Delving into the Latest Updates on Ulevostinag with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

MK 1454, MK-1454, MK1454

Target

STING

Mechanism

STING agonists(Stimulator of interferon genes agonists)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases

Active Indication-

Inactive Indication

LymphomaRecurrent Squamous Cell Carcinoma of the Head and Neck

Originator Organization

Merck Sharp & Dohme Corp.

Active Organization-

Inactive Organization

Merck Sharp & Dohme Corp.

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC20H22F2N10O9P2S2

InChIKeyYSUIQYOGTINQIN-DGVVHPOBSA-N

CAS Registry2082743-96-0

The purpose of this study is to assess the efficacy and safety of intratumoral (IT) ulevostinag PLUS pembrolizumab (MK-3475) compared to pembrolizumab alone as a first line treatment of adults with metastatic or unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).
The primary study hypotheses are that IT ulevostinag in combination with pembrolizumab results in a superior Objective Response Rate (ORR), per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), compared to pembrolizumab alone:
In participants with a tumor that has a programmed cell death-ligand 1 (PD-L1) Combined Positive Scoring (CPS) ≥ 1, and
In participants with a tumor that has a PD-L1 CPS ≥ 20.

Start Date04 Mar 2020

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

NCT03010176 / CompletedPhase 1

Phase 1 Open-label, Multicenter Study of MK-1454 Administered by Intratumoral Injection as Monotherapy and in Combination With Pembrolizumab for Patients With Advanced/Metastatic Solid Tumors or Lymphomas

The purpose of this study is to identify a maximum tolerated dose (MTD) or maximum administered dose (MAD) of ulevostinag alone and of ulevostinag in combination with pembrolizumab in participants with advanced/metastatic solid tumors or lymphomas in Part 1, and to evaluate the safety and efficacy of ulevostinag via intratumoral (IT) injection in combination with pembrolizumab in selected solid tumors in Part 2.
Ulevostinag will be administered IT; pembrolizumab (pembro) will be administered via intravenous (IV) infusion. In Part 1, participants will be allocated to one of three treatment arms: ulevostinag monotherapy (cutaneous/subcutaneous [cut/subcut] lesions), ulevostinag +pembro (cut/subcut lesions), or ulevostinag +pembro (visceral lesions).
In Part 2, participants with head and neck squamous cell carcinoma (HNSCC) who are anti-programmed cell death-protein 1 or anti-programmed cell death-ligand 1 (anti-PD-1/PD-L1) refractory or with anti-PD-1/PD-L1 treatment (TrT)-naïve triple-negative breast cancer (TNBC) or with anti-PD-1/PD-L1 TrT-naïve solid tumors with liver metastases/lesions will receive ulevostinag via IT injection at the preliminary Recommended Phase 2 Dose (RP2D) determined in Part 1 PLUS pembrolizumab via IV infusion for up 35 cycles (up approximately 2 years).

Start Date03 Feb 2017

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

100 Clinical Results associated with Ulevostinag

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100 Translational Medicine associated with Ulevostinag

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100 Patents (Medical) associated with Ulevostinag

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9

Literatures (Medical) associated with Ulevostinag

21 Oct 2022·Organic letters

A Unified Strategy to Fluorinated Nucleoside Analogues Via an Electrophilic Manifold

Article

Author: Wang, Lu ; Johnson, Heather C. ; Chung, Cheol K. ; Carson, William P. ; Neel, Andrew J. ; Song, Zhiguo Jake ; Liu, Zhuqing ; Peng, Feng ; Tan, Lushi ; Rummelt, Stephan M. ; Benkovics, Tamas ; Turnbull, Ben W. H. ; Xu, Feng

Herein, we present a strategy for the preparation of 3'-fluorinated nucleoside analogues via the aminocatalytic, electrophilic fluorination of readily accessible and bench-stable 2'-ketonucleosides. Initially developed to facilitate the manufacture of 3'-fluoroguanosine (3'-FG)─a substructure of anticancer therapeutic MK-1454─this strategy has been extended to the synthesis of a variety of 3'-fluoronucleosides. Finally, we demonstrate the utility of the 2'-ketonucleoside synthon as a platform for further diversification and suggest that this methodology should be broadly applicable to the discovery of novel nucleoside analogues.

01 Oct 2022·Pharmaceutical research

Photo-Oxidation Mechanisms in Liquid Pharmaceutical Formulations: The Overlooked Role of Singlet Oxygen Presented as a Case Study

Article

Author: Tignor, Steven ; Walsh, Paul L ; Pierson, Elizabeth ; Brunell, Margaret

PURPOSE:

Oxidation is one of the most common degradation pathways for active pharmaceutical ingredients (APIs) in pharmaceutical formulations, mostly involving 1-electron processes via peroxy radicals and 2-electron processes by peroxides. In liquid pharmaceutical formulations, several factors can impact oxidative instabilities including pH, excipient impurities, headspace oxygen, and the potential for photo-oxidation. Photo-oxidation can be particularly challenging to characterize given the number of oxidative mechanisms which can occur. This was observed during formulation development of a new chemical entity, MK-1454, where a degradation peak was observed during photostability studies which was not previously observed during peroxide and peroxyradical forced stress studies.

METHODS:

To gain a fundamental understanding of reactive oxygen species generation and its role in degradation of MK-1454, experiments were performed with materials which either generate or measure reactive oxygen species including organic hydroperoxides, singlet oxygen, and superoxide to fundamentally understand a photodegradation mechanism which was observed in the original formulation. LC-MS experiments further elucidated the structure and mechanism of this observed degradation pathway.

RESULTS:

A clear relationship between the decrease in dissolved oxygen after light exposure and the loss of MK-1454 was established. The data indicate that singlet oxygen is the most likely contributor of a particular photodegradation product. The singlet oxygen was generated by the inactive ingredients in the formulation, and LC-MS confirm this as the most likely pathway.

CONCLUSION:

This work highlights the importance of understanding photochemical degradation of APIs in solution formulations and provides approaches which can better elucidate those mechanisms and thereby control strategies.

26 Sep 2022·Angewandte Chemie (International ed. in English)

Cascades of Evolved Enzymes for the Synthesis of Complex Molecules

Review

Author: Lütz, Stephan ; Bornscheuer, Uwe T. ; Rosenthal, Katrin

Abstract:

Thanks to advances in enzyme discovery and protein engineering combined with the development of enzymatic multistep reaction cascades, new efficient routes for drug synthesis have been created that are superior to chemical syntheses. This supports the goal of the chemical and pharmaceutical industries to move to more sustainable and environmentally friendly processes. Recently described outstanding examples include the biocatalytic cascade syntheses of the cyclic dinucleotide MK‐1454, molnupiravir, and islatravir, as well as the efficient fixation of CO2 to make starch using an artificial enzyme cascade.

100 Deals associated with Ulevostinag

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB14721

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Recurrent Squamous Cell Carcinoma of the Head and Neck	Phase 2	US	Merck Sharp & Dohme Corp.	04 Mar 2020
Recurrent Squamous Cell Carcinoma of the Head and Neck	Phase 2	AU	Merck Sharp & Dohme Corp.	04 Mar 2020
Recurrent Squamous Cell Carcinoma of the Head and Neck	Phase 2	AT	Merck Sharp & Dohme Corp.	04 Mar 2020
Recurrent Squamous Cell Carcinoma of the Head and Neck	Phase 2	BR	Merck Sharp & Dohme Corp.	04 Mar 2020
Recurrent Squamous Cell Carcinoma of the Head and Neck	Phase 2	FR	Merck Sharp & Dohme Corp.	04 Mar 2020
Recurrent Squamous Cell Carcinoma of the Head and Neck	Phase 2	IL	Merck Sharp & Dohme Corp.	04 Mar 2020
Recurrent Squamous Cell Carcinoma of the Head and Neck	Phase 2	NO	Merck Sharp & Dohme Corp.	04 Mar 2020
Recurrent Squamous Cell Carcinoma of the Head and Neck	Phase 2	KR	Merck Sharp & Dohme Corp.	04 Mar 2020
Recurrent Squamous Cell Carcinoma of the Head and Neck	Phase 2	ES	Merck Sharp & Dohme Corp.	04 Mar 2020
Recurrent Squamous Cell Carcinoma of the Head and Neck	Phase 2	GB	Merck Sharp & Dohme Corp.	04 Mar 2020

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03010176 (MK-1454-001 \| 1454-001, CTgov)	Phase 1	Solid tumor \| Lymphoma	156	Ulevostinag (Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions))	afjgpbbcpd(mdwciehlot) = sdxcnyepte gymkofvmpp (kdzycyxzwi, kekrrtabpj - aftrisxpvg) View more	-	26 Feb 2024
				Pembrolizumab+Ulevostinag (Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions))	afjgpbbcpd(mdwciehlot) = lioynurjlq gymkofvmpp (kdzycyxzwi, lmnqpybzma - bzkuowwsgn) View more
NCT04220866 (MK-1454-002 \| 1454-002, CTgov)	Phase 2	Recurrent Squamous Cell Carcinoma of the Head and Neck	18	pembrolizumab	sfyikntzss(boeckxstqk) = myqdemzxay imaaglukvb (dlyntcxmye, ftbkbhjwnz - jdnyrphald) View more	-	27 Oct 2023
NCT03010176 (Corporate Publications) Manual	Phase 1	Solid tumor \| Lymphoma	51	MK-1454	pxhvepxwhb(sjzbuuhwxw) = zysbrxdqkb wudjhgaeqc (nbauxkogps ) View more	Positive	20 Oct 2018
				Pembrolizumab+MK-1454	pxhvepxwhb(sjzbuuhwxw) = ljzuasmyhz wudjhgaeqc (nbauxkogps ) View more
NCT03010176 (MK-1454-001 \| 1454-001, ESMO2018)	Phase 1	HR-positive/HER2-low Solid Tumors \| Lymphoma	157	MK-1454	flqypttxvr(bbdkrogvoq) = resulted in discontinuation of 7% of pts in Arm 2 (0% in Arm 1) kjjmufhxsq (zpistttlxq ) View more	Positive	20 Oct 2018
				MK-1454 + Pembrolizumab