Real-World Safety and Efficacy of Biosimilar CT-P13 in Patients with Immune-Mediated Inflammatory Diseases: Integrated Analysis of Three Japanese Prospective Observational Studies.

Introduction: Biosimilar CT-P13 was approved with limited data from clinical trials compared to the originator infliximab in biologic-naïve patients with rheumatoid arthritis. Three prospective post-marketing surveillance studies have been conducted in Japanese biologic-naïve patients and switched patients from biologics including the originator infliximab.

Objective: We performed an integrated analysis of final data from three post-marketing studies to provide long-term safety and efficacy data of CT-P13 in a real-world clinical setting.

Safety, efficacy, and drug survival of the infliximab biosimilar CT-P13 in post-marketing surveillance of Japanese patients with psoriasis.

Based on extrapolation of similar clinical outcomes in rheumatoid arthritis to the originator infliximab (IFX) in randomized clinical trials, the first biosimilar antibody CT-P13 was approved for the treatment of psoriasis. To evaluate the safety, efficacy, and drug survival of CT-P13 for psoriasis in real-world clinical practice, prospective post-marketing surveillance was conducted in 165 Japanese psoriasis patients. During a 1-year follow-up period, adverse drug reactions (ADRs) occurred in 29 patients (17.

Real-world safety and efficacy of CT-P13, an infliximab biosimilar, in Japanese rheumatoid arthritis patients naïve to or switched from biologics.

Objectives: The aim of this post-marketing surveillance (PMS) study is to evaluate the real-world safety and efficacy of CT-P13, the first biosimilar of infliximab (IFX).

Methods: Japanese patients with rheumatoid arthritis were prospectively registered from November 2014 and followed up for 1 year.

Results: Of 794 patients in the analysis set, 318 patients naïve to biological disease-modifying antirheumatic drugs (bDMARDs) showed an immediate decrease in Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP) and increased remission rate (DAS28-CRP < 2.

Post-marketing analysis for biosimilar CT-P13 in inflammatory bowel disease compared with external data of originator infliximab in Japan.

Background And Aim: CT-P13, an infliximab (IFX) biosimilar, was approved for treatment of inflammatory bowel disease. However, no comparison with the originator IFX in this indication has been conducted in Japan where endemic levels of tuberculosis and hepatitis virus infection are not low. We evaluated the safety and efficacy in real-world data of CT-P13 and compared with originator IFX data in Japan.

Infliximab biosimilar CT-P13 is interchangeable with its originator for patients with inflammatory bowel disease in real world practice.

Background/aims: An interim analysis of post-marketing surveillance of CT-P13, an infliximab biosimilar, was performed to evaluate its safety and efficacy in Japanese patients with inflammatory bowel disease.

Methods: Patients were prospectively enrolled between November 2014 and March 2017, after the launch of CT-P13 in Japan, and case report forms of patients followed for at least 4 months were analyzed as of July 2018.

Results: Of 523 patients in the analysis set, 372 remained on CT-P13 therapy, while 54 (20.

Clinical safety and efficacy of "filgrastim biosimilar 2" in Japanese patients in a post-marketing surveillance study.

We conducted a post-marketing surveillance to evaluate the safety and efficacy of TKN732, approved as "filgrastim biosimilar 2", in Japanese patients who developed neutropenia in the course of cancer chemotherapy or hematopoietic stem cell transplantation. A total of 653 patients were registered during the 2-year enrollment period starting from May 2013, and 627 and 614 patients were eligible for safety and efficacy analyses of the G-CSF biosimilar, respectively. Forty-three adverse drug reactions were reported in 33 patients (5.

A novel compound, NK150460, exhibits selective antitumor activity against breast cancer cell lines through activation of aryl hydrocarbon receptor.

Antiestrogen agents are commonly used to treat patients with estrogen receptor (ER)-positive breast cancer. Tamoxifen has been the mainstay of endocrine treatment for patients with early and advanced breast cancer for many years. Following tamoxifen treatment failure, however, there are still limited options for subsequent hormonal therapy.

DNA-dependent protein kinase and ataxia telangiectasia mutated (ATM) promote cell survival in response to NK314, a topoisomerase IIα inhibitor.

4-Hydroxy-5-methoxy-2,3-dihydro-1H-[1,3]benzodioxolo[5,6-c]pyrrolo[1,2-f]-phenanthridium chloride (NK314) is a benzo[c] phenanthridine alkaloid that inhibits topoisomerase IIα, leading to the generation of DNA double-strand breaks (DSBs) and activating the G(2) checkpoint pathway. The purpose of the present studies was to investigate the DNA intercalating properties of NK314, to evaluate the DNA repair mechanisms activated in cells that may lead to resistance to NK314, and to develop mechanism-based combination strategies to maximize the antitumor effect of the compound. A DNA unwinding assay indicated that NK314 intercalates in DNA, a property that likely cooperates with its ability to trap topoisomerase IIα in its cleavage complex form.

Comparative study of peripheral neurotoxicity after injection of two different paclitaxel formulations in rats.

Paclitaxel Inj. [NK] (test; paclitaxel, CAS 33069-62-4) is a generic version of the drug from the originator (reference). Both drugs contain the same active ingredient and showed identical pharmacokinetics in patients in the previous study; however, these two drugs may have different safety profiles because they contain different inactive ingredients.

Suppression of mutant androgen receptors by flutamide.

Objectives: To examine the effects of flutamide and hydroxyflutamide on the transactivation of mutant androgen receptors.

Methods: Androgen-independent human prostate cancer cell line PC3 was transfected with plasmids expressing wild-type, W741C mutant, T877A mutant or W741C+T877A mutant androgen receptors. The effects of bicalutamide, hydroxyflutamide or flutamide on the basal and dihydrotestosterone-induced transcriptional activities of the wild-type and mutant androgen receptors were evaluated by luciferase assays using a reporter plasmid containing the prostate-specific antigen (PSA) promoter.

Pharmacokinetic analysis of a combined chemoendocrine treatment with paclitaxel and toremifene for metastatic breast cancer.

Background: Multidrug resistance protein could be a target for improving the efficacy of paclitaxel (PXL). Toremifene (TOR) may moderate P-gp-related drug resistance in vitro. Some P-gp moderators may change the pharmacokinetic parameters of PXL in vivo.

Azaspirene, a fungal product, inhibits angiogenesis by blocking Raf-1 activation.

Angiogenesis is an inevitable event in tumor progression and metastasis, and thus has been a compelling target for cancer therapy in recent years. Effective inhibition of tumor progression and metastasis could become a promising way to treat tumor-induced angiogenesis. We discovered that a fungus, Neosartorya sp.

NK314, a topoisomerase II inhibitor that specifically targets the alpha isoform.

Topoisomerase II (Top2) is a ubiquitous nuclear enzyme that relieves torsional stress in chromosomal DNA during various cellular processes. Agents that target Top2, involving etoposide, doxorubicin, and mitoxantrone, are among the most effective anticancer drugs used in the clinic. Mammalian cells possess two genetically distinct Top2 isoforms, both of which are the target of these agents.

Epoxyquinol B shows antiangiogenic and antitumor effects by inhibiting VEGFR2, EGFR, FGFR, and PDGFR.

Angiogenesis is the development of new blood vessels to provide oxygen and nutrients and is indispensable for solid tumor growth. Therefore, the inhibition of angiogenesis is an important modality for cancer chemotherapy. Here we report the antiangiogenic mechanism and antitumor effects of epoxyquinol B (EPQB), which was isolated from fungal metabolites.

Small molecules destabilize cIAP1 by activating auto-ubiquitylation.

Overexpression of an anti-apoptotic protein cIAP1 caused by its genetic amplification was reported in certain cancers, such as hepatocellular carcinoma, esophageal squamous cell carcinoma, cervical cancer, and lung cancer, which confers resistance to chemotherapy and radiotherapy. Here we report cIAP1 to be selectively down-regulated by a class of small molecules ((-)-N-[(2S,3R)-3-amino-2-hydroxy-4-phenyl-butyryl]-l-leucine methyl ester (ME-BS)), resulting in a sensitization of cancer cells to apoptosis. ME-BS directly interacts with the BIR3 domain of cIAP1, promotes auto-ubiquitylation dependent on its RING domain, and facilitates proteasomal degradation of cIAP1.

NK314, a novel topoisomerase II inhibitor, induces rapid DNA double-strand breaks and exhibits superior antitumor effects against tumors resistant to other topoisomerase II inhibitors.

NK314 is a novel synthetic benzo[c]phenanthridine alkaloid that shows strong antitumor activity. It inhibited topoisomerase II activity and stabilized topoisomerase II-DNA cleavable complexes. The DNA breaks occurred within 1h after treatment with NK314 even without digestion of topoisomerase II by proteinase K, whereas etoposide required digestion of the enzyme protein in cleavable complex to detect DNA breaks.

Inhibition of topoisomerase IIalpha and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials.

NK314 is a novel synthetic benzo[c]phenanthridine alkaloid that has recently entered clinical trials as an antitumor compound, based on impressive activities in preclinical models. The present investigations were directed at determining the mechanism of action of this agent. NK314 induced significant G(2) cell cycle arrest in several cell lines, independent of p53 status, suggesting the existence of a common mechanism of checkpoint activation.

Immunohistochemical expression of aminopeptidase N (CD13) in human lung squamous cell carcinomas, with special reference to Bestatin adjuvant therapy.

Bestatin, a specific inhibitor of aminopeptidase N (CD13), has been reported to prolong survival time in patients with completely resected stage I lung squamous cell carcinoma. Considering the antitumor mechanism of Bestatin, it is interesting to know whether CD13 is expressed in human lung squamous cell carcinoma. The immunohistochemical expression of CD13 was examined in human lung carcinoma and the question of whether CD13 was immunohistochemically expressed in the interstitial tissue was investigated, mainly in the fibroblasts and blood vessels, surrounding the tumor nests of various kinds of non-small cell lung cancers, especially of squamous cell carcinomas.

Metabolism and hepatic toxicity of flutamide in cytochrome P450 1A2 knockout SV129 mice.

Background: Flutamide, a nonsteroidal antiandrogen used for treatment of prostate cancer, causes a temporary increase in transaminase and in some cases severe liver dysfunction. It is dominantly metabolized by cytochrome P450 (CYP) 1A2 into 2-hydroxyflutamide (OH-flutamide), which has stronger antiandrogenic activity without obvious cytotoxicity to cultured hepatocytes. We hypothesized that another subsidiary metabolite might be responsible for induction of hepatotoxicity.

Detection of a new N-oxidized metabolite of flutamide, N-[4-nitro-3-(trifluoromethyl)phenyl]hydroxylamine, in human liver microsomes and urine of prostate cancer patients.

Flutamide (2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide), a nonsteroidal antiandrogen, is used in the treatment of prostate cancer but is occasionally associated with hepatic dysfunction. In the present study, the metabolism of flutamide including the formation of the possible reactive toxic metabolites was investigated using human liver microsomes and 10 isoforms of recombinant human cytochrome P450 (P450). 2-Hydroxyflutamide (OH-flutamide) and 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1) were the main products of flutamide metabolism in human liver microsomes.

Aminopeptidase N (APN/CD13) is selectively expressed in vascular endothelial cells and plays multiple roles in angiogenesis.

Proteolytic enzyme-mediated degradation of the extracellular matrix (ECM) is crucial for the formation of both tumor metastasis and angiogenesis. Recently, several reports have suggested that aminopeptidases are involved in this process, but precisely how is largely unknown. We found here that aminopeptidase N (APN/CD13) was selectively expressed in vascular endothelial cells including human umbilical vein endothelial cells (HUVEC) and human aortic endothelial cells (HAEC), and was not detectable in a majority of normal cells and tumor cell lines we examined.

NK95806, a newly synthesized microtubule-disrupting agent that suppresses collagen-induced arthritis in mice.

We investigated the anti-arthritic effects of NK95806, a novel inhibitor of microtubule polymerization, on collagen-induced arthritis in mice. The suppressive effect of NK95806 on the induction and development of arthritis was shown as a significant reduction in clinical arthritis scores. Histological analysis of the hind paws confirmed the improvement in clinical severity and showed marked decreases in granulomatous formation and further bone destruction.

Expression profiling to predict postoperative prognosis for estrogen receptor-negative breast cancers by analysis of 25,344 genes on a cDNA microarray.

Estrogen receptor (ER) status is an essential determinant of clinical and biological behavior of human breast cancers. While ER-positive breast cancers respond well to adjuvant hormone therapy, ER-negative tumors are generally resistant. To date, no attempts have succeeded in finding molecular markers for classifying ER-negative breast cancers with respect to postoperative prognosis.