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Younes A.,University of Houston | Connors J.M.,Cancer Agency Center for Lymphoid Cancer | Park S.I.,University of North Carolina at Chapel Hill | Fanale M.,University of Houston | And 4 more authors.
The Lancet Oncology | Year: 2013

Background: Roughly 70-80% of patients with advanced stage Hodgkin's lymphoma are cured with various first-line and second-line treatments, including ABVD, BEACOPP, and stem-cell transplantation. Brentuximab vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkin's lymphoma. We aimed to assess the safety and early clinical efficacy of this drug as first-line treatment in combination with standard or modified-standard treatment in patients with previously untreated Hodgkin's lymphoma. Methods: We did a phase 1, open-label, dose-escalation safety study comparing brentuximab vedotin in combination with standard (ABVD) or a modified-standard (AVD) treatment. Patients were enrolled into the groups sequentially. Main entry criteria were newly diagnosed, treatment-naive, CD30-positive patients with Hodgkin's lymphoma who had histologically confirmed stage IIA bulky disease or stage IIB-IV disease and an Eastern Cooperative Oncology Group performance status of two or less. Patients received doses of 0·6, 0·9, or 1·2 mg/kg brentuximab vedotin by intravenous infusion every 2 weeks with either ABVD (25 mg/m2 doxorubicin, 10 units/m2 bleomycin, 6 mg/m2 vinblastine, and 375 mg/m2 dacarbazine) or AVD (ABVD modified regimen without the inclusion of bleomycin) for up to six cycles. Our primary objectives were to assess the safety profile and establish the maximum tolerated dose (MTD) of brentuximab vedotin in combination with ABVD and AVD. The safety profile and MTD was assessed for the safety population. The study has completed and the final analysis is presented. This study was registered with ClinicalTrials.gov, number NCT01060904. Findings: Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab vedotin. The maximum tolerated dose of brentuximab vedotin when combined with ABVD or AVD was not exceeded at 1·2 mg/kg. 21 (95%) of 22 patients given brentuximab vedotin and ABVD achieved complete remission, as did 24 (96%) of 25 patients given brentuximab vedotin and AVD. Adverse events were generally grade 1 or 2; however, an unacceptable number of patients in the brentuximab vedotin and ABVD groups had pulmonary toxic effects (11 [44%] of 25), which exceeded the historical incidence for ABVD alone. No patients experienced pulmonary toxic effects when treated with brentuximab vedotin plus AVD. The most common grade 3 or worse events were neutropenia (20 [80%] of 25 patients in the brentuximab vedotin and ABVD group vs 20 [77%] of 26 patients in the brentuximab vedotin and AVD group), anaemia (five [20%] vs three [12%]), febrile neutropenia (five [20%] vs two [8%]), pulmonary toxic effects (six [24%] vs 0), syncope (three [12%] vs two [8%]), dyspnoea (three [12%] vs one [4%]), pulmonary embolism (three [12%] vs 0), fatigue (one [4%] each), and leucopenia (one [4%] each). Serious events occured in 41% of all patients (14 [56%] in the brentuximab vedotin and ABVD group and seven [27%] in the brentuximab vedotin and AVD group). Serious events occurring in 10% of patients or more overall were febrile neutropenia (four [16%] in the brentuximab vedotin and ABVD group vs two [8%] in the brentuximab vedotin and AVD group), and, in the brentuximab vedotin and ABVD group only, pulmonary toxic effects (six [24%]). Interpretation: Brentuximab vedotin should not be given with bleomycin in general or specifically as first-line therapy for patients with treatment naive, advanced stage Hodgkin's lymphoma. 1·2 mg/kg brentuximab vedotin combined with AVD given every 2 weeks was generally well tolerated by patients. At present, a phase 3 trial comparing brentuximab vedotin plus AVD to ABVD alone is ongoing (ClinicalTrials.gov, number NCT01712490) and will formally assess whether brentuximab vedotin plus AVD might redefine therapy in treatment-naive patients with Hodgkin's lymphoma. Funding: Seattle Genetics Inc and Takeda Pharmaceuticals International Co. © 2013 Elsevier Ltd. Source


Gualberto A.,Takeda Cambridge | Gualberto A.,Brown University
Expert Opinion on Investigational Drugs | Year: 2012

Introduction: CD30-positive hematological malignancies are potentially curable with frontline combination chemotherapy regimens; however, those patients who relapse or are refractory to initial therapies have less favorable prognosis. Areas covered: Brentuximab vedotin is an antibodydrug conjugate (ADC) composed of the anti-CD30 chimeric IgG1 monoclonal antibody cAC10 and the potent antimicrotubule drug monomethylauristatin E connected by a protease-cleavable linker. Treatment with single-agent brentuximab vedotin resulted in unprecedented objective response rates and complete response rates of 75 and 34%, respectively, in relapsed or refractory Hodgkin lymphoma, and of 86 and 57%, respectively, in relapsed or refractory systemic anaplastic large-cell lymphoma patients. Peripheral sensory neuropathy and neutropenia were observed with brentuximab vedotin but were generally grade 1 and 2 in severity and manageable. In August 2011, brentuximab vedotin was approved in the US for the treatment of Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in ASCT-ineligible candidates, and for the treatment of systemic anaplastic large-cell lymphoma after failure of at least one prior multiagent chemotherapy regimen. Expert opinion: These data support an expanded development program for brentuximab vedotin in multiple CD30-positive indications. © 2012 Informa UK, Ltd. Source


LONDON & CAMBRIDGE, England--(BUSINESS WIRE)--UCL (University College London) and Takeda Pharmaceutical Company Limited (TSE:4502) today announced a new research collaboration to identify and validate novel target genes for the treatment of neurodegenerative disease. This collaboration will focus on mechanistic approaches for the identification of genes or signalling pathways that modify neurodegenerative disease processes affecting neuronal health (for example motor neurone disease (MND or ALS), Huntington’s disease and Parkinson’s disease). The collaboration, which includes support from the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, will initially run for a three-year period. It will be carried out by Takeda Cambridge Limited, Takeda’s research unit based in Cambridge, UK. It is one of the largest university partnerships formed by Takeda in the United Kingdom. Dr. Tetsuyuki Maruyama, General Manager of Takeda’s Pharmaceutical Research Division said: “At Takeda, we work with partners to accelerate innovation. We are looking forward to collaborating with UCL’s world-class researchers. This cooperation will help us to identify and validate novel therapeutic pathways in central nervous system diseases, which is one of Takeda’s core therapeutic areas – ultimately leading to new treatments for patients suffering from neurodegenerative disorders.” Professor Nicholas Wood, Neuroscience Programme Director at the NIHR University College London Hospitals Biomedical Research Centre, said: “I am delighted and excited with the potential of this initiative. It combines Takeda’s strengths in central nervous system (CNS) therapeutics with our research at UCL but importantly focuses on projects with huge experimental medicine potential". Professor Alan Thompson, Dean of the Faculty of Brain Sciences, UCL said: “Developing new treatments for devastating neurodegenerative diseases is an absolutely essential but very challenging goal and requires the complementary expertise of academia and industry, if it is to be achieved. This UCL-Takeda collaboration represents just such a partnership and as Dean of the Faculty of Brain Sciences, I am delighted to see it evolving so well.” UCL is a world leading university in CNS research with a world class reputation in the field of neurodegeneration and rare neurological disorders. UCL’s Institute of Neurology is a centre of significant investment for dementia research with a highly engaged and interactive faculty. Takeda Cambridge is a subsidiary of Takeda Pharmaceutical Company Limited, a research-based global pharmaceutical company. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to strive towards better health for people worldwide through leading innovation in medicine. Takeda Cambridge is Takeda’s research unit in the UK focused on target identification and drug discovery, with CNS being one of its key focus areas.


Wyant T.,Takeda Cambridge | Leach T.,Takeda Cambridge | Sankoh S.,Takeda Cambridge | Wang Y.,Takeda Cambridge | And 4 more authors.
Gut | Year: 2015

Design: In this randomised, double-blind, placebo-controlled, phase I trial, healthy participants received a single intravenous dose of vedolizumab 750 mg (n=64) or placebo (n=63). After 4 days, participants began intramuscular hepatitis B vaccine (HBV; days 4, 32, 60) and oral cholera vaccine (OCV; days 4, 18) regimens. The study was designed to demonstrate a 15% non-inferiority margin for the between-group difference in the primary end point: percentage of participants with HBV seroconversion at day 74 (serum hepatitis B surface antigen (HBs) antibody titre ≥10 IU/L). OCV seroconversion at day 74 (>4-fold increase in serum cholera toxin (CT) antibodies) was a secondary end point.Objective: The α4β7 integrin monoclonal antibody vedolizumab is hypothesised to be gut selective. Effects of vedolizumab on immune responses to parenterally or enterally administered antigens were investigated.Conclusions: Vedolizumab did not alter the response to parenterally administered antigens but reduced the response to oral antigens, demonstrating its gut-selective mechanism of action.Results: A total of 56 (90.3%) placebo-treated and 54 (88.5%) vedolizumab-treated participants responded to HBV. Geometric mean anti-HBs titres were similar for placebo (114.4 IU/L) and vedolizumab (129.6 IU/L) at day 74. A total of 60 (96.8%) placebo-treated and 52 (82.5%) vedolizumab-treated participants responded to OCV at day 74. Geometric mean anti-CT IgG levels were higher for placebo than for vedolizumab at day 74 (9210.08 vs 3007.8 ELISA Units (EU)/mL) and day 32 (11629.3 vs 1575.4 EU/mL). Anti-CT IgA results were similar. Adverse events were consistent with previous experience. One serious adverse event (spontaneous abortion) was reported for placebo. Source


Cognition deficits in schizophrenia remain an untreated area, and one in which R&D investment by pharmaceutical companies is high. However, whilst many preclinical assays demonstrate pro-cognitive activity with new drugs, in the main, they have not yet been translated successfully to the clinic. In an attempt to address this and reduce the high attrition rate for drugs in the clinic, selected pre-clinical researchers are re-focusing their efforts on the development and validation of more translational assays. The attentional set-shifting task is an example of such an assay, which has been back-translated from the clinic to a preclinical setting. Here we review its application in schizophrenia research across humans and animals, specifically with regards to the neural basis underlying cognitive performance, the various disease-like or symptom models employed in rodents to mimic cognitive dysfunction in schizophrenia, and the resulting impact of drug treatment on executive function. Using the attentional set-shifting task, we highlight the potential promise a more translational approach can bring, whilst demonstrating the need for closer alignment in the validation and integration of this task to fully realize this promise. © 2014 Bentham Science Publishers. Source

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