INNOVATION FOR UNMET MEDICAL NEEDS
About Qurient Co. Ltd. Founded in 2008 Headquarter in Seongnam, Gyeonggi-do, Korea Listed on KOSDAQ market with ticker: 115180 Network R&D company: Virtual R&D with a small pharmacology laboratory Focus on small molecule therapeutics Covers the R&D stages from discovery to clinical pr oof-of-concept Qurient Highlights ü Strategic partnership with top research organizations for sourcing early discovery progra ms (Lead Discovery Center/Max Planck Innovation, Germany and Institut Pasteur Korea) ü Excellence in project management capabilities to facilitate discovery and development thr ough virtual R&D ü Two clinical programs in the U.S., one preclinic and two discovery programs ongoing
Q203 Molecular weight: 557.02
General in vitro profile Q203 Activity (nm) Solubility (µg/ml) Metabolic stability (min) Plasma stability (% after 4h) Plasma protein binding (%) CYP inhibition (IC 50, µm) Mode of Action CYP 3A induction (IC 50, µm) QUM* MIC 80 QIM* MIC 80 Unknown (Novel target) <1 (<0.5ng/ml) <1 (<0.5ng/ml) ph=7.4 0.71 ph=2.1 30.57 Human 121.5 Mouse 166.2 Human Mouse Stable Stable Human 99.9% Mouse 99.8% 3A4 >100 2D6 >100 1A2 >100 2C9 >100 2C19 >100 herg (µm) >30 No * QUM: TB bacteria only assay QIM: TB in human macrophage assay
Activity against MDR/XDR/TDR TB Q203 shows good activity against MDR/XDR/TDR human patient isolates MDR XDR (MIC90 Unit: nm) (MIC90 Unit: nm) Isolate INH RIF SM OFX Q203 04 R R R S 0.43 05 R R S R <0.43 06 R R S R <0.43 07 R R S R <0.43 08 R R S R <0.43 09 R R R S <0.43 10 R R S S <0.43 11 R R S R <0.43 12 R R S R 0.88 13 R R S S <0.43 14 R R S S 0.88 15 R R S R 3.50 16 R R R S <0.43 Isolate INH RIF SM OFX Q203 17 R R R R 0.43 18 R R R R <0.43 19 R R R R <0.43 20 R R R R <0.43 21 R R R R <0.43 22 R R R R <0.43 23 R R R R <0.43 24 R R R R <0.43 25 R R R R <0.43 26 R R R R <0.43 27 R R R R 7.02 28 R R R R <0.43 29 R R R R 7.02 30 R R R R <0.43 31 R R R R 28.01
Activity against TB in the anaerobic culture condition Q203 shows good activity against TB in the anaerobic condition (Wayne s model) MIC 50 against M.tuberculosis H37Rv in aerobic and anaerobic condition (nm)
Activity against other micro-organism Q203 has no activity against other micro-organisms < MIC90 against other micro-organisms> Bacteria MIC90 (um) Acinetobacter baumannii AYE >20 Escherichia coli ATCC25922 >20 Acinetobacter baumannii 107292 >20 Enterobacter aerogenes >20 0705A0867 Klebsiella oxytoca 0705C0187 >20 Salmonella enteritidis 4 >20 Pseudomonas aeruginosa >20 ATCC27853 Vibrio mimicus >20 Bacillus subtilis CIP 5262 >20 Staphylococcus aureus >20 ATCC25923 MR Staphylococcus aureus >20 0706C0025 Enterococcus faecalis ATCC >20 Enterococcus faecium >20 Corynebacterium urealyticum >20 Corynebacterium jeikeium >20 Corynebacterium striatum >20 Candida albicans ATCC66396 >20 Candida glabrata Candida parapsilosis Candida tropicalis Saccharomyces cerevisiae >20 >20 >20 >20!
Activity against Non-tuberculosis mycobacteria Q203 has no activity against other mycobacteria: TB specific
Q203 Mechanism of action study Q203 inhibits ATP synthesis in tuberculosis more potently than TMC207 both in aerobic and hypoxic conditions 150 Aerobic 250 200 Hypoxic RLU (x100) 100 50 Q203 TMC207 RLU (x100) 150 100 50 0-11 -10-9 -8-7 -6-5 Concentration (M) 0 0.5 4 12 Q203 333 0.5 4 12 333 TMC207 ATP IC 50 (nm) ATP IC 50 (nm) Q203 1.12 TMC207 27.7 Q203 7.57 TMC207 82
Q203 against resistant mutant strains Q203 blocks M. tb. cytochrome bc1 complex qcrb (Rv2196): ubiquinol cytochrome C reductase Essential key sub-unit of the cytochrome bc1 complex Required for maintenance of proton gradient and ATP synthesis Substitution of codon Thr 313 to Ile 313 / Ala 313 confers resistance in M. tuberculosis (24/24 resistant mutants)
Q203 MOA < Complexes of Mycobacterial respiratory chain and targets of drugs >!! Q203!!! bedaquiline!
Q203 in vivo efficacy in the chronic mouse model 6-8 week old BALB/c female mice (n = 5/group) Test compound: Q203, INH, Bedaquiline oral gavage Dosing starts on 21st day post-infection (Infection: 10 2 CFU aerosol infection) 4 weeks (5 days/week) of treatment given
In vivo efficacy in the chronic mouse model Q203 Q203 shows significant activity at 0.4mpk and also show good dose response between 0.4~10mpk 0EQD SDDIP AC HLHPQ AQHML + QH DP SDDI 14 8 LF N DDL 5 M NP 8MF 3 9 L 8MF 3 9 L 2 ( D Q DAQ DLQ MLQ M - (. + () + 0EQD SDDIP AC HLHPQ AQHML DGH D L Q DAQ,.+ ) + + ( / + 7 6 MLQ M ) ++ + + (, ) + 91( -, (+ NI ) -) +- + ),, /- + ( ) NI ) -( + (,( + ( ) ( NI,, ). + -. + ( ) NI +. + + + / + Log CFU/ lung 8 7 6 5 4 3 2 1 0 Day-1 EFF12-03(Q203) Lung-4weeks treated Day-21 Untreat-Day49 INH 15 mpk TMC207 6.25mpk Q203 10mpk Q203 2mpk Q203 0.4mpk Log CFU/ spleen EFF12-03(Q203) Spleen-4weeks treated 7 6 5 4 3 2 1 0 Day-21 Untreat-Day49 INH 15 mpk TMC207 6.25mpk Q203 10mpk Q203 2mpk Q203 0.4mpk
In vivo efficacy in the chronic mouse model Q203 shows stable plasma level after 1 week in the 28 day repeat dose PK study At 2mg/kg QD dosing 5 days/week, where Q203 shows ~2 log reduction in lung bacterial load C trough -C max : ~0.5uM - ~1uM
In vivo efficacy in the chronic mouse model Q203 shows good synergy with bedaquiline Groups Lung Spleen Log 10 SEM n Log 10 SEM n Day 21 Pre-treatment 7.70 0.19 5 4.57 0.23 5 After 4 weeks administration (5days/week) Vehicle 6.91 0.18 5 5.29 0.17 5 Q203 2mpk 3.95 1.00 5 3.74 0.23 5 Q203 10mpk 5.23 0.18 5 3.99 0.12 5 Bedaquline 6.25mpk 4.89 0.24 5 1.00 0.63 5 Q203 10mpk/Bedaquline 6.25mpk 2.11 0.52 5 0.00 0.00 5 Q203 10mpk/PLZ 150mpk (8wks)* 1.00 0.1 (?) 5 - - - * Preliminary results: To be confirmed
In vivo efficacy in mouse Q203 Granuloma Untreated (vehicle) x20 INH(15mpk) x20 Q203 (10mpk) x20 Number of granulomatous foci 60 P<0.01 50 40 30 20 10 0 P<0.05 Vehicle Isoniazid Q203 Q203 shows significant reduction of granuloma in lung after 4 weeks treatment
Toxicology Phase I in the U.S. Safety margin secured in the GLP rodent/non-rodent toxicology studies No herg activity nor QTc prolongation in dog Clean on in vitro DDI profile (CYP inhibition, induction, pgp substrate/inhibitor) No Genotoxicity No inhibition of mammalian electron transfer system Oxygen consumption rate in human hepatocyte 1uM 10uM 50uM 100uM
Q203 Phase I Design
Summary Is a novel anti-tuberculosis agent targeting cytochrome bc1 complex of M. tb. Active against MDR/XDR human isolates Maintain potency under anaerobic condition Shows ~3log reduction of TB burden in lung at 10mpk in the mouse established infection model Blocks granuloma formation in mouse lung Non-clinical PK profile supports once a day or less frequent regimen Shows good safety margin in the non-clinical studies Under Phase I development in the U.S. Orphan Drug Designation
Acknowledgement