Cell culture engineering and biosimilars: The physician’s perspective

Biosimilars promise to increase access to life-saving and life-enhancing therapeutics, while creating cost savings that can fund further innovations in health care. Achievement of these goals is critically dependent on acceptance by prescribing physicians. This session will explore the following questions: What do clinicians care about? What do they know about the manufacture and characterization of biosimilars? What should they know? These questions will be addressed in the context of specific examples arising in the development of biosimilars to Neupogen, Infliximab, Humira, and Rituximab

Results of a phase-I/II randomized, masked, placebo-controlled trial of recombinant human interleukin-11 (rhIL-11) in the treatment of subjects with active rheumatoid arthritis

Interleukin-11 (IL-11) is a pleiotropic cytokine that regulates the growth and development of hematopoietic stem cells and decreases the proinflammatory mediators of cytokine and nitric oxide production. In animal models of arthritis, treatment with recombinant human IL-11 (rhIL-11) reduces both the level of synovitis and the histologic lesion scores in the joints. The goal of this phase-I/II study in adults with rheumatoid arthritis (RA) was to evaluate the safety and clinical activity of different doses and schedules of rhIL-11 in patients with active RA for whom treatment with at least one disease-modifying antirheumatic drug had failed. This was a multicenter, randomized, placebo-controlled trial that evaluated the safety and tolerability of rhIL-11 in 91 patients with active RA. rhIL-11 was administered subcutaneously; patients were randomized into one of five treatment groups (ratio of rhIL-11 to placebo, 4:1). Patients were treated for 12 weeks with either 2.5 or 7.5 μg/kg of rhIL-11 or placebo twice per week or 5 or 15 μg/kg of rhIL-11 or placebo once per week. The status of each subject's disease activity in accordance with the American College of Rheumatology (ACR) criteria was assessed before, during, and after completion of administration of the study drug. Administration of rhIL-11 was well tolerated at all doses and schedules. The most frequent adverse event was a reaction at the injection site. The data suggest a statistically significant reduction in the number of tender joints (P < 0.008) at the 15 μg/kg once-weekly dose schedule but showed no overall significant benefit at the ACR criterion of a 20% response. The trial showed rhIL-11 to be safe and well tolerated at a variety of doses and schedules over a 12-week treatment period in patients with active RA. The only adverse event clearly associated with rhIL-11 administration was reaction at the injection site

Integrating isotopes and documentary evidence : dietary patterns in a late medieval and early modern mining community, Sweden

We would like to thank the Archaeological Research Laboratory, Stockholm University, Sweden and the Tandem Laboratory (Ångström Laboratory), Uppsala University, Sweden, for undertaking the analyses of stable nitrogen and carbon isotopes in both human and animal collagen samples. Also, thanks to Elin Ahlin Sundman for providing the δ13C and δ15N values for animal references from Västerås. This research (Bäckström’s PhD employment at Lund University, Sweden) was supported by the Berit Wallenberg Foundation (BWS 2010.0176) and Jakob and Johan Söderberg’s foundation. The ‘Sala project’ (excavations and analyses) has been funded by Riksens Clenodium, Jernkontoret, Birgit and Gad Rausing’s Foundation, SAU’s Research Foundation, the Royal Physiographic Society of Lund, Berit Wallenbergs Foundation, Åke Wibergs Foundation, Lars Hiertas Memory, Helge Ax:son Johnson’s Foundation and The Royal Swedish Academy of Sciences.Peer reviewedPublisher PD

Abatacept for lupus nephritis: alternative definitions of complete response support conflicting conclusions.

ObjectiveRecent clinical trials in lupus nephritis have all used different criteria to assess complete response. The objective of this analysis was to compare several previously proposed criteria, using the same data set from a large trial of abatacept in lupus nephritis (IM101075). In so doing, we sought to determine which criteria are most sensitive to differences among treatment groups and to further examine the potential of abatacept in lupus nephritis.MethodsPatients in the IM101075 trial received abatacept at 1 of 2 different dose regimens or placebo, both on a background of mycophenolate mofetil and corticosteroids. Using data from this trial, we assessed rates of complete response at 12 months according to 5 sets of criteria, from 1) the trial protocol, 2) the Aspreva Lupus Management Study (ALMS) trial of mycophenolate mofetil, 3) the Lupus Nephritis Assessment with Rituximab (LUNAR) trial of rituximab, 4) an ongoing National Institutes of Health trial of abatacept (Abatacept and Cyclophosphamide Combination: Efficacy and Safety Study [ACCESS]), and 5) published recommendations of the American College of Rheumatology.ResultsAccording to the complete response definition from the IM101075 study protocol, there was no difference among treatment groups in the IM101075 study. In contrast, according to the ALMS, LUNAR, and ACCESS criteria, rates of complete response among patients in the IM101075 study were higher in both treatment groups relative to control. The largest differences were obtained with use of the LUNAR criteria (complete response rate of 6% in the control group, compared to 22% and 24% in the 2 abatacept groups).ConclusionThe choice of definition of complete response can determine whether a lupus nephritis trial is interpreted as a success or a failure. The results of this analysis provide an evidence-based rationale for choosing among alternative definitions and offer a strong rationale for conducting further studies of abatacept in lupus nephritis

Comparison of alternative primary outcome measures for use in lupus nephritis clinical trials.

ObjectiveClinical trials of therapies for lupus nephritis have used many different primary outcome measures, ranging from complete response to time to end-stage renal disease. The objective of this study was to compare several possible outcome measures, using data from a large, multicenter trial of abatacept in lupus nephritis, to gain insight into which outcome measure, if any, was best able to discern differences among treatment groups.MethodsStudy patients received either abatacept or placebo, on a background of mycophenolate mofetil and glucocorticoids. Using data from this trial, the following primary outcome measures at 24 and 52 weeks were compared: complete response rate, major clinical response rate, total response rate (complete plus partial response), improvement in proteinuria, improvement in estimated glomerular filtration rate, and frequency of treatment failure. Time to complete response was also evaluated.ResultsComplete response rate, major clinical response rate, and time to complete response were the measures that best discriminated between the abatacept groups and placebo, and the sensitivities of these 3 measures were comparable. For these measures, sample sizes of 50 patients would have been sufficient to demonstrate a statistically significant difference between treatment and control at 52 weeks. Each of the other measures also discriminated between treatment and control, but much larger group sizes would have been required to determine statistical significance.ConclusionThe choice of primary outcome measure can substantially influence the ability to detect therapeutic benefit in lupus nephritis trials. This study suggests that complete response rate, major clinical response rate at 52 weeks, and time to complete response may be the most sensitive outcome measures for detecting differences among therapeutic regimens

Comparison of alternative primary outcome measures for use in lupus nephritis clinical trials.

ObjectiveClinical trials of therapies for lupus nephritis have used many different primary outcome measures, ranging from complete response to time to end-stage renal disease. The objective of this study was to compare several possible outcome measures, using data from a large, multicenter trial of abatacept in lupus nephritis, to gain insight into which outcome measure, if any, was best able to discern differences among treatment groups.MethodsStudy patients received either abatacept or placebo, on a background of mycophenolate mofetil and glucocorticoids. Using data from this trial, the following primary outcome measures at 24 and 52 weeks were compared: complete response rate, major clinical response rate, total response rate (complete plus partial response), improvement in proteinuria, improvement in estimated glomerular filtration rate, and frequency of treatment failure. Time to complete response was also evaluated.ResultsComplete response rate, major clinical response rate, and time to complete response were the measures that best discriminated between the abatacept groups and placebo, and the sensitivities of these 3 measures were comparable. For these measures, sample sizes of 50 patients would have been sufficient to demonstrate a statistically significant difference between treatment and control at 52 weeks. Each of the other measures also discriminated between treatment and control, but much larger group sizes would have been required to determine statistical significance.ConclusionThe choice of primary outcome measure can substantially influence the ability to detect therapeutic benefit in lupus nephritis trials. This study suggests that complete response rate, major clinical response rate at 52 weeks, and time to complete response may be the most sensitive outcome measures for detecting differences among therapeutic regimens

Abatacept for lupus nephritis: alternative definitions of complete response support conflicting conclusions.

ObjectiveRecent clinical trials in lupus nephritis have all used different criteria to assess complete response. The objective of this analysis was to compare several previously proposed criteria, using the same data set from a large trial of abatacept in lupus nephritis (IM101075). In so doing, we sought to determine which criteria are most sensitive to differences among treatment groups and to further examine the potential of abatacept in lupus nephritis.MethodsPatients in the IM101075 trial received abatacept at 1 of 2 different dose regimens or placebo, both on a background of mycophenolate mofetil and corticosteroids. Using data from this trial, we assessed rates of complete response at 12 months according to 5 sets of criteria, from 1) the trial protocol, 2) the Aspreva Lupus Management Study (ALMS) trial of mycophenolate mofetil, 3) the Lupus Nephritis Assessment with Rituximab (LUNAR) trial of rituximab, 4) an ongoing National Institutes of Health trial of abatacept (Abatacept and Cyclophosphamide Combination: Efficacy and Safety Study [ACCESS]), and 5) published recommendations of the American College of Rheumatology.ResultsAccording to the complete response definition from the IM101075 study protocol, there was no difference among treatment groups in the IM101075 study. In contrast, according to the ALMS, LUNAR, and ACCESS criteria, rates of complete response among patients in the IM101075 study were higher in both treatment groups relative to control. The largest differences were obtained with use of the LUNAR criteria (complete response rate of 6% in the control group, compared to 22% and 24% in the 2 abatacept groups).ConclusionThe choice of definition of complete response can determine whether a lupus nephritis trial is interpreted as a success or a failure. The results of this analysis provide an evidence-based rationale for choosing among alternative definitions and offer a strong rationale for conducting further studies of abatacept in lupus nephritis

Streamlining the Design-to-Build Transition with Build-Optimization Software Tools.

Scaling-up capabilities for the design, build, and test of synthetic biology constructs holds great promise for the development of new applications in fuels, chemical production, or cellular-behavior engineering. Construct design is an essential component in this process; however, not every designed DNA sequence can be readily manufactured, even using state-of-the-art DNA synthesis methods. Current biological computer-aided design and manufacture tools (bioCAD/CAM) do not adequately consider the limitations of DNA synthesis technologies when generating their outputs. Designed sequences that violate DNA synthesis constraints may require substantial sequence redesign or lead to price-premiums and temporal delays, which adversely impact the efficiency of the DNA manufacturing process. We have developed a suite of build-optimization software tools (BOOST) to streamline the design-build transition in synthetic biology engineering workflows. BOOST incorporates knowledge of DNA synthesis success determinants into the design process to output ready-to-build sequences, preempting the need for sequence redesign. The BOOST web application is available at https://boost.jgi.doe.gov and its Application Program Interfaces (API) enable integration into automated, customized DNA design processes. The herein presented results highlight the effectiveness of BOOST in reducing DNA synthesis costs and timelines

Streamlining the Design-to-Build Transition with Build-Optimization Software Tools

Scaling-up capabilities for the design, build, and test of synthetic biology constructs holds great promise for the development of new applications in fuels, chemical production, or cellular-behavior engineering. Construct design is an essential component in this process; however, not every designed DNA sequence can be readily manufactured, even using state-of-the-art DNA synthesis methods. Current biological computer-aided design and manufacture tools (bioCAD/CAM) do not adequately consider the limitations of DNA synthesis technologies when generating their outputs. Designed sequences that violate DNA synthesis constraints may require substantial sequence redesign or lead to price-premiums and temporal delays, which adversely impact the efficiency of the DNA manufacturing process. We have developed a suite of build-optimization software tools (BOOST) to streamline the design-build transition in synthetic biology engineering workflows. BOOST incorporates knowledge of DNA synthesis success determinants into the design process to output ready-to-build sequences, preempting the need for sequence redesign. The BOOST web application is available at https://boost.jgi.doe.gov and its Application Program Interfaces (API) enable integration into automated, customized DNA design processes. The herein presented results highlight the effectiveness of BOOST in reducing DNA synthesis costs and timelines

Peginterferon Lambda-1a, a New Therapeutic for Hepatitis C Infection, from Bench to Clinic

Abstract Chronic infection with hepatitis C virus (HCV) is estimated to affect approximately 3% of the world&apos;s population and cause 350,000 deaths each year. For a number of years, the standard of care has been combination therapy with recombinant alfa interferons-originally as native proteins but more recently as polyethyleneglycol-modified derivatives-and ribavirin, with the recent addition of an NS3 protease inhibitor for HCV genotype 1. However, therapeutic alfa interferons are associated with a significant burden of treatment-limiting adverse events, including musculoskeletal and influenza-like symptoms, hematologic cytopenias, autoimmune disease, fatigue, and other neurologic events. In 2003, a team at ZymoGenetics (now a fully owned subsidiary of Bristol-Myers Squibb) and a second, independent group simultaneously identified a new class of interferons-the type III lambda interferons-with near-identical activity to the type I alfa interferons in hepatocytes but with an unrelated and less ubiquitous receptor. Subsequent evaluation of the type III interferon system demonstrated antiviral activity against HCV in vitro with limited activity in peripheral blood mononuclear cells and other nonhepatocyte cell types, supporting its development as a potentially better-tolerated therapy for viral hepatitis. Peginterferon lambda-1a (Lambda) is an investigational type III therapeutic agent originally developed at ZymoGenetics that is currently in Phase 3 studies for the treatment of HCV. In this review, we describe the selection of the Lambda molecule and its preclinical and early clinical development, and how the resulting data have helped to establish the differentiated safety profile for Lambda-with fewer influenza-like and musculoskeletal symptoms and less hematologic toxicity than the alfa interferons-that was seen in later studies