Population Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Modeling of Serum M-Protein Response for Modakafusp Alfa in a Phase 1/2 Study of Patients With Relapsed or Refractory Multiple Myeloma.

Modakafusp alfa (TAK-573) is a novel, first-in-class fusion protein of a humanized anti-CD38 IgG4 kappa antibody fused to attenuated human interferon alfa-2b. It acts as an agonistic innate immunity enhancer through targeted interferon (IFN) signaling and has been investigated as an immune-oncology therapeutic agent in patients with relapsed/refractory multiple myeloma (RRMM). Population PK analysis and sequential PK-PD analysis of serum M-protein (MP) as a primary marker of tumor burden in RRMM were conducted using dose escalation (Part 1) and dose expansion (Part 2) data from 96 RRMM patients enrolled in the Phase 1/2 iinnovate-1 trial.

A phase 2 randomized study of modakafusp alfa as a single agent for patients with relapsed/refractory multiple myeloma.

Modakafusp alfa is a first-in-class immunocytokine-directing interferon alfa to CD38+ cells. Our previous phase 1/2 trial identified 2 potential phase 2 doses of modakafusp alfa for patients with relapsed/refractory multiple myeloma (RRMM): 1.5 or 3 mg/kg every 4 weeks.

Targeted interferon therapy with modakafusp alfa for relapsed or refractory multiple myeloma.

Interferon alfa has activity against multiple myeloma (MM). Modakafusp alfa is an immunocytokine comprising 2 attenuated interferon alfa-2b molecules and an anti-CD38 immunoglobulin G4 antibody, targeting delivery of interferon alfa to CD38-expressing (CD38+) immune and myeloma cells. This phase 1/2 trial enrolled patients with relapsed/refractory multiple myeloma with ≥3 prior lines of treatment and refractory to, or intolerant of, ≥1 proteasome inhibitor and ≥1 immunomodulatory drug.

A phase Ib study evaluating the recommended phase II dose, safety, tolerability, and efficacy of mivavotinib in combination with nivolumab in advanced solid tumors.

Mivavotinib (TAK-659/CB-659), a dual SYK/FLT3 inhibitor, reduced immunosuppressive immune cell populations and suppressed tumor growth in combination with anti-PD-1 therapy in cancer models. This dose-escalation/expansion study investigated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mivavotinib plus nivolumab in patients with advanced solid tumors. Patients received oral mivavotinib 60-100 mg once-daily plus intravenous nivolumab 3 mg/kg on days 1 and 15 in 28-day cycles until disease progression or unacceptable toxicity.

Population Pharmacokinetics of Mivavotinib (TAK-659), a Dual Spleen Tyrosine Kinase and FMS-Like Tyrosine Kinase 3 Inhibitor, in Patients With Advanced Solid Tumors or Hematologic Malignancies.

Mivavotinib (TAK-659), an orally administered, small-molecule, dual inhibitor of spleen tyrosine kinase and FMS-like tyrosine kinase 3 (SYK/FLT3), is under development for the treatment of patients with advanced malignancies. In this analysis, we evaluated the population pharmacokinetics (PK) of mivavotinib and its sources of variability (covariates) in adult patients with advanced solid tumors, or relapsed/refractory B-cell lymphomas or acute myeloid leukemia, using pooled data from 159 patients enrolled in 2 phase 1/2 clinical studies. A 2-compartment model with first-order linear elimination and a first-order absorption rate (and associated lag time) adequately described the PK of mivavotinib in this patient population.

A phase Ib trial of mivavotinib (TAK-659), a dual SYK/FLT3 inhibitor, in patients with relapsed/refractory acute myeloid leukemia.

Mivavotinib (TAK-659) is an investigational type 1 tyrosine kinase inhibitor with dual activity against spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 (FLT3). We conducted a phase Ib study to investigate the safety, tolerability, and efficacy of mivavotinib in patients with refractory and/or relapsed (R/R) acute myeloid leukemia (AML). Both daily (QD) and twice daily (BID) dosing regimens were evaluated.

Obesity protects against sepsis-induced and norepinephrine-induced white adipose tissue browning.

Sepsis is a dysregulated systemic response to infection and can lead to organ damage and death. Obesity is a significant problem worldwide and affects outcomes from sepsis. Our laboratory demonstrated that white adipose tissue (WAT) undergoes browning during sepsis, a process whereby WAT adopts a brown adipose tissue phenotype.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06650833, a selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, in single and multiple ascending dose randomized phase 1 studies in healthy subjects.

Background: PF-06650833 is a potent, selective inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). Two randomized, double-blind, sponsor-open phase 1 studies evaluated the safety, pharmacokinetics, and pharmacodynamics of single (SAD) and multiple ascending doses (MAD) of PF-06650833 immediate-release (IR) and modified-release (MR) oral formulations in healthy adult subjects.

Methods: Study 1 (NCT02224651) was a 96-day, placebo-substitution, SAD study of once-daily (QD) oral PF-06650833 IR 1 to 6000 mg and MR 30 to 300 mg in fasted and fed states.

Population pharmacokinetic modeling of PF-06439535 (a bevacizumab biosimilar) and reference bevacizumab (Avastin) in patients with advanced non-squamous non-small cell lung cancer.

Purpose: The objectives of this analysis were to characterize the population pharmacokinetics (PK) of PF-06439535 (a bevacizumab biosimilar) and reference bevacizumab (Avastin) sourced from the European Union (bevacizumab-EU) in patients with advanced non-squamous non-small cell lung cancer (NSCLC), and to quantify the difference in PK parameters between the two drug products via covariate analysis.

Methods: Pooled PF-06439535 and bevacizumab-EU serum concentration data from a comparative clinical efficacy and safety study (NCT02364999) in patients with NSCLC (N = 719) were analyzed using a non-linear mixed-effects modeling approach. Patients received PF-06439535 plus chemotherapy or bevacizumab-EU plus chemotherapy every 21 days for 4-6 cycles, followed by monotherapy with PF-06439535 or bevacizumab-EU.

Correction to: Population pharmacokinetics of PF‑05280014 (a trastuzumab biosimilar) and reference trastuzumab (Herceptin) in patients with HER2‑positive metastatic breast cancer.

The article "Population pharmacokinetics of PF-05280014 (a trastuzumab biosimilar) and reference trastuzumab (Herceptin) in patients with HER2-positive metastatic breast cancer" written by Xiaoying Chen, Cheryl Li, Reginald Ewesuedo, Donghua Yin was originally published electronically on the publisher's internet portal (currently SpringerLink) on 3rd May 2019 without open access.

Population pharmacokinetics of PF-05280014 (a trastuzumab biosimilar) and reference trastuzumab (Herceptin) in patients with HER2-positive metastatic breast cancer.

Purpose: PF-05280014 is a biosimilar to trastuzumab (Herceptin). Following demonstration of pharmacokinetic (PK) similarity in healthy volunteers, a comparative clinical study in patients with HER2-positive metastatic breast cancer (mBC) compared the efficacy, safety and immunogenicity of PF-05280014 and trastuzumab sourced from the EU (trastuzumab-EU), both with paclitaxel.

Methods: Population PK of PF-05280014 and trastuzumab-EU was evaluated.

Quantitative Translational Analysis of Brain Kynurenic Acid Modulation via Irreversible Kynurenine Aminotransferase II Inhibition.

Kynurenic acid (KYNA) plays a significant role in maintaining normal brain function, and abnormalities in KYNA levels have been associated with various central nervous system disorders. Confirmation of its causality in human diseases requires safe and effective modulation of central KYNA levels in the clinic. The kynurenine aminotransferases (KAT) II enzyme represents an attractive target for pharmacologic modulation of central KYNA levels; however, KAT II and KYNA turnover kinetics, which could contribute to the duration of pharmacologic effect, have not been reported.

Pharmacokinetics and C-reactive protein modelling of anti-interleukin-6 antibody (PF-04236921) in healthy volunteers and patients with autoimmune disease.

Aims: The purpose of this study was to characterize pharmacokinetics (PK) of PF-04236921, a novel anti-interleukin-6 monoclonal antibody, and its pharmacokinetic/pharmacodynamic (PK/PD) relationship on serum C-reactive protein (CRP) in healthy volunteers and patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Crohn's disease (CD).

Methods: Population modelling analyses were conducted using nonlinear mixed effects modelling. Data from two phase 1 healthy volunteer studies, a phase 1 RA study, a Phase 2 CD study and a Phase 2 SLE study were included.

Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn's disease (ANDANTE I and II).

Objective: Neutralising pro-inflammatory interleukin-6 (IL-6) may effectively treat Crohn's disease (CD). Effects of PF-04236921, an anti-IL-6 antibody, in adults with CD are reported.

Design: Parallel-group, dose-ranging, double-blind trial with 4-week screening and 12-week treatment periods.

Epigenetic inheritance of proteostasis and ageing.

Abundant evidence shows that the genome is not as static as once thought and that gene expression can be reversibly modulated by the environment. In some cases, these changes can be transmitted to the next generation even if the environment has reverted. Such transgenerational epigenetic inheritance requires that information be stored in the germline in response to exogenous stressors.

Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomised controlled trial.

Objectives: This phase II trial evaluated the efficacy and safety of an interleukin (IL) 6 monoclonal antibody for systemic lupus erythematosus (SLE).

Methods: Patients with active disease were randomised to placebo or PF-04236921 10 mg, 50 mg or 200 mg, subcutaneously, every 8 weeks with stable background therapy. SLE Responder Index (SRI-4; primary end point) and British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) were assessed at week 24.

Membrane proteome analysis of glioblastoma cell invasion.

Glioblastoma multiforme (GBM) tumor invasion is facilitated by cell migration and degradation of the extracellular matrix. Invadopodia are actin-rich structures that protrude from the plasma membrane in direct contact with the extracellular matrix and are proposed to participate in epithelial-mesenchymal transition. We characterized the invasiveness of 9 established GBM cell lines using an invadopodia assay and performed quantitative mass spectrometry-based proteomic analyses on enriched membrane fractions.

Defining the factors that contribute to on-target specificity of antisense oligonucleotides.

To better understand the factors that influence the activity and specificity of antisense oligonucleotides (ASOs), we designed a minigene encoding superoxide dismutase 1 (SOD-1) and cloned the minigene into vectors for T7 transcription of pre-mRNA and splicing in a nuclear extract or for stable integration in cells. We designed a series of ASOs that covered the entire mRNA and determined the binding affinities and activities of the ASOs in a cell-free system and in cells. The mRNA bound known RNA-binding proteins on predicted binding sites in the mRNA.

Expanding the spectrum of IDH1 mutations in gliomas.

Mutations in isocitrate dehydrogenase -1 or -2 (IDH1 or IDH2) are found in the majority of WHO grade II and III diffuse gliomas and secondary glioblastomas. IDH mutation screening is rapidly becoming part of the routine pathological work up of human brain tumors, providing both diagnostic and prognostic information. Here, we characterize four rare and novel IDH1 mutations identified in surgical human glioma samples: two instances of an IDH1 p.

Promoter Methylation Analysis of IDH Genes in Human Gliomas.

Mutations in isocitrate dehydrogenase (IDH)-1 or -2 are found in the majority of WHO grade II and III astrocytomas and oligodendrogliomas, and secondary glioblastomas. Almost all described mutations are heterozygous missense mutations affecting a conserved arginine residue in the substrate binding site of IDH1 (R132) or IDH2 (R172). But the exact mechanism of IDH mutations in neoplasia is not understood.