The Opportunity: Superior treatment of narcolepsy and cataplexy SKL-N05 1
TABLE OF CONTENTS Highlights Clinical Trials Narcolepsy Profile Ancillary Pharmacology Mechanism of Action Preclinical Pharmacology & Safety 2
HIGHLIGHTS Preclinical Efficacy Preclinical Safety Novel mechanism Potential efficacy in Excessive Daytime Sleepiness and Cataplexy Induced wakefulness in narcoleptic mice as well as wild type Decreased REM and DREM, possibly reducing cataplexy as well Sleep onset is increased in a dose-dependent manner without immediate NREM sleep rebound Confirmed as a wakefulness-promoting agent in humans Additional indications: ADHD, Neuropathic pain, Drug dependence Safe and well-tolerated in toxicology studies No genotoxicity or teratogenicity observed Excellent bioavailability with no active metabolites 3 Clinical PI and PIIa clinical trial data available Dose-dependent, linear pharmacokinetics in human Well-tolerated with few adverse events in Phase I & II trials Once-a-day dosing Current Development Status: Phase IIb for Narcolepsy Open IND with US FDA
CLINICAL TRIALS COMPLETED TO DATE Phase Title I Single dose-escalation study in 24 healthy subjects I Multiple dose-escalation study in 50 healthy subjects I Safety study in 120 healthy subjects I AME study in 4 male healthy volunteers I Abuse-liability study in 18 healthy subjects (no PK) II Proof of Principle study in 35 outpatients with Major Depressive Disorder (no PK) II Tolerability study in 77 patients with MDD II Proof of Efficacy study in 490 outpatients with MDD II Safety & Effectiveness in the treatment of Excessive Daytime Sleepiness (Data available under confidentiality) 4
PHARMACOKINETICS : SINGLE DOSE ESCLATAION 5000 Average Human Plasma Levels of SKL N05: 50, 100, 200, 400, 600, 800 1000 & 1200 mg Plasma Conc, ng/ml 4500 4000 3500 3000 2500 2000 1500 1000 500 0 0 1 2 3 4 6 8 12 24 Time, hrs 50 mg 100 mg 200 mg 400 mg 600 mg 800 mg 1000 mg 1200 mg Dose-proportional pharmacokinetics Rapid absorption with t max of 1-2 h Rapid elimination (mean t 1/2 5.0-6.7 h) Low variability (intersubject %CV 20-30%) 5
NARCOLEPSY PROFILE In normal rats, 30mg/kg SKL-N05 induced increased wakefulness and a pattern of recovery of deep sleep similar to that of 1 mg/kg amphetamine Vehicle SKL N05 (mg/kg i.p.) 3 10 30 State amounts (% recording time) 100 Active Wake 80 60 40 20 0 1 2 3 4 5 6 7 8 9 10111213141516 20 15 10 5 0 2 1.5 1 0.5 0 1 2 3 4 5 6 7 8 9 10111213141516 Passive wake 1 2 3 4 5 6 7 8 9 10111213141516 Intermediate stage 70 60 50 40 30 20 10 0 30 20 10 0 1 2 3 4 5 6 7 8 9 10111213141516 90 80 70 60 50 40 25 20 15 10 5 0 1 2 3 4 5 6 7 8 9 10111213141516 Light sleep Deep sleep REM sleep 1 2 3 4 5 6 7 8 9 10111213141516 Time (# hours post administration) 6
NARCOLEPSY PROFILE SKL-N05 increased latency to sleep onset in genetically narcoleptic mice in a dosedependent fashion No abnormal or stereotyped behavior observed Hara et al. (2001) SKL-N05 [mg/kg] 7
NARCOLEPSY PROFILE SKL-N05 strongly suppressed DREM sleep, suggesting a potential beneficial effect on cataplexy (narcoleptic mouse model) In contrast, modafinil did not reduce DREM. SKL-N05 8
NARCOLEPSY PROFILE Narcoleptic mice Wakefulness Non-REM sleep REM DREM SKL-N05 Modafinil No effect No effect SKL-N05 induced wakefulness and suppressed sleep stages whereas modafinil did not Decreased REM and DREM may signal reduced cataplexy as well as EDS (excessive daytime sleepiness) in humans SKL-N05 showed a normalization of the sleep/wake pattern of narcoleptic mice 9
SUMMARY OF NARCOLEPSY PROFILE SKL-N05 has potential competitive advantages over modafinil (Provigil) & sodium oxybate (Xyrem): Efficacy in excessive daytime sleepiness and cataplexy SKL-N05 showed A normalization of sleep/wake pattern of narcoleptic mice Induced potent wakefulness while NREM and REM sleep were suppressed, distinct from modafinil Dose-dependent increase in sleep latency with no immediate NREM sleep rebound Genotype-independent increased wakefulness Increased wakefulness and recovery of deep sleep with a pattern similar to that of amphetamine 10
COMPETITIVENESS SKL-N05 shows potential superiority over Provigil and Xyrem: Provigil has been quite successful in the market; however there are still approximately 50% non-responders and provigil is effective for only excessive daytime sleepiness (not cataplexy) SKL-N05 shows advantages compared to provigil: Increased potency: 50 mg/kg of SKL-N05 is equal to 200 mg/kg of provigil Increased response: SKL-N05 induced wakefulness in narcoleptic and wild type mice, while provigil was not as effective in narcoleptic mice SKL-N05 is expected to have a broad spectrum of response in EDS Cataplexy: Decreased REM and DREM (no DREM decrease with provigil) Xyrem is the only drug approved for Cataplexy, but shows high abuse potential (Schedule I itself, Schedule III only for Narcolepsy) therefore limited in market expansion Low abuse potential: Rats do not self-administer SKL-N05 minimal restrictions expected with potentially larger market 11
ANCILLARY PHARMACOLOGY - ADHD 12 Increased beta/gamma (20-40hz) power may be associated with attentional processes
ANCILLARY PHARMACOLOGY - ADHD SKL-N05 and amphetamine show similar enhanced acquisition of visual discrimination reversal in rats. SKL N05 SKL N05 SKL N05 SKL-N05 p <0.05 from vehicle 13
MECHANISM OF ACTION SKL-N05 appears to work by novel mechanisms Receptor Screening: Not a ligand for DA receptor isoforms Not a ligand for 5-HT receptor isoforms Not a ligand for NE receptor isoforms Weak ligand for DA, not 5-HT, transporter Functional Assays: Weak inhibitor of DA and NE (but not 5-HT) uptake May increase DA release at high concentrations Small increase in DA availability at high doses (microdialysis) 14
PRECLINICAL PHARMACOLOGY SUMMARY Potent activity following oral administration Potent effects in animal models for narcolepsy Minimal effect on motor activity Very high Therapeutic Index compared to bupropion and imipramine No potentiation of barbiturates, ethanol or amphetamine No potential anticholinergic side effects Selective activity in the [D]-enantiomer form Potential for multiple indications: ADHD, neuropathic pain, and drug dependence 15
PRECLINICAL PHARMACOKINETIC SUMMARY Excellent bioavailability in mice, rats and dogs Low plasma protein binding High level of total mass recovery Rapid tissue distribution Efficacy duration exceeds the plasma or tissue level duration No active metabolites 16
PRECLINICAL TOXICITY SUMMARY Safe and well-tolerated Behavioral and physiological signs noted at high doses No permanent target organ changes Minimal cardiovascular effects Negative in genotoxicity assays (Ames, chromosome aberration, and in vivo micronucleus) No teratogenicity 17
PHARMACOKINETICS : MULTIPLE DOSE ESCALATION Dose-proportional Steady-state by Day 3 Acc. Ratio 1.43 t max 1-2 h t 1/2 (Day 14) 6-8 h 18 Plasma Conc, ng/ml 2500 2000 1500 1000 500 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Time, hrs Mean 100 D14 Mean 200 D14 Mean 300 D14 Mean 400 D14 Mean 500 D14
SKL-N05 SUMMARY Good market opportunity as a Narcolepsy treatment Potential competitor for Provigil (Sales > $700M) Still many modafinil non-responders (~ 50%) SKL-N05 differentiated MOA compared to modafinil Unscheduled drug low abuse potential Provigil (Schedule IV drug), Xyrem (Schedule III drug) Orphan Drug Designation (US FDA) SKL-N05 is a potential drug candidate for Narcolepsy Excessive Daytime Sleepiness Cataplexy Safe and well-tolerated profile in animal toxicology studies and in human subjects SKL-N05 confirmed low abuse potential in self-administration studies Excellent bioavailability and no active metabolites Phase II for Narcolepsy: Open IND with US FDA Looking for a Partner for Development in Asia 19
IF YOU HAVE QUESTIONS, WE HAVE ANSWERS Duncan Taylor, PhD. dtaylor@sklsi.com 201-421-3842