Delving into the Latest Updates on Prezalumab with Synapse

Overview

Basic Info

Drug Type

Monoclonal antibody

Synonyms

Anti-B7RP1-MAb

+ [2]

Target

ICOSLG

Mechanism

ICOS ligand inhibitors

Therapeutic Areas

Immune System DiseasesEye DiseasesMouth and Tooth Diseases+ [3]

Active Indication-

Inactive Indication

ArthritisLupus Erythematosus, CutaneousLupus Vulgaris+ [3]

Originator Organization

Amgen, Inc.

Active Organization-

Inactive Organization

Amgen, Inc.

MedImmune LLC

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Gene Sequence

Sequence Code 9697699H

Source: *****

Sequence Code 78566L

Source: *****

ObjectiveCD28 and inducible T cell costimulator (ICOS) appear to have nonredundant roles in T cell activation and adaptive immunity. We undertook this study to characterize in vitro and in vivo the therapeutic potential of acazicolcept (ALPN‐101), an Fc fusion protein of a human variant ICOS ligand (ICOSL) domain designed to inhibit both CD28 and ICOS costimulation, in inflammatory arthritis.MethodsAcazicolcept was compared in vitro with inhibitors of either the CD28 or ICOS pathways (abatacept and belatacept [CTLA‐4Ig], prezalumab [anti‐ICOSL monoclonal antibody]) in receptor binding and signaling assays, and in a collagen‐induced arthritis (CIA) model. Acazicolcept was also compared in cytokine and gene expression assays of peripheral blood mononuclear cells (PBMCs) from healthy donors or rheumatoid arthritis (RA) or psoriatic arthritis (PsA) patients stimulated with artificial antigen‐presenting cells (APCs) expressing CD28 and ICOS ligands*.ResultsAcazicolcept bound CD28 and ICOS, prevented ligand binding, and inhibited human T cell functional interactions, matching or exceeding the activity of CD28 or ICOS costimulatory single‐pathway inhibitors tested individually or in combination. Acazicolcept administration significantly reduced disease in the CIA model and more potently than abatacept. Acazicolcept also inhibited proinflammatory cytokine production from stimulated PBMCs in cocultures with artificial APCs and demonstrated unique effects on gene expression distinct from those induced by abatacept, prezalumab, or a combination of both.ConclusionBoth CD28 and ICOS signaling play critical roles in inflammatory arthritis. Therapeutic agents such as acazicolcept that coinhibit both ICOS and CD28 signaling may mitigate inflammation and/or disease progression in RA and PsA more effectively than inhibitors of either pathway alone.

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01 Jun 2020·Journal of AutoimmunityQ1 · MEDICINE

Sjögren's syndrome: Old and new therapeutic targets

Q1 · MEDICINE

Review

Author: Mavragani, Clio P ; Moutsopoulos, Haralampos M

Sjögren's syndrome (SS) is a prototype autoimmune disease characterized by oral and ocular mucosal dryness following chronic inflammation of salivary and lachrymal glands, respectively. Profound B cell hyperactivity along with systemic manifestations including fatigue, musculoskeletal complaints, features related to hepatic, pulmonary, renal and nervous system involvement, as well as lymphoma development can be also present. Despite that activation of both innate and adaptive immune pathways has been long well documented in SS pathogenesis, systemic immunosuppression in SS, in contrast to other autoimmune diseases, has been largely inefficacious. Biological agents previously implemented in successful therapeutic outcomes in rheumatoid arthritis (RA), such as anti-TNF agents, anakinra, tocilizumab and rituximab failed to reach primary outcomes in randomized double-blind controlled trials in the context of SS. Abatacept and belimumab, already licensed for the treatment of RA and lupus respectively, as well combination regimens of both rituximab and belimumab hold some promise in alleviation of SS-specific complaints, but data from large controlled trials are awaited. Recent advances in dissecting the molecular pathways underlying SS pathogenesis led to an expanding number of novel biological compounds directed towards type I interferon system, antigen presentation, costimulatory pathways, B and T cell activation, as well as germinal center formation. While targeting of cathepsin-S (Petesicatib), inducible costimulator of T cells ligand (prezalumab), and lymphotoxin beta receptor (baminercept) failed to fulfil the primary outcome measures, preliminary results from two randomized placebo controlled trials on CD40 blockade (Iscalimab) and B-cell activating factor receptor (Ianalumab) inhibition resulted in significant reduction of SS disease activity, with a favorable so far safety profile. Results from administration of other kinase inhibitors, a transmembrane activator and calcium-modulator and cytophilin ligand interactor TACI fusion protein (RC18), as well as low dose recombinant interleukin-2 to expand T-regulatory cells are currently awaited.

01 Jul 2018·Arthritis & RheumatologyQ1 · MEDICINE

Brief Report: A Randomized, Double‐Blind, Parallel‐Group, Placebo‐Controlled, Multiple‐Dose Study to Evaluate AMG 557 in Patients With Systemic Lupus Erythematosus and Active Lupus Arthritis

Q1 · MEDICINE

Article

Author: Tsuji, Wayne H. ; Sullivan, Barbara A. ; Zhou, Lei ; Amoura, Zahir ; Cheng, Laurence E. ; Cheah, Benjamin ; Chung, James B. ; Hiepe, Falk ; Merrill, Joan T. ; Arnold, Gregory E.

ObjectiveTo evaluate the safety and potential efficacy of AMG 557, a fully human antibody directed against the inducible T cell costimulator ligand (ICOSL) in patients with systemic lupus erythematosus (SLE) with arthritis.MethodsIn this phase Ib, randomized, double‐blind, placebo‐controlled study, patients received AMG 557 210 mg (n = 10) or placebo (n = 10) weekly for 3 weeks, then every other week for 10 additional doses. The corticosteroid dosage was tapered to ≤7.5 mg/day by day 85, and immunosuppressants were discontinued by day 29. Primary end points on day 169 were safety, immunogenicity, the Lupus Arthritis Response Index (LARI; defined by a reduction in the tender and swollen joint counts), ≥1‐letter improvement in the musculoskeletal domain of the British Isles Lupus Assessment Group (BILAG) index, and medication discontinuation. The secondary/exploratory end points were changes in the tender and swollen joint counts, BILAG index scores (musculoskeletal, global), and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).ResultsThe incidence of adverse events, most of which were mild, was similar between groups. LARI responses occurred in 3 of 10 patients receiving AMG 557 and 1 of 10 patients receiving placebo (P = 0.58). More patients in the AMG 557 group achieved a ≥4‐point improvement in the SLEDAI score on day 169 (7 of 10 patients) compared with the placebo group (2 of 10 patients) (P = 0.07). Patients treated with AMG 557 (versus placebo) had greater improvements from baseline in the global BILAG index scores (–36.3% versus –24.7%) and the SLEDAI score (–47.8% versus –10.7%) and in tender (–22.8% versus –13.5%) and swollen (–62.1% versus –7.8%) joint counts on day 169.ConclusionAMG 557 showed safety and potential efficacy, supporting further evaluation of the clinical efficacy of ICOSL blockade in patients with SLE.

100 Deals associated with Prezalumab

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Primary Sjögren's syndrome	Phase 2	FR	MedImmune LLC	08 Jun 2015
Primary Sjögren's syndrome	Phase 2	US	Amgen, Inc.	08 Jun 2015
Primary Sjögren's syndrome	Phase 2	SE	Amgen, Inc.	08 Jun 2015
Primary Sjögren's syndrome	Phase 2	GB	Amgen, Inc.	08 Jun 2015
Primary Sjögren's syndrome	Phase 2	US	MedImmune LLC	08 Jun 2015
Primary Sjögren's syndrome	Phase 2	GB	MedImmune LLC	08 Jun 2015
Primary Sjögren's syndrome	Phase 2	FR	Amgen, Inc.	08 Jun 2015
Primary Sjögren's syndrome	Phase 2	SE	MedImmune LLC	08 Jun 2015
Systemic Lupus Erythematosus	Phase 2	-	MedImmune LLC	-
Systemic Lupus Erythematosus	Preclinical	-	MedImmune LLC	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02334306 (CTgov)	Phase 2	Primary Sjögren's syndrome	32	AMG 557/MEDI5872	mebaeihslf(orvlredbal) = drwabueghs oostgyqzdq (czltmmeduj, sfmglvbqku - wbluyeeiev) View more	-	19 Mar 2019
NCT01683695 (Pubmed \| Arthritis Rheumatol) Manual	Phase 1	Arthritis \| Systemic Lupus Erythematosus	20	AMG 557	biqdvmfgnt(itgmmhbomw) = mzncpzjnwi sqhkasyhug (tiizwkjmge ) View more	Positive	01 Jul 2018
				Placebo	biqdvmfgnt(itgmmhbomw) = wvqznqdfue sqhkasyhug (tiizwkjmge ) View more
phase 1b study (EULAR2017)	Phase 1	Arthritis	20	AMG 557 210 mg	(bictgpcgei) = Treatment-emergent adverse events (AEs) were similar between placebo and AMG 557 arms; most commonly headache and upper respiratory tract infection jlhemnpaon (qotwgzjwgs )	Positive	14 Jun 2017
				Placebo