Ocular iontophoresis of EGP-437 (dexamethasone phosphate) in dry eye patients: results of a randomized clinical trial

Michael A Patane¹, Amy Cohen¹, Stephen From¹, Gail Torkildsen², Donna Welch³, George W Ousler III³¹Eyegate Pharmaceuticals, Inc, Waltham, MA, USA; ²Andover Eye Associates, Andover, MA, USA; ³Ora, Inc, Andover, MA, USAPurpose: To assess safety and efficacy of EGP-437 (dexamethasone phosphate 40 mg/mL [DP]) in dry eye patients.Methods: The study employed a prospective, single-center, double-masked design utilizing a Controlled Adverse Environment (CAE). Patients (n = 103) with confirmed signs and symptoms of dry eye syndrome were randomized into 1 of 3 iontophoresis treatment groups: 7.5 mA-min at 2.5 mA (DP 7.5, n = 41); 10.5 mA-min at 3.5 mA (DP 10.5, n = 37); or 10.5 mA-min at 3.5 mA (placebo, n = 25). Three CAE visits and 4 follow-up visits occurred over 3 weeks. Patients meeting enrollment criteria received iontophoresis in both eyes after the second CAE exposure (visit 3) and before the third CAE exposure (visit 5). Primary efficacy endpoints were corneal staining and ocular discomfort. Secondary endpoints included tear film break-up time, ocular protection index (OPI), and symptomatology.Results: The DP 7.5 and DP 10.5 treatment groups showed statistically significant improvements in signs and symptoms of dry eye at various time points; however, the primary endpoints were not achieved. The DP 7.5 treatment group exhibited statistically significant improvements in corneal staining (when comparing the differences between study entry and exit, 3 weeks, P = 0.039), OPI (immediately following the second treatment, P = 0.048) and ocular discomfort at follow-up visits (a week after the first treatment, P = 0.032; 24 hours after the second treatment, P = 0.0032). Treatment-emergent adverse events (AEs) were experienced by 87% of patients and were consistent across all treatment groups. Most AEs were mild and no severe AEs were observed.Conclusion: Ocular iontophoresis of EGP-437 demonstrated statistically and clinically significant improvements in signs and symptoms of dry eye syndrome within a CAE model.Keywords: iontophoresis, dry eye, Controlled Adverse Environment (CAE), ocular protection index (OPI

Antibiotic Optimization and Chemical Structure Stabilization of Thiomuracin A

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (<b>1</b>) were initiated to improve chemical stability and physicochemical properties. Functional group modifications of <b>1</b> included removing the C2–C7 side chain, derivatizing the C84 epoxide region, and altering the C44 hydroxyphenylalanine motif. The resulting derivatives simplified and stabilized the chemical structure and were evaluated for antibacterial activity relative to <b>1</b>. The simplified structure and improved organic solubility of the derivatives facilitated isolation yields from fermentation broths and simplified the procedures involved for the process. These advancements increased material supply for continued medicinal chemistry optimization and culminated in the identification of <b>2</b>, a structurally simplified and chemically stable analogue of <b>1</b> which retained potent antibiotic activity

Selective PPARδ Modulators Improve Mitochondrial Function: Potential Treatment for Duchenne Muscular Dystrophy (DMD)

The X-ray structure of the previously reported PPARδ modulator <b>1</b> bound to the ligand binding domain (LBD) revealed that the amide moiety in <b>1</b> exists in the thermodynamically disfavored <i>cis</i>-amide orientation. Isosteric replacement of the <i>cis</i>-amide with five-membered heterocycles led to the identification of imidazole <b>17</b> (MA-0204), a potent, selective PPARδ modulator with good pharmacokinetic properties. MA-0204 was tested <i>in vivo</i> in mice and <i>in vitro</i> in patient-derived muscle myoblasts (from Duchenne Muscular Dystrophy (DMD) patients); <b>17</b> altered the expression of PPARδ target genes and improved fatty acid oxidation, which supports the therapeutic hypothesis for the study of MA-0204 in DMD patients

Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases

p300 and its paralog CBP can acetylate histones and other proteins and have been implicated in a number of diseases characterized by aberrant gene activation, such as cancer. A novel, highly selective, orally bioavailable histone acetyltransferase (HAT) domain inhibitor has been identified through virtual ligand screening and subsequent optimization of a unique hydantoin screening hit. Conformational restraint in the form of a spirocyclization followed by substitution with a urea led to a significant improvement in potency. Replacement of the hydantoin moiety with an oxazolidinedione followed by fluoro substitution led to <b>A-485</b>, which exhibits potent cell activity, low clearance, and high oral bioavailability

Antibacterial and Solubility Optimization of Thiomuracin A

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (<b>1</b>) provided access to analogues in the Northern region (C2–C10). Selective hydrolysis of the C10 amide of lead compound <b>2</b> and subsequent derivatization led to novel carbon- and nitrogen-linked analogues (e.g., <b>3</b>) which improved antibacterial potency across a panel of Gram-positive organisms. In addition, congeners with improved physicochemical properties were identified which proved efficacious in murine sepsis and hamster <i>C. difficile</i> models of disease. Optimal efficacy in the hamster model of <i>C. difficile</i> was achieved with compounds that possessed both potent antibacterial activity and high aqueous solubility

Parham et al_Online Appendix 1

Example of a justified calibration from hominin primates: (human-chimpanzee node)