The Experts below are selected from a list of 123 Experts worldwide ranked by ideXlab platform
Paolo Pozzilli - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Otelixizumab use in new onset type 1 diabetes mellitus
Expert Opinion on Biological Therapy, 2016Co-Authors: Chiara Guglielmi, Stefan Rhys Williams, Rossella Del Toro, Paolo PozzilliAbstract:ABSTRACTIntroduction: Type 1 diabetes (T1DM) is an immune-mediated disease induced by antigen-specific T cells infiltrating pancreatic beta cells leading to the progressive loss of endogenous insulin secretion.Areas covered: The identification of specific components of the autoimmune response favoured the implementation of several immunomodulatory therapies including antiCD3 monoclonal antibody (mAb) called Otelixizumab. Otelixizumab is a chimeric monoclonal antibody that targets the e-chain of the CD3T-lymphocyte surface receptor that has been developed with the aim of short therapeutic courses capable of inducing a remission of T1DM. Clinical trials have been carried out with Otelixizumab to evaluate its safety and efficacy, but despite positive results of Phase I and II studies, the results of Phase III studies have been contradictory.Expert opinion: High doses of Otelixizumab have shown beneficial effects on beta cell function whereas a lower dose, which was tested to avoid the adverse effects associa...
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low dose Otelixizumab anti cd3 monoclonal antibody defend 1 study results of the randomized phase iii study in recent onset human type 1 diabetes
Diabetes Care, 2014Co-Authors: Ronnie Aronson, Peter A Gottlieb, Jens Sandahl Christiansen, Thomas Donner, Emanuele Bosi, Bruce W Bode, Paolo PozzilliAbstract:OBJECTIVE Previous studies demonstrated that the anti-CD3 monoclonal antibody Otelixizumab, administered at a total dose of 48–64 mg, can slow the loss of C-peptide in recent-onset type 1 diabetes patients, with frequent reactivation of Epstein Barr virus (EBV). The DEFEND-1 (Durable Response Therapy Evaluation for Early or New-Onset Type 1 Diabetes) trial was designed to test whether a lower dose of Otelixizumab could preserve C-peptide secretion in new-onset type 1 diabetes patients. RESEARCH DESIGN AND METHODS A multicenter, randomized, placebo-controlled trial was performed in sites in the U.S., Canada, and Europe. Two hundred eighty-one patients were randomized to treatment with 3.1 mg Otelixizumab administered over 8 days or placebo. The primary end point of the study was the change in C-peptide area under the curve (AUC) from a 2-h mixed-meal tolerance test at month 12. RESULTS The change in 2-h C-peptide AUC was not different between placebo-treated patients and Otelixizumab-treated patients (−0.20 vs. −0.22 nmol/L, P = 0.81). Secondary end points, including HbA 1c , glucose variability, and insulin dose, were also not statistically different between the two groups. More patients in the Otelixizumab group than in the placebo group experienced adverse events, mostly grade 1 or grade 2. There was no EBV reactivation (viral load >10,000 copies/10 6 peripheral blood mononuclear cells) in the Otelixizumab group, in contrast with previously published studies at higher doses of Otelixizumab. CONCLUSIONS Otelixizumab was well tolerated in patients with recent-onset type 1 diabetes at a total dose of 3.1 mg, but did not achieve preservation of levels of C-peptide or other markers of metabolic control.
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Immunotherapy for Type 1 diabetes: getting beyond a negative first impression
Immunotherapy, 2012Co-Authors: Paolo Pozzilli, Rocky StrolloAbstract:GAD-alum; two injections of 20 μg GAD-alum and one of alum; or three injections of alum. However, the primary end point of a higher area under the curve of stimulated C-peptide at 1 year (9 months after the end of the treatment), as compared with placebos, was not met [3]. The second one, conducted on a larger sample (434 T1D subjects) and using a higher total dose (four injections of 20 μg) obtained similar results [2]. Although disappointing, these findings are not completely unexpected. Experimental studies in the nonobese diabetic mouse have shown that several factors such as timing of the disease process, route of administration and dose may affect effectiveness of the intervention. Experimental studies showed that an effective antigen therapy needs to be started before the disease develops, a timing that is certainly different from the clinical trial settings. Moreover, antigen-based therapies have also failed in other autoimmune diseases such as multiple sclerosis [4]. Broad-based immunosuppressive therapies aiming to restore the altered balance between ‘effector’ T cells and Tregs have also been tested. Teplizumab and Otelixizumab are two humanized anti-CD3 antibodies that target the T-cell receptor complex for antigen recognition. Phase III trials with antibodies were meant to confirm on a large scale encouraging results obtained in previous academic trials. Although the trial with teplizumab, Protege, did not meet the primary composite end point (glycated hemoglobin A1c [HbA1c]
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Clinical Update on the Use of Immuno Modulators (antiCD3, GAD, Diapep277, Anti-IL1) in Type 1 Diabetes
Current Pharmaceutical Design, 2011Co-Authors: Paolo Pozzilli, Chiara Guglielmi, Daria Maggi, Angela Carlone, Raffaella Buzzetti, Silvia ManfriniAbstract:In type 1 diabetes, beta cells are attacked and destroyed by auto reactive T cells causing major impairment of blood glucose metabolism and, ultimately, the development of life-threatening complications. Currently, the treatment of this chronic disease is based on the use of endogenous insulin and no curative therapies are available. Treatment approaches in this respect need to be directed toward the primary causes of the disease tackling beta cells auto reactive T cells. The goal of any curative intervention in type 1 diabetes is the preservation of insulin-secreting cells. This may be achieved by the abrogation of the pathogenic reactivity to beta cell auto antigens while preserving full capacity to generate a normal immune response against foreign antigens. In this review, some of the most promising drugs for immune intervention in type 1 diabetes are presented and discussed including phase 3 clinical trials that involve: DiaPep277, Anti-CD3 Otelixizumab, Glutamic Acid Decarboxylase (GAD) and anti-IL1 receptor antagonist. These approaches are currently being tested in international multicenter trials and all of them have a very similar outcome in terms of a beneficial effect on beta cells.
Bart Keymeulen - One of the best experts on this subject based on the ideXlab platform.
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target engagement and cellular fate of Otelixizumab a repeat dose escalation study of an anti cd3e mab in new onset type 1 diabetes mellitus patients
British Journal of Clinical Pharmacology, 2019Co-Authors: Georgios Vlasakakis, Antonella Napolitano, Ruth M Barnard, Kim Brown, Jonathan Bullman, David Inman, Bart Keymeulen, David Lanham, Quentin Leirens, Alexander MacdonaldAbstract:AIMS: This paper describes the pharmacological findings from a study where Otelixizumab, an anti-CD3ɛ mAb, was dosed in new onset Type 1 diabetes mellitus (NOT1DM) patients. This is the first time that the full dose-response of an anti-CD3ɛ mAb has been investigated in the clinic. The data have been validated using a previously developed pharmacokinetic/pharmacodynamic (PK/PD) model of Otelixizumab to simulate the interplay between drug administration, CD3ɛ target engagement and downmodulation. METHODS: Patients were randomized to control or active treatment with Otelixizumab (1:4), administered via infusion over 6 days, in a dose-ascending study consisted of three cohorts (n = 10 per cohort) at doses of 9, 18 or 27 mg respectively. The study allowed quantification of Otelixizumab PK, CD3ɛ target engagement and its pharmacodynamic effect (CD3e/TCR modulation on circulating T lymphocytes). RESULTS: Otelixizumab concentrations increased and averaged to 364.09 (54.3), 1625.55 (72.5) and 2781.35 (28.0) ng ml-1 (Geom.mean, %CV) at the 9, 18 and 27 mg dose respectively. CD3ɛ target engagement was found to be rapid (within the first 30 min), leading to a receptor occupancy of ~60% within 6 h of dosing in all three doses. A dose-response relationship was observed with the two highest doses achieving a ~90% target engagement and consequential CD3ɛ/TCR downmodulation by Day 6. CONCLUSIONS: Data from this study revealed maximum target engagement and CD3ɛ/TCR modulation is achieved at doses of 18, 27 mg of Otelixizumab. These findings can be useful in guiding dose selection in clinical trials with anti-CD3ɛ mAbs.
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Target engagement and cellular fate of Otelixizumab; a repeat dose escalation study of an anti‐CD3ε mAb in New‐Onset Type 1 Diabetes Mellitus Patients
British Journal of Clinical Pharmacology, 2019Co-Authors: Georgios Vlasakakis, Antonella Napolitano, Ruth M Barnard, Kim Brown, Jonathan Bullman, David Inman, Bart Keymeulen, David Lanham, Quentin Leirens, Alexander MacdonaldAbstract:AIMS: This paper describes the pharmacological findings from a study where Otelixizumab, an anti-CD3ɛ mAb, was dosed in new onset Type 1 diabetes mellitus (NOT1DM) patients. This is the first time that the full dose-response of an anti-CD3ɛ mAb has been investigated in the clinic. The data have been validated using a previously developed pharmacokinetic/pharmacodynamic (PK/PD) model of Otelixizumab to simulate the interplay between drug administration, CD3ɛ target engagement and downmodulation. METHODS: Patients were randomized to control or active treatment with Otelixizumab (1:4), administered via infusion over 6 days, in a dose-ascending study consisted of three cohorts (n = 10 per cohort) at doses of 9, 18 or 27 mg respectively. The study allowed quantification of Otelixizumab PK, CD3ɛ target engagement and its pharmacodynamic effect (CD3e/TCR modulation on circulating T lymphocytes). RESULTS: Otelixizumab concentrations increased and averaged to 364.09 (54.3), 1625.55 (72.5) and 2781.35 (28.0) ng ml-1 (Geom.mean, %CV) at the 9, 18 and 27 mg dose respectively. CD3ɛ target engagement was found to be rapid (within the first 30 min), leading to a receptor occupancy of ~60% within 6 h of dosing in all three doses. A dose-response relationship was observed with the two highest doses achieving a ~90% target engagement and consequential CD3ɛ/TCR downmodulation by Day 6. CONCLUSIONS: Data from this study revealed maximum target engagement and CD3ɛ/TCR modulation is achieved at doses of 18, 27 mg of Otelixizumab. These findings can be useful in guiding dose selection in clinical trials with anti-CD3ɛ mAbs.
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preexisting insulin autoantibodies predict efficacy of Otelixizumab in preserving residual β cell function in recent onset type 1 diabetes
Diabetes Care, 2015Co-Authors: Simke Demeester, Bart Keymeulen, Leonard Kaufman, Annelien Van Dalem, Eric V Balti, Ursule Van De Velde, P Goubert, Katrijn Verhaeghen, Howard W Davidson, Janet M WenzlauAbstract:OBJECTIVE Immune intervention trials in recent-onset type 1 diabetes would benefit from biomarkers associated with good therapeutic response. In the previously reported randomized placebo-controlled anti-CD3 study (Otelixizumab; GlaxoSmithKline), we tested the hypothesis that specific diabetes autoantibodies might serve this purpose. RESEARCH DESIGN AND METHODS In the included patients ( n = 40 Otelixizumab, n = 40 placebo), β-cell function was assessed as area under the curve (AUC) C-peptide release during a hyperglycemic glucose clamp at baseline (median duration of insulin treatment: 6 days) and every 6 months until 18 months after randomization. (Auto)antibodies against insulin (I[A]A), GAD (GADA), insulinoma-associated protein-2 IA-2 (IA-2A), and zinc transporter 8 (ZnT8A) were determined on stored sera by liquid-phase radiobinding assay. RESULTS At baseline, only better preserved AUC C-peptide release and higher levels of insulin autoantibodies (IAA) were associated with better preservation of β-cell function and lower insulin needs under anti-CD3 treatment. In multivariate analysis, IAA ( P = 0.022) or the interaction of IAA and C-peptide ( P = 0.013) independently predicted outcome together with treatment. During follow-up, good responders to anti-CD3 treatment (i.e., IAA+ participants with relatively preserved β-cell function [≥25% of healthy control subjects]) experienced a less pronounced insulin-induced rise in I(A)A and lower insulin needs. GADA, IA-2A, and ZnT8A levels were not influenced by anti-CD3 treatment, and their changes showed no relation to functional outcome. CONCLUSIONS There is important specificity of IAA among other diabetes autoantibodies to predict good therapeutic response of recent-onset type 1 patients to anti-CD3 treatment. If confirmed, future immune intervention trials in type 1 diabetes should consider both relatively preserved functional β-cell mass and presence of IAA as inclusion criteria.
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pharmacokinetics and antibody responses to the cd3 antibody Otelixizumab used in the treatment of type 1 diabetes
The Journal of Clinical Pharmacology, 2010Co-Authors: Geoff Hale, Pawel Wiczling, William J Jusko, Bart Keymeulen, Peppy Rebello, Ibrahim Al Bakir, Emma Bolam, Evy Vandemeulebroucke, Chantal Mathieu, Annetteg ZieglerAbstract:Otelixizumab is a chimeric CD3 antibody that has been genetically engineered to remove the glycosylation site in the Fc domain. This limits its ability to bind to complement or Fc receptors and reduces the risk of adverse clinical reactions due to cytokine release. In a trial for treatment of type 1 diabetes, a short treatment with Otelixizumab resulted in a reduced requirement for insulin lasting at least 18 months. In the course of this trial, the blood concentrations of the antibody were measured by flow cytometry to determine its pharmacokinetic profile. Dose-dependent accumulation of Otelixizumab was demonstrated and modeling of the data indicated that the terminal half-life was approximately 1.5 days. Antibody responses to Otelixizumab were measured by 2 methods: a bridging enzyme-linked immunosorbent assay and surface plasmon resonance. The surface plasmon resonance method had a greater sensitivity and was able to detect responses in all patients, starting at 8 days after the commencement of therapy. Neutralizing antibodies were detected in a significant proportion of patients by days 22 to 29. Although no adverse clinical effects were associated with these antibody responses and they did not appear to affect the clearance of the drug, they might have important implications for possible retreatment of the patients.
Andre Van Maurik - One of the best experts on this subject based on the ideXlab platform.
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temporal pharmacokinetic pharmacodynamic interaction between human cd3e antigen targeted monoclonal antibody Otelixizumab and cd3e binding and expression in human peripheral blood mononuclear cell static culture
Journal of Pharmacology and Experimental Therapeutics, 2015Co-Authors: Kevin Page, Enrica Mezzalana, Alexander J Macdonald, Stefano Zamuner, Giuseppe De Nicolao, Andre Van MaurikAbstract:Otelixizumab is a monoclonal antibody (mAb) directed to human CD3 e , a protein forming part of the CD3/T-cell receptor (TCR) complex on T lymphocytes. This study investigated the temporal interaction between varying concentrations of Otelixizumab, binding to human CD3 antigen, and expression of CD3/TCR complexes on lymphocytes in vitro, free from the confounding influence of changing lymphocyte frequencies observed in vivo. A static in vitro culture system was established in which primary human peripheral blood mononuclear cells (PBMCs) were incubated over an extended time course with titrated concentrations of Otelixizumab. At each time point, free, bound, and total CD3/TCR expression on both CD4+ and CD8+ T cells and the amount of free Otelixizumab antibody in the supernatant were measured. The pharmacokinetics of free Otelixizumab in the culture supernatants was saturable, with a shorter apparent half-life at low concentration. Correspondingly, a rapid, Otelixizumab concentration–, and time-dependent reduction in CD3/TCR expression was observed. These combined observations were consistent with the phenomenon known as target-mediated drug disposition (TMDD). A mechanistic, mathematical pharmacokinetic/pharmacodynamic (PK/PD) model was then used to characterize the free Otelixizumab-CD3 expression-time relationship. CD3/TCR modulation induced by Otelixizumab was found to be relatively fast compared with the re-expression rate of CD3/TCR complexes following Otelixizumab removal from supernatants. In summary, the CD3/TCR receptor has been shown to have a major role in determining Otelixizumab disposition. A mechanistic PK/PD model successfully captured the PK and PD in vitro data, confirming TMDD by Otelixizumab.
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Temporal pharmacokinetic/pharmacodynamic interaction between human CD3ε antigen-targeted monoclonal antibody Otelixizumab and CD3ε binding and expression in human peripheral blood mononuclear cell static culture.
Journal of Pharmacology and Experimental Therapeutics, 2015Co-Authors: Kevin Page, Enrica Mezzalana, Alexander J Macdonald, Stefano Zamuner, Giuseppe De Nicolao, Andre Van MaurikAbstract:Otelixizumab is a monoclonal antibody (mAb) directed to human CD3 e , a protein forming part of the CD3/T-cell receptor (TCR) complex on T lymphocytes. This study investigated the temporal interaction between varying concentrations of Otelixizumab, binding to human CD3 antigen, and expression of CD3/TCR complexes on lymphocytes in vitro, free from the confounding influence of changing lymphocyte frequencies observed in vivo. A static in vitro culture system was established in which primary human peripheral blood mononuclear cells (PBMCs) were incubated over an extended time course with titrated concentrations of Otelixizumab. At each time point, free, bound, and total CD3/TCR expression on both CD4+ and CD8+ T cells and the amount of free Otelixizumab antibody in the supernatant were measured. The pharmacokinetics of free Otelixizumab in the culture supernatants was saturable, with a shorter apparent half-life at low concentration. Correspondingly, a rapid, Otelixizumab concentration–, and time-dependent reduction in CD3/TCR expression was observed. These combined observations were consistent with the phenomenon known as target-mediated drug disposition (TMDD). A mechanistic, mathematical pharmacokinetic/pharmacodynamic (PK/PD) model was then used to characterize the free Otelixizumab-CD3 expression-time relationship. CD3/TCR modulation induced by Otelixizumab was found to be relatively fast compared with the re-expression rate of CD3/TCR complexes following Otelixizumab removal from supernatants. In summary, the CD3/TCR receptor has been shown to have a major role in determining Otelixizumab disposition. A mechanistic PK/PD model successfully captured the PK and PD in vitro data, confirming TMDD by Otelixizumab.
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A CD3-specific antibody reduces cytokine production and alters phosphoprotein profiles in intestinal tissues from patients with inflammatory bowel disease.
Gastroenterology, 2014Co-Authors: Anna Vossenkämper, Kevin Page, Andre Van Maurik, Christian Hundsrucker, Theodore J. Sanders, Andrew J. Stagg, Thomas T. MacdonaldAbstract:Background & Aims T cells mediate the development of inflammation in inflammatory bowel disease (IBD). We investigated the effects of an antibody against CD3 called Otelixizumab, which induces immune tolerance, in intestinal mucosa samples from patients. Methods Intestinal tissues were isolated from patients undergoing routine endoscopy or from patients undergoing intestinal surgery for colon cancer or IBD; healthy surrounding tissues were collected as controls. Isolated lamina propria mononuclear cells (LPMCs) and mucosal tissue explants were incubated with Otelixizumab for 24 or 48 hours. Production of inflammatory cytokines was determined by enzyme-linked immunosorbent assay. Levels of 36 cytokines and chemokines and phosphorylation of 39 receptor tyrosine kinases and signaling molecules were measured using protein arrays. Immunoblot analysis was used to analyze T-cell transcription factors. Results Incubation of intestinal tissues or LPMCs with Otelixizumab reduced production of interferon gamma, interleukin (IL)-17A, and other inflammatory cytokines and chemokines, simultaneously increasing production of IL-10. Mucosal biopsy specimens from patients with IBD retained inflammation-associated tyrosine phosphoprotein profiles ex vivo. Incubation of the inflamed tissue with Otelixizumab reduced phosphorylation of these proteins to levels observed in control tissues. Otelixizumab also markedly reduced phosphorylation of proteins associated with T-cell receptor activation. Neutralization of IL-10 blocked the anti-inflammatory effects of Otelixizumab. Conclusions We observed anti-inflammatory effects of anti-CD3 in inflamed intestinal tissues from patients with IBD. The antibody appears to down-regulate T-cell activation via IL-10.
P Ambery - One of the best experts on this subject based on the ideXlab platform.
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urinary c peptide analysis in an intervention study experience from the defend 2 Otelixizumab trial
Diabetic Medicine, 2016Co-Authors: P Ambery, Jill Donaldson, J Parkin, D J AustinAbstract:AIMS: To demonstrate that analysis of urinary C-peptide across multiple study sites in the context of an intervention trial (DEFEND-2) is a viable alternative to mixed meal testing and delivers results that correlate to mixed meal testing estimation of endogenous insulin production. METHODS: Second morning void urine was collected for analysis and was available from 161 subjects at baseline (55 placebo, 106 Otelixizumab), and 146 subjects (47 placebo, 99 Otelixizumab) at month 12. Urinary C-peptide concentration was corrected for urinary creatinine [urinary C-peptide/creatinine ratio (UCPCR)] and serum C-peptide from the mixed meal tolerance test was calculated using area under the plasma concentration-time curve (AUC) normalized over 120 min. The correlation between mixed meal stimulated C-peptide AUC (mmol/l/min) and UCPCR (nmol/mmol), as well as the correlation between insulin use (IU/kg), and HbA1c (%) with UCPCR, was determined. RESULTS: UCPCR and mixed meal testing C-peptide AUC were correlated, with a correlation coefficient of 0.4172. UCPCR was not correlated with exogenous insulin use (r = -0.089) or with HbA1c (r = -0.032). CONCLUSIONS: Urinary C-peptide estimation should be considered as a measure of endogenous insulin production in future Type 1 diabetes mellitus outcome trials. A change in the timing for urine collection (to 120 min post standard meal) may provide a tighter correlation to C-peptide measured via a traditional mixed meal test.
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subcutaneous administration of Otelixizumab is limited by injection site reactions results of an exploratory study in type 1 diabetes mellitus patients
Experimental and Clinical Endocrinology & Diabetes, 2016Co-Authors: A Macdonald, P Ambery, Jill Donaldson, B Keymeulen, K Hicks, J ParkinAbstract:Targeting CD3 antigens on human T lymphocytes with monoclonal antibodies has been shown to reduce the rate of decline of C-peptides in recent-onset type 1 diabetes mellitus patients. However, effective doses are associated with infusion reactions typical of “cytokine release syndrome” and appear to be dose-limiting when administered as short-duration infusions. A possible alternative approach, which may reduce the rate of T cell activation and consequent systemic cytokine release, is to inject subcutaneously. We investigated single- and repeat-dose subcutaneous administration of the anti-CD3 monoclonal antibody Otelixizumab in small cohorts of patients with type 1 diabetes. Transient reductions in free or unbound CD3 antigen on CD4+ and CD8+ cells and absolute lymphocyte count were observed in the blood of these patients during treatment, consistent with the known mechanism of action of Otelixizumab and other anti-CD3 monoclonal antibodies. This was despite the very low systemic exposure of antibodies measured during the same time period. With the exception of sporadic headaches, other symptoms associated with cytokine release syndrome, such as fever, nausea, vomiting, myalgia, and arthralgia, were absent in treated patients. However, treatment-related injection site reactions were consistently observed. The reactions were erythematous and their sizes were dose-dependent; in some cases, reactions persisted for up to 2 weeks following the start of treatment. While patients responded well to topical corticosteroid treatment and prophylaxis reduced the intensity of injection site reactions, the reactions were considered dose-limiting and higher doses were not investigated.
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Urinary C–peptide analysis in an intervention study: experience from the DEFEND–2 Otelixizumab trial
Diabetic Medicine, 2016Co-Authors: P Ambery, Jill Donaldson, J Parkin, D J AustinAbstract:AIMS: To demonstrate that analysis of urinary C-peptide across multiple study sites in the context of an intervention trial (DEFEND-2) is a viable alternative to mixed meal testing and delivers results that correlate to mixed meal testing estimation of endogenous insulin production. METHODS: Second morning void urine was collected for analysis and was available from 161 subjects at baseline (55 placebo, 106 Otelixizumab), and 146 subjects (47 placebo, 99 Otelixizumab) at month 12. Urinary C-peptide concentration was corrected for urinary creatinine [urinary C-peptide/creatinine ratio (UCPCR)] and serum C-peptide from the mixed meal tolerance test was calculated using area under the plasma concentration-time curve (AUC) normalized over 120 min. The correlation between mixed meal stimulated C-peptide AUC (mmol/l/min) and UCPCR (nmol/mmol), as well as the correlation between insulin use (IU/kg), and HbA1c (%) with UCPCR, was determined. RESULTS: UCPCR and mixed meal testing C-peptide AUC were correlated, with a correlation coefficient of 0.4172. UCPCR was not correlated with exogenous insulin use (r = -0.089) or with HbA1c (r = -0.032). CONCLUSIONS: Urinary C-peptide estimation should be considered as a measure of endogenous insulin production in future Type 1 diabetes mellitus outcome trials. A change in the timing for urine collection (to 120 min post standard meal) may provide a tighter correlation to C-peptide measured via a traditional mixed meal test.
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efficacy and safety of low dose Otelixizumab anti cd3 monoclonal antibody in preserving c peptide secretion in adolescent type 1 diabetes defend 2 a randomized placebo controlled double blind multi centre study
Diabetic Medicine, 2014Co-Authors: P Ambery, T W Donner, N Biswas, Jill Donaldson, J Parkin, Colin M DayanAbstract:AIMS: Phase III DEFEND-2 investigated whether Otelixizumab (3.1 mg over 8 days) preserved C-peptide secretion in patients with new-onset Type 1 diabetes, focusing on adolescents (12-17 years). METHODS: One hundred and seventy-nine patients (54 adolescents) were randomized to Otelixizumab or placebo. The primary endpoint was change in 2-h mixed-meal-stimulated C-peptide area under the curve at month 12. Enrolment was suspended in April 2011 following negative efficacy results from DEFEND-1. DEFEND-2 terminated early after 12 months' efficacy and safety follow-up. RESULTS: Change from baseline C-peptide was not significantly different [∆ = -0.09 nmol/l (95% CI -0.17 to 0; P = 0.051)]. No differential C-peptide effect was seen for Otelixizumab in adolescents and more adverse events were reported. CONCLUSIONS: Efficacy and tolerability of Otelixizumab was similar to DEFEND-1. The 3.1-mg dose was non-efficacious in adults and adolescents. Further investigation of the mechanism of action seen at higher doses and therapeutic window is required. Clinical Trials Registry No: NCT 00763451.
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Efficacy and safety of low‐dose Otelixizumab anti‐CD3 monoclonal antibody in preserving C‐peptide secretion in adolescent type 1 diabetes: DEFEND‐2, a randomized, placebo‐controlled, double‐blind, multi‐centre study
Diabetic Medicine, 2013Co-Authors: P Ambery, T W Donner, N Biswas, Jill Donaldson, J Parkin, Colin M DayanAbstract:AIMS: Phase III DEFEND-2 investigated whether Otelixizumab (3.1 mg over 8 days) preserved C-peptide secretion in patients with new-onset Type 1 diabetes, focusing on adolescents (12-17 years). METHODS: One hundred and seventy-nine patients (54 adolescents) were randomized to Otelixizumab or placebo. The primary endpoint was change in 2-h mixed-meal-stimulated C-peptide area under the curve at month 12. Enrolment was suspended in April 2011 following negative efficacy results from DEFEND-1. DEFEND-2 terminated early after 12 months' efficacy and safety follow-up. RESULTS: Change from baseline C-peptide was not significantly different [∆ = -0.09 nmol/l (95% CI -0.17 to 0; P = 0.051)]. No differential C-peptide effect was seen for Otelixizumab in adolescents and more adverse events were reported. CONCLUSIONS: Efficacy and tolerability of Otelixizumab was similar to DEFEND-1. The 3.1-mg dose was non-efficacious in adults and adolescents. Further investigation of the mechanism of action seen at higher doses and therapeutic window is required. Clinical Trials Registry No: NCT 00763451.
Alexander Macdonald - One of the best experts on this subject based on the ideXlab platform.
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target engagement and cellular fate of Otelixizumab a repeat dose escalation study of an anti cd3e mab in new onset type 1 diabetes mellitus patients
British Journal of Clinical Pharmacology, 2019Co-Authors: Georgios Vlasakakis, Antonella Napolitano, Ruth M Barnard, Kim Brown, Jonathan Bullman, David Inman, Bart Keymeulen, David Lanham, Quentin Leirens, Alexander MacdonaldAbstract:AIMS: This paper describes the pharmacological findings from a study where Otelixizumab, an anti-CD3ɛ mAb, was dosed in new onset Type 1 diabetes mellitus (NOT1DM) patients. This is the first time that the full dose-response of an anti-CD3ɛ mAb has been investigated in the clinic. The data have been validated using a previously developed pharmacokinetic/pharmacodynamic (PK/PD) model of Otelixizumab to simulate the interplay between drug administration, CD3ɛ target engagement and downmodulation. METHODS: Patients were randomized to control or active treatment with Otelixizumab (1:4), administered via infusion over 6 days, in a dose-ascending study consisted of three cohorts (n = 10 per cohort) at doses of 9, 18 or 27 mg respectively. The study allowed quantification of Otelixizumab PK, CD3ɛ target engagement and its pharmacodynamic effect (CD3e/TCR modulation on circulating T lymphocytes). RESULTS: Otelixizumab concentrations increased and averaged to 364.09 (54.3), 1625.55 (72.5) and 2781.35 (28.0) ng ml-1 (Geom.mean, %CV) at the 9, 18 and 27 mg dose respectively. CD3ɛ target engagement was found to be rapid (within the first 30 min), leading to a receptor occupancy of ~60% within 6 h of dosing in all three doses. A dose-response relationship was observed with the two highest doses achieving a ~90% target engagement and consequential CD3ɛ/TCR downmodulation by Day 6. CONCLUSIONS: Data from this study revealed maximum target engagement and CD3ɛ/TCR modulation is achieved at doses of 18, 27 mg of Otelixizumab. These findings can be useful in guiding dose selection in clinical trials with anti-CD3ɛ mAbs.
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Target engagement and cellular fate of Otelixizumab; a repeat dose escalation study of an anti‐CD3ε mAb in New‐Onset Type 1 Diabetes Mellitus Patients
British Journal of Clinical Pharmacology, 2019Co-Authors: Georgios Vlasakakis, Antonella Napolitano, Ruth M Barnard, Kim Brown, Jonathan Bullman, David Inman, Bart Keymeulen, David Lanham, Quentin Leirens, Alexander MacdonaldAbstract:AIMS: This paper describes the pharmacological findings from a study where Otelixizumab, an anti-CD3ɛ mAb, was dosed in new onset Type 1 diabetes mellitus (NOT1DM) patients. This is the first time that the full dose-response of an anti-CD3ɛ mAb has been investigated in the clinic. The data have been validated using a previously developed pharmacokinetic/pharmacodynamic (PK/PD) model of Otelixizumab to simulate the interplay between drug administration, CD3ɛ target engagement and downmodulation. METHODS: Patients were randomized to control or active treatment with Otelixizumab (1:4), administered via infusion over 6 days, in a dose-ascending study consisted of three cohorts (n = 10 per cohort) at doses of 9, 18 or 27 mg respectively. The study allowed quantification of Otelixizumab PK, CD3ɛ target engagement and its pharmacodynamic effect (CD3e/TCR modulation on circulating T lymphocytes). RESULTS: Otelixizumab concentrations increased and averaged to 364.09 (54.3), 1625.55 (72.5) and 2781.35 (28.0) ng ml-1 (Geom.mean, %CV) at the 9, 18 and 27 mg dose respectively. CD3ɛ target engagement was found to be rapid (within the first 30 min), leading to a receptor occupancy of ~60% within 6 h of dosing in all three doses. A dose-response relationship was observed with the two highest doses achieving a ~90% target engagement and consequential CD3ɛ/TCR downmodulation by Day 6. CONCLUSIONS: Data from this study revealed maximum target engagement and CD3ɛ/TCR modulation is achieved at doses of 18, 27 mg of Otelixizumab. These findings can be useful in guiding dose selection in clinical trials with anti-CD3ɛ mAbs.
