmacokinetics (PK), target engagement (TE), and pharmacodynamic activity (PD) of BMS-986165, a novel inhibitor of Tyk2.MethodsSafety, PK, TE, and PD were assessed in a randomized, double-blind, single and multiple ascending dose study of 108 (83 active: 25 placebo) healthy participants (NCT02534636). Target engagement was assessed by an ex vivo assay, IL-12 and IL-18 induced IFNγ production. Roferon-A was administered to assess in vivo pharmacodynamic effects of BMS-986165 on physiological manifestations of IFN exposure and on IFN-regulated gene (IRG) expression.ResultsBMS-986165 was safe and overall well-tolerated. There were no serious adverse events and the frequency of non-serious adverse events were similar in the active (75%) and placebo (76%) groups. The most frequently reported adverse events by preferred term were headache (23% active versus 28% placebo), nausea (12% active versus 8% placebo), rash (12% active versus 8% placebo), and upper respiratory tract infection (11% active versus 12% placebo).After oral administration, BMS-986165 was rapidly absorbed and exhibited an apparent elimination half-life of 8–15 hours. Modest accumulation (1.4x-1.9x) was observed after multiple dosing. BMS-986165 inhibited IL-12/IL-18-induced IFNγ production in ex vivo assays in a dose and concentration dependent manner. Following an in vivo challenge with a clinical dose of Interferon-alfa-2A, BMS-986165 demonstrated dose-dependent inhibition of lymphocyte count decreases and expression of 53 IRGs in blood (Figure 1).ConclusionsBMS-986165 is a safe and potent Tyk2 inhibitor with clear evidence of ex vivo and in vivo biologic activity in healthy participants, and the potential for once daily dosing. Overall, Inhibition of IL-12/23 and type I IFN pathways support further testing of BMS-986165 in diseases such as lupus and psoriasis. A Phase 2 study in patients with moderate-to-severe psoriasis is ongoing (NCT02931838).References Liang Y, Zhu Y, Xia Y, Peng H, Yang XK, et al. Therapeutic potential of tyrosine kinase 2 in autoimmunity. Expert Opin Ther Targets. 2014 May;18(5):...

The effect of phenethyl isothiocyanate (PEITC), a component of cruciferous vegetables, on the initiation and progression of cancer was investigated in a chemically induced estrogen-dependent breast cancer model. Breast cancer was induced in female Sprague Dawley rats (8 weeks old) by the administration of N-methyl nitrosourea (NMU). Animals were administered 50 or 150 µmol/kg oral PEITC and monitored for tumor appearance for 18 weeks. The PEITC treatment prolonged the tumor-free survival time and decreased the tumor incidence and multiplicity. The time to the first palpable tumor was prolonged from 69 days in the control, to 84 and 88 days in the 50 and 150 µmol/kg PEITC-treated groups. The tumor incidence in the control, 50 µmol/kg, and 150 µmol/kg PEITC-treated groups was 56.6%, 25.0% and 17.2%, while the tumor multiplicity was 1.03, 0.25 and 0.21, respectively. Differences were statistically significant (p < 0.05) from the control, but there were no significant differences between the two dose levels. The intratumoral capillary density decreased from 4.21 ± 0.30 vessels per field in the controls to 2.46 ± 0.25 in the 50 µmol/kg and 2.36 ± 0.23 in the 150 µmol/kg PEITC-treated animals. These studies indicate that supplementation with PEITC prolongs the tumor-free survival, reduces tumor incidence and burden, and is chemoprotective in NMU-induced estrogen-dependent breast cancer in rats. For the first time, it is reported that PEITC has anti-angiogenic effects in a chemically induced breast cancer animal model, representing a potentially significant mechanism contributing to its chemopreventive activity.

This randomized, double‐blind, single‐ and multiple‐ascending dose study assessed the pharmacokinetics (PKs), pharmacodynamics, and safety of deucravacitinib (Sotyktu™), a selective and potent small‐molecule inhibitor of tyrosine kinase 2, in 100 (75 active, 25 placebo) healthy volunteers (NCT02534636). Deucravacitinib was rapidly absorbed, with a half‐life of 8–15 h, and 1.4–1.9‐fold accumulation after multiple dosing. Deucravacitinib inhibited interleukin (IL)‐12/IL‐18‐induced interferon (IFN)γ production ex vivo in a dose‐ and concentration‐dependent manner. Following in vivo challenge with IFNα‐2a, deucravacitinib demonstrated dose‐dependent inhibition of lymphocyte count decreases and expression of 53 IFN‐regulated genes. There were no serious adverse events (AEs); the overall frequency of AEs was similar in the deucravacitinib (64%) and placebo (68%) groups. In this first‐in‐human study, deucravacitinib inhibited IL‐12/IL‐23 and type I IFN pathways in healthy volunteers, with favorable PK and safety profiles. Deucravacitinib is a promising therapeutic option for immune‐mediated diseases, including Crohn's disease, psoriasis, psoriatic arthritis, and systemic lupus erythematosus.

Timing of the anti-angiogenic agent with respect to the chemotherapeutic agent may be crucial in determining the success of combination therapy in cancer. We investigated the effects of sequential therapy with the potent VEGF inhibitor, aflibercept, and doxorubicin (DOX) in preclinical acute myeloid leukemia (AML) models. Mice were engrafted with human HL-60 and HEL-luciferase leukemia cells via S.C. and/or I.V. injection and treated with two to three doses of aflibercept (5-25 mg/kg) up to 3-7 days prior to doxorubicin (30 mg/kg) administration. Leukemia growth was determined by local tumor measurements (days 0-16) and systemic bioluminescent imaging (days 0-28) in animals receiving DOX (3 mg/kg) with or without aflibercept. A PK/PD model was developed to characterize how prior administration of aflibercept altered intratumoral DOX uptake. DOX concentration-time profiles were described using a four-compartment PK model with linear elimination. We determined that intratumoral DOX concentrations were 6-fold higher in the aflibercept plus DOX treatment group versus DOX alone in association with increased drug uptake rates (from 0.125 to 0.471 ml/h/kg) into tumor without affecting drug efflux. PD modeling demonstrated that the observed growth retardation was mainly due to the combination of DOX plus TRAP group; 0.00794 vs. 0.0043 h(-1). This PK/PD modeling approach in leukemia enabled us to predict the effects of dosing frequency and sequence for the combination of anti-VEGF and cytotoxic agents on AML growth in both xenograft and marrow, and may be useful in the design of future rational combinatorial dosing regimens in hematological malignancies.