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Project ppt antibiotic

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  • 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.
  • Currently we are preparing the Phase 1 study.
  • Transcript

    • 1. Cephalosporins& Oxazolidinones
      Novel Antibiotic Small Molecules
      Prepared on April 2011
      Please contact LCB for
      more recent updated version
      1
    • 2. 2
      Cephalosporin Program
    • 3. 3
      K.pneumoniae
    • 4. 4
      K. pneumoniae(4 ug/ml Tazobactam)
    • 5. 5
      E. coli
    • 6. 6
      E. coli (+ 4 ug/ml Tazobactam)
    • 7. 7
      E. cloacae
    • 8. 8
      E. cloacae (+ 4 ug/ml Tazobactam)
    • 9. 9
      P. aeruginosa CXA-S
    • 10. 10
      P. aeruginosa CXA-S (+ 4 ug/ml Tazobactam)
    • 11. 11
      P. aeruginosa CXA-R
    • 12. 12
      P. aeruginosa CXA-R (+ 4 ug/ml Tazobactam)
    • 13. 13
      S. aureus
    • 14. 14
      various species
    • 15. 15
    • 16. LCB oxazolidinones programS. aureus
      16
      VenatoRx
    • 17. LCB oxazolidinones programVarious species
      17
      VenatoRx
    • 18. 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.
    • 19. What is LCB01-0371?
      A novel oxazolidinone analogue.
      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
      19
    • 20. 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
      20
    • 21. 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. Carbapenems and 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
      21
    • 22. 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
      22
    • 23. Market growth of MRSA Drugs
      7
      6
      5
      4
      3
      Global sales (US$ billion)
      2
      1
      0
      2005
      2006
      2007
      2008
      2009
      2010
      2011
      2012
      2013
      2014
      2015
      Pipeline drugs+
      Vancomycin
      Cubicin
      Tygacil
      Zyvox
      Datamonitor forecast* for drugs mainly indicated for treatment of infections caused by MRSA
      Global forecast* until 2015
      Summary
      Background
      Competition
      Development
      In Vitro
      In vivo
      Patents
      Company
      BACKGROUND
      Zyvox(Linezolid)
      • Oxazolidinone marketed by Pfizer
      • 24. Indications include adult treatment of HAP (MRSA), CAP (S. pneumoniae), complicated and uncomplicated skin infections (MRSA), and VRE infections
      • 25. Oral and IV formulations enable smooth transition from hospital to home treatment
      MRSA drugs are a main source of overall antibacterial market growth
      23
    • 26. 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
      24
    • 27. 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
      25
    • 28. 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
      26
    • 29. 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
      27
    • 30. 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
      28
    • 31. 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
      29
    • 32. 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
      30
    • 33. 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
      31
    • 34. 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
      32
    • 35. 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
      33
    • 36. 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
      34
    • 37. Discontinued Oxazolidinones
      Summary
      Background
      Competition
      Development
      In Vitro
      In vivo
      Patents
      Company
      COMPETITION
      35
    • 38. 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
      36
      Summary
      Background
      Competition
      Development
      In Vitro
      In vivo
      Patents
      Company
      COMPETITION
    • 39. Novel Scaffold
      Summary
      Background
      Competition
      Development
      In Vitro
      In vivo
      Patents
      Company
      DEVELOPMENT
      37
    • 40. 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
      38
    • 41. Synthetic Scheme Process
      Summary
      Background
      Competition
      Development
      In Vitro
      In vivo
      Patents
      Company
      DEVELOPMENT
      39
    • 42. 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
      40
    • 43. MICs of Clinical Isolates
      l
      Summary
      Background
      Competition
      Development
      In Vitro
      In vivo
      Patents
      Company
      IN VITRO
      41
    • 44. Pharmacokinetic Profiles
      Summary
      Background
      Competition
      Development
      In Vitro
      In vivo
      Patents
      Company
      42
      LCB01-0371
      LCB01-0371
      LCB01-0371
      Linezolid
      Linezolid
      (mg*h/L)
      (mg*h/L)
      (mg/L)
      (kg/L)
      (h)
      IN VIVO
      (h)
      (%)
    • 45. In vivo : 1. Systemic Infection Model in Mice
      Summary
      Background
      Competition
      Development
      In Vitro
      In vivo
      Patents
      Company
      43
      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
    • 46. In Vivo : 2. Soft Tissue Infection Model (air pouch)
      • Infection : S. aureusgiorgio (MSSA)
      • 47. Oral treatment(once) and then CFU counted after 1 day
      Summary
      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
      44
    • 48. In Vivo : 3. Lung Infection Model
      • Infection pathogen: S. pneumoniae ATCC6305 (1X107)
      • 49. Treatment : PO, 4 times (1 hr, 4 hr, 24 hr, 48 hr)
      Summary
      Background
      Competition
      Development
      In Vitro
      In vivo
      Patents
      Company
      IN VIVO
      45
    • 50. In Vivo : 4. Thigh Infection Model
      • Infection : S. aureusgiorgio (MSSA)
      • 51. 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
      46
    • 52. Toxicology: 1. Mice (4-days)
      Summary
      Background
      Competition
      Development
      In Vitro
      In vivo
      Patents
      Company
      IN VIVO
      Linezolid
      TR-700
      LCB01-0371
      TR-701
      • Compounds were orally administered for 4 days (QD) to female C3H mice.
      • 53. Blood samples weredrawn at day 5 and analyzed.
      • 54. % reticulocyte was determined.
      • 55. Reference - Therapy, 2006, 3(4), 521-526
      47
    • 56. Toxicology: 2. Rats (7-days)
      • Compounds were orally administered for 7 days to male SD rats.
      • 57. Blood samples weredrawn at day 8 and analyzed.
      • 58. % reticulocyte was determined.
      Summary
      Background
      Competition
      Development
      In Vitro
      In vivo
      Patents
      Company
      IN VIVO
      Linezolid(bid)
      TR-701 (qd)
      LCB01-0371 (bid)
      48
    • 59. 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 reticulocyte counts.
      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
      49
    • 60. Toxicology: 4. TK in Rats (7-day)
      Summary
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      IN VIVO
      Dose dependency without accumulation was observed
      50
    • 61. Toxicology: 5. TK in Dogs (4-weeks)
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      Lower AUC
      higher Cmax
      thanLinezolid
      (lower NOAEL)
      No accumulation was observed
      IN VIVO
      51
    • 62. 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
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      52
    • 63. Head-to-Head Comparison Pharmacokinetic Profiles
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      53
    • 64. 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
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      IN VIVO
      54
    • 65. Patents
      Summary
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      PATENTS
      55
    • 66. Claimed Chemical Structures
      Each independent claim is followed by dependent Markush claim.
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      PATENTS
      56
    • 67. Company Profile
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      Established in May 2006 (Daeduk Science 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
      57
    • 68. 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.
      58
      Summary
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      COMPANY