A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study to Evaluate Safety, Tolerability, and Pharmacokinetics of IRL201104 in Healthy Volunteers

The purpose of this clinical study is to assess the safety, tolerability and pharmacokinetics of repeat doses of IRL201104 given to healthy volunteers.

开始日期2023-05-26

申办/合作机构

Revolo Biotherapeutics Ltd.

NCT05098522

/ Completed临床2期

A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Allergen Challenge Trial of 6 Repeat Doses of IRL201104 in Adult Participants With Seasonal Allergic Rhinitis.

The purpose of this allergen challenge study is to assess the efficacy of IRL201104 compared with placebo in adult participants with seasonal allergic rhinitis.

开始日期2021-11-04

申办/合作机构

Revolo Biotherapeutics Ltd.

NCT05084963

/ Completed临床2期

A Phase 2a, Double-blind, Placebo-Controlled, Multi-Center Study to Assess the Efficacy, Safety, and Tolerability of IRL201104 in Adult Participants With Active Eosinophilic Esophagitis (EoE)

The purpose of this study is to asses the efficacy, safety and tolerability of repeat doses of IRL201104 in Adult Participants with Active Eosinophilic Esophagitis (EoE)

开始日期2021-10-29

申办/合作机构

Revolo Biotherapeutics Ltd.

100 项与 PIN-201104 相关的临床结果

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100 项与 PIN-201104 相关的转化医学

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100 项与 PIN-201104 相关的专利（医药）

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项与 PIN-201104 相关的文献（医药）

2021-11-01·American journal of physiology. Lung cellular and molecular physiology2区 · 医学

A peptide derived from chaperonin 60.1, IRL201104, inhibits LPS-induced acute lung inflammation

2区 · 医学

Article

作者: Page, Clive P. ; Kanabar, Varsha ; Federici Canova, Donata ; Perretti, Mauro ; Riffo-Vasquez, Yanira ; Nadkarni, Suchita ; Gomes Ferreira, Sueli ; Man, Francis ; e-Lacerda, Rodrigo R.

Chaperonin 60.1 (Cpn60.1) is a protein derived from Mycobacterium tuberculosis that has been shown, along with its peptide fragment IRL201104, to have beneficial effects in models of allergic inflammation. To further investigate the anti-inflammatory properties of Cpn60.1 and IRL201104, we have investigated these molecules in a model of nonallergic lung inflammation. Mice were treated with Cpn60.1 (0.5–5,000 ng/kg) or IRL201104 (0.00025–2.5 ng/kg), immediately before intranasal instillation of bacterial lipopolysaccharide (LPS). Cytokine levels and cell numbers in mouse bronchoalveolar lavage (BAL) fluid were measured 4 h after LPS administration. In some experiments, mice were depleted of lung-resident phagocytes. Cells from BAL fluid were analyzed for inflammasome function. Human umbilical vein endothelial cells (HUVECs) were analyzed for adhesion molecule expression. Human neutrophils were analyzed for integrin expression, chemotaxis, and cell polarization. Cpn60.1 and IRL201104 significantly inhibited neutrophil migration into the airways, independently of route of administration. This effect of the peptide was absent in TLR4 and annexin A1 knockout mice. Intravital microscopy revealed that IRL201104 reduced leukocyte adhesion and migration into inflamed tissues. However, IRL201104 did not significantly affect adhesion molecule expression in HUVECs or integrin expression, chemotaxis, or polarization of human neutrophils at the studied concentrations. In phagocyte-depleted animals, the anti-inflammatory effect of IRL201104 was not significant. IRL201104 significantly reduced IL-1β and NLRP3 expression and increased A20 expression in BAL cells. This study shows that Cpn60.1 and IRL201104 potently inhibit LPS-induced neutrophil infiltration in mouse lungs by a mechanism dependent on tissue-resident phagocytes and to a much lesser extent, the proresolving factor annexin A1.

2020-04-01·Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology2区 · 医学

Modulation of allergic inflammation in the lung by a peptide derived from Mycobacteria tuberculosis chaperonin 60.1

2区 · 医学

Article

作者: Page, Clive P. ; Corrigall, Valerie ; Jackson, David J. ; Man, Francis ; Keir, Sandra D. ; e‐Lacerda, Rodrigo R. ; Riffo‐Vasquez, Yanira ; Kanabar, Varsha ; Coates, Anthony R. M.

Abstract:

Background:

We have previously demonstrated that Mycobacteria tuberculosis chaperonin 60.1 inhibits leucocyte diapedesis and bronchial hyperresponsiveness in a murine model of allergic lung inflammation.

Methods:

In the present study, we have investigated the effect of a shorter peptide sequence derived from Cpn 60.1, named IRL201104, on allergic lung inflammation induced by ovalbumin (OVA) in mice and by house dust mite (HDM) in guinea pigs, as well as investigating the action of IRL201104 on human cells in vitro.

Results:

Pre‐treatment of mice or guinea pigs with IRL201104 inhibits the infiltration of eosinophils to the lung, cytokine release, and in guinea pig skin, inhibits allergen‐induced vascular permeability. The protective effect of intranasal IRL201104 against OVA‐induced eosinophilia persisted for up to 20 days post‐treatment. Moreover, OVA‐sensitized mice treated intranasally with 20 ng/kg of IRL201104 show a significant increase in the expression of the anti‐inflammatory molecule ubiquitin A20 and significant inhibition of the activation of NF‐κB in lung tissue. Our results also show that A20 expression was significantly reduced in blood leucocytes and ASM obtained from patients with asthma compared to cells obtained from healthy subjects which were restored after incubation with IRL201104 in vitro, when added alone, or in combination with LPS or TNF‐α in ASM.

Conclusions:

Our results suggest that a peptide derived from mycobacterial Cpn60.1 has a long‐lasting anti‐inflammatory and immunomodulatory activity which may help explain some of the protective effects of TB against allergic diseases.

1988-10-01·Journal of virology2区 · 医学

Effects of anti-gp120 monoclonal antibodies on CD4 receptor binding by the env protein of human immunodeficiency virus type 1

2区 · 医学

Article

作者: Kinney-Thomas, E ; Ledbetter, J A ; Linsley, P S ; Hu, S L

Monoclonal antibodies (MAbs) to defined peptide epitopes on gp120 from human immunodeficiency virus type 1 were used to investigate the involvement of their epitopes in gp120 binding to the CD4 receptor. Recombinant vaccinia viruses were constructed that expressed either full-length gp120 (v-ED6), or a truncated gp120 lacking 44 amino acids at the carboxyl terminus (v-ED4). Binding of these glycoproteins to the CD4 receptor was detected directly with metabolically labeled gp120 or indirectly with the gp120 MAbs. Truncated gp120 from v-ED4 bound to CD4-positive cells less than 1/12 as well as gp120 from v-ED6, indicating that the C-terminal region of gp120, which is conserved in numerous isolates of human immunodeficiency virus type 1, is critical for CD4 binding. However, MAb 110-1, which recognizes a peptide contained in the region deleted from v-ED4 (amino acids 489 through 511), did not inhibit binding of gp120 to CD4. MAb 110-1 also reacted with gp120 bound to the CD4 receptor, indicating that the epitope for this antibody does not directly interact with CD4. A second MAb, 110-4, which recognizes a peptide epitope located between amino acids 303 and 323 and has potent viral neutralizing activity, also bound to gp120 on the CD4 receptor. Furthermore, pretreatment of gp120 with MAb 110-4 at concentrations approximately 1,000-fold higher than those required for complete virus neutralization inhibited subsequent CD4 binding by only about 65%. Taken together, these data suggest that neutralization mediated by antibody 110-4 does not result from binding of this MAb to the CD4-binding site of gp120.

项与 PIN-201104 相关的新闻（医药）

2024-12-12

·GlobeNewswire-Health Care

Revolo Announces New Preclinical Data Supporting Subcutaneous ‘1104 for Atopic Dermatitis and Other Clinical Programs

In allergen-driven models of atopic dermatitis, subcutaneous (SQ) administration of ‘1104 demonstrated comparable performance to intravenous administration (IV)In multiple preclinical models evaluated in single-dose toxicity studies, there were no ‘1104-related local tolerability adverse effects after treatment with the ‘1104 SQ formulation at dose levels substantially higher than planned for clinical evaluationData reinforces Revolo’s commitment to prioritizing SQ ‘1104 in clinical studies GAITHERSBURG, Md. and CAMBRIDGE, United Kingdom, Dec. 12, 2024 (GLOBE NEWSWIRE) -- Revolo Biotherapeutics Limited (“Revolo”) today announced new preclinical data demonstrating that subcutaneous (SQ) administration of ‘1104 performed comparably to intravenous (IV) administration in allergen-driven models of atopic dermatitis (AD), effectively reducing key markers of skin inflammation and inflammatory mediators, with excellent local tolerability. "The comparable and consistent response of SQ and IV dosing of ‘1104 in AD, now observed across multiple disease models, reinforces our commitment to prioritizing a SQ formulation in our clinical studies,” said Woody Bryan, Ph.D., President and Chief Executive Officer of Revolo. “Our top priority is to initiate a clinical study with SQ formulation in eosinophilic esophagitis early in 2025, while also planning to evaluate the SQ formulation in a clinical study in AD. Our combined preclinical and clinical datasets continue to demonstrate the disease-agnostic mechanism of action of ‘1104 and its potential for flexible dosing through SQ and sublingual routes. This, together with the upstream mechanism of action and favorable safety, offers a highly competitive profile with the potential to disrupt the current treatment landscape for patients with eosinophilic esophagitis, our lead indication for ‘1104, and other allergic conditions. We look forward to launching Phase 2 trials early next year while continuing productive partnering discussions to advance our growing pipeline.” Key results when comparing SQ versus IV administration in a murine allergen-driven model of AD: Comparable reductions in inflammatory biomarkers in serum, reaching levels similar to naïve control individuals and equivalent to those observed in positive control individuals treated with the anti-inflammatory dexamethasone. This includes key T helper 2 (Th2) cytokines, like interleukin 4 (IL-4), IL-5, and IL-13, to cytokines specific to AD, including CCL17 and CCL22, and IL-31, a cytokine specific to itch, overall consistent with the mechanism of action for ‘1104. Comparable reductions in skin pathology indicators were observed, including a reduction in skin thickness and a reduction of skin pathology indicators such as erythema and skin erosion. Key results of single-dose toxicity studies evaluating tolerability and pharmacokinetics (PK) of the SQ formulation in two preclinical models: There were no local tolerability adverse effects (redness or swelling) in preclinical models administered the SQ formulation at dose levels substantially higher than planned for clinical evaluation.PK profiles from SQ administration in two preclinical models across a range of doses were dose proportional and showed similar exposure profiles when compared to PK profiles generated from IV administration in prior toxicity studies in the same models and at the same dose levels. About ‘1104‘1104 is a first-in-class peptide that is involved in restoring immune homeostasis, impacting both the regulatory and effector arms of the immune system. Revolo has recently advanced ‘1104 through two Phase 2a trials: one in patients with eosinophilic esophagitis (EoE) and one in patients with allergen sensitivity, while exploring its potential for other allergic diseases. Revolo is planning to advance a commercially differentiated subcutaneous dosage form into clinical studies for EoE and other type 2 allergic conditions. About Revolo BiotherapeuticsRevolo is developing therapies that restore immune homeostasis, targeting the immune system upstream for the treatment of autoimmune and allergic diseases. Its two drug candidates, ‘1805 and ‘1104, a protein and a peptide respectively, offer a unique mechanism of action through impact on both the regulatory and effector arms. This upstream, disease-agnostic and dual-action approach results in a rapid and prolonged effect without broad immune suppression, providing a platform for the development of treatments for multiple autoimmune and allergic conditions. Revolo’s assets also have the potential to offer dosing optionality through subcutaneous and sublingual routes, offering a highly competitive profile. For further information, please visit www.revolobio.com. Company ContactWoody Bryan, Ph.D.President and CEOwbryan@revolobio.com Media ContactMichael RubensteinLifeSci Communications+1 561-289-7981mrubenstein@lifescicomms.com

临床2期临床结果

2024-10-21

·GlobeNewswire-Health Care

Revolo Shares New Preclinical Data Showcasing the Potential of Sublingual ‘1104 in Allergic Disease

Sublingual (SL) formulation of ‘1104 achieved comparable responses to subcutaneous (SQ) and intravenous (IV) injections‘1104 SC and SL dosing options create opportunities for highly differentiated product profiles in eosinophilic esophagitis (EoE) and other allergic diseases versus currently available therapiesData provides additional validation for the differentiated upstream mechanism of action (MOA) of ‘1104, already confirmed in the clinic GAITHERSBURG, Md. and CAMBRIDGE, United Kingdom, Oct. 21, 2024 (GLOBE NEWSWIRE) -- Revolo Biotherapeutics Limited (“Revolo”) today announced new preclinical data demonstrating the potential of its lead allergic-disease treatment candidate, ‘1104, as a SL formulation. The data shows that when administered sublingually via a dissolvable tablet in a lung model of allergic disease, ‘1104 achieves comparable positive results across multiple inflammatory immune cells and other markers of allergic inflammation to those seen with SQ or IV injections of ‘1104. Additionally, the data continues to demonstrate the differentiated upstream MOA of ‘1104, restoring immune homeostasis by impacting both the effector and regulatory arms of the immune system with a persistence of effect for multiple weeks. Specifically, SL dosing of ‘1104 resulted in reduced inflammatory cell infiltration, including eosinophils and neutrophils, comparable to SQ and IV routes. SL dosing of ‘1104 also led to a reduction of key T2 cytokines and allergen specific immunoglobulin (Ig)E, similar to reductions seen with SQ and IV administration. “If successfully translated to the clinic, a sublingual option could represent a breakthrough in the treatment landscape for people living with EoE and other allergic diseases,” said Kari Brown, M.D., Chief Medical Officer at Revolo. “The differentiated upstream MOA by which ‘1104 acts, alongside a favorable safety profile across multiple Phase 1-2 clinical studies and its potential flexibility in route of administration, highlights its potential use as a future first-line therapy.” There is a strong need for additional treatment options for patients with EoE and other allergic diseases. Current therapeutics for EoE, the lead indication for ‘1104, include chronic subcutaneous monoclonal antibodies and oral options with significant safety considerations. Woody Bryan, Ph.D., President and Chief Executive Officer of Revolo, added, “Following data announced earlier this year, which supports the development of a subcutaneous formulation of ‘1104, these positive oral results provide Revolo with an exciting path forward. As we look to the future, we will prioritize the SQ formulation of ‘1104, with plans to initiate a new Phase 2 study in EoE in 2025 and potentially atopic dermatitis. However, we will continue to gather data on the SL formulation in parallel to inform our future strategy, including ongoing discussions with strategic partners. Our goal is to provide people with chronic allergic conditions a new effective and convenient treatment option without the burden of limiting side effects.” About ‘1104‘1104 is a first-in-class peptide that is involved in restoring immune homeostasis, uniquely impacting both the regulatory and effector arms of the immune system. Revolo has recently advanced ‘1104 through a Phase 2a trial in eosinophilic esophagitis (EoE) and a clinical mapping study in patients with allergic rhinitis, while exploring its potential for other allergic diseases. Revolo is planning to advance a commercially differentiated subcutaneous dosage form into clinical studies for EoE and other type 2 allergic conditions while advancing development of a sublingual formulation. About Revolo BiotherapeuticsRevolo is developing therapies that work upstream in the immune cascade for the treatment of allergic and autoimmune diseases, without the immune system suppression seen with current therapies. Its two drug candidates, ‘1104 and ‘1805, a peptide and a protein respectively, restore immune homeostasis to prevent the chronic pro-inflammatory immune response that results in allergic or autoimmune disease. The disease-agnostic mechanism of action of Revolo Biotherapeutic’s assets provides a potential platform for the development of treatments for multiple allergic and autoimmune diseases. For further information, please visit www.revolobio.com. Company ContactWoody Bryan, Ph.D.President and CEOwbryan@revolobio.com Media ContactMichael RubensteinLifeSci Communications+1 561-289-7981mrubenstein@lifescicomms.com

临床2期临床结果免疫疗法

2024-09-18

·GlobeNewswire-Health Care

Revolo Announces New Preclinical Data Further Validating Atopic Dermatitis as a Target Indication for ‘1104

Data continues to differentiate ‘1104 as a potential allergic disease treatment that acts upstream in the immune cascade‘1104 reduces key indices of skin inflammation and inflammatory mediators in a chronic allergen-driven model of atopic dermatitis (AD) GAITHERSBURG, Md. and CAMBRIDGE, United Kingdom, Sept. 18, 2024 (GLOBE NEWSWIRE) -- Revolo Biotherapeutics Limited (“Revolo”) today announced new data from preclinical studies that validate atopic dermatitis (AD) as a target indication for the Company’s lead clinical asset, ‘1104. The data reinforces the broad clinical applicability of ‘1104, through a novel upstream mechanism of action (MOA), demonstrating its impact across skin disease measures and a wide range of inflammatory cytokines and chemokines associated with AD pathology. Key results include: In a chronic allergen-driven murine model of atopic dermatitis, ‘1104 significantly reduced skin pathology indicators and serum biomarkers of AD to levels close to naïve control individuals and comparable to positive control individuals treated with the anti-inflammatory dexamethasone. This includes a reduction in skin thickness and a reduction of skin pathology indicators such as erythema and skin erosion. ‘1104 reduced allergen-specific immunoglobulin E (IgE) levels and key T helper 2 (Th2) cytokines in serum, such as interleukin 4 (IL-4), IL-5 and IL-13, in addition to non-Th2 cytokines like tumor necrosis factor (TNF) alpha, IL-1 beta, interferon (IFN) gamma, and IL-17.‘1104 also reduced key serum biomarkers classically associated with AD pathology such as chemokine ligand 17 (CCL-17), CCL-22, and Th2 cytokine IL-31, which is associated with pruritus and disruption of the skin barrier. “The ability of ‘1104 to affect a broad range of inflammatory mediators associated with allergic disease, while also impacting disease pathology, is both unique and impressive,” said Kari Brown, M.D., Chief Medical Officer at Revolo. “These new data support the initiation of a clinical trial evaluating ‘1104 in patients with atopic dermatitis. ‘1104 has the potential to offer patients a treatment that addresses the underlying inflammatory response, rather than just targeting inflammation after it occurs, which differentiates it from current treatments.” Woody Bryan, Ph.D., President and Chief Executive Officer of Revolo, added, “At Revolo, our priority has been to develop a product for patients with allergic diseases that can offer increased efficacy and dosing convenience. This compelling dataset in a preclinical model of atopic dermatitis is yet another convincing validation of the potential that ’1104 has across an array of allergic diseases, including Th-2 and non-Th2 conditions. We look forward to evaluating ‘1104 in a new clinical trial in AD and continuing to build on the positive data shown in the completed Phase 2 study of ‘1104 in eosinophilic esophagitis.” About ‘1104‘1104 is a first-in-class peptide that is involved in restoring immune homeostasis, impacting both the regulatory and effector arms of the immune system. Revolo has recently advanced ‘1104 through two Phase 2a trials: one in patients with eosinophilic esophagitis (EoE) and one in patients with allergen sensitivity while exploring its potential for other allergic diseases. Revolo is planning to advance a commercially differentiated subcutaneous dosage form into clinical studies for EoE and other type 2 allergic conditions. About Revolo BiotherapeuticsRevolo is developing therapies that work upstream in the immune cascade for the treatment of autoimmune and allergic diseases, without the immune system suppression seen with current therapies. Its two drug candidates, ‘1805 and ‘1104, a protein and a peptide respectively, restore immune homeostasis to prevent the chronic pro-inflammatory immune response that results in autoimmune or allergic disease. The disease-agnostic mechanism of action of Revolo Biotherapeutic’s assets provides a potential platform for the development of treatments for multiple autoimmune and allergic diseases.For further information, please visit www.revolobio.com. Company ContactWoody Bryan, Ph.D.President and CEOwbryan@revolobio.com Media ContactMichael RubensteinLifeSci Communications+1 561-289-7981mrubenstein@lifescicomms.com

临床2期临床结果免疫疗法

100 项与 PIN-201104 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
季节性过敏性鼻炎	临床2期	英国	Revolo Biotherapeutics Ltd.	2021-11-04
嗜酸粒细胞性食管炎	临床2期	美国	Revolo Biotherapeutics Ltd.	2021-10-29
新型冠状病毒感染	临床1期	英国	Revolo Biotherapeutics Ltd.	2021-01-29
哮喘	临床1期	英国	Peptinnovate Ltd	2017-01-01
特应性皮炎	临床1期	美国	Revolo Biotherapeutics Ltd.	-
嗜酸粒细胞性胃肠炎	临床1期	美国	Revolo Biotherapeutics Ltd.	-
食物过敏	临床1期	美国	Revolo Biotherapeutics Ltd.	-

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临床结果

适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05084963 (CTgov)	临床2期	嗜酸粒细胞性食管炎	36	Placebo	鑰餘簾鏇積醖選糧願繭(築範齋膚齋襯窪網選醖) = 鹹範夢積壓構廠憲艱淵範構積網夢製鬱獵鹹蓋 (蓋遞淵壓窪鑰艱襯憲糧, 104.02) 更多	-	2025-05-21
NCT05098522 (GlobeNewswire) 人工标引	临床2期	季节性过敏性鼻炎	63	1104	餘醖積網網築選鹹夢選(獵憲襯製觸顧壓積網鹽) = not observed 製壓蓋顧壓憲繭蓋獵選 (憲憲艱衊製願遞鏇膚顧 )	积极	2023-10-25
NCT05084963 (GlobeNewswire) 人工标引	临床2期	嗜酸粒细胞性食管炎	36	IRL201104	餘憲遞積齋齋襯醖簾艱(壓繭艱鏇獵襯壓餘繭鑰) = 願製糧夢網鬱齋糧衊襯獵遞鑰蓋醖遞構鏇憲製 (憲壓鑰遞積廠窪淵顧簾 )	积极	2023-07-18
NCT05084963 (GlobeNewswire) 人工标引	临床2期	嗜酸粒细胞性食管炎	36	Placebo	-	积极	2023-07-18
NCT05084963 (NEWS \| Corporate Publications) 人工标引	临床2期	嗜酸粒细胞性食管炎	36	IRL-201104	鑰衊淵齋廠艱製鬱襯築(廠齋鹹艱餘選觸鹹簾顧) = shows achievement of primary endpoint of decreasing esophageal intraepithelial eosinophil count and positive impact on an array of histological measures of EoE 鹹網蓋糧網壓積築鑰鏇 (觸鹹獵觸窪鬱鹹網獵範 ) 达到更多	积极	2023-04-19
NCT05084963 (NEWS \| Corporate Publications) 人工标引	临床2期	嗜酸粒细胞性食管炎	36	Placebo		积极	2023-04-19
ERS2018	临床1期	哮喘	-	PIN201104	衊構簾憲鹹廠鹹積鑰糧(繭簾構衊遞壓夢淵獵艱) = 104 (≤10µg/ml), overall, did not affect antigen-induced cell proliferation or IFN-γ release in human T cells. In contrast, the steroid dexamethasone led to nearly 100% reduction in antigen-induced IFN-γ release and >50% reduction in cell proliferation, for 2 out of 3 donors 簾艱遞構鑰糧獵製齋築 (願齋壓遞壓襯淵鑰蓋範 ) 更多	积极	2018-09-15