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L-410198 GoNo-Go to Phase III an Powered By Docstoc
					Approaches to First-In-Man and
Beyond: Early Evidence of Target
Engagement with Biomarkers and
Innovative Clinical Trial Designs

Rajesh Krishna, PhD, FCP
Clinical Pharmacology


AGAH-ACCP Annual Meeting 2006
Transatlantic Strategies in Early Development
Düsseldorf, Germany
Overview

• Part I
   – Experimental medicine and biomarkers for
     early evidence of concept and target
     engagement

• Part II
   – Adaptive designs to maximize dose-response
     information and select the “winners”
Part I:
Experimental Medicine and
Biomarkers
Experimental Medicine
• Scope:
   – Designed to provide a preliminary assessment of pharmacologic
     activity, efficacy, and/or safety of new compounds in early clinical
     development
       • Predictive of Phase III clinical efficacy / clinical outcomes
• Approaches
   – Experimental medicine tools
       • Biomarkers and surrogate endpoints
       • Experimental models
   – Imaging
   – Molecular profiling
       • Unique role as experimental medicine tool and in biomarker
         discovery
Experimental Medicine

• Goals:
   – Increase efficiency of drug development
   – Accelerate and improve quality of drug
     development decisions
   – Augment understanding of test drugs, dose
     response, biology, and mechanisms of action
   – Aid in regulatory evaluation and, where possible,
     regulatory approval of test drugs
                DPP-IV Inhibitor Biomarkers
                                                                   Disease or distal biomarkers
                          Meal bolus
                                             GI tract

                                                                                   Skeletal muscle
                                                    GLP-1 neuroendocrine
                                                    cells in ileum
                  Delayed
                                   Neural
                  gastric
                                   innervation
                 emptying                                                                Glucose


                                              Active-GLP1            Insulin ( cell)
                      DPP-IV
                                              inactive GLP-1


                                                              Pancreatic islet

Target
engagement
or proximal
                                                                     Glucagon ( cell)
biomarkers CNS
                                 Food intake/body weight                                     Hepatic glucose
                                                                                               production
  GI=gastrointestinal; CNS=central nervous system
                                                                                                               6
                                          DPP-IV and Active GLP-1 levels
                               >80% Plasma DP-IV Inhibition
                                     DPP-IV inhibition                                                                        ~2-fold increases in
                                                                                                                     25
                      100
                                        Percent Inhibition† From Baseline
                                                                                                                              active GLP-1 levels
                       90                                                                                            20
                       80




                                                                                                 Active GLP-1 (pM)
                       70
 Percent Inhibition
  From Baseline




                                                                                                                     15
                       60
                       50
                       40                                                                                            10
                       30
                       20
                                                                                                                     5
                       10
                        0
                      -10                                                                                            0
                            0 1 2   4    6     8     10    12 14        16   18   20   22   24                            0   1    2   3          4   5       6
                                                           Hour                                                                            Hour
    Placebo
  Placebo (n=56)                                                                                            Placebo
                                                                                                          Placebo (n=56)
    MK-0431 25 mg
  L-224715 25 mg (n=56)                                                                                     MK-0431 25 mg
                                                                                                          L-224715 25 mg (n=56)
  L-224715 200 mg (n=56)
    MK-0431 200 mg                                                                                          MK-0431 mg (n=56)
                                                                                                          L-224715 200200 mg
† Back-transformed from the log scale




                                                                                                                                                          7
 Herman et al., Diabetes 53(Suppl. 2): A82, 2004
                                       Insulin and glucose levels post-OGTT
                                    MK-0431 Enhanced                                                     MK-0431 Reduced Glycemic
                                    Insulin Levels by ~22-23%                                            Excursion by ~22-26%
                           40                                                                 320
                                                                                              310
                                                                                              300
                                                                                              290
                                                                                                               OGTT
Plasma Insulin (mcIU/mL)




                                                                     Plasma Glucose (mg/dL)
                           30                                                                 280
                                                                                              270
                                                                                              260
                                                                                              250
                                                                                              240
                           20                                                                 230
                                                                                              220
                                                                                              210
                                                                                              200
                           10                                                                 190
                                                                                              180
                                                                                              170
                                                                                              160
                           0                                                                  150
                                0       1    2    3          4   5                                  06     1     2    3          4   5       6
                                                      Hour                                                                Hour

             Placebo (n=56)                                                      Placebo (n=56)
             MK-0431 25 mg (n=56)                                                MK-0431 25 mg (n=56)
             MK-0431 200 mg (n=56)                                               MK-0431 200 mg (n=56)




                                                                                                                                         8
        Herman et al., Diabetes 53(Suppl. 2): A82, 2004
         DPP-IV Inhibitor Biomarkers
      Tie Mechanism of Action Together
                                                                   Disease or distal biomarkers
                          Meal bolus
                                             GI tract

                                                                                   Skeletal muscle
                                                    GLP-1 neuroendocrine
                                                    cells in ileum
                  Delayed
                                   Neural
                  gastric
                                   innervation
                 emptying                                                                Glucose


                                              Active-GLP1            Insulin ( cell)
                      DPP-IV
                                              inactive GLP-1


                                                              Pancreatic islet

Target
engagement
or proximal
                                                                     Glucagon ( cell)
biomarkers CNS
                                  Food intake/body weight                                    Hepatic glucose
                                                                                               production
  GI=gastrointestinal; CNS=central nervous system
                                                                                                               9
         DPP-IV Biomarkers Allow Assessment of
                   Target Engagement




                                                    EC50 ~26 nM
                                                    EC80 ~100 nM




                                                           10
Herman et al. Clin Pharmacol Ther 78:675-88, 2005
         DPP-IV Biomarkers Allow Assessment of
                   Target Engagement




                                                    11
Herman et al. Clin Pharmacol Ther 78:675-88, 2005
                       Biomarker: PPARg MOA
                                                   FFA’s
          specific            FA uptake
         gene                   FA release
         expression
                                               insulin sensitizing
         in adipocytes
                                              factor(s): Acrp30

PPARg
ligand                                         expression / action
                                              of insulin resistance
Selection strategy:                           factor(s): TNF
•Examine gene
expression data
•Select significantly up
and down regulated genes
•Select putative secreted
proteins (derived from a
                                   Small-                               insulin action
search of databases
                                   insulin                             in muscle / liver
containing annotation of
                                   sensitive                            hyperglycemia
"secreted or extracellular")
                                   adipocytes
•Derive MOA hypotheses
                                    visceral                                      12
for further testing
                                   adiposity
                                                                 Reviewed in Wagner, 2002
               WAT gene expression in lean and db/db mice
               •Adiponectin is up regulated in lean mice by PPARg agonist treatment
               •Adiponectin is down regulated in db/db mice relative to lean, but not
               regulated by PPARg agonist treatment as assessed by microarray
               •Adiponectin is up regulated in db/db mice by RT-PCR
                              C57B/6                                 db/db

                                                                             Lean
                                                        Rosi           Rosi  vs
                Rosi      Gamma        Alpha
                                                        Gamma          Gamma db/db




      ACRP30


                                                                               13
Reviewed in Wagner, J Clin Endocrinol Metab. 87:5362-6, 2002
                                                            Biomarker: Adiponectin

    • Expression is correlated with                                                                                                                         100
      glucose lowering in db/db




                                                                                                                                          ACRP30 ( ug/ml)
                                                                                                                                                             75
      mice
    • Recombinant ACRP30 has                                                                                                                                 50



      glucose lowering properties                                                                                                                            25



                                                                                                                                                              0
                                                                                                                                                                  0   2   4   6   8

                                                                                                                                                       350
                                              120                                               120
                                                                                                      Plasma Acrp30 (% Max Increase)
          Plasma Glucose (% of Day 0 level)




                                              100                                               100                                                    300




                                                                                                                                       (mg/dl)
                                               80                                               80
                                                                                                                                                       250

                                               60                                               60



                                                                                                                                       GLUCOSE
                                                                                                                                                       200
                                               40                                               40


                                               20                                               20
                                                                                 Glucose
                                                                                 Acrp30
                                                                                                                                                       150                *       *
                                               0                                                0
                                                    0   2       4     6     8     10       12                                                          100
                                                            Days of TZD dosing                                                                                    0   2   4   6   8


                                                                                                                                                                                      14
Reviewed in Wagner, J Clin Endocrinol Metab. 87:5362-6, 2002
                                   Biomarker: Adiponectin

                 At the protein level, ACRP30 is robustly regulated by PPARg treatment in db/db mice

                 800                                                          800




                                                             Glucose, mg/dl
Glucose, mg/dl




                 600                                                          600


                 400                                                          400


                 200                                                          200


                  0                                                            0
                       0   50    100     150    200    250                          0    50    100    150     200   250
                                Acrp30, g/ml                                                 Acrp30, g/ml

                                                       PPARg                     Full
                                                       Agonist                  (Rosi)                        15
  Reviewed in Wagner, J Clin Endocrinol Metab. 87:5362-6, 2002
                   Biomarker: Adiponectin
• Pilot Study                             
                                              g



        14 day treatments
          – Placebo,
          – Fenofibrate
          – Fenofibrate +
            rosiglitazone
          – Rosiglitazone
        Plasma levels
         increased in healthy
         volunteers treated with
         PPARg but not PPAR
         agonists
        Supports use as
         biomarker
                                                  16
Wagner et al, J Clin Pharmacol. 45:504-13, 2005
                                                           Biomarker: Adiponectin
         % Change in insulin sensitivity (Dsi)   500
                                                                  In patients with type 2 diabetes,
                                                                  ACRP30 rises with PPARg treatment
                                                 400
                                                                  TRIPOD Study, Tom Buchanan,UCLA

                                                 300



                                                 200



                                                 100



                                                   0



                                                 -100
                                                    -100      0         100        200       300      400

                                                              % Change in total Adiponectin                 17
Pajvani et al. JBC 279:12152-62, 2004
                                                  Biomarker: Adiponectin
% Change in insulin sensitivity (Dsi)



                                        500
                                                                               But, some patients will:
                                        400
                                                                               •Increase ACRP30
                                        300                                    Without Concomitant
                                                                               Increase in Insulin
                                        200                                    Sensitivity

                                        100                                    •Improve Insulin
                                                                               Sensitivity Without
                                         0                                     Concomitant
                                                                               Increase in
                                    -100                                       ACRP30
                                       -100   0     100    200    300    400

                                              % Change in total Adiponectin
                                                                                                 18
       Pajvani et al. JBC 279:12152-62, 2004
                                        19
Pajvani et al. JBC 279:12152-62, 2004
 Change in Insulin Sensitivity vs. Change in HMW/Total Adiponectin
   Pre- vs. Post-TZD Treatment (TRIPOD Study, Tom Buchanan)

            % Change in insulin sensitivity (Dsi)
                                                    500
                                                          n=40
                                                    400


                                                    300


                                                    200


                                                    100


                                                      0


                                                    -100
                                                        -50          0         50        100

                                                                 % Change in HMW/Total
                                                                                               20
Pajvani et al. JBC 279:12152-62, 2004
                     Imaging as a Biomarker
         Target Engagement and Dose of Aprepitant
                                                                          Mean (± SE) Plasma Trough Concentrations of
                                                                                           Aprepitant
  Binding of PET




                                       Brain NK1 Receptor Occupancy (%)
                                                                                                40/25   125/80 375/125
  tracer to NK1
                                                            100
  receptors
                                                             90
                                                             80
                                                             70
                                                             60
                                                             50
                                                             40
  Blockade of
                                                             30
  NK1 receptors
                                                             20
  after aprepitant
                                                             10
  dosing
                                                              0
                                                        0       1     10    100   1000 10000
                                                   Aprepitant Plasma Trough Concentration (ng/mL)
                Tracer Binding
   Low                                                                      High                                 21
Hargreaves J Clin Psych 63: (suppl 11): 18-24, 2003
                                   Imaging as a Biomarker
                          Aprepitant: CINV Dose Finding Study

                                     Time to First Emesis or Rescue
                         100
with Complete Response
   Percent of Patients




                                             APR 375/250
                         80                                             APR 125/80


                         60
                                                                              APR 40/25

                         40                                                   Control
                          0
                               0     24    48        72            96              120
                                                Hours
                                                                                             22
                                                      869-acm 40-42 Time Cr3 Feb. 15, 2003
Part II:
Novel Clinical Trial Designs
Issues in Dose Selection
Standard Parallel Group Design

      Response




                     Dose
Issues in Dose Selection
Increased Number of Doses to Confirm ED95

      Response




                                   ED95


                 Wasted            Wasted
                 Doses             Doses


                           Dose
Bayesian Adaptive Designs

• Increase number of doses
   – placebo + a large number of actives
• Adaptive learning about dose response
• Prevent allocating patients to ineffective doses
• Borrowing strength from neighbouring doses and
  insuring continuity of response
• Stop dose-ranging trial when response at ED95 is
  known reasonably well
Issues in Dose Selection
Increased Number of Doses and Adaptation

       Response




                           ED95




                       Dose
Up and Down Design

• Yields distribution of doses clustered around dose with
  50% responders (ED50)
• 1st subject receives dose chosen based on prior
  information
• Subsequent subjects receive next lower dose if
  previous subject responded, next higher dose if no
  response
• Inference based on conditional distribution of response
  given the doses yielded by the dosing scheme
Up & Down Design
Simulated from Past Trial Results

• Single-dose dental pain study (total 399 patients)
   –   51   placebo patients
   –   75   Dose 1 patients
   –   76   Dose 2 patients
   –   74   Dose 3 patients
   –   76   Dose 4 patients
   –   47   ibuprofen patients


• Primary endpoint is Total Pain Relief (AUC) during 0-8
  hours post dose (TOPAR8)

• Up & Down design in sequential groups of 12 patients
  sampled from study results.
Simulated Up & Down Design
Completed Dental Pain Study
• Sequential groups of 12 patients (3 placebo, 6 test drug, 3
  ibuprofen)

• First group receives Dose 2

• Subsequent group receives next higher dose if previous group is
  non-response, next lower dose if response

• Response (both conditions satisfied):
   – Mean test drug – mean placebo ≥ 15 units TOPAR8
   – Mean test drug – mean ibuprofen > 0

• Algorithm continues until all ibuprofen data exhausted
    – originally planned precision for ibuprofen vs placebo
    – (16 groups = 191 total patients)
Dental Pain Randomized Design
vs Up & Down Design Results
Dental Pain Randomized Design
vs Up & Down Design Results
 Number of Patients Studied




                                             75          76          74         76
                              80
                              60   51 48                                                  47 47
                                                              42
                              40                  24                       24
                              20                                                      6
                               0
                                   placebo   Dose 1      Dose 2     Dose 3      Dose 4    Active
                                                                                          Control
                                                         Treatment Group

                                                   parallel group design    up&down
Key Conclusions
Simulated Up & Down Design in Dental Pain

• Up & Down design is viable for dose-ranging in dental
  pain
   – yields similar dose-response information as
      parallel group design

• Can use substantially fewer patients than parallel
  group design

• Logistics of implementation more complicated than
  usual parallel group design
   – Can be accomplished in single center or small
     number of centers
Acknowledgements

• John Wagner
• James Bolognese
• Gary Herman

				
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