Delving into the Latest Updates on Petesicatib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Petesicatib (USAN), RG 7625, RG-7625

+ [2]

Target

CTSS

Mechanism

CTSS inhibitors(Cathepsin S inhibitors)

Therapeutic Areas

Immune System DiseasesEye DiseasesMouth and Tooth Diseases+ [4]

Active Indication-

Inactive Indication

Celiac DiseaseHypersensitivity, DelayedPrimary Sjögren's syndrome

Originator Organization

F. Hoffmann-La Roche Ltd.

Active Organization-

Inactive Organization

Hoffmann-La Roche, Inc.

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC25H23F6N5O4S

InChIKeyKXAAIORSMACJSI-AEFFLSMTSA-N

CAS Registry1252637-35-6

This is a randomized, double-blind, placebo-controlled, two-treatment arm, parallel-group study designed to evaluate the effects of RO5459072 treatment on disease activity and symptoms of Sjogren's syndrome in adult participants with moderate to severe primary Sjogren's syndrome. The total duration of the study for each participant will be approximately 18 weeks (including screening).

Start Date05 Jul 2016

Sponsor / Collaborator

Hoffmann-La Roche, Inc.

NCT02679014 / CompletedPhase 1

A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose, Parallel Study to Investigate the Pharmacokinetics, Pharmacodynamic Effects, Safety and Tolerability of Repeated Dosing of RO5459072 in Volunteers With Celiac Disease

A randomized, double-blind, placebo-controlled, two treatment, parallel group study to investigate the effects of RO5459072, a cathepsin S inhibitor, on the immune response to a gluten challenge in volunteers with celiac disease. Volunteers with previously diagnosed celiac disease will be randomized to receive either 100 milligrams (mg) RO5459072 or placebo twice daily with food for 28 days (Days 1 to 28).

Start Date06 Mar 2016

Sponsor / Collaborator

Hoffmann-La Roche, Inc.

100 Clinical Results associated with Petesicatib

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100 Translational Medicine associated with Petesicatib

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100 Patents (Medical) associated with Petesicatib

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4

Literatures (Medical) associated with Petesicatib

01 Nov 2022·JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGYQ1 · MEDICINE

An open-label phase 2a study investigating the efficacy and safety of a cathepsin S inhibitor in patients with moderate-to-severe psoriasis

Q1 · MEDICINE

Article

Author: Posch, Maximilian G ; Färber, Petra ; Nagel, Sandra ; Gadola, Stephan D ; Canducci, Filippo

Around 20% of psoriasis patients have moderate-to-severe disease requiring systemic treatment with cytokine-targeting biologics.Thus, there is a need for new therapies that provide sustained long-term efficacy and safety.We propose that the absence of any therapeutic effect of RO5459072 in this trial indicates the redundancy of IL-36 dedependent proinflammatory pathways involved in psoriasis.Altogether, these highlight the challenges in targeting a single component of an inflammatory pathway involved in systemic disorders such as psoriasis.In conclusion, targeting cathepsin S-mediated IL36 activation with a highly potent and selective cathepsin S antagonist had no therapeutic effect on psoriasis.

01 Sep 2021·British journal of clinical pharmacologyQ2 · MEDICINE

Population pharmacokinetic analysis of RO5459072, a low water‐soluble drug exhibiting complex food–drug interactions

Q2 · MEDICINE

Article

Author: Frey, Nicolas ; Stillhart, Cordula ; Al Kotbi, Nada ; Diack, Cheikh ; Nagel, Sandra ; Kratochwil, Nicole A.

Aims:

RO5459072, a cathepsin‐S inhibitor, Biopharmaceutics Classification System class 2 and P‐glycoprotein substrate, exhibited complex, nonlinear pharmacokinetics (PK) while fasted that seemed to impact both the absorption and the disposition phases. When given with food, all nonlinearities disappeared. Physiologically based PK (PBPK) modelling attributed those nonlinearities to dose‐dependent solubilisation and colonic absorption. The objective of this population PK analysis was to complement the PBPK analysis.

Methods:

PK profiles in 39 healthy volunteers after first oral dosing (1–600 mg) while fasted or fed in single and multiple ascending dose studies were analysed using population compartmental modelling.

Results:

The PK of RO5459072 while fed was characterized by a 1‐compartmental PK model with linear absorption and elimination. The nonlinearities while fasted were captured using dose dependent bioavailability and 2 sequential first‐order absorption phases: one following drug administration and one occurring 11 hours later and only for doses >10 mg. The bioavailability in the first absorption phase increased between 1 and 10 mg and then decreased with dose, in agreement with in vitro dissolution and solubility studies. The remaining fraction of doses to be absorbed by the second absorption phase was found to have a bioavailability similar to that in the first absorption phase.

Conclusion:

The population PK model supported that dissolution‐ and solubility‐limited absorption from the proximal and distal intestine alone explains the nonlinear PK of RO5459072 in fasted state and the linear PK in fed state. This work, together with the PBPK analysis, raised our confidence in the understanding of this complex PK.

01 Dec 2019·Arthritis research & therapyQ2 · MEDICINE

Differential effects of specific cathepsin S inhibition in biocompartments from patients with primary Sjögren syndrome

Q2 · MEDICINE

ArticleOA

Author: Theron, Michel ; Bannert, Bettina ; Kyburz, Diego ; Kolb, Fabrice A ; Reis, Bernhard ; Manchester Young, Marianne ; Manigold, Tobias ; Tiaden, Andre ; Daoudlarian, Douglas ; Hargreaves, Patrick

OBJECTIVE:

Primary Sjögren syndrome (pSS) is characterized by T and B cell infiltration of exocrine glands. The cysteine protease cathepsin S (CatS) is crucially involved in MHCII processing and T cell stimulation, and elevated levels have been found in patients with RA, psoriasis and pSS. However, little is known about the functional characteristics and mechanisms of SS-A- and SS-B-specific T cells in pSS patients. We herein investigated the inhibition of CatS activity in different biocompartments of pSS patients including antigen-specific T cell responses.

METHODS:

Ex vivo CatS activity was assessed in tears, plasma and saliva of 15 pSS patients and 13 healthy controls (HC) and in the presence or absence of the specific CatS inhibitor RO5459072. In addition, antigen (SS-A (60kD), SS-B, influenza H₃N₂, tetanus toxoid and SEB)-specific T cell responses were examined using ex vivo IFN-γ/IL-17 Dual ELISPOT and Bromdesoxyuridin (BrdU) proliferation assays in the presence or absence of RO5459072. Supernatants were analysed for IL-1β, IL-6, IL-10, TNF-α, IL-21, IL-22 and IL-23, using conventional ELISA.

RESULTS:

CatS activity was significantly elevated in tear fluid, but not other biocompartments, was inversely associated with exocrinic function in pSS patients and could significantly be suppressed by RO5459072. Moreover, CatS inhibition by RO5459072 led to strong and dose-dependent suppression of SS-A/SS-B-specific T cell effector functions and cytokine secretion by CD14⁺ monocytes. However, RO5459072 was incapable of suppressing SS-A/SS-B-induced secretion of cytokines in CD14⁺ monocytes when T cells were absent, confirming a CatS/MHCII-mediated mechanism of suppression.

CONCLUSION:

CatS activity in tear fluid seems to be a relevant biomarker for pSS disease activity. Conversely, CatS inhibition diminishes T cell and associated monokine responses towards relevant autoantigens in pSS. Thus, CatS inhibition may represent a promising novel treatment strategy in pSS.

100 Deals associated with Petesicatib

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External Link

KEGG	Wiki	ATC	Drug Bank
D11376	-	-	DB15297

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	US	Hoffmann-La Roche, Inc.	05 Jul 2016
Primary Sjögren's syndrome	Phase 2	FR	Hoffmann-La Roche, Inc.	05 Jul 2016
Primary Sjögren's syndrome	Phase 2	DE	Hoffmann-La Roche, Inc.	05 Jul 2016
Primary Sjögren's syndrome	Phase 2	PL	Hoffmann-La Roche, Inc.	05 Jul 2016
Primary Sjögren's syndrome	Phase 2	PT	Hoffmann-La Roche, Inc.	05 Jul 2016
Primary Sjögren's syndrome	Phase 2	GB	Hoffmann-La Roche, Inc.	05 Jul 2016
Celiac Disease	Phase 1	GB	Hoffmann-La Roche, Inc.	06 Mar 2016
Hypersensitivity, Delayed	Phase 1	NL	Hoffmann-La Roche, Inc.	01 Aug 2015

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02701985 (CTgov)	Phase 2	Primary Sjögren's syndrome	75	Placebo (Placebo)	zcwjbvzrtx(shwcokbckz) = jzmqlilmnd brzqqrsaou (akvhlliqct, azkytaseds - gphzjlnjas) View more	-	01 Aug 2018
				RO5459072 (RO5459072)	zcwjbvzrtx(shwcokbckz) = distlxpgwx brzqqrsaou (akvhlliqct, rjqhzvzbtl - dngyfqrigj) View more