ezutromid (SMT C1100) / Sarepta Therap - LARVOL DELTA

Phenotypic screening and target deconvolution of small molecules to manipulate cell fate: towards new therapies for degenerative diseases (ACS-Fall 2024) - "This will include the discovery and translation of the first generation utrophin modulator (ezutromid) into a Phase 2 clinical study, the deconvolution of ezutromid’s molecular target and mechanism of action, and our most recent work to incorporate our learnings into second generation utrophin modulators. Our extension of this approach into other degenerative diseases will then be described, exemplified by the discovery of small molecules to stimulate cardiac regeneration; from in vitro to in vivo efficacy studies, and deconvolution of an unexpected mechanism of action."

Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

PEPR112, A Repurposable AhR Antagonist Discovered Using AI/ML For Duchenne Muscular Dystrophy (MDA 2024) - "Ezutromid, an Aryl hydrocarbon receptor (AhR) antagonist, attracted attention as a promising therapeutic approach due to its ability for utrophin (a surrogate of dystrophin) upregulation, leading to enhanced muscle tissue function and decreased inflammation & dystrophy in DMD patients...PEPR112 is an US FDA approved oral generic drug with excellent PK and broader safety profile including in paediatric population (3 to 16 years). Our findings show that the repurposing of PEPR112 as a drug to upregulate utrophin for the treatment of DMD represents a significant breakthrough in the field of DMD therapeutics and could reduce the time and cost of development to give a quick access to DMD patients, a potential therapeutic intervention."

Duchenne Muscular Dystrophy • Genetic Disorders • Inflammation • Muscular Dystrophy • Pediatrics • Rare Diseases

Development of next generation utrophin modulators for Duchenne muscular dystrophy: Learning from clinical setbacks (ACS-Sp 2023) - "Our demonstration through a series of target identification and validation studies that ezutromid binds to the arylhydrocarbon receptor (AhR) with high affinity, and antagonism of AhR by ezutromid leads to utrophin upregulation will be described, confirming AhR as a viable target for utrophin functional replacement therapies. The identification of new lead molecule AhR antagonists with better efficacy and improved properties compared to ezutromid will also be described, as will the implementation of an alternative screening strategy leading to the discovery of new molecules with a distinct mechanism of action to ezutromid."

Clinical • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

Structure-activity relationships of 2-pyrimidinecarbohydrazides as utrophin modulators for the potential treatment of Duchenne muscular dystrophy. (PubMed, Bioorg Med Chem) - "Ezutromid, a first generation utrophin modulator which was later found to act via antagonism of the arylhydrocarbon receptor, progressed to Phase 2 clinical trials...The new analogues had significantly improved potency in cell-based assays, increased sp character and reduced lipophilicity, which also improved their physicochemical properties. A representative new analogue combining these attributes increased utrophin protein in dystrophic mouse cells showing it can be used as a chemical tool to reveal new insights regarding utrophin upregulation as a strategy for DMD therapeutic intervention."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Cu-Catalyzed Synthesis of Benzoxazole with Phenol and Cyclic Oxime. (PubMed, Org Lett) - "With this protocol, large-scale syntheses of Ezutromid and Flunoxaprofe in one or two steps are demonstrated. A catalytic mechanism, which includes Cu-catalyzed amination via inner-sphere electron transfer and consequent annulation, is proposed."

Journal

Utrophin modulator drugs as potential therapies for Duchenne and Becker muscular dystrophies. (PubMed, Neuropathol Appl Neurobiol) - "In this manuscript, we discuss the current knowledge on utrophin protein and the different mechanisms that modulate its expression in skeletal muscle. We also include a comprehensive review of compounds proposed as utrophin regulators and, as such, potential therapeutic candidates for these muscular dystrophies."

Journal • Becker Muscular Dystrophy • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Discovery and mechanism of action studies of 4,6-diphenylpyrimidine-2-carbohydrazides as utrophin modulators for the treatment of Duchenne muscular dystrophy. (PubMed, Eur J Med Chem) - "We have discovered and performed a preliminary optimisation of a novel class of utrophin modulators using an improved phenotypic screen, where reporter expression is derived from the full genomic context of the utrophin promoter. We further demonstrate through target deconvolution studies, including expression analysis and chemical proteomics, that this compound series operates via a novel mechanism of action, distinct from that of ezutromid."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Decreasing HepG2 Cytotoxicity by Lowering the Lipophilicity of Benzo[d]oxazolephosphinate Ester Utrophin Modulators. (PubMed, ACS Med Chem Lett) - "To improve the suboptimal profile of ezutromid, the first-in-class clinical candidate, a second generation of utrophin modulators bearing a phosphinate ester moiety was developed...Notably, ClogP was found to directly correlate with pIC in HepG2 cells, hence leading to a potentially safer toxicological profiles in this series. Compound 21 showed a balanced profile (H2K EC: 4.17 μM, solubility: 477 μM, mouse hepatocyte T > 240 min) and increased utrophin protein 1.6-fold in a Western blot assay."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Hepatology • Muscular Dystrophy

Isolation, structural identification, synthesis, and pharmacological profiling of 1,2-trans-dihydro-1,2-diol metabolites of the utrophin modulator ezutromid. (PubMed, J Med Chem) - "Herein, we describe the structural elucidation of the main metabolites of ezutromid, the regio- and relative stereochemical assignments of DHD1 and DHD3, their de novo chemical synthesis and their production in in vitro systems. We further elucidate the likely metabolic pathway and CYP450 isoforms responsible for DHD1 and DHD3 production and characterise their physicochemical, ADME, pharmacological properties and preliminary toxicological profile."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

A Phase 1b Trial to Assess the Pharmacokinetics of Ezutromid in Pediatric Duchenne Muscular Dystrophy Patients on a Balanced Diet. (PubMed, Clin Pharmacol Drug Dev) - "No severe or serious adverse events and no study discontinuations due to adverse events were reported. This study provides assurance that, with the formulation tested (F3) and instructions regarding food (balanced diet and whole-fat milk), 2500 mg BID of ezutromid achieves plasma concentrations that, based on preclinical studies, should be able to modulate utrophin expression in future clinical trials."

Clinical • Journal • P1 data • PK/PD data • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy • Pediatrics

Synthesis of SMT022357 enantiomers and in vivo evaluation in a Duchenne muscular dystrophy mouse model. (PubMed, Tetrahedron) - "Following on from ezutromid, the first-in-class benzoxazole utrophin modulator that progressed to Phase 2 clinical trials for the treatment of Duchenne muscular dystrophy, a new chemotype was designed to optimise its physicochemical and ADME profile...The pharmacological properties of both enantiomers were evaluated in vitro and in vivo. No significant difference in the activity or efficacy was observed between the two enantiomers; activity was found to be comparable to the racemic mixture."

Journal • Preclinical • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

2-Arylbenzo[d]oxazole phosphinate esters as second-generation modulators of utrophin for the treatment of Duchenne Muscular Dystrophy. (PubMed, J Med Chem) - "The improved physicochemical and ADME properties, further reflected in the enhanced pharmacokinetic profile of the most advanced compounds, 30 and 27, led to significantly better in vivo exposure compared to ezutromid, and alleviation of the dystrophic phenotype in mdx mice. While 30 was found to have dose-limiting hepatotoxicity, 27 and its enantiomers exhibited limited off-target effects, resulting in a safe profile and highlighting their potential utility as next generation utrophin modulators suitable for progression towards a future DMD therapy."

Journal • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

Modified Diet Trial: A Study of SMT C1100 in Paediatric Patients With DMD Who Follow a Balanced Diet (clinicaltrials.gov) - P1; N=12; Completed; Sponsor: Summit Therapeutics; Active, not recruiting ➔ Completed

Trial completion • Biosimilar

Modified Diet Trial: A Study of SMT C1100 in Paediatric Patients With DMD Who Follow a Balanced Diet (clinicaltrials.gov) - P1; N=12; Recruiting; Sponsor: Summit Corporation Plc.

New P1 trial • Biosimilar

Proof of Concept Study to Assess Activity and Safety of SMT C1100 (Ezutromid) in Boys With Duchenne Muscular Dystrophy (DMD) (clinicaltrials.gov) - P2; N=43; Terminated; Sponsor: Summit Therapeutics; Completed ➔ Terminated; The study was terminated due to lack of efficacy in Cohorts 1 and 2.

Clinical • Trial termination • MRI

Chemical Proteomics and Phenotypic Profiling Identifies the Aryl Hydrocarbon Receptor as a Molecular Target of the Utrophin Modulator Ezutromid. (PubMed, Angew Chem Int Ed Engl) - "Several lines of evidence demonstrate that ezutromid binds AhR with an apparent KD of 50 nM and behaves as an AhR antagonist. Furthermore, other reported AhR antagonists also upregulate utrophin, showing that this pathway, which is currently being explored in other clinical applications including oncology and rheumatoid arthritis, could also be exploited in future DMD therapies."

Journal • AHR

Characterisation of utrophin modulator SMT C1100 as a non-competitive inhibitor of firefly luciferase. (PubMed, Bioorg Chem) - "Employing a photoaffinity strategy to identify SMT C1100's binding site, a photolabelled SMT C1100 probe instead underwent FLuc-dependent photooxidation. Our findings support novel binding sites on FLuc for non-competitive inhibitors."

Journal

PoC Study to Assess Activity and Safety of SMT C1100 (Ezutromid) in Boys With DMD (clinicaltrials.gov) - P2; N=40; Completed; Sponsor: Summit Therapeutics; Active, not recruiting ➔ Completed

Clinical • Trial completion

Target identification studies of a utrophin modulator for treatment of Duchenne muscular dystrophy (ACS-Sp 2019) - "...A novel small molecule utrophin modulator, ezutromid (Summit Therapeutics; formerly SMT C1100), which was identified using a phenotypic screen, progressed to Phase II clinical trials in DMD patients...These probes were used in AfBPP experiments followed by LC-MS/MS. Integration of the hits identified by these strategies has led to a shortlist of targets which are currently being validated."