MR04A3 An isoindoline derivative, New Sedative/Anesthetic Agent

Transcription

1 MR04A3 An isoindoline derivative, ew Sedative/Anesthetic Agent ovember Introduction Sedatives are widely used in: Settings providing stressful and painful procedures Gastroenterology (colonoscopy and other GI endoscopies) Cardiology (interventional procedures) Radiology, etc. peration room Major and minor surgeries Intensive care unit Emergency room Dentistry Hospital ward ovember

2 Market overview - Procedural sedation market World $1,552M 613 BZDs Propofol Dexmedetomidine thers 78 US 54 EU* 54 $563M 268 $707M * UK, DE, FR, IT, ES IMS 2008: Sales data of drugs possibly used for procedural sedation, i.e., Benzodiazepins (BZDs; midazolam, diazepam, lorazepam, flunitrazepam), propofol, dexmedetomidine, hydroxyzine, droperidol, etomidate, thiopental and ketamine ovember Market overview - 5B (sedative/hypnotic) market - 1,597 World $4,439M 1,429 on-bzds: Zolpidem Eszopiclone Zopiclone Zaleplon US $2,125M , EU* $693M BZDs thers IMS * UK, DE, FR, IT, ES 101 ovember

3 Market overview - Estimated number of procedures - Procedures GI endoscopies Cardiological procedures Minor Surgeries Total procedures US 24 million 12 million 12 million million Europe million Total: approx. 200 million procedures Source: Data in 2003, from website of the Department of Anesthesia, Stanford School of Medicine (accessed, July 1st, 2009) ovember Facts and unmet needs BZDs are most commonly used sedatives But their long duration of action often causes problems BZDs are antagonized by flumazenil But there is possibility of re-sedation Propofol is also widely used for precedural sedation But it must be administered by anesthesia professionals due to safety concerns Propofol is commonly used for general anesthesia But it causes vascular pain Propofol is emulsified formulation It causes fat overload and is susceptible to bacterial infection ovember

4 Disadvantages of BZDs Respiratory depression Muscle relaxant effect Prolonged action Drug tolerance/dependency Zolpidem is one of the most successful non-bzd agents ovember MR04A3 product positioning Faster than midazolam, the shortest-acting BZD Safer than propofol, the most popular intravenous anesthetic on-bzd structure to overcome the weaknesses of BZDs Aqueous formulation ovember

5 ew structure MR04A3 H CH3 Zolpidem Benzodiazepine skeleton Cl Cl F Br Diazepam Midazolam CS 7056 ovember Chemical properties on-bzd isoindoline derivative Code ame: JM-1232(-) MW: Stable at RT Docking simulation on BZD binding pocket of GABA A -R MR04A3 (in red) was overlaid with diazepam Patent Information Application: ovember, 2003 PCT Pub o.: W2004/ US Pat o.: EP Pub o.: Filed in 27 other countries (granted in some countries) ovember

6 on-bzd-mr04a3 shows BZD-like action GABA (3 μm) MR04A3 (1 μm) 350 Flu (10 μm) pA 5sec. Flu: Flumazenil I/ I 3 μm GABA (%) GABA alone + MR04A3 +MR04A3 +Flu Patch-clamp analysis showed that MR04A3 acts on the central BZD receptor and its action is antagonized by flumazenil ovember Product properties Ready-to-use clear aqueous solution ver 12 months stability (in progress, RT) ovember

7 Phase I study design Study site: UK ( ) Endpoint: Ramsay, BIS, safety, PK, cognitive function Subject: Healthy male volunteer (18-35 yr) Type Administration method Control groups o. of subjects /group Dosage (mg/kg) Step1 10-min i.v. infusion 3 (placebo 1) 0.05, 0.1, , 0.8 Single blind, Dose escalation Placebo Step2 6 (placebo 1) 0.025, 0.05, , 0.2, 0.3, min i.v. bolus Step3 (PoC) pen-label, Crossover Midazolam Propofol , 0.2 (M: 0.06, P: 2.0) ovember Completed nonclinical studies Pharmacodynamics Action mechanism Pharmacological profile Pharmacodynamic drug interactions Safety pharmacology (CS, cardiovascular, respiratory, autonomic, gastrointestinal) Pharmacokinetics ADME study (in vitro, rat, monkey) Drug interaction Toxicity Single-dose toxicity (rat, monkey (bolus), monkey (infusion)) Repeated-dose toxicity (rat 4w, monkey 2w) Genotoxicity Reproductive and developmental toxicity (rat I, III, rabbit III) Local Tolerance Antigenicity ovember

8 Summary Faster than midazolam, the shortest-acting BZD MR04A3 showed more rapid clearance than midazolam with clearer recovery profile Safer than propofol, the most popular intravenous anesthetic MR04A3 showed less respiratory depression than propofol with comparable onset time to that of propofol on-bzd structure overcoming the weaknesses of BZDs Several nonclinical studies suggested that difference in action mechanism between MR04A3 and other BZDs provides clinical benefits Aqueous formulation MR04A3 is a ready-to-use clear aqueous solution with over 1yr RT stability And more... ther market opportunities are expected based on that MR04A3 is confirmed effective also when administered orally ovember Conclusions It was confirmed that MR04A3 had the profiles that are suitable for procedural sedation, in terms of efficacy and safety It was strongly suggested that MR04A3 could be also used for general anesthesia ur findings show that MR04A3 has a possibility to be developed as a hypnotic (a sleep-inducing narcotic drug) ovember

9 Major publications riginal article ovel Water-Soluble Sedative-Hypnotic Agents: Isoindolin-1-one Derivatives: Chem Pharm Bull. 2007; 55(12): Presentation A new benzodiazepine site agonist, JM-1232(-), as the short acting sedative-hypnotic agent: euroscience 2007 First human administration of MR04A3 (1.0% JM-1232(-)), a novel isoindoline derivative benzodiazepine agonist: Euroanesthesia 2008 ovel Sedative-Hypnotic Compound, JM-1232(-): JSA 2008 GABA A receptor α subunit selectivity of a novel sedative/hypnotic agent, JM-1232(-): euroscience 2008 Effects of a novel sedative/hypnotic agent, JM-1232(-) on rats EEG: JSA 2009 Phase I study results (Efficacy/Safety, PK/PD): ASA 2009 ovember