KB001 04 Jean Chastre ATS 2010 Presentation by iYfC33Vl

VIEWS: 20 PAGES: 21

									New Treatment Options for
Infections Caused by
Pseudomonas aeruginosa

Jean Chastre,
www.reamedpitie.com
Conflicts of interest: Consulting or
Lecture fees:
–   KaloBios, Nektar-Bayer, Pfizer, Brahms,
    Wyeth, Johnson-Johnson, Astellas
                                              1
        Pseudomonas aeruginosa (Pa)
        An opportunistic pathogen
   Ubiquitous gram negative bacterium
   Frequent opportunistic pathogen
   Colonizes lungs of critically ill patients
    –   Damages epithelium by injecting multiple toxins by Type III
        secretion system (TTSS)

   Paralyzes immune system
    –   Kills macrophages and neutrophils via direct perforation of cell
        membrane by TTSS

   Disables bacterial clearance
   Develops multi-drug resistance
    –   Multiple efflux pumps constitutively expressed or up-regulated by
        mutation (at least 10 efflux operons in genome)
    –   Other mechanisms include blockade of entry (sturdy outer lipid
        coating), enzymatic degradation, target structure alteration
    –   Antibiotics exert selective pressure for multi-drug resistant Pa    2
Bacterial Causes of VAP
Bronchoscopic isolates, 24 studies, 1,689
episodes, 2,450 pathogens
                                       Chastre and Fagon. AJRCCM 2002


      P s eudomonas
           S .aureus *
E nterobacteriaceae§
  Haemophilus s pp.
 S treptococcus s pp.
  Acinetobacter s pp.
                                            * 56% MRSA
     S . pneumoniae                         § E. coli, Proteus, Enterobacter,
      Neis s eria s pp.                     Klebsiella, Serratia, Citrobacter spp.
                                            §§ Coagulase neg. Staphylococci,
      S . maltophilia                       Anaerobes, Fungi, Corynebacterium,
           O thers §§                       Moraxella, Enterococcus spp.


                          0   5   10   15     20      25     30                      3
Antibiotics Often do not Clear Pa in
VAP        Garrard et al. Clin Intensive Care 2000;11:319-326




                    Days to Treatment



105




104


                   Days to Treatment
                                                                5
        Since Pa is Not Cleared by Antibiotics
        in VAP, Relapses are Frequent
                             8-day               15-day
                            regimen             regimen
                           (n = 197)           (n = 204)
Pa VAP                        18%                 20%
D28 mortality (all pts)       19%                 17%
D28 mortality                  23%                30%
(NF GNB; 86% Pa)
Relapse by D28 (all pts)       17%                11%
Relapse by D28 (NF GNB)        33%                19%
                           Chastre et al. JAMA 2003;290:2588-98   8
        Type III Secretion System and
        Antibody-based Blockage of this
        Virulence System
                           Kubori et al. Science 1998

o The type III secretion
  system involves a
  needle-like complex
  that traverses the
  bacterial bi-layer,
  crowned by PcrV
  proteins at the distal
  tip.
                                                        11
Type III Secretion System and
Antibody-based Blockage of this
Virulence System




                                  12
                 Anti-PcrV Antibodies Preserve
                 Phagocytes and their Function
                                                 Sawa et al. Nature Medicine 1999;5:392-8




                                    Phagocytic capabilities of J774 cells infected with PA103 were measured by the
                                    uptake of opsonized fluorescent yeast particles. Cells were pre-treated with IgG 30
                                    min before exposure to PA103


Cytotoxicity of J774 cells pre-
treated with antibodies then
exposed to PA103 (hashed bars 1 x
107CFU/ml; filled bars 1 x
109CFU/ml)
                                                                                                                          13
Anti-PcrV Antibodies Reduce
Inflammation in Acute Model
         Sawa et al. Nature Medicine 1999;5:392-398
 PA103 + control IgG                 PA103 + anti-PcrV IgG




   5x105 bacteria + 5 mg IgG instilled into mouse lungs.
   Histology at 8 h post-infection
                                                             14
Pegylated Anti-PcrV Fab Protects
Mice Against Pa-mediated Lethality
            Shime et al, J Immunol 2001;167:5880-6




                                                     15
       KB001, a novel anti-Pa biologic
       agent that blocks TTSS function
                         Cell Membrane                                  Unique KB001 MOA
                                                    Host Cell
                                                  Host Cell
Pseudomonas                                                          Detoxifies Pseudomonas by
aeruginosa                                                            binding to PcrV
                                                                        Prevents oncosis of WBC
                                                                        Prevents toxin release
                                                                        Facilities clearance of Pa by
                                                                         preserving immune system

                       PcrV Protein                                  Reduces lung inflammation
                                         Membrane disruption         Avoids 15 known internal
                                         and toxin injection into     resistance mechanisms
     TTSS
                                         cell
                                                                     Works as single agent or in
  Anti-PcrV Antibody                                                  combination with antibiotics
        (KB001)
                                                                     Binds only to Pseudomonas
                                                                        Likely low toxicity to humans
  KB001 inhibits activity of the Type Three
                                                                        Unlikely to exacerbate
 Secretion System (TTSS) of Pseudomonas                                  bacterial MDR
                aeruginosa
                                                                                                         16
                 KB001 MVP (Mechanically
                 Ventilated Patients) Study Schema
                                                                                            Endpoints
                                                                                    Day 1-3
                                                        KB001                       • Change vs. placebo
                                          12 pts       10mg/kg
                                                                         Add               • Pa burden
Surveillance in MVP                                                                        • Bact diversity
                                     R                 KB001          antibiotics
 pts at high Pa risk                                                                       • Inflammation
                       Pa
                                              12 pts
                                                       3mg/kg         at clinical
                                                                         VAP               • Lung function
                       > 103 ETA         12 pts
                                                       Placebo                      Day 28
                       >   102 BAL
                                                                                    • Frequency
                                                                                           •Pa VAP/sepsis
                                                                                           •Pa relapse
  Number developed Pa VAP during surveillance                    46                 • Time to VAP
  Number received KB001                                          39                 • Clinical and MV endpts
                                                                                    • Pharmacokinetics
  Number with Pa infection on Day 0-1                            4                  • KB001 airway penetration
  Number evaluable                                               35                 • Immunogenicity
                                                                                                                 17
     KB001 MVP Trial: Key Entry Criteria

   Inclusion criteria
    - On MV and expected to remain ventilated for ≥3
      days
    - Documented pulmonary Pa colonization
       - ≥ 103 CFU/mL by endotracheal aspirate or ≥ 102
         CFU/mL by BAL quantitative culture
   Exclusion criteria
    - patients with cystic fibrosis
    - Currently diagnosed with Pa VAP
    - Change in systemic antibiotic therapy active
      against Pa within 72 hours prior to culture used
      for documenting pulmonary Pa colonization for
      study entry
                                                          18
         KB001 MVP Trial: Baseline
         Characteristics
Safety Population                    Placebo    3 mg/kg    10 mg/kg
(N=39)                                (N=12)     (N=13)     (N=14)
Male, n (%)                          10 (83%)   8 (62%)    8 (57%)
Age, mean                              66         62         61
Days on MV, median                     15          7         16
Antibiotics in past 14 days, n (%)   11 (92%)   12 (92%)   13 (93%)
Trauma, n (%)                         1 (8%)    2 (15%)     1 (7%)
Surgery, n (%)                       6 (50%)    11 (85%)   7 (50%)
Coma, n (%)                          3 (25%)    2 (15%)    2 (14%)
Organ transplant, n (%)               1 (8%)    6 (46%)     1 (7%)
COPD, n (%)                          5 (42%)    5 (39%)    2 (14%)
Tracheostomy at baseline, n (%)      4 (33%)    4 (31%)    9 (64%)


                                                                      19
KB001 MVP Trial: PK Data
     Half-life of 8-9 days
     No immunogenicity




                             20
                                 KB001 MVP Trial: Serum and
                                 Endotracheal Aspirate (ETA) Exposure
                                             ETA concentration 2-6% serum

                                                           Study KB001-04
                                                                                             Serum KB001 Concn (3 mg/kg)
                              1000000                                                        ETA KB001 Concn (3 mg/kg)
                                                                                             Serum KB001 Concn (10 mg/kg)
Mean (+/- SD) Concn (ng/mL)




                                                                                             ETA KB001 Concn (10 mg/kg)

                               100000


                                                                                                                                 Serum
                                10000



                                 1000

                                                                                                                                 ETA

                                   100                                          ETA LOQ = 80 ng/mL


                                                                               Serum LOQ = 20 ng/mL


                                    10
                                         0           7             14                         21                            28

                                                               Elapsed Time (days)


                                                                                                                                         21
                  KB001 MVP Trial: Adverse Events

Safety Population                Placebo                   3 mg/kg     10 mg/kg
(N=39)                            (N=12)                   (N=13)       (N=14)
AEs, n (%)                       11 (92%)                 13 (100%)    11 (79%)
Mild, n (%)                       7 (58%)                  13 (100%)   10 (71%)
Moderate, n (%)                   7 (58%)                   7 (54%)    9 (64%)
Severe, n (%)                     5 (42%)                   7 (54%)    3 (21%)
Life-threatening, n (%)           0 (0%)                    1 (8%)     2 (14%)
Fatal, n (%)                      3 (25%)                   1 (8%)     2 (14%)
Study-drug related, n (%)         2 (17%)                   1 (8%)      1 (7%)
SAEs, n (%)                       7 (58%)                  8 (62%)     7 (50%)



                            Possibly Related AEs (all Mild)
                            Placebo – cholestasis, leukocytosis.
                            3 mg/kg – cytolytic hepatitis
                            10 mg/kg – Diarrhoea

                                                                                  22
            KB001 MVP Trial: Pneumonia
                  Decreased Incidence of Pneumonia




                           Evaluable Population
All VAPs were Pa VAP
                                                     23
KB001 MVP Trial: Day 28 Outcome
      Increased Pa Event Free Survival




              Evaluable Population   Excluding subjects with Pa UTI
                                                                      24
          KB001 MVP Trial: Summary
   KB001 was safe and non-immunogenic
   KB001 has serum half life of 8-9 days
   KB001 penetrates the lung
    - Median ETA concentration ~2-6% of serum
   Reduced VAP with KB001 treatment
       60% placebo vs. 31-33% KB001
   Increased survival to Day 28 without a Pa
    infection
       20% placebo vs. 33-46% KB001
   Larger randomized studies are warranted to
    confirm KB001’s ability to prevent Pa pneumonia
    and other serious infections
                                                      25
        Investigators

   Jean Chastre (La Pitié-Salpêtrière)
   Jen-Luc Diehl (HEGP)
   Anthony Dugard (Limoges)
   Samir Jaber (Montpeillier)
   Benoit Guery (Lille)
   Alexandre Mebazaa (Lariboisière)
   Laurent Papazian (Marseille)
   Dominique Perrotin (Tours)
   Michel Wolff (Bichat)
   Benoît Misset (St Joseph)



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