Delving into the Latest Updates on Abrilumab with Synapse

Overview

Basic Info

Drug Type

Monoclonal antibody

Synonyms

Abrilimumab, Abrilumab (USAN/INN), Anti-α4β7 integrin monoclonal antibody

+ [2]

Target

α4β7

Action

antagonists, modulators

Mechanism

α4β7 antagonists(Integrin alpha-4/beta-7 antagonists), Immunomodulators

Therapeutic Areas

Immune System DiseasesDigestive System Disorders

Active Indication-

Inactive Indication

Colitis, UlcerativeCrohn Disease

Originator Organization

Amgen, Inc.

Active Organization-

Inactive Organization

License Organization

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Sequence Code 319372627H

Source: *****

Sequence Code 319372695L

Source: *****

AbstractAcute graft-versus-host disease (aGVHD) of the lower gastrointestinal (GI) tract is a major cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vedolizumab is a gut-selective anti-α4β7 integrin monoclonal antibody that reduces gut inflammation by inhibiting migration of GI-homing T lymphocytes. The efficacy and safety of vedolizumab added to standard GVHD prophylaxis (calcineurin inhibitor plus methotrexate/mycophenolate mofetil) was evaluated for prevention of lower-GI aGVHD after unrelated donor allo-HSCT in a randomized, double-blind, placebo-controlled phase 3 trial. Enrollment closed early during the COVID-19 pandemic with 343 patients randomized (n = 174 vedolizumab, n = 169 placebo), and 333 received ≥1 intravenous dose of 300 mg vedolizumab (n = 168) or placebo (n = 165) and underwent allo-HSCT. The primary end point was met; Kaplan–Meier (95% confidence interval) estimated rates of lower-GI aGVHD-free survival by day +180 after allo-HSCT were 85.5% (79.2–90.1) with vedolizumab versus 70.9% (63.2–77.2) with placebo (hazard ratio, 0.45; 95% confidence interval, 0.27–0.73; P < 0.001). For the 5 key secondary efficacy end points analyzed by day +180 after allo-HSCT, rates of lower-GI aGVHD-free and relapse-free survival and grade C–D aGVHD-free survival were significantly higher with vedolizumab versus placebo. No significant treatment differences were found for the other key secondary end points of non-relapse mortality, overall survival and grade B–D aGVHD-free survival, respectively. Incidence of treatment-related serious adverse events analyzed in patients receiving ≥1 dose of study treatment (n = 334) was 6.5% (n = 11 of 169) vedolizumab versus 8.5% (n = 14 of 165) placebo. When added to standard calcineurin inhibitor-based GVHD prevention, lower-GI aGVHD-free survival was significantly higher with vedolizumab versus placebo. ClinicalTrials.gov identifier: NCT03657160.

01 Apr 2024·Drug Safety

Drug-Induced Progressive Multifocal Leukoencephalopathy (PML): A Systematic Review and Meta-Analysis

Review

Author: Malagnino, Vincenzo ; Braccialarghe, Neva ; Rindi, Lorenzo Vittorio ; Massa, Barbara ; Fato, Ilenia ; Iannetta, Marco ; Zaçe, Drieda ; Sarmati, Loredana ; Iannazzo, Roberta ; De Maria, Francesco ; Kontogiannis, Dimitra ; Barchi, Virginia

INTRODUCTIONProgressive multifocal leukoencephalopathy (PML) was first described among patients affected by hematological or solid tumors. Following the human immunodeficiency virus (HIV) epidemic, people living with HIV have represented most cases for more than a decade. With the diffusion of highly active antiretroviral therapy, this group progressively decreased in favor of patients undergoing treatment with targeted therapy/immunomodulators. In this systematic review and meta-analysis, the objective was to assess which drugs are most frequently related to PML development, and report the incidence of drug-induced PML through a meta-analytic approach.METHODSThe electronic databases MEDLINE, EMBASE, ClinicalTrials.gov, Web of Science and the Canadian Agency for Drugs and Technologies in Health Database (CADTH) were searched up to May 10, 2022. Articles that reported the risk of PML development after treatment with immunomodulatory drugs, including patients of both sexes under the age of 80 years, affected by any pathology except HIV, primary immunodeficiencies or malignancies, were included in the review. The incidence of drug-induced PML was calculated based on PML cases and total number of patients observed per 100 persons and the observation time. Random-effect metanalyses were conducted for each drug reporting pooled incidence with 95% confidence intervals (CI) and median (interquartile range [IQR]) of the observation time. Heterogeneity was measured by I² statistics. Publication bias was examined through funnel plots and Egger's test.RESULTSA total of 103 studies were included in the systematic review. In our analysis, we found no includible study reporting cases of PML during the course of treatment with ocrelizumab, vedolizumab, abrilumab, ontamalimab, teriflunomide, daclizumab, inebilizumab, basiliximab, tacrolimus, belimumab, infliximab, firategrast, disulone, azathioprine or danazole. Dalfampridine, glatiramer acetate, dimethyl fumarate and fingolimod show a relatively safe profile, although some cases of PML have been reported. The meta-analysis showed an incidence of PML cases among patients undergoing rituximab treatment for multiple sclerosis (MS) of 0.01 cases/100 persons (95% CI - 0.08 to 0.09; I² = 20.4%; p = 0.25) for a median observation period of 23.5 months (IQR 22.1-42.1). Treatment of MS with natalizumab carried a PML risk of 0.33 cases/100 persons (95% CI 0.29-0.37; I² = 50%; p = 0.003) for a median observation period of 44.1 months (IQR 28.4-60) and a mean number of doses of 36.3 (standard deviation [SD] ± 20.7). When comparing data about patients treated with standard interval dosing (SID) and extended interval dosing (EID), the latter appears to carry a smaller risk of PML, that is, 0.08 cases/100 persons (95% CI 0.0-0.15) for EID versus 0.3 cases/100 persons (95% CI 0.25-0.34) for SID.CONCLUSIONSA higher risk of drug-related PML in patients whose immune system is not additionally depressed by means of neoplasms, HIV or concomitant medications is found in the neurological field. This risk is higher in MS treatment, and specifically during long-term natalizumab therapy. While this drug is still routinely prescribed in this field, considering the efficacy in reducing MS relapses, in other areas it could play a smaller role, and be gradually replaced by other safer and more recently approved agents.

01 Jan 2024·Brain, Behavior, and Immunity

Effects of a gut-selective integrin-targeted therapy in male mice exposed to early immune activation, a model for the study of autism spectrum disorder

Article

Author: Ricceri, Laura ; Di Carlo, Nazzareno ; De Simone, Roberta ; Sanchez, Massimo ; Butera, Alessia ; Campanile, Doriana ; Armida, Monica ; Boirivant, Monica ; Potenza, Rosa Luisa ; Trenta, Francesco

To clarify the role of gut mucosal immunity in ASD, we evaluated, in the early-life immune activation (EIA) mouse model, the effects of administration of a monoclonal antibody directed against the integrin alpha4 beta7 (α4β7 mAb), blocking the leukocyte homing into the gut mucosa. EIA is a double-hit variant of the maternal immune-activation (MIA) model, including both prenatal (Poly I:C) and postnatal (LPS) immune challenges. In C57BL6/J EIA male adult offspring mice, IL-1β and IL-17A mRNA colonic tissue content increased when compared with controls. Cytofluorimetric analyses of lymphocytes isolated from mesenteric lymph-nodes (MLN) and spleens of EIA mice show increased percentage of total and CD4⁺α4β7⁺, unstimulated and stimulated IL-17A⁺ and stimulated IFN-γ⁺ lymphocytes in MLN and CD4⁺α4β7⁺ unstimulated and stimulated IL-17A⁺ and stimulated IFN-γ⁺ lymphocytes in the spleen. Treatment with anti-α4β7 mAb in EIA male mice was associated with colonic tissue IL-1β, and IL-17A mRNA content and percentage of CD4⁺ IL-17A⁺ and IFN-γ⁺ lymphocytes in MLN and spleens comparable to control mice. The anti-α4β7 mAb treatment rescue social novelty deficit showed in the three-chamber test by EIA male mice. Increased levels of IL-6 and IL-1β and decreased CD68 and TGF-β mRNAs were also observed in hippocampus and prefrontal cortex of EIA male mice together with a reduction of BDNF mRNA levels in all brain regions examined. Anti-α4β7 mAb treatment restored the expression of BDNF, TGF-β and CD68 in hippocampus and prefrontal cortex. Improvement of the gut inflammatory status, obtained by a pharmacological agent acting exclusively at gut level, ameliorates some ASD behavioral features and the neuroinflammatory status. Data provide the first preclinical indication for a therapeutic strategy against gut-immune activation in ASD subjects with peripheral increase of gut-derived (α4β7+) lymphocytes expressing IL-17A.

100 Deals associated with Abrilumab

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External Link

KEGG	Wiki	ATC	Drug Bank
D10540	Abrilumab	-	DB15076

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Colitis, Ulcerative	Phase 2	Switzerland	Amgen, Inc.	16 Nov 2012
Colitis, Ulcerative	Phase 2	Norway	Amgen, Inc.	16 Nov 2012
Colitis, Ulcerative	Phase 2	Netherlands	Amgen, Inc.	16 Nov 2012
Colitis, Ulcerative	Phase 2	United Kingdom	Amgen, Inc.	16 Nov 2012
Colitis, Ulcerative	Phase 2	Austria	Amgen, Inc.	16 Nov 2012
Colitis, Ulcerative	Phase 2	Germany	Amgen, Inc.	16 Nov 2012
Colitis, Ulcerative	Phase 2	Greece	Amgen, Inc.	16 Nov 2012
Colitis, Ulcerative	Phase 2	Belgium	Amgen, Inc.	16 Nov 2012
Colitis, Ulcerative	Phase 2	Russia	Amgen, Inc.	16 Nov 2012
Colitis, Ulcerative	Phase 2	Latvia	Amgen, Inc.	16 Nov 2012

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01959165 (CTgov)	Phase 2	Colitis, Ulcerative	44	Matching Placebo	fqtuxucipg(khrdtcyqku) = rnngfmoptt bphdlpjkil (jmijtfppyd, uijycafxmn - oyqltczrjw) View more	-	05 Jul 2019
NCT01959165 (Pubmed) Manual	Phase 2	Colitis, Ulcerative	45	abrilumab	(qcwsyldipf) = bpxpqfnclg ppysbmbwhz (ftarbbzbxh )	Positive	01 Jul 2019
NCT01959165 (Pubmed) Manual	Phase 2	Colitis, Ulcerative	45	Placebo	(qcwsyldipf) = evaonxwhjf ppysbmbwhz (ftarbbzbxh )	Positive	01 Jul 2019
ECCO2012	Not Applicable	-	-	AMG 181	uvazyynesj(laynnjlpkz) = sccpuhddmn hthhnbybwy (acmcwbznxh ) View more	Positive	01 Feb 2012
NCT01290042 (P225, ECCO2012)	Phase 1	Inflammatory Bowel Diseases	-	AMG 181 0.7 mg SC	umarpejknw(qscjptxdyg) = flvvjybkdr falxbsbrwg (sgpapzjnik )	Positive	01 Feb 2012
NCT01290042 (P225, ECCO2012)	Phase 1	Inflammatory Bowel Diseases	-	AMG 181 2.1 mg SC	umarpejknw(qscjptxdyg) = dkrvnayikz falxbsbrwg (sgpapzjnik )	Positive	01 Feb 2012
ECCO2012	Not Applicable	Inflammatory Bowel Diseases CD4 memory	-	AMG 181	zoqcgvxzlb(fiwgqhrzev) = increased more than dose proportionally, indicating the presence of target-mediated disposition and the effect of immunogenicity hzmglnseuv (edqgtgnsmc ) View more	Positive	01 Feb 2012

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Biosimilar

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Competitive landscape of biosimilars in different countries/locations. Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3.

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Abrilumab

Overview

Basic Info

Structure/Sequence

Related

External Link

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Biosimilar

Regulation