Delving into the Latest Updates on LYS-006 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

LTA4H

Mechanism

LTA4H inhibitors(Leukotriene A-4 hydrolase inhibitors)

Therapeutic Areas

Immune System DiseasesDigestive System DisordersSkin and Musculoskeletal Diseases

Active Indication-

Inactive Indication

Acne VulgarisColitis, Ulcerative

Originator Organization

Novartis Pharma AG

Active Organization-

Inactive Organization

Novartis Pharmaceuticals Corp.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC16H14ClFN6O3

InChIKeyZEGMEJVULDALSH-NSHDSACASA-N

CAS Registry1799681-85-8

NASH EXploratory Single and COmbination Treatment (NEXSCOT): An Open Label, Multicenter, Platform Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of Various Single and Combination Treatments in Patients With Non-alcoholic Fatty Liver Disease (NAFLD) Who Manifest a Non-alcoholic Steatohepatitis (NASH)-Like Biomarker Phenotype

This clinical study was designed to evaluate the safety, tolerability, pharmacokinetics and efficacy of various single and combination treatments in adult patients with non-alcoholic fatty liver disease (NAFLD) who manifest a non-alcoholic steatohepatitis (NASH)-like biomarker phenotype.

Start Date04 Jun 2020

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

NCT04074590 / TerminatedPhase 2

A Randomized, Multi-center, Subject and Investigator-blinded, Placebo-controlled, Parallel-group Study to Assess the Efficacy Safety and Tolerability of LYS006 in Patients With Mild to Moderate Ulcerative Colitis

The purpose of the study was to assess preliminary efficacy, safety, and tolerability of LYS006 in adult patients with mild to moderate ulcerative colitis and to determine if LYS006 has an adequate clinical profile for further development in this indication.

Start Date03 Feb 2020

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

100 Clinical Results associated with LYS-006

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100 Translational Medicine associated with LYS-006

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100 Patents (Medical) associated with LYS-006

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3

Literatures (Medical) associated with LYS-006

01 Feb 2024·Clinical and Translational Science

LTA4H inhibitor LYS006: Clinical PK/PD and safety in a randomized phase I clinical trial

Article

Author: Jäger, Petra ; Fink, Martin ; Otto, Heike ; Weiss, H. Markus ; Loesche, Christian ; Schuhler, Carole ; Picard, Damien ; Thoma, Gebhard ; Markert, Christian ; Klein, Kai ; Poller, Birk ; Schuhmann, Imelda ; Van Hoorick, Benjamin ; Zamurovic, Natasa ; Röhn, Till A.

AbstractLYS006 is a novel, highly potent and selective, new‐generation leukotriene A4 hydrolase (LTA4H) inhibitor in clinical development for the treatment of neutrophil‐driven inflammatory diseases. We describe the complex pharmacokinetic to pharmacodynamic (PD) relationship in blood, plasma, and skin of LYS006‐treated nonclinical species and healthy human participants. In a randomized first in human study, participants were exposed to single ascending doses up to 100 mg and multiple ascending doses up to 80 mg b.i.d.. LYS006 showed rapid absorption, overall dose proportional plasma exposure and nonlinear blood to plasma distribution caused by saturable target binding. The compound efficiently inhibited LTB4 production in human blood and skin blister cells, leading to greater than 90% predose target inhibition from day 1 after treatment initiation at doses of 20 mg b.i.d. and above. Slow re‐distribution from target expressing cells resulted in a long terminal half‐life and a long‐lasting PD effect in ex vivo stimulated blood and skin cells despite low plasma exposures. LYS006 was well‐tolerated and demonstrated a favorable safety profile up to highest doses tested, without any dose‐limiting toxicity. This supported further clinical development in phase II studies in predominantly neutrophil‐driven inflammatory conditions, such as hidradenitis suppurativa, inflammatory acne, and ulcerative colitis.

14 Dec 2023·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of Amino Alcohols as Highly Potent, Selective, and Orally Efficacious Inhibitors of Leukotriene A4 Hydrolase

Q1 · MEDICINE

Article

Author: Thoma, Gebhard ; Penno, Carlos A ; Miltz, Wolfgang ; Gajewska, Monika ; Markert, Christian ; Beerli, Christian ; Bollbuck, Birgit ; Bednarczyk, Dallas ; Spanka, Carsten ; Röhn, Till A ; Evans, Amanda ; Srinivas, Honnappa ; Wieczorek, Grazyna ; Wolf, Romain M ; Lueoend, Rainer ; Kiffe, Michael

The discovery of chiral amino alcohols derived from our previously disclosed clinical LTA4H inhibitor LYS006 is described. In a biochemical assay, their optical antipodes showed similar potencies, which could be rationalized by the cocrystal structures of these compounds bound to LTA4H. Despite comparable stabilities in liver microsomes, they showed distinct in vivo PK properties. Selective O-phosphorylation of the (R)-enantiomers in blood led to clearance values above the hepatic blood flow, whereas the (S)-enantiomers were unaffected and exhibited satisfactory metabolic stabilities in vivo. Introduction of two pyrazole rings led to compound (S)-2 with a more balanced distribution of polarity across the molecule, exhibiting high selectivity and excellent potency in vitro and in vivo. Furthermore, compound (S)-2 showed favorable profiles in 16-week IND-enabling toxicology studies in dogs and rats. Based on allometric scaling and potency in whole blood, compound (S)-2 has the potential for a low oral efficacious dose administered once daily.

25 Feb 2021·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A₄ Hydrolase

Q1 · MEDICINE

Article

Author: Hinrichs, Jurgen ; Rohn, Till A. ; Klein, Kai ; Penno, Carlos A. ; Beerli, Christian ; Loetscher, Pius ; Littlewood-Evans, Amanda ; Thoma, Gebhard ; Miltz, Wolfgang ; Wack, Nathalie ; Numao, Shin ; Srinivas, Honnappa ; Dawson, Janet ; Wolf, Romain ; Markert, Christian ; Bergsdorf, Christian ; Jager, Petra ; Hasler, Franziska ; Azzaoui, Kamal ; Walchli, Rudolf ; Luond, Rainer M. ; Wieczorek, Grazyna ; Bollbuck, Birgit

The cytosolic metalloenzyme leukotriene A₄ hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B₄ (LTB₄). Preclinical studies have validated this enzyme as an attractive drug target in chronic inflammatory diseases. Despite several attempts, no LTA4H inhibitor has reached the market, yet. Herein, we disclose the discovery and preclinical profile of LYS006, a highly potent and selective LTA4H inhibitor. A focused fragment screen identified hits that could be cocrystallized with LTA4H and inspired a fragment merging. Further optimization led to chiral amino acids and ultimately to LYS006, a picomolar LTA4H inhibitor with exquisite whole blood potency and long-lasting pharmacodynamic effects. Due to its high selectivity and its ability to fully suppress LTB₄ generation at low exposures in vivo, LYS006 has the potential for a best-in-class LTA4H inhibitor and is currently investigated in phase II clinical trials in inflammatory acne, hidradenitis suppurativa, ulcerative colitis, and NASH.

100 Deals associated with LYS-006

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Colitis, Ulcerative	Phase 2	PL	Novartis Pharmaceuticals Corp.	03 Feb 2020
Colitis, Ulcerative	Phase 2	BG	Novartis Pharmaceuticals Corp.	03 Feb 2020
Colitis, Ulcerative	Phase 2	SK	Novartis Pharmaceuticals Corp.	03 Feb 2020
Colitis, Ulcerative	Phase 2	DE	Novartis Pharmaceuticals Corp.	03 Feb 2020
Acne Vulgaris	Phase 2	FR	Novartis Pharmaceuticals Corp.	10 Sep 2018
Acne Vulgaris	Phase 2	NL	Novartis Pharmaceuticals Corp.	10 Sep 2018
Acne Vulgaris	Phase 2	US	Novartis Pharmaceuticals Corp.	10 Sep 2018
Acne Vulgaris	Phase 2	CZ	Novartis Pharmaceuticals Corp.	10 Sep 2018
Acne Vulgaris	Phase 2	DE	Novartis Pharmaceuticals Corp.	10 Sep 2018
Acne Vulgaris	Phase 2	HU	Novartis Pharmaceuticals Corp.	10 Sep 2018

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04074590 (CTgov)	Phase 2	Colitis, Ulcerative	23	Placebo	khgridtogp(hshoxpppds) = bfvqtvjtrg dzkneztnux (lvxylhfaac, qbnclofmhr - gxjqheefkb) View more	-	09 Nov 2023
NCT03497897 (CTgov)	Phase 2	Acne Vulgaris	66	LYS006 20 mg (LYS006 20 mg BID)	otywmmyhna(fjjsxkjcex) = bkrerjumhm argrzyldnx (ieypvggokn, afnsqqqums - mxfkcbdfpg) View more	-	20 Mar 2023
				LYS006 2 mg (LYS006 2 mg BID)	otywmmyhna(fjjsxkjcex) = ooymmgcuai argrzyldnx (ieypvggokn, yksrtlzjpd - yhqvoiackd) View more
NCT04147195 (CTgov)	Phase 2	Nonalcoholic Steatohepatitis	41	LYS006 (LYS006)	(qtjwwjjnym) = asqkpxexun uhbcgvshvg (tbebrlrvfr, rqiihupxga - nawmdpghsk) View more	-	26 Jan 2023
				Tropifexor (LYS006 + LJN452)	(qtjwwjjnym) = hbpnqsgytl uhbcgvshvg (tbebrlrvfr, mzcmiakejp - mphoweitzt) View more