Novel Neurotherapeutic YKP3089 Novel Neurotherapeutic ASENT March 2009 Martin Brecher, MD Life Science Fair Lawn, New Jersey New Jersey, U.S.A. Seoul, Korea Daejeon, Korea Shanghai, China

YKP3089 Preclinical Summary Animal Model Profile Anticonvulsant Profile Broad spectrum activity in Rat & Mice (i.p., p.o.) Anxiolytic Profile Active in diverse AX models in Rat & Mice (i.p., p.o.) Pain Profile Potent efficacy in Chung & Bennett models in Rat Additional Profile Hypoxia model in Mice Conditioned Avoidance Rat model

Anticonvulsant Profile YKP3089 Compounds (Mice, i.p., ED50 mg/kg) Electrical Tonic Generalized Seizures Chemical Myoclonic/Generalized Absence Seizures MES PTZ PIC YKP3089 9.8 28.5 34.5 Lamotrigine 7.5 >40.0 Topiramate 33.0 >800 >500 Phenytoin 6.5 >50 Carbamazepine 9.9 Valproate 287 209 Ethosuximide >1000 130 Data Source: NIH

Anticonvulsant Profile YKP3089 Compounds (Rat, ip, ED50 mg/kg) Refractory epilepsy Partial Complex Formation/Progression of Epilepsy Intractable Seizures Kindling Hippocampal Lithium-pilocarpine intractable seizures YKP3089 16.4 7.0 Lamotrigine ++ ND Topiramate - Phenytoin +/- Carbamazepine Valproate + Ethosuximide

Anticonvulsant Profile YKP3089 Anticonvulsant Profile Compounds (Mice, i.p., ED50 mg/kg) 6 Herz Partial Psychomotor Test Therapy-Resistant Partial Seizures 22mA 32mA 44mA YKP3089* 11.0 17.9 16.5 Lamotrigine ND 50% at 20 Phenytoin 58% at 40 Carbamazepine 75% at 40 & 80 Topiramate >300 Data Source: NIH

Fear-Potentiated Startle Anxiolytic Profile YKP3089 Effective in a wide variety of anxiety models Light-Dark Box Social Interaction Fear-Potentiated Startle Marble-Burying Elevated Plus Maze Defensive withdrawal, etc. Active in Rats and Mice Anxiolytic Test YKP3089 Buspirone Light-Dark Box (Mice, IP) +++ Social Interaction (Rat,PO) ++ Fear-Potentiated Startle (Rat, IP) Marble-Burying +++ - ED50 <20mg/kg ++ - ED50 <30mg/kg

Analgesic (Neuropathic Pain) Profile YKP3089 Excellent activity in models of neuropathic pain Improved efficacy compared to gabapentin Chung Model Bennett Model YKP3089 Gabapentin Mechanical allodynia +++ Cold allodynia ++ Heat hyperalgesia +++ - ED50 <50mg/kg ++ - ED50 <100mg/kg

Additional Indication Profile YKP3089 Additional Indication Profile Model Efficacy Indication Hypoxia (mice, mg/kg, IP) √ Neuroprotective Conditioned Avoidance (rat, mg/kg, IP) Antipsychotic DOI-Induced Head Twitch Antipsychotic; Tourette’s Hippocampal Kindling Bipolar, Anticonvulsant Formalin test Inflammatory pain Acetylcholine antagonist인 scopolamine을 처리하여 cognition deficit을 유발한 쥐에 YKP3089를 처리한 결과, 10 mg/kg, i.p에서 개체간 차이가 커서 유의하진 않지만 뚜렷한 경향성 (p<0.0665)을 보이면서 memory deficit이 회복됨을 관찰할 수 있었음. 이러한 경향성은, YKP3089가 anti-dementia indication으로 적용가능성이 있음을 시사함. 참고적으로 본 모델은, 대표적인 Alzheimer’s disease의 치료제인 physostigmine (cholinesterase inhibitor)으로 validate됨. Stroke와 Dementia는 Parkinson’s disease와 함께, 대표적인 Neurodegenerative Disease로서, 이들에 YKP3089가 효과를 보이고 있음은, YKP3089가 전반적인 neuroprotection activities를 지닐 가능성이 높음. YKP509의 경우 역시 MCAO와 같은 Stroke model에선 효과를 보이고 있고, 6-OHDA test와 같은 Parkinson model에서 실험이 완료되었으나 결과는 아직 확보되지 않음.

Preclinical ADME/Safety/Toxicity YKP3089 ADME Excellent PK parameters Rat PO Monkey PO Good metabolic stability Moderate plasma protein binding Good Tissue Distribution Safety/Toxicity Good Safety hERG Channel Monkey CV Telemetry Respiratory Gastric Negative Gene Toxicity Typical CNS clinical signs Low teratogenicity potential Biological Screen Flow Chart

Phase Ia and Ib Clinical Trials (USA) YKP3089 Clinical Summary YKP3089 Phase Ia and Ib Clinical Trials (USA) No clinically significant changes in both single and multiple dose study ECG Vital signs Hematology Serum chemistry Urinalysis YKP3089 shows dose-response relation of clinical signs and adverse events Excellent PK Parameters Data suggest once-per-day dosing YKP3089 is well-tolerated Adverse events were mild and CNS related

YKP3089 Single Dose PK

YKP3089 Multiple Dose PK Both Cmax and AUC linearly correlated with dose Steady State occurred by Day 12

YKP3089 Food Effect Study PK

YKP3089 Highlights Efficacy Safety & Toxicity Potential versatile CNS drug: Epilepsy, Anxiety, Neuropathic Pain, Bipolar Disorder, Dementia, Schizophrenia, etc. Broad spectrum: Epilepsy Possible novel mechanism Safety & Toxicity High safety margin Low QTc prolongation potential Low teratogenic potential Phase I Clinical Trials in USA Favorable PK profile Once a day dosing potential Low adverse effects