1. Oxazolidinone Analogues Novel Antibiotic Small Molecule Prepared on July 2010 Please contact LCB for more recent updated version 1
2. Executive Summary Summary Background Competition Development In Vitro In vivo Patents Company SUMMARY Opportunity Type: Small Molecule Therapeutic Area : Infectious disease, Antibacterials Target : Gram+ (MRSA, VRE, S. pneumoniae) Stage : Pre-clinical Latest Data : Pre-clinical Objective : License-out / Co-development 2 Novel oxazolidinone analogues were developed and they showed substantiallyimproved potency and safety features thanLinezolid. LCB01-0371 possesses overalladvanced potency, safety, and PK/PD data in vitroand in various in vivo and ex vivo experiments.
3. What is LCB01-0371? A novel oxazolidinoneanalogue. Potency in vitro: Superior to Linezolid against MRSA, VRE, and H. Influenzae. in vivo: 1.5~5 times superior to Linezolid. In vitro ADME/T Good metabolic profile, low drug-drug interaction, and high plasma stability. Safety Myelosuppression : Comparable or less bone marrow toxicity than Linezolid. MAO inhibition : Significantly better than Linezolid. NOAEL : 10~20 mpk (4 weeks, Dog) hERG assay & Ames test : Proved to be safe Solubility Freely soluble in salt form (>25%, Linezolid: 0.3 % in water) Summary Background Competition Development In Vitro In vivo Patents Company SUMMARY 3
4. 2004 IDSA Report Most important resistant bacterial pathogens Summary Background Competition Development In Vitro In vivo Patents Company BACKGROUND Current treatment Current treatment Gram-negative Gram-positive Vancomycin,Linezolid, Daptomycin, Pristinamycin MRSA MDR-GNB Cephalosporins, Carbapenems, Aminoglycosides, Tigecycline P. aeruginosa, Acinetobacter, ESBL-producing Enterobacteriaceae Linezolid, Daptomycin VRE *IDSA : The Infectious Diseases Society of America Datamonitor commercial insight antibacterials 12/2006 4
5. Unmet Needs in Antibiotics 1. Most compounds currently in development are derivatives of existing drugs with low potential to overcome resistance in the mid to long term. 2. All currently available drugs and late-stage candidates for MRSA treatment are injectables. With MRSA incidence rising in the community, oral drugs have a large commercial potential. 3. Carbapenemsand tigecycline are the only available treatment options for severe gram-negative infections. Upon emergence of resistances, novel drugs are a crucial need. Summary Background Competition Development In Vitro In vivo Patents Company 1. Compounds outside previous drug classes BACKGROUND Unmet needs 3. Gram- negative resistance 2. Oral MRSA drugs 5
6. HA-MRSA and CA-MRSA Hospital-associated infection The burden of invasive (bloodstream) MRSA disease in the U.S. was evaluated using population-based, active case finding (at 9 sites) for the first time. The authors estimated there were 94,360 invasive MRSA infections in the U.S. in 2005 with 18,650 of them ending in death. Kievens, R. M. et al. JAMA 2007, 298, 1763-1771 Community-associated infections MRSA was the most common cause of kin and soft-tissue infections in patients presented to emergency department in 11 U.S. cities studies. Incidence of MRSA infections in patients at 33 U.S. children’s hospitals increased ~300% from 2002 to 2007 while incidence of MSSA was stable Gerber, J. S. et al. Clin Infect Dis 2009, 49, 65-71 Summary Background Competition Development In Vitro In vivo Patents Company BACKGROUND 6
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8. Indications include adult treatment of HAP (MRSA), CAP (S. pneumoniae), complicated and uncomplicated skin infections (MRSA), and VRE infections
9. Oral and IV formulations enable smooth transition from hospital to home treatment MRSA drugs are a main source of overall antibacterial market growth 7
10. ZyvoxTM - From nichebuster to blockbuster 2012-2015 CAGR: -14.7% Sales decline following 7MM patent expiry (US: 2013). 2002-2007 CAGR: 43.8% Strong growth after launch in 2000 due to increasing incidence of MRSA and lack of competitors. 2007-2012 CAGR: 9.8% Growth rate diminishes as a consequence of emerging resistances and several competitors entering the market from 2007 onwards. 30 2,000 1,800 25 1,600 1,400 20 Sales 1,200 Volume use Sales (US$m) 15 1,000 Volume use (SU m) 800 10 600 400 5 200 0 0 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Summary Background Competition Development In Vitro In vivo Patents Company BACKGROUND 8
11. ZyvoxTM - Adverse Event Reports I All cases (305) Platelet Count Decreased (44), Thrombocytopenia (31), Death (26), Anaemia (23), Multi-Organ Failure (14), Pyrexia (13), Sepsis (13), Vomiting (11), Convulsion (11), Respiratory Failure (10) Cases resulting in a serious event (296) Platelet Count Decreased (42), Thrombocytopenia (30), Death (26), Anaemia (23), Multi-Organ Failure (14), Pyrexia (13), Sepsis (13), Vomiting (11), Convulsion (11), Respiratory Failure (10) Cases resulting in death (103) Platelet Count Decreased (29), Multi-Organ Failure (13), Sepsis (12), Thrombocytopenia (12), Respiratory Failure (10), Pneumonia (8), Septic Shock (7), Renal Failure Acute (6), Disseminated Intravascular Coagulation (5) Summary Background Competition Development In Vitro In vivo Patents Company BACKGROUND 9
12. ZyvoxTM - Adverse Event Reports II In one case, Linezolid was successfully restarted at a reduced dose after resolution of myelotoxicity. Thrombocytopenia (platelets less than 100,000/mm3) has been reported in 32% of patients (n=19) receiving Linezolid for more than 10 days. In another study (n=295), thrombocytopenia (platelets less than150 x 10(9)/L) occurred in 6.4% of patients and severe thrombocytopenia (platelets less than 50 x 10(9)/L) occurred in 0.3% receiving Linezolid for more than 5 days. It has been suggested that the mechanism of Linezolid-associated thrombocytopenia is immune-mediated. Summary Background Competition Development In Vitro In vivo Patents Company BACKGROUND 10
13. Linezolid : First-in-class Oxazolidinone I Effectiveness and safety in the treatment of G-positive bacteria infection (9studies with a total 2498 patients) Treatment success : No difference was observed between Lzd and Vancomycin Linezolid was more effective than Vancomycin in skin and soft-tissue infections No difference in treatment success for patients with bacterimia or pneumonia MRSA-cSSTI (Complicatedskin and soft-tissue infection) (5studies with a total 2652 patients (Linezolid : 1361, Vancomycin : 1291)) Microbiologicaleradication : favored the use of Linezolid over vancomycin. Mortality : No difference was observed Higher proportions of Linezolid Side-effect Diarrhea(119/1361 vs. 52/1291), nausea (102/1361 vs. 46/1291), thrombocytopenia (54/1121 vs. 8/1071) Higher proportions of Vancomycin Side-effect : Renal insufficiency(16/634 vs. 4/703) Summary Background Competition Development In Vitro In vivo Patents Company BACKGROUND 11
14. Linezolid : First-in-class Oxazolidinone II Linezolid is as effective as vancomycin in patients with gram-positive infection Linezolid is more likely to consistently achieve microbiologic eradication in MRSA Apparent risks of thrombocytopenia, nausea, diarrhea, and possibly anemia may limit Linezolid use in treating MRSA cSSTI Summary Background Competition Development In Vitro In vivo Patents Company BACKGROUND 12
15. Linezolid : First-in-class Oxazolidinone III First member of a new class of antibacterial agents to be approved (2000) in over 35 years FDA Approved Indications Vancomycin-resistant Enterococcusfaecium infections, * including cases with concurrent bacteremia Nosocomial pneumonia caused by: Staphylococcus aureus (MSSA & MRSA*) Streptococcus pneumoniae(penicillin-susceptible & MDRSP) Complicated skin and skin-structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by: Staphylococcus aureus (MSSA & MRSA*) Streptococcus pyogenes Streptococcus agalactiae Uncomplicated skin and skin-structure infections Community-acquired pneumonia Summary Background Competition Development In Vitro In vivo Patents Company BACKGROUND * Only oral medicine approved by FDA for treatment of infections due to these organisms 13
16. Linezolid : Mechanism of Action Summary Background Competition Development In Vitro In vivo Patents Company Inhibition of Mitochondrial Protein Synthesis BACKGROUND Leach et al. Molecular Cell 2007, 26, 393-402 14
17. Clinical Stage: TOREZOLIDTM Summary Background Competition Development In Vitro In vivo Patents Company Trius Therapeutics Licensed from Dong-A pharmaceutical in Korea Trial data and PK/PD support 200mg QD as lowest effective dose for selection in Phase III pivotal cSSSI studies COMPETITION 15
18. Clinical Stage: RADEZOLIDTM Summary Background Competition Development In Vitro In vivo Patents Company Radezolid is significantly more potent than LZD against S. pneumoniae, the enterococci, and respiratory tract pathogens (including H. influenzae) Radezolid is comparable or better than LZD in animal infection models Radezolid was well tolerated in Phase I studies Phase II trial of Radezolid in CAP recently concluded RDZ at 300mg QD was comparable to 450mg QD or BID (Rib-X press release, Aug 4, 2009) COMPETITION 16
19. Clinical Stage: PNU-100480 Summary Background Competition Development In Vitro In vivo Patents Company PNU-100480 is Pfizer’s early oxazolidione with efficacy superior to LZD in murine TB models Despite similar MICs, LZD is static while PNU-100480 is cidal at human-equivalent doses Sulfoxide metabolite comprises 84% of the composite AUC (in mice) In mice, PNU-100480 conferred an additional 2-log reduction in lung CFU counts when added to RIF-INH-PZA Phase I trial to assess safety, tolerability, and PK began in May 2009 COMPETITION 17
20. Pre-Clinical Stage Candidates Novel ‘reverse amide’ C-5 side chain analog Excellent PK profile in rats and dogs. Reduced potential for MAO-A inhibition (Ki=546uM vs. 56uM for Linezolid) NOAEL of 200mg/kg/day in 2 week rat study Vicuron-Pfizer collaboration Summary Background Competition Development In Vitro In vivo Patents Company COMPETITION 18
22. Next-Generation Opportunities Improved potency to enable lower dose; Once-daily dosing Better water solubility to reduce volume for IV administration Expanded spectrum to encompass more indications E.g. coverage of H. influenzae& M. catarrhalis Coverage of Linezolid-resistant organisms Reduced or eliminate reversible myelosuppressive effects For use in the community and for longer-term therapy (e.g., osteomyelitis, etc.) Need a better understanding of binding vs. mitichondrialribosomes Improved MAOi profile desirable for broad community use 20 Summary Background Competition Development In Vitro In vivo Patents Company COMPETITION
23. Novel Scaffold Summary Background Competition Development In Vitro In vivo Patents Company DEVELOPMENT 21
24. Chemical properties Among oxazolidinone analogs, LCB01-0371 has the lowest Molecular Weight of (C14H17FN4O3) 308.3 (Linezolid : 337) Chemical Stability (stressed condition) : Stable up to 3 months in 60℃, 75% humidity condition (>98% remaining) Aqueous Solubility : HCl salt form is freely soluble in water Hygroscopicity of LCB01-0371 : Weight change was < 0.3% for a week pKa estimation of LCB01-0371-HCl salt : Estimated pKa ~ 4.3 (Calculated value : pKa = 5.0). Acetic acid: pKa = 4.76 Synthesis : 7 steps overall yield was 39% (without column chromatography) Summary Background Competition Development In Vitro In vivo Patents Company DEVELOPMENT 22
25. Synthetic Scheme Process Summary Background Competition Development In Vitro In vivo Patents Company DEVELOPMENT 23
26. In vitro ADME-T and PK profiles Summary Background Competition Development In Vitro In vivo Patents Company Mouse PPB is relatively higher than human PPB IN VITRO Clinical efficacy will be improved than mouse model efficacy 24
27. MICs of Clinical Isolates l Summary Background Competition Development In Vitro In vivo Patents Company IN VITRO 25
28. Pharmacokinetic Profiles Summary Background Competition Development In Vitro In vivo Patents Company 26 LCB01-0371 LCB01-0371 LCB01-0371 Linezolid Linezolid (mg*h/L) (mg*h/L) (mg/L) (kg/L) (h) IN VIVO (h) (%)
29. In vivo : 1. Systemic Infection Model in Mice Summary Background Competition Development In Vitro In vivo Patents Company 27 2 1 (2.69~7.22) (4.93~10.1) (PO) (PO) 0 (PO) IN VIVO LCB01-0371 showed 1.5~4 times more potent than Linezolid E. faecalis : similar MIC but more potent in in vivo S. pneumoniae : 2 times more potent in MIC but 4 times more potent in in vivo Considering PPB, efficacy could be more improved in clinical study than in mouse study
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31. Oral treatment(once) and then CFU counted after 1 daySummary Background Competition Development In Vitro In vivo Patents Company IN VIVO LCB01-0371 showed 3 times (25 mpk) ~ 20 times (50 mpk) reduction in CFU thanLinezolid 28
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33. Treatment : PO, 4 times (1 hr, 4 hr, 24 hr, 48 hr)Summary Background Competition Development In Vitro In vivo Patents Company IN VIVO 29
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35. Treatment : PO, 3 times (1 hr, 4 hr, 24 hr)Summary Background Competition Development In Vitro In vivo Patents Company Linezolid(12.5 mpk) Linezolid(25 mpk) LCB01-0371 (12.5 mpk, 25 mpk) Treatment: 1, 4, 24 hr post infection IN VIVO LCB01-0371 showed significant reduction in CFU thanLinezolid 30
42. % reticulocyte was determined.Summary Background Competition Development In Vitro In vivo Patents Company IN VIVO Linezolid(bid) TR-701 (qd) LCB01-0371 (bid) 32
43. Toxicology: 3. Rats (14-day) No toxic sign was seen in 2 weeks repeated dose. Compared to linezolid, 0371 showed reduced myelosuppression as measured by reticulocytecounts. Summary Background Competition Development In Vitro In vivo Patents Company 100mpk 200mpk 100mpk 200mpk vehicle Linezolid LCB01-0371 IN VIVO 100mpk 200mpk 100mpk 200mpk vehicle Linezolid LCB01-0371 33
44. Toxicology: 4. TK in Rats (7-day) Summary Background Competition Development In Vitro In vivo Patents Company IN VIVO Dose dependency without accumulation was observed 34
45. Toxicology: 5. TK in Dogs (4-weeks) Summary Background Competition Development In Vitro In vivo Patents Company Lower AUC higher Cmax thanLinezolid (lower NOAEL) No accumulation was observed IN VIVO 35
46. Pre-clinical Study Summary MTD in Rat : 2000 mpk Two-weeks DRF in Rats : MTD 100 mpk Four-weeks repeated dose toxicity in Dogs Male : NOAEL 20 mpk Female : NOAEL 10 mpk Four-weeks repeated dose toxicity in Rats : will be completed in July 2010 (GLP) NOAEL (Non-GLP) : 50 mpk (male, female) hERG binding assay : low inhibition at 0.1~100 uM Ames test : Negative Summary Background Competition Development In Vitro In vivo Patents Company IN VIVO 36
48. In Progress and Future Plan Pre-clinical study 4-weeks repeated dose toxicity in dogs : Completed in March 2010 and waiting for the report 4-weeks repeated dose toxicity in rats : started in June 2010 Safety pharmacology : will be finished in August 2010 IND filing and preparing Phase I Back-up program Discovering more potent and more safe candidates Application to MDR-TB In vivo study with lead compounds Summary Background Competition Development In Vitro In vivo Patents Company IN VIVO 38
50. Claimed Chemical Structures Each independent claim is followed by dependent Markushclaim. Summary Background Competition Development In Vitro In vivo Patents Company PATENTS 40
51. Company Profile Summary Background Competition Development In Vitro In vivo Patents Company Established in May 2006 (DaedukScience Town, Daejeon, Korea). Raised 10 million US$ since inception. Retains 20+ novel scaffolds thus called “Lego blocks” and able to design novel drugs. Has built sustainable pipelines in the therapeutic areas of antibiotics, anticoagulants, oncology. Experienced and seasoned executive and scientific management team mostly from LG Life Science. COMPANY 41
52. Contact COMPANY: LegoChem Biosciences, Inc. Daejeon Bio Venture Town 461-8 Jeonmin-dong, Yuseong-gu Daejeon, 305-811, South Korea http://www.legochembio.com/ CONTACT: Sung-Ho Woo, Ph.D. Biology Director & Senior VP [Tel] +82-42-861-0688 [Fax] +82-42-861-0689 E-mail: sungwoo@legochembio.com Request for More Materials ONE PAGE: One page snapshot of proposal. 5MIN VIDEO: Easy to view & understand video proposal. COMPANY DOC: A comprehensive overview of company information in written format. COMPANY PPT: A comprehensive overview of company information in presentation format. 42 Summary Background Competition Development In Vitro In vivo Patents Company COMPANY
Notas del editor
In summary,Our candidate is Superior-to-Linezolid against MRSA, VRE, and H. Influenzae, in In vitro and in vivo. Additionally,safety profile was significantly improved than Linezolid.
The infectious Diseases Society of America proposed solutions in its 2004 policy report, “ Bad bugs no drugs : as antibiotic R&D stagnates, a public health crisis brews”The infectious Diseases Society of America identified a “hit list” of important pathogens based on two criteria :1. 1 current public health concern due to a high incidence of infection, substantial morbidity, high mortality, unique virvulence or resistance factors, or a combination of two or more of these characteristics.Second, few or no new antimicrobial candidate in the late-stage development pipeline The most important resistant pathogens are MRSA, VRE, PA, A. Baumannii, KP, E species. Treatment option in MRSA and VRE are Linezolid and daptomycin and in GNB sone beta lactam class antibioticsActually MRSA is the most important superbug so its drug is highly important and several pipeline is in clinical development. But in GNB pathogens, there’s no drug at all until now
Most compounds currently in development are derivatives of existing drugs with low potential to overcome resistances in the mid- to long term.All currently available drugs and late-stage candidates for MRSA treatment are injectables. With MRSA incidence rising in the community, oral drugs have a large commercial potential.Carbapenems and tigecycline are the only available treatment options for severe gram-negative infections. Upon emergence of resistances, novel drugs are a crucial need.
There are two kind of MRSA infections. The one is hospital associated and the other is community associated. Actually hospital associated infection is more important and 100,000 patients are infected and the motality is about 20%. Now it’s number of patients are more than AIDS infection patients.Until now, community associated infection is not so popular but the rate is highly increaed. So in the near future it will be serious problem in worldwide.
The adult dose of Linezolid is 600mg twice daily orally or intravenously for a maximum of 14 days.Thrombocytopenia is uncommon in patients who receive Linezolid for 14 days or less (the manufacturer's recommendation), but in patients who receive longer courses, or who have renal failure, the rate is much higher
mechanism of action of Linezolid is Inhibition of Mitochondrial Protein Synthesis .It is binding with 50S subunit of ribosome specially peptidyltransferase center. So protein synthesis was inhibited.Until 2007, it was unclear how to act the Linezolid. But now most of mechanism and some resistance mechanism were solved by X-ray crystallography.
Currently, only 3 oxazolidinones are in clinic stage. And the only one, torezolid is for MRSA target.This compound was developed by Dong-A pharmaceutical in Korea, but now they licence out to Triuspharmacetical. Torezolid is prodrug of TR-700.This compound showed good potency. Owing to it’s great potency, it can be once-a-day dosing is possible and reducing dose to 200 mg and shortened the treating days to only 5~7 day therapy. (usually Linezolid takes 2 weeks therapy) . According to shortened dosing quantity and period, it could be overcome the toxicity problems.
Pharmacia &Upjohn (now part of Pfizer) started its own oxazolidinone research program in the 1990. and most of big pharma has their own antibiotics program and lots compounds were tested in clinical stage but Until now only a few candidates have progressed beyond phase 1.These candidates were all discontinued now.
As mentioned before, The only oral MRSA drug is Linezolid, so next generation is urgently needed.The next generation drugs have to solve these problems.The first, improved potency. Linezolid is BID dosing, twice-a-day dosing is needed for it’s low potency, so next generation drug need high potency to enough to once-a-day dosing.The next is solubility, Linezolid is slightly soluble in water about 5 mg/mL, so only IV infusion is possible. If solubility is increased, it has some adventages.The next is expended spectrum. Linezolid acts only in gram-positive pathogen. If some gram negative pathogens such as H. influenzae & M. catarrhalis can be treated, it can be used much more indications. Actually it is very important in next generation drug.The next is covering Linezolid-resistant pathogens. But until now Linezolid resistance is not so serious and only a rare case were reported.The next is, myelosuppressive effects. It’s Bone marrow suppression, characterized particularly by thrombocytopenia (low platelet count ), It’s the most important toxicity in Linezolid. If we reduce the toxicity it can be used in the community.The last point MAO-I. Linezolid is a weak monoamine oxidase inhibitor (MAOI), and should not be used concomitantly with other MAOIs, large amounts of tyramine-rich foods (such as pork, aged cheeses, alcoholic beverages, or smoked and pickled foods), or serotonergic drugs. So it’s use in community is very limited.All these properties have to improved, so it’s really difficult to find a good next generation agent.
The last one is our company compound. It’s the only compound in pre-clinic stage except Pfizer compounds as promising candidate.We presented this at ICAAC meeting last year.Our initial lead was LCB01-0062, it showed great potency but showed bad PK profile and MAO-I profiles.So we cyclized the amidoxime to increase bioavailability.And this cyclic amidrazone moiety retain proper basicity, so it can make a salt and freely soluble in water.So we chose the LCB01-371 as preclinical candidate and it is currently under preclinical evaluations.
We improved synthetic scheme like this for process. In this scheme, only 7 steps and No column chromatography is needed and reasonable yields.
ADMET profiles are like this.The LCB-0371 showed comparable ADMET profiles with Linezolid. It showed no cytotoxicity, low protein binding, good metabolic stability, and improved MAO inhibition profiles.Plasma protein binding of LCB-0371 is relatively higher in mouse than human, so we expect the clinical efficacy will be improved than in mouse model efficacy.
The LCB-0371 showed comparable AUC and bioavailability.
The in vivo efficacies are tested four kind of animal model with mice.First animal model is systemic infection model.In systemic infection model, the LCB01-0371 showed 1.5~4 times more potent than Linezolid.Interestingly, it showed similarMIC but more potent in in vivo efficacy against E. faecalisand 2 times more potent in MIC but 4 times more potent inin vivo efficacy against S. pneumoniae.
LCB01-0371 was tested in another animal model, soft tissue infection model using air pouch.In this model, colony forming unit (CFU) was recorded after treatment with oral gavage.After 1 day, LCB01-0371 showed 3 times (25 mpk) ~ 20 times (50 mpk) reduction in CFU than Linezolid.
The 3rd animal model is lung infection model.After infection, treated 4 times oral gavage and recorded survival rates.LCB01-0371 showed higher survival rates than Linezolid.
The last animal model is thigh infection model.After infection, treated 3 times oral gavage and recorded the CFU.After 2 day, LCB01-0371 showed significantly reduced in CFU than Linezolid at all doses.
In Linezolid, one of the most serious side effect is bone marrow tox (thrombocytopenia). To evaluate the bone marrow tox, reduction % of reticulocyte was counted.In mice, LCB01-0371 showed less reduction % of reticulocyte, which means more safe than Linezolid and TR-701(Torezolid) compounds.
In rats, LCB01-0371 showed less reduction of reticulocytes than Linezolid and TR compound for 7 day study.
In TK study, 371 showed dose dependency and no accumulation.
Pre-clinical study of 4 weeks repeated tox in dogs, LCB01-0371 showed no accumulations.
Pre-clinical study is in progress at MPI (MI, USA) and will be finished within 1 month.
The LCB-0371 showed comparable AUC and bioavailability.
