The Opportunity: Parkinson s disease, RLS, ADHD, and disease modification YKP10461 1
TABLE OF CONTENTS Profile Summary Mechanism of Action Clinical Study Results Pharmacologic Profile Safety and Toxicity Summary ADME Summary Current Status 2
PROFILE SUMMARY YKP10461 has excellent potential for the treatment of Parkinson s disease with likely extension to RLS, possibly ADHD, and potential to modify disease progression Category Differentiated Profile Evidence Superior efficacy potential Clear motor symptom improvement predicted Potential benefit for dyskinesia, RLS, ADHD Potential to modify disease progression - Strong anti-pd effect in mouse at 0.1 po and monkey at 1po - Potent and selective MAO-B inhibition - Dyskinesia delay effect in rodent - Potential to reduce levodopa dosing in PD, RLS - Effective in monkey neuroprotection model - Multipath Neuroprotection MoA - Functional neurorestoration effect Superior safety No serious toxicities observed - No blood pressure change in animal testing - 28-day toxicity study result - Genotoxicity and CNS & lung toxicity clean Commercial opportunity Long patent life - Patent applications in 2009 & 2010 Simple CMC - 3 step synthesis 3
MECHANISM OF ACTION: Antiparkinsonian Effects Very potent, selective, and reversible MAO B inhibition In vitro inhibition: human MAO-A/B enzyme Compound YKP10461 Rasagiline MAO B (IC 50 ) MAO A (IC 50 ) 0.056nM 1.4% @10μM 24nM (14nM*) 710nM** Selectivity >100,000 (50) * Literature data, human brain resources ** Literature data, rat brain resources Reversibility test : MAO-B enzymatic activities were fully recovered in YKP10461 group after wash-out, but not in the rasagiline-treated group 100 100.0 MAO-B Inhibition % 80 60 40 20 SKL-PD IC50 curve SKL-PD wash out 80.0 60.0 40.0 20.0 Rasagiline IC50 curve Rasagiline wash out 0-13 -11-9 -7-5 Concentration(log scale) 0.0-13 -11-9 -7-5 Concentration(log scale)
CLINICAL STUDY: PHASE 1a Oral YKP10461 formulation delivers dose-responsive linear C MAX and AUC Mean YKP10461 Plasma Concentrations (N = 7 per Dose Group) 5
EFFECT OF MAO B INHIBITORS ON MAO B ACTIVITY MAO B activities are elevated in PD compared to controls; Treatment with selegiline decreases these 2500 2000 MAO B activity (pmol/10 7 platelets/30 min) * * p < 0.05 vs Control; p < 0.05 vs PD alone 1500 1000 500 0 control PD PD + selegiline Adapted from Zhou et al. J Neurol Neurosurg Psychiat; 2001 6
EFFECT OF MAO B INHIBITORS ON PHENYLETHYLAMINE (PEA) LEVELS PEA levels are decreased in PD; selegiline increases these PEA (pg/ml) 2500 2000 * * p < 0.05 vs Control 1500 1000 500 * 0 control PD PD + selegiline Adapted from Zhou et al. J Neurol Neurosurg Psychiat; 2001 7
OVERALL BIOMARKER SUMMARY YKP10461 is a selective MAO B inhibitor in humans and no MAO A inhibition is expected In subjects administered YKP10461: MAO B levels were depressed at all dose levels compared to placebo Phenethylamine levels were elevated at all dose levels compared to placebo Dihydroxyphenylglycol levels were unchanged 8
YKP10461 IN ANIMAL MODELS OF PARKINSON S DISEASE YKP10461 potentiates the effect of L-DOPA to elevate striatal DA levels YKP10461 potentiates the effect of L-DOPA to increase rotational behavior MPTP-lesioned mouse 6-OHDA-lesioned rat YKP10811 YKP YKP
POTENTIAL BENEFIT IN L-DOPA-INDUCED DYSKINESIA YKP10461 delayed the development of dyskinesia in rats treated chronically with L-DOPA Dyskinetic behaviors in L-dopa-induced dyskinesia rat ALO: axial, forelimb, orolingual AIMS AIMS: Abnormal involuntary movements ALO AIMs change from Day 1 25 20 15 10 5 0-5 Vehicle+L-dopa SKL-PD+L-dopa YKP10811 + L-DOPA 1 5 8 11 14 19 DAY *, P< 0.05 vs Day 1 :friedman ANOVA followed by Dumm's test #, P<0.05, (YKP10461 vs Vehicle) Mann Whitney test SKL-PD YKP (10mg/kg, po) and L-dopa (12 mg/kg,ip) * # Locomotor AIMs change from Day 1 25 20 15 10 5 0-5 -10 Vehicle+L-dopa YKP10811 SKL-PD+L-dopa + L-DOPA 1 5 8 11 14 19 DAY
YKP10461: SAFETY Tyramine-induced hypertension test (in rat) SKL PD has no significant change at 80 po Rasagiline and selegiline show elevated blood pressure at 80 po 60 YKP10461 has no cheese effect: no blood pressure change with tyramine % change in MAP 50 40 30 20 10 Rasagiline (80po) Selegiline (80po) YKP10811 (80po) Tyramine (40po) 0-10 -50-28 -22-16 -10-4 2 8 14 20 26 32 38 44 50 56 70 100 Compound Tyramine Time (min)
YKP10461: POTENTIAL FOR DISEASE MODIFICATION 1. Chronic Administration of MPTP to Monkeys Produces Parkinsonian Symptoms Initiate Administration of SKL PD Day 56
YKP10461: POTENTIAL FOR DISEASE MODIFICATION SKL-PD showed to retard disease progression very efficiently in Monkey 2. Monkeys Treated with YKP10811 after MPTP Exhibit Significant Symptom Improvement SKL-PD showed the activity-increase gradually from the treatment day 28 activity: significantly higher than the vehicle SKL-PD significantly reduced parkinsonian disability compared to the vehicle group The effects of SKL PD on PD disability score MPTP (0.2 mg/kg, iv)+vehicle MPTP + SKL-PD (1 mg/kg, po) MPTP + Rasagiline (1 mg/kg, po) Day of Worst Score Day of Last Score
YKP10461: POTENTIAL FOR DISEASE MODIFICATION Monkeys Treated with SKL-PD after MPTP Appear to Have Preserved Function 2 1.5 DAT Binding 1 Vehicle SKL-PD Rasagiline 0.5 0 Caudal Caudate DAT: Dopamine Transporter Caudal DM Putamen
YKP10461: POTENTIAL FOR DISEASE MODIFICATION YKP10461 has neuroprotective effects in MAO B -/- Cells Inhibits Apoptosis: elevates Extracellular signal-related Kinases (ERKs) and anti-apoptotic proteins (Bcl-2, Bcl-xL) Induces Neurotrophic Factors: Nerve Growth Factor, Brain Derived Neurotrophic Factor, Glial-Derived Neurotrophic Factor Activates Antioxidant Enzymes: Glutathione Peroxidase, Catalase decreased Reactive Oxygen Species Elevates Mitochondrial Membrane Potential Decreases Cytochrome C release, Caspase 3 activity, and nuclear translocation of GAPDH
YKP10461: POTENTIAL FOR DISEASE MODIFICATION Progression of PD Toxins (MPP + ) YKP10461 Normal condition Neurodegeneration Cell loss & Breakage of dendrites and circuits Functional restoration Reorganization of dendrites & circuits Synaptic Plasticity Number of Neurites Number of Spines P< 0.001 vs Ctrl * P<0.001 vs MPTP
YKP10461: PHARMACOLOGY SUMMARY Reduction of Motor Complication Anti-PD MPTP model 6-OHDA model & L-DOPA sparing test Showed a positive effect at 1 & 10 mg/kg po (monkey) MED(acute) < 0.1 po, MED(chronic) < 0.01 po (mouse) Significant efficacy at 5 mg/kg po in 6-OHDA (rat) Longer & higher effect at 0.01 mg/kg po (mouse) Antidyskinesia L-DOPA induced dyskinesia model Delayed development of dyskinesia at 10 mg/kg po (rat) MOA Multifunctional mechanism of neuroprotection Disease Modifying Treatment Neuroprotectio n In vitro In vivo Showed positive effects after serum starvation, MPP+ and 6-OHDA induced toxicity Effective at 5 mg/kg ip in malonate-treated mouse and kainic acid rat model Effective at 1 mg/kg po in MPTP-lesioned monkey & mouse model Neurorestoratio n Neurite outgrowth Increased number and length of neurites Spinogenesis Increased number of spines Ancillary Ancillary Cognition, Anti-pain Potential additional commercial benefits You can see detailed data under CDA
YKP10461: SAFETY AND TOXICITY SUMMARY No CV risk No significant effect in herg channel inhibition No QT C prolongation in Monkey No change blood pressure up to 80 mg/kg after tyramine challenge Safety No CNS toxicity No Lung toxicity No Genotoxicity No toxic signs in rat FOB study up to 500mg/kg No toxic signs in pulmonary study up to 250mg/kg Bacterial reverse mutation assay Mouse Lymphoma assay Micronucleus assay Toxicity Mouse (acute toxicity) Rat (28 day oral toxicity) Monkey (28 day oral toxicity) Monkey (28 day i.v. toxicity) Showed excellent oral safety in all test species Confirmed no accumulation in 28 days No toxic sign up to 10mg/kg, during 28-day repeated i.v. injection 18
YKP10461: DMPK SUMMARY YKP10461 has druggable ADME profiles PK profile Once a day dosing expected Metabolic stability Highly stable in microsomal & hepatic metabolism ADME Brain penetration Good brain penetration ability Drug-Drug interaction Low risk based on CYP 450 testing 19
YKP10461: STATUS IND was authorized by US FDA in 1Q 2011 Clinical Phase Ia study completed Patent status Filed the Composition of Matter patent application in 2009 Filed the Method of Use patent application in 2010
YKP10461: STATUS Monoamine systems have been implicated in the pathophysiology of ADHD Many ADHD treatments show effects on monoamine levels in the synaptic cleft including binding to dopamine and/or norepinephrine transporters as well as the inhibition of the reuptake and metabolism of these neurotransmitters YKP10461 may be helpful in treating the ADHD symptoms: preclinical evidence Strong MAO-B inhibitory effects in the mouse brain Cognitive enhancing activities in a model of cognitive deficits in rats Effect of YKP10461 on MK-801 induced memory deficit in rats The number of errors in radial arm maze on day 9 400 8 # latency time (sec) 300 200 100 # ** number of errors 6 4 2 0 control MK-801 alone YKP10461 0 control MK-801 YKP10461
IF YOU HAVE QUESTIONS, WE HAVE ANSWERS Duncan Taylor, PhD. dtaylor@sklsi.com 201-421-3842 22