Kyowa Hakko Kirin Pharma Inc.
Kyowa Hakko Kirin Pharma Inc.
Kelley M.,MKelley Consulting LLC |
Beaver C.,inVentiv Health |
Stevenson L.F.,Biogen Idec |
Bamford R.,Covance |
And 7 more authors.
AAPS Journal | Year: 2014
The L1 Global Harmonization Team provides recommendations specifically for run acceptance of ligand binding methods used in bioanalysis of macromolecules in support of pharmacokinetics. The team focused on standard curve calibrators and quality controls for use in both pre-study validation and in-study sample analysis, including their preparation and acceptance criteria. The team also considered standard curve editing and the concept of total error. © 2014 American Association of Pharmaceutical Scientists.
Narita M.,Cancer Research UK Research Institute |
Young A.R.J.,Cancer Research UK Research Institute |
Arakawa S.,Tokyo Medical and Dental University |
Samarajiwa S.A.,Cancer Research UK Research Institute |
And 13 more authors.
Science | Year: 2011
Protein synthesis and autophagic degradation are regulated in an opposite manner by mammalian target of rapamycin (mTOR), whereas under certain conditions it would be beneficial if they occurred in unison to handle rapid protein turnover. We observed a distinct cellular compartment at the trans side of the Golgi apparatus, the TOR-autophagy spatial coupling compartment (TASCC), where (auto)lysosomes and mTOR accumulated during Ras-induced senescence. mTOR recruitment to the TASCC was amino acid- and Rag guanosine triphosphatase -dependent, and disruption of mTOR localization to the TASCC suppressed interleukin-6/8 synthesis. TASCC formation was observed during macrophage differentiation and in glomerular podocytes; both displayed increased protein secretion. The spatial coupling of cells' catabolic and anabolic machinery could augment their respective functions and facilitate the mass synthesis of secretory proteins.
Duvic M.,University of Houston |
Pinter-Brown L.C.,University of California at Los Angeles |
Foss F.M.,Yale New Haven Hospital |
Sokol L.,H. Lee Moffitt Cancer Center and Research Institute |
And 8 more authors.
Blood | Year: 2015
This phase 1/2 study evaluated the efficacy of mogamulizumab, a defucosylated, humanized, anti-CC chemokine receptor 4 monoclonal antibody, in 41 pretreated patients with cutaneous T-cell lymphoma. No dose-limiting toxicity was observed and the maximum tolerated dose was not reached in phase 1 after IV infusion of mogamulizumab (0.1, 0.3, and 1.0 mg/kg) once weekly for 4 weeks followed by a 2-week observation. In phase 2, patients were dosed with 1.0 mg/kg mogamulizumab according to the same schedule for the first course followed by infusion every 2 weeks during subsequent courses until disease progression. The most frequent treatment-emergent adverse events were nausea (31.0%), chills (23.8%), headache (21.4%), and infusion-related reaction (21.4%); the majority of events were grade 1/2. There were no significant hematologic effects. Among 38 evaluable patients, the overall response rate was 36.8%: 47.1% in Sézary syndrome (n = 17) and 28.6% in mycosis fungoides (n = 21). Eighteen of 19 (94.7%) patients with ≥B1 blood involvement had a response in blood, including 11 complete responses. Given the safety and efficacy of mogamulizumab, phase 3 investigation of mogamulizumab is warranted in cutaneous T-celllymphoma patients. © 2015 by The American Society of Hematology.
Fernandez H.H.,University of Florida |
Greeley D.R.,Northwest Neurological |
Zweig R.M.,Louisiana State University in Shreveport |
Wojcieszek J.,Indiana University |
And 2 more authors.
Parkinsonism and Related Disorders | Year: 2010
Objective: 6002-US-051 was a 12-week, double-blind study evaluating the safety and efficacy of istradefylline, a selective A2A adenosine receptor antagonist, as monotherapy in patients with Parkinson's disease (PD). Methods: Patients with Hoehn-Yahr stages 1-2.5 who had not received dopaminergic drugs in the past 30 days or levodopa for >30 days at anytime were randomized to 40 mg/day istradefylline or placebo. The primary efficacy outcome was the change from Baseline to Endpoint in the Unified Parkinson's Disease Rating Scale (UPDRS) Subscale III score. Safety was assessed by physical examination, laboratory tests, electrocardiograms, and adverse event monitoring. Results: 176 patients comprised the intent-to-treat population. Although istradefylline showed numerically greater improvements in UPDRS Subscale III at each time point and reached statistical significance at Week 2 (LS mean difference = -1.47), it did not show statistically significant improvement from placebo for the primary endpoint (least square [LS] mean difference = -1.11). Similar proportions of patients in each group experienced treatment-emergent adverse events (63% istradefylline, 65% placebo). Conclusions: Istradefylline, as monotherapy in patients with PD, is safe and well tolerated. However, efficacy in improving motor symptoms in early PD was not statistically demonstrated by this study.
Dalbeth N.,University of Auckland |
Lauterio T.J.,URL Pharma Inc |
Wolfe H.R.,Kyowa Hakko Kirin Pharma Inc.
Clinical Therapeutics | Year: 2014
Purpose The aims of this article were to systematically review the literature about the mechanism of action of colchicine in the multimodal pathology of acute inflammation associated with gout and to consider the clinical utility of colchicine in other chronic inflammatory diseases.Methods The English-language literature on PubMed was searched for articles published between 1990 and October 2013, with a cross-reference to citations across all years. Relevant articles pertaining to the mechanism of action of colchicine and the clinical applications of colchicine in gout and other inflammatory conditions were identified and reviewed.Findings The molecular pathology of acute inflammation associated with gouty arthritis involves several concurrent pathways triggered by a variety of interactions between monosodium urate crystals and the surface of cells. Colchicine modulates multiple pro- and antiinflammatory pathways associated with gouty arthritis. Colchicine prevents microtubule assembly and thereby disrupts inflammasome activation, microtubule-based inflammatory cell chemotaxis, generation of leukotrienes and cytokines, and phagocytosis. Many of these cellular processes can be found in other diseases involving chronic inflammation. The multimodal mechanism of action of colchicine suggests potential efficacy of colchicine in other comorbid conditions associated with gout, such as osteoarthritis and cardiovascular disease.Implications Colchicine has multiple mechanisms of action that affect inflammatory processes and result in its utility for treating and preventing acute gout flare. Other chronic inflammatory diseases that invoke these molecular pathways may represent new therapeutic applications for colchicine. © 2014 The Authors. Published by Elsevier HS Journals, Inc.
Pourcher E.,Laval University |
Fernandez H.H.,Cleveland Clinic |
Stacy M.,Duke University |
Mori A.,Kyowa Hakko Kirin Co. |
And 2 more authors.
Parkinsonism and Related Disorders | Year: 2012
Background: Istradefylline (KW-6002) is a selective adenosine A 2A receptor antagonist investigated as adjunctive therapy to levodopa in PD patients with motor response complications. In Phase 2b/3 studies, Istradefylline reduced OFF time without worsening troublesome dyskinesia and was well tolerated. Methods: A randomized, 12-week, double-blind, placebo-controlled parallel-group study evaluated the efficacy of 10, 20, and 40mg/day of Istradefylline in patients on levodopa therapy with motor response complications. The primary outcome measure was change from baseline to endpoint in the percentage of awake time/day spent in the OFF state as determined by patient diary. Results: Six hundred and ten patients were randomized. Five hundred and eighty four patients were included in the Intent-to-treat (ITT) group-146 placebo patients and 149 in the 10mg, 144 in the 20, and 145 patients in the 40mg Istradefylline groups. Baseline demographics were similar between groups. Treatment cohorts had been diagnosed an average of 9 years diagnosis and 3.6 years from the onset of motor fluctuations; at baseline they had an average of 6.7h of OFF time and an average UPDRS motor score of 22 when ON. At endpoint, the amount and percentage of OFF time did not differ between Istradefylline and placebo, however a dose-ordering response was observed. Changes from baseline in the UPDRS motor score in the on state for the 40mg were modest but significant compared to placebo (2.9 vs. 0.8; p<0.05). Conclusions: Although Istradefylline did not impact OFF time duration, it significantly improved motor score at 40mg/day. © 2011 Elsevier Ltd.
Yamaguchi J.,University of Tokyo |
Tanaka T.,University of Tokyo |
Eto N.,Kyowa Hakko Kirin Pharma Inc. |
Nangaku M.,University of Tokyo
Kidney International | Year: 2015
Tubulointerstitial hypoxia plays a critical role in the pathogenesis of kidney injury, and hypoxia-inducible factor (HIF)-1 is a master regulator of cellular adaptation to hypoxia. Aside from oxygen molecules, factors that modify HIF-1 expression and functional operation remain obscure. Therefore, we sought to identify novel HIF-1-regulating genes in kidney. A short-hairpin RNA library consisting of 150 hypoxia-inducible genes was derived from a microarray analysis of the rat renal artery stenosis model screened for the effect on HIF-1 response. We report that CCAAT/enhancer-binding protein δ (CEBPD), a transcription factor and inflammatory response gene, is a novel HIF-1 regulator in kidney. CEBPD was induced in the nuclei of tubular epithelial cells in both acute and chronic hypoxic kidneys. In turn, CEBPD induction augmented HIF-1α expression and its transcriptional activity. Mechanistically, CEBPD directly bound to the HIF-1α promoter and enhanced its transcription. Notably, CEBPD was rapidly induced by inflammatory cytokines, such as IL-1β in a nuclear factor-κB-dependent manner, which not only increased HIF-1α expression during hypoxia, but was also indispensable for the non-hypoxic induction of HIF-1α. Thus our study provides novel insight into HIF-1 regulation in tubular epithelial cells and offers a potential hypoxia and inflammation link relevant in both acute and chronic kidney diseases. © 2015 International Society of Nephrology.
Nakano N.,Imamura Bun in Hospital |
Kusumoto S.,Nagoya City University |
Tanaka Y.,Nagoya City University |
Ishida T.,Nagoya City University |
And 6 more authors.
Hepatology Research | Year: 2014
The introduction of molecularly targeted drugs has increased the risk of reactivation of hepatitis B virus (HBV), which is a potentially fatal complication following anticancer chemotherapy even in patients who have previously resolved their HBV infection. CC chemokine receptor 4 (CCR4) has been identified as a novel molecular target in antibody therapy for patients with adult T-cell leukemia-lymphoma (ATL) and peripheral T-cell lymphoma, and the humanized anti-CCR4 monoclonal antibody mogamulizumab has been developed. We reported HBV reactivation of an ATL patient with previously resolved HBV infection after mogamulizumab treatment in a dose-finding study for this antibody. Our retrospective analysis using preserved samples also revealed the detailed kinetics of HBV DNA levels before and just after HBV reactivation. © 2013 The Japan Society of Hepatology.
News Article | July 29, 2015
In what may be a sign of the times, an independent, nonprofit biomedical research institute in San Diego that is focused on immune diseases and disorders has officially established ties with the UC San Diego Health System. The agreement signed by the La Jolla Institute for Allergy & Immunology and the UC San Diego Health System formalizes an informal relationship that began when the institute was founded 27 years ago. The institute’s first board included prominent leaders from UC San Diego and The Scripps Research Institute, and informal agreements with the UCSD Medical Center allowed joint research activities, consultation, and training in allergy and immunology. But as federal research funding has come under pressure in recent years, the institute has sought to bolster its funding by seeking other partnerships, according to Mitchell Kronenberg, who has served as the institute’s president and chief scientific officer since 2003. The institute, which has 272 scientists and a total headcount of 375, usually gets about $51 million in annual funding, mostly through federal grants from the National Institutes of Health and from the Japanese pharmaceutical company Kyowa Hakko Kirin. As part of the new agreement, UCSD will provide $36 million over the next 12 years, enabling the La Jolla institute to recruit and retain leading scientists. That will provide an extra $3 million a year for the institute, “so that’s really helpful,” Kronenberg said. He anticipates the institute will get about $53 million in funding in the coming fiscal year. All of the institute’s scientists will become adjunct professors at UC San Diego, dramatically expanding the university’s focus on the immune system. That includes the development of therapeutic vaccines to inhibit the inflammatory response in coronary heart disease, and new approaches to treating cancers by engineering a patients’ own immune cells to recognize and attack their tumors. The institute’s Center for Infectious Disease also has been working to identify antibodies that could be used to defend people against bioterrorism.. “We had interest from several academic centers,” Kronenberg said of the new partnership. “We had extensive discussions with two other entities besides UC San Diego.” One of those other entities was the University of Southern California, according to The San Diego Union-Tribune. With $4.5 billion in private donations raised to heighten USC’s academic profile, the school has been aggressively expanding its capabilities in life sciences research and development, and spending freely to recruit prominent scientists in biomedical research. Kronenberg declined to confirm the Union-Tribune report in an interview with me, explaining that he was bound to maintain the confidentiality of his discussions with other centers. Nevertheless, many UC San Diego leaders have been angry and defensive since a fight erupted last month between USC and UCSD over a program that coordinates research in Alzheimer’s disease (including many clinical trials) among scores of sites throughout the United States and Canada. UCSD founded the program with the National Institute on Aging (NIA) in 1991 as a kind of joint venture to facilitate the discovery, development, and testing of new drugs for the treatment of Alzheimer’s disease. “All of the institutions in San Diego collaborate; there’s a very collegial atmosphere,” David Brenner, dean of the UC San Diego School of Medicine, told Union-Tribune reporter Gary Robbins. “USC doesn’t want that. It wants to buy, rather than build, academic programs.” In 2014, USC attempted to join forces with The Scripps Research Institute—reportedly offering $15 million a year for 40 years for a partnership or wholesale acquisition of the biomedical research center. The proposal triggered a revolt among Scripps’ scientists, who stridently opposed the idea. The universities’ feud over the Alzheimer’s program led UC San Diego to sue USC, former UCSD scientist Paul Aisen, and others—alleging that they conspired to “misappropriate” the Alzheimer’s study while USC was recruiting Aisen to lead a new San Diego-based Alzheimer’s research institute for USC. After hearing arguments in the dispute at a hearing Friday, San Diego Superior Court Judge Judith Hayes granted UCSD’s request for a preliminary injunction against USC, Aisen, and other defendants in the dispute. The order represents the first step in restoring ownership of the Alzheimer’s program to UC San Diego, as well as control over a computer network and database that holds 24 years’ worth of Alzheimer’s research data. But arguments in the case have continued, and a final resolution of the dispute remains unclear. Meanwhile, Kronenberg said the La Jolla immunology institute determined that UC San Diego is “our natural partner” because of proximity (the institute is a few hundred feet east of UCSD’s Moores Cancer Center) and the institute’s longstanding ties with UCSD. “We don’t have any debt, and we weren’t in a rescue situation,” he said. Research at the institute includes work on autoimmune diseases like Type 1 (juvenile) diabetes and rheumatoid arthritis, developing immunotherapies to trigger an immune response to cancer, creating new vaccines, dampening harmful immune reactions to allergies and asthma, and finding new ways to battle infectious diseases. Under the institute’s new agreement with UC San Diego, the CEO of UC San Diego’s Health System will join the institute’s board as an ex officio member, and the dean of UCSD’s medical school will join the institute’s scientific advisory board. As the institute’s president, Kronenberg also will serve as an unpaid adviser to UCSD’s vice president of health sciences.