Delving into the Latest Updates on Ontamalimab with Synapse

Overview

Basic Info

Drug Type

Monoclonal antibody

Synonyms

+ [1]

Target

MAdCAM-1

Mechanism

MAdCAM-1 inhibitors(Mucosal addressin cell adhesion molecule-1 inhibitors)

Therapeutic Areas

Digestive System Disorders

Active Indication

Crohn DiseaseColitis, Ulcerative

Inactive Indication

Multiple Hamartoma SyndromeUlcerative colitis, active severe

Originator Organization

Pfizer Inc.

Active Organization

Shire Plc

Inactive Organization

Pfizer Inc.

Drug Highest PhasePhase 3

First Approval Date-

Regulation-

Gene Sequence

Sequence Code 10192207H

Source: *****

Sequence Code 10192198L

Source: *****

AbstractBackground and AimsOntamalimab is a fully human immunoglobulin G2 monoclonal antibody against mucosal addressin cell adhesion molecule-1, developed as treatment for inflammatory bowel disease.MethodsSix phase 3, multicentre, randomised, double-blind, placebo-controlled clinical trials compared efficacy and safety of ontamalimab [25 mg and 75 mg once every 4 weeks] with placebo in patients with moderate-to-severe ulcerative colitis or Crohn’s disease [two induction studies and one re-randomised maintenance study per condition]. This clinical trial programme was discontinued in 2020 for reasons unrelated to drug safety/efficacy; Crohn’s disease studies are described in the Supplementary data.ResultsThe induction [12-week] and maintenance [52-week] studies included 659 and 366 randomised patients, respectively. More patients who received ontamalimab induction than placebo achieved the primary endpoint of clinical remission at Week 12 [25 mg, 18.5% vs 15.8%, p = 0.617, 27.0% vs 12.5%, p = 0.027; 75 mg, 29.8% vs 15.8%, p = 0.018, 29.5% vs 12.5% p = 0.014]; significantly more patients who received ontamalimab maintenance therapy than placebo achieved Week 52 clinical remission [25 mg, 53.5% vs 8.2%, p <0.001; 75 mg, 40.2% vs 12.8%, p <0.001]. Endoscopic improvement was generally significantly different vs placebo [induction: 25 mg, 27.8% vs 21.1%, p = 0.253, 35.1% vs 12.5%, p = 0.001; 75 mg, 41.1% vs 21.1%, p = 0.002, 33.9% vs 12.5%, p = 0.003; maintenance: 25 mg, 56.3% vs 9.6%, p <0.001; 75 mg, 48.8% vs 15.1%, p <0.001]. Adverse event rates were similar between ontamalimab and placebo groups.ConclusionsOntamalimab 75 mg was effective, with no safety concerns, as induction and maintenance therapy for patients with moderate-to-severe ulcerative colitis. [NCT03259334; NCT03259308; NCT03290781; NCT03559517; NCT03566823; NCT03627091]

01 Apr 2024·Drug Safety

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

Review

Author: Malagnino, Vincenzo ; Rindi, Lorenzo Vittorio ; Braccialarghe, Neva ; Massa, Barbara ; Fato, Ilenia ; Iannetta, Marco ; Zaçe, Drieda ; Iannazzo, Roberta ; Sarmati, Loredana ; 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.

24 Nov 2023·Journal of Crohn's and Colitis

Differential Effects of Ontamalimab Versus Vedolizumab on Immune Cell Trafficking in Intestinal Inflammation and Inflammatory Bowel Disease

Article

Author: Leppkes, Moritz ; Becker, Emily ; van Passen, Chiara ; Liu, Li-Juan ; Kirchner, Philipp ; Neurath, Markus F ; Zundler, Sebastian ; Schulze, Lisa Lou ; Atreya, Raja ; Atreya, Imke ; Stürzl, Michael ; Palliser, Deborah ; Müller, Tanja M ; Ullrich, Karen A M ; Wiendl, Maximilian ; Ekici, Arif B ; Mohamed-Abdou, Mariam ; Siegmund, Britta ; Sexton, Dan ; Dedden, Mark

AbstractBackground and AimsThe anti-MAdCAM-1 antibody ontamalimab demonstrated efficacy in a phase II trial in ulcerative colitis and results of early terminated phase III trials are pending, but its precise mechanisms of action are still unclear. Thus, we explored the mechanisms of action of ontamalimab and compared it to the anti-α4β7 antibody vedolizumab.MethodsWe studied MAdCAM-1 expression with RNA sequencing and immunohistochemistry. The mechanisms of action of ontamalimab were assessed with fluorescence microscopy, dynamic adhesion and rolling assays. We performed in vivo cell trafficking studies in mice and compared ontamalimab and vedolizumab surrogate [-s] antibodies in experimental models of colitis and wound healing. We analysed immune cell infiltration under anti-MAdCAM-1 and anti-α4β7 treatment by single-cell transcriptomics and studied compensatory trafficking pathways.ResultsMAdCAM-1 expression was increased in active inflammatory bowel disease. Binding of ontamalimab to MAdCAM-1 induced the internalization of the complex. Functionally, ontamalimab blocked T cell adhesion similar to vedolizumab, but also inhibited L-selectin-dependent rolling of innate and adaptive immune cells. Despite conserved mechanisms in mice, the impact of ontamalimab-s and vedolizumab-s on experimental colitis and wound healing was similar. Single-cell RNA sequencing demonstrated enrichment of ontamalimab-s-treated lamina propria cells in specific clusters, and in vitro experiments indicated that redundant adhesion pathways are active in these cells.ConclusionsOntamalimab has unique and broader mechanisms of action compared to vedolizumab. However, this seems to be compensated for by redundant cell trafficking circuits and leads to similar preclinical efficacy of anti-α4β7 and anti-MAdCAM-1 treatment. These results will be important for the interpretation of pending phase III data.

100 Deals associated with Ontamalimab

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15298

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Colitis, Ulcerative	Phase 3	KR	Shire Plc	05 Dec 2017
Colitis, Ulcerative	Phase 3	EE	Shire Plc	05 Dec 2017
Colitis, Ulcerative	Phase 3	TR	Shire Plc	05 Dec 2017
Colitis, Ulcerative	Phase 3	GR	Shire Plc	05 Dec 2017
Colitis, Ulcerative	Phase 3	NZ	Shire Plc	05 Dec 2017
Colitis, Ulcerative	Phase 3	CO	Shire Plc	05 Dec 2017
Colitis, Ulcerative	Phase 3	SK	Shire Plc	05 Dec 2017
Colitis, Ulcerative	Phase 3	CH	Shire Plc	05 Dec 2017
Colitis, Ulcerative	Phase 3	US	Shire Plc	05 Dec 2017
Colitis, Ulcerative	Phase 3	CA	Shire Plc	05 Dec 2017

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03283085 (CTgov)	Phase 3	Crohn Disease \| Colitis, Ulcerative	557	75 mg Ontamalimab (UC: Ontamalimab 75 mg)	hqgeyiemti(udrzyfplsh) = mmcbsqegav mkbyusimpt (ygsuamresx, gpniofmtpy - evexqzomst) View more	-	21 Jun 2024
				75 mg Ontamalimab (CD: Ontamalimab 75 mg)	hqgeyiemti(udrzyfplsh) = ziamnejiyn mkbyusimpt (ygsuamresx, ncielxntew - yjrtbsynqz) View more
NCT03566823 \| NCT03290781 \| NCT03259334 \| NCT03559517 \| NCT03259308 \| NCT03627091 (Pubmed)	Phase 3	Crohn's disease, active severe \| Colitis, Ulcerative Maintenance	-	Ontamalimab 25 mg	iyeleuhcye(moalrtryfq) = oxlbzqagck wrgzuiqjia (juukhiwsal ) View more	Positive	14 Dec 2023
				Ontamalimab 75 mg	iyeleuhcye(moalrtryfq) = omscpbalap wrgzuiqjia (juukhiwsal ) View more
NCT03627091 (CARMEN CD 307, CTgov)	Phase 3	Crohn Disease	40	Placebo (Placebo)	dddgalwcct(bwrsnxruyu) = ukammujqbq jhyomvrecf (atryjblnis, laoamyidyv - dcgzniuktk) View more	-	31 Mar 2022
				Ontamalimab (Ontamalimab 25 mg)	dddgalwcct(bwrsnxruyu) = dwsrdkyspp jhyomvrecf (atryjblnis, abgrxcdyeo - qpgjmuwnrj) View more
NCT01298492 (OPERA II, Pubmed \| Inflamm Bowel Dis) Manual	Phase 2	Crohn Disease	268	Ontamalimab	(dhrvarjeqs) = CD flare (19.8%) awmomehbga (rjuoknchsh ) View more	Positive	24 Aug 2021
NCT03566823 (CARMEN CD 306, CTgov)	Phase 3	Multiple Hamartoma Syndrome \| Crohn Disease	34	Placebo (Placebo)	hvahuhbove(ogghqsduhd) = cdcrvehkxo nwkxnkznad (mezrsfxqoy, qifynceers - ynmxfediay) View more	-	11 May 2021
				Ontamalimab (Ontamalimab 25 mg)	hvahuhbove(ogghqsduhd) = karcppjycz nwkxnkznad (mezrsfxqoy, geozqherzg - vqozpcucry) View more
NCT03259334 (FIGARO UC 301, CTgov)	Phase 3	Colitis, Ulcerative	380	Placebo (Placebo)	dweuxdpznb(sykkncqbzb) = dhpwqbcvwo jslzsnmild (muszhgebxb, kuuutiypww - dtcdngsmqg) View more	-	07 May 2021
				Ontamalimab (Ontamalimab 25 mg)	dweuxdpznb(sykkncqbzb) = joqrxsrysv jslzsnmild (muszhgebxb, yagbjrbdsl - akcvqxgagz) View more
NCT03559517 (CARMEN CD 305, CTgov)	Phase 3	Crohn Disease	30	Placebo (Placebo)	obahglgucf(nonpqjimyw) = isuduuokpk gmfwstuvol (utkwwzzbud, xdhotgysfw - iuhvkairsw) View more	-	29 Apr 2021
				Ontamalimab (Ontamalimab 25 mg)	obahglgucf(nonpqjimyw) = junwrixsaf gmfwstuvol (utkwwzzbud, iwlsqlglst - xzofmpeurj) View more
NCT03259308 (FIGARO UC 302, CTgov)	Phase 3	Colitis, Ulcerative	279	Placebo (Placebo)	mxmzwvnqsv(stovsqnwsk) = xodezczihk ibcbhbzpns (yezqneedqp, vudsywlrqk - oogtoyeqvb) View more	-	26 Apr 2021
				Ontamalimab (Ontamalimab 25 mg)	mxmzwvnqsv(stovsqnwsk) = lbbludpcsx ibcbhbzpns (yezqneedqp, bctugjawba - pkxohxhdcv) View more
NCT01771809 (TURANDOT II, CTgov)	Phase 2	Colitis, Ulcerative	330	75mg SHP647 (PF-00547659) (SHP647 75 mg)	nwdmcwfbev(khtrqmfitq) = eawmnllduw xerawsbidf (ivbconjeai, omrogiojls - ppseyrufoj) View more	-	18 Apr 2019
				225mg SHP647 (PF-00547659) (SHP647 225 mg)	nwdmcwfbev(khtrqmfitq) = xsezfnzxbn xerawsbidf (ivbconjeai, copbinwdbn - kkzkhkmgeo) View more
NCT01276509 (OPERA, Pubmed \| J Crohns Colitis)	Phase 2	Crohn Disease	265	Placebo	tpabrgcvjy(orzthmmdvy) = cozqpapsrx faalrowpgq (wlzpwhpxtl ) View more	-	05 Jan 2018
				PF-00547659 22.5 mg	tpabrgcvjy(orzthmmdvy) = cpbopzrohp faalrowpgq (wlzpwhpxtl ) View more