Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46-0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13-0.63). Both patients with intermediate-2- or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2-risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544).
Copyright© Ferrata Storti Foundation.

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Specific bile acids are potent signaling molecules that modulate metabolic pathways affecting lipid, glucose and bile acid homeostasis, and the microbiota. Bile acids are synthesized from cholesterol in the liver, and the key enzymes involved in bile acid synthesis (Cyp7a1, Cyp8b1) are regulated transcriptionally by the nuclear receptor FXR. We have identified an FXR-regulated pathway upstream of a transcriptional repressor that controls multiple bile acid metabolism genes. We identify MafG as an FXR target gene and show that hepatic MAFG overexpression represses genes of the bile acid synthetic pathway and modifies the biliary bile acid composition. In contrast, loss-of-function studies using MafG(+/-) mice causes de-repression of the same genes with concordant changes in biliary bile acid levels. Finally, we identify functional MafG response elements in bile acid metabolism genes using ChIP-seq analysis. Our studies identify a molecular mechanism for the complex feedback regulation of bile acid synthesis controlled by FXR.
Copyright © 2015 Elsevier Inc. All rights reserved.

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The purpose of this study was to assess the pharmacokinetic (PK) properties and safety of single and multiple doses of subcutaneous (SC) pasireotide and a single-dose intramuscular (IM) long-acting release (LAR) formulation of pasireotide in Chinese healthy volunteers (HVs) versus the PK properties in Western HVs (pooled from previous PK studies).
In this phase I, single-center, open-label study, 45 Chinese male HVs were evenly randomized to 1 to 9 treatment sequences: each volunteer received a single dose of 300, 600, or 900 μg of pasireotide SC on day 1, followed by administration of the same dose BID from day 15 to the morning of day 19, and then a single IM dose of 20, 40, or 60 mg of pasireotide LAR on day 33. The PK parameters were assessed with noncompartmental analysis. Statistical comparison of PK parameters, including AUC, Cmax, and CL/F from both formulations, was made for Chinese versus Western male HVs. The safety profile was also assessed. Metabolic parameters, including blood glucose, insulin, and glucagon, and measures that reflect the effects of pasireotide LAR on relatively long-term glucose control, lipid metabolism, and systemic concentrations of pancreatic enzymes and thyrotropin were evaluated.
Of the 45 randomized HVs, 42 completed the study per protocol, 1 withdrew his informed consent for personal reasons, and 2 prematurely discontinued the study because of adverse events (AEs). Concentration-time and safety profiles of both formulations were similar to those reported in Western HVs. Mean geometric mean ratios (GMRs) of Chinese versus Western HVs ranged from 0.79 to 1.42. For most primary PK parameters, 90% CIs for GMRs were within a predefined ethnic insensitivity interval (90% CI, 0.70-1.43). After considering age and weight as covariates in the statistical model, the GMRs and 90% CIs for other PK parameters were within the predefined interval (Cmax in single-dose SC administration) or significantly decreased (Cmin,ss in multiple BID SC doses and first peak Cmax in the single-dose LAR formulation). No serious AEs were reported. Both formulations were well tolerated; pasireotide SC caused transient changes in glucose metabolism. Owing to the differential binding affinity to the somatostatin receptor subtypes, pasireotide LAR elicited a concentration-dependent increase of fasting blood glucose, substantial reduction in triglyceride, and a mild decrease in cholesterol. The most frequently reported AEs after single-dose and multiple-dose pasireotide SC were injection site reaction, nausea, dizziness, and diarrhea; most HVs developed diarrhea with single-dose pasireotide LAR.
The pasireotide formulations had similar PK and safety profiles between Chinese and Western male HVs. Thus, no ethnic sensitivity was found for pasireotide SC or LAR.
Copyright © 2014 The Authors. Published by EM Inc USA.. All rights reserved.

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Monoclonal antibody (mAb) therapy has been successfully used for the treatment of B-cell lymphomas and is currently extended for the treatment of multiple myeloma (MM). New developments in MM therapeutics have achieved significant survival gains in patients but the disease still remains incurable. Elotuzumab (HuLuc63), an anti-CS1 monoclonal IgG1 antibody, is believed to induce anti-tumor activity and MM cytotoxicity through antibody dependent cellular cytotoxicity (ADCC) and inhibition of MM cell adhesion to bone marrow stromal cells (BMSCs). Modulations of the Fc glycan composition at the N297 site by selective mutations or afucosylation have been explored as strategies to develop bio-better therapeutics with enhanced ADCC activity. Afucosylated therapeutic antibodies with enhanced ADCC activity have been reported to possess greater efficacy in tumor growth inhibition at lower doses when compared to fucosylated therapeutic antibodies. The N-linked glycosylation pathway in Pichia pastoris has been engineered to produce human-like N-linked glycosylation with uniform afucosylated complex type glycans. The purpose of this study was to compare afucosylated anti-CS1 mAb expressed in glycoengineered Pichia pastoris with fucosylated anti-CS1 mAb expressed in mammalian HEK293 cells through in vitro ADCC and in vivo tumor inhibition models. Our results indicate that Fc glycosylation is critical for in vivo efficacy and afucosylated anti-CS1 mAb expressed in glycoengineered Pichia pastoris shows a better in vivo efficacy in tumor regression when compared to fucosylated anti-CS1 mAb expressed in HEK293 cells. Glycoengineered Pichia pastoris could provide an alternative platform for generating homogeneous afucosylated recombinant antibodies where Fc mediated immune effector function is important for efficacy.
Copyright © 2015 Elsevier B.V. All rights reserved.

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On March 22, 2016 Verastem, Inc. (NASDAQ:VSTM), focused on discovering and developing drugs to treat cancer, reported the presentation of scientific data at the Society of Gynecologic Oncology’s 2016 Annual Meeting on Women’s Cancer being held March 19-22, 2016 in San Diego, CA (Press release, Verastem, MAR 22, 2016, View Source;p=RssLanding&cat=news&id=2150260 [SID:1234509826]).

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"The data presented today at SGO 2016 are important because they provide further scientific evidence that chemotherapy can lead to an increase in ovarian cancer stem cells (CSCs), making the tumor more aggressive and resistant to further treatment," said Dr. Jonathan Pachter, Verastem Head of Research. "At Verastem, we believe that our compounds in development may be especially beneficial as therapeutics when used in combination with other agents, including current and emerging standard of care treatments and immunotherapies, and have the potential to create a more durable clinical response. We look forward to the initiation of a Phase 1/1b clinical trial of the combination of VS-6063 and avelumab, in collaboration with Pfizer and Merck KGaA, for patients with ovarian cancer in the second half of this year."

Verastem, and its collaborators, are presenting these scientific data in support of Verastem’s development programs which utilize a multi-faceted approach to treat cancer by reducing cancer stem cells, enhancing anti-tumor immunity, and modulating the local tumor microenvironment. The Company’s most advanced clinical product candidates are the Focal Adhesion Kinase inhibitors, VS-6063 and VS-4718, and the dual PI3K/mTOR inhibitor, VS-5584. Research on the FAK and PI3K/mTOR signaling pathways has revealed critical roles for each in cancer stem cell survival and disease progression.

Details for the SGO presentation are as follows:

Oral Presentation

Title: Standard chemotherapy for ovarian cancer increases expression of cancer stem cell biomarkers which is predictive of survival

Session: Scientific Plenary IX: Ovary

Date and time: Tuesday, March 22, 2016 at 8:30 – 10:05 AM

Location: Hall A

Summary: In ovarian cancer, certain molecular mediators are thought to possess CSC characteristics and the presence of these mediators, which is linked to earlier recurrence and shorter survival, is possibly brought about by chemotherapy. The aim of this study was to explore the effect of chemotherapy on ovarian cancer stem-like mediators and to determine if there was a relationship to survival. Researchers obtained matched pre- and post-chemotherapy tumor specimens from stage IIIC/IV ovarian cancer patients (n=22) who all underwent neoadjuvant chemotherapy with interval debulking surgery. Samples were then analyzed for expression of 27 CSC markers. CSC markers were then validated in tumorsphere model and in vivo tumor initiating studies.

All 27 CSC markers demonstrated a mean increase in gene expression after exposure to chemotherapy. A 3-fold or greater increase in gene expression after exposure to chemotherapy was seen in 8 of 27 (30%) markers: ABCG2, ALDH1A1, CTGF, DPP4, MYC, CD133, SOX2, and POSTN. Three markers demonstrated a significant fold increase that correlated with platinum resistance: POSTN (4.1-fold), ALDH1A1 (5-fold), and SOX2 (14.5-fold). When implanted into immunocompromised mice, SOX2(hi) cells exhibited significantly higher levels of tumorsphere forming potential than SOX2(lo) cells and were more tumorigenic. High gene expression in these 3 markers demonstrated shorter progression free survival, compared to low expression. These results support the further investigation of directed agents to inhibit these CSC markers to potentially extend survival for patients with ovarian cancer.

A copy of the oral presentation will be available at http://bit.ly/R3M6wc