Delving into the Latest Updates on LYS-006 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

LTA4H

Action

inhibitors

Mechanism

LTA4H inhibitors(Leukotriene A-4 hydrolase inhibitors)

Therapeutic Areas

Immune System DiseasesDigestive System DisordersSkin and Musculoskeletal Diseases

Active Indication-

Inactive Indication

Acne VulgarisColitis, UlcerativeNonalcoholic Steatohepatitis

Originator Organization

Novartis Pharma AG

Active Organization-

Inactive Organization

Novartis Pharmaceuticals Corp.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

Login to view timeline

Structure/Sequence

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

Login to view more data

100 Translational Medicine associated with LYS-006

Login to view more data

100 Patents (Medical) associated with LYS-006

Login to view more data

6

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.

01 Dec 2022·Drug Metabolism and Disposition

Human Pharmacokinetics of LYS006, an Oral Leukotriene A4 Hydrolase Inhibitor Displaying Target-Mediated Drug Disposition

Article

Author: Leuthold, Luc Alexis ; Schweigler, Patrick ; Tor Carreras, Ester ; Fink, Martin ; Poller, Birk ; Jullion, Astrid ; Weiss, H Markus ; Pearson, David ; Marvalin, Cyrille ; Loesche, Christian

LYS006 is a potent leukotriene A4 hydrolase inhibitor currently in clinical development for long-term treatment of various neutrophil-driven inflammatory conditions. Here, we present pharmacokinetics from the first-in-human study with complementary metabolism and transporter profiling data. The randomized first-in-human study included nine cohorts receiving 5-2*100 mg of LYS006 or placebo, a crossover food-effect part, and a multiple-dose part consisting of two fasted (5 mg and 15 mg once daily) and three fed cohorts (20-80 mg twice a day) of LYS006 or placebo. LYS006 and metabolites were assessed in plasma and urine, and transporters involved in LYS006 disposition were analyzed in vitro. Systemic plasma exposure increased with dose; steady-state exposure was dose proportional up to 40 mg twice a day. Steady state was achieved after ∼3 days, with mean accumulation of 2.1-fold for 5 mg once daily and ≤1.4-fold for all higher doses. Despite limited accumulation, a long terminal half-life (T_1/2) was observed. The long T_1/2 and saturable binding to blood cells, which causes a highly nonlinear blood-to-plasma distribution, reflect a strong impact of target binding on drug distribution at lower concentrations. Skin biopsy and blister fluid concentration data indicated saturable binding in the former but not the latter, suggesting saturable binding in tissues beyond blood. Major excretion of LYS006 (∼90% of dose) through urine at steady state triggered renal transporter investigations that identified LYS006 as a substrate of organic anion transporter (OAT)3, OAT4, breast cancer resistance protein, and multidrug resistance-associated protein 4. Seven metabolites were identified in human plasma and urine, comprising only 4% of the dose recovered in urine at steady state. SIGNIFICANCE STATEMENT: Pharmacokinetic data from a first-in-human study combined with in vitro work support dose and regimen selection for patient studies with LYS006 and provide guidance on drug interaction investigations and other clinical pharmacology work needed for further development. Mass balance information at steady state without the use of a radiolabel, skin concentrations, and identification of the major clearance pathway, as well as the transporters driving elimination, make this a particularly conclusive early study despite nonlinear pharmacokinetics impacted by target binding.

100 Deals associated with LYS-006

Login to view more data

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Colitis, Ulcerative	Phase 2	Russia	Novartis Pharmaceuticals Corp.	03 Feb 2020
Colitis, Ulcerative	Phase 2	Bulgaria	Novartis Pharmaceuticals Corp.	03 Feb 2020
Colitis, Ulcerative	Phase 2	Slovakia	Novartis Pharmaceuticals Corp.	03 Feb 2020
Colitis, Ulcerative	Phase 2	Germany	Novartis Pharmaceuticals Corp.	03 Feb 2020
Acne Vulgaris	Phase 2	France	Novartis Pharmaceuticals Corp.	10 Sep 2018
Acne Vulgaris	Phase 2	Netherlands	Novartis Pharmaceuticals Corp.	10 Sep 2018
Acne Vulgaris	Phase 2	United States	Novartis Pharmaceuticals Corp.	10 Sep 2018
Acne Vulgaris	Phase 2	Czechia	Novartis Pharmaceuticals Corp.	10 Sep 2018
Acne Vulgaris	Phase 2	Germany	Novartis Pharmaceuticals Corp.	10 Sep 2018
Acne Vulgaris	Phase 2	Hungary	Novartis Pharmaceuticals Corp.	10 Sep 2018

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04074590 (CTgov)	Phase 2	Colitis, Ulcerative	23	Placebo	fawvnqjvot(nfnttuhshs) = zieshmljgy pdumssfdif (sqjcupyska, cnmwxbjoit - uivvaumzvv) View more	-	09 Nov 2023
NCT03497897 (CTgov)	Phase 2	Acne Vulgaris	66	LYS006 20 mg (LYS006 20 mg BID)	yeekchpinv(kivlrllnoo) = ysanxybuav byzkmthwgb (kdpjwkekxa, mwmammljuv - zvvdxbftlj) View more	-	20 Mar 2023
				LYS006 2 mg (LYS006 2 mg BID)	yeekchpinv(kivlrllnoo) = ogltdbanar byzkmthwgb (kdpjwkekxa, kbcmsbfgzt - skytqnmuml) View more
NCT04147195 (NEXSCOT, CTgov)	Phase 2	Nonalcoholic Steatohepatitis	41	LYS006 (LYS006)	(jcvtmhyxkz) = vmsggpbsst httfvhrhlc (eggaywvtym, pvsnvqskht - downdlbapq) View more	-	26 Jan 2023
				Tropifexor (LYS006 + LJN452)	(jcvtmhyxkz) = bxelhmtlhd httfvhrhlc (eggaywvtym, gwukcenoew - fzdlrcdrkb) View more