Transcript First Time in Human Trials An industry perspective

Human pharmacology for biologicals
– First into man studies
Daren Austin PhD
Clinical Pharmacology Discovery Medicine
GlaxoSmithKline
London - March 13, 2006
27/04/2007
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London - March 13, 2006
27/04/2007
AGAH/Club Phase I Annual Mtg
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Some perspective
 Developing new medicines is a collaborative effort
– industry, academia and regulatory bodies
 FTIH studies are generally very safe
– protocols represent a high standard of science and medicine
 TGN1412 underscores the importance of translational
science, clinical pharmacology and study design for
safe drug development
 Most antibodies are very safe
– At least one marketed antibody has the same cytokine profile
as TGN1412
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A few successes…
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Applications of therapeutic antibodies
ALTER CELL
FUNCTION
Abciximab
Basiliximab
Daclizumab
Efalizumab
Natalizumab
Palivizumab
DESTROY
TARGET CELLS
Alefacept
Cetuximab
Muronomab
Trastuzumab
Gemtuzumab
ozogamacin
Ibritumomab
tiuxetan
Tositumomab
TARGETED DRUG
DELIEVRY
NEUTRALIZE “TOXINS”
IMMUNOTOXICOTHERAPY
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Adalimumab
Bavacizumab
Etanercept
Infliximab
Omalizumab
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The wrong way …
We’ve got a new wonder drug!
… we give it to you and
wonder what it will do
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The right way…Outline
 Understand the mechanism
 Understand the pharmacology
 Design the right study (theory)
 Define the right dose
 Understand the population
 Design the right study (practice)
 Conduct the study right
www.prairierivers.org
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Understand the mechanism
 Soluble or cell-associated target
 Pleiotropy
 Redundancy
 Potential for biological amplification
 Downstream signalling
 Tissue expression and homeostasis
 Translation plan for human systems
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Understand the pharmacology
Big molecules – small differences?
Characteristic
Small Molecule
Antibody
Molecular weight
< 700
150,000 (300x higher)
Potency
pM – nM
(agonist/antagonist)
pM – nM
(typically antagonists)
Clearance
Linear at low doses, Nonlinear at high doses
Non-linear at low doses,
linear at high doses
Volume
Wide range, < 1000 L/kg
70 ml/kg, 2x plasma
Bioavailability
0 – 100%, predictable from
Phys Chem properties
0% via oral, 30 – 90% via
sub-cut
PK/PD timeframe
PD slower than PK
PK slower than PD
Preclincal NOAEL
Dose limiting, non-specific,
off-target binding
Exaggerated pharmacology
FTIH design
Multi-cohort, cross-over
design
Multi-cohort, parallel
group design
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Understand the pharmacology
 Antagonists
– possess affinity without activity
 acts by blocking a receptor, occupying or
inhibiting messenger
 Agonists
– possess affinity with efficacy,
 binds and activates a response via downstream
signalling
Hence, an agonist activates a receptor, an antagonist binds but
doesn’t activate it (i.e., it blocks access of agonist)
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Design the right study (theory)
What dose range? What starting dose?
www.pbase.com
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Dose ranges: are they adequate?
Data from 100 GSK FTIH studies
Median of 6 dose levels (8 periods)
Cumulative escalation is 60x (2–20000x)
Distribution is different to industry benchmark#
30
25
Percent
20
Data
BPCEDD
Industry
15
10
5
0
#
2
4
8
16
32
Buoen et al. (2005) J. Clin Pharm 45: 1123-1136
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64
128
256
512
1,024
2,048
4,096
8,192
16,384
32,768
Log2 (Dose range)
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Design the right study
Typical GSK FTIH designs
 For small molecules typically five period (incl.
placebo) with repeated dose across cohorts and 2-3
fold escalations:
– P, X, 2X, 4X, 8X then P, 8X, 16X, 32X, 64X
– 23 x 23 = 64-fold
– 3 x 3 x 2 x 2 x 1.5 x 1.33 = 72-fold
 For large molecules typically six period parallel
group with log/semi-log decreases
– X, 10X, 10X, 3X, 3X, 3X
– 102 x 33 = 2700-fold
 Overall dose range defined by number of cohorts
 Define starting dose to give top dose
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Exposure ranges for responses
 Agonists are very
efficient at signalling
(80/20)
Antagonists must block
most receptors before
signal is turned off
Desired
response
Exposure
Ratio
Shallow
Antagonist
Agonist
"Switch"
90%
ED90/ED10
4
2
1
<1
95%
ED95/ED5
5
3
1
<1
99%
ED99/ED1
8
4
2
1
Orders of magnitude for exposure range
GOOD (<100x)
POSSIBLE (100 – 1000x)
IMPOSSIBLE (>1000x)
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Relative Response

120%
100%
Shallow
Antagonist
Agonist
Switch
80%
60%
40%
20%
0%
0.001 0.01
0.1
1
10
100 1000
Relative Dose
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Exposure ranges for responses
 Agonists are very
efficient at signalling
(80/20)
Antagonists must block
most receptors before
signal is turned off
Desired
response
Exposure
Ratio
Shallow
Antagonist
Agonist
"Switch"
90%
ED90/ED10
4
2
1
<1
95%
ED95/ED5
5
3
1
<1
99%
ED99/ED1
8
4
2
1
Orders of magnitude for exposure range
GOOD (<100x)
POSSIBLE (100 – 1000x)
IMPOSSIBLE (>1000x)
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Relative Response

120%
100%
Shallow
Antagonist
Agonist
Switch
80%
60%
40%
20%
0%
0.001 0.01
0.1
1
10
100 1000
Relative Dose
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Exposure ranges for responses
 Agonists are very
efficient at signalling
(80/20)
Antagonists must block
most receptors before
signal is turned off
Desired
response
Exposure
Ratio
Shallow
Antagonist
Agonist
"Switch"
90%
ED90/ED10
4
2
1
<1
95%
ED95/ED5
5
3
1
<1
99%
ED99/ED1
8
4
2
1
Orders of magnitude for exposure range
GOOD (<100x)
POSSIBLE (100 – 1000x)
IMPOSSIBLE (>1000x)
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Relative Response

120%
100%
Shallow
Antagonist
Agonist
Switch
80%
60%
40%
20%
0%
0.001 0.01
0.1
1
10
100 1000
Relative Dose
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Define the right dose
http://pixelsoap.com/photos/album32/roulette
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Define the right dose
What starting dose?
Define No Observable Adverse Effect Level
Safety cover for top dose (1 – 5x)
Low dose based
on enhanced cover
(100 – 500x)
Low dose based
on expected
pharmacology
For NMEs, low dose will be typically 100x lower based on design arguments
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Define the right dose
What starting dose?
Define NOAEL
Safety cover for
top dose (1 – 5x)
Define MABEL
Safety cover for
low dose
(100 – 500x)
Minimally
Active
Biological
Effect Level
Low dose based on pharmacology
Low dose = Min(MABEL, NOAEL/cover, Binding)
 Define lowest level of biological activity preclinically
 Equivalent to “Minimally effective” Phase IIB dose
 Will require downward preclinical dose titration for antibodies
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MABEL based on PD/PD of orthologues
 Raptiva™ targets CD11a did not bind to preclinical species
 muM17 is an anti-mouse CD11a Mab developed as a surrogate
molecule to assess reproductive toxicity in mouse
 Mechanistic PK/PD model used to determine dose equivalence to
humans
Wu (2006) J Pharm Sci 96 (6) 1258
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PK/PD and orthologues
Wu (2006) J Pharm Sci 96 (6) 1258
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PK/PD and orthologues model
validation
Wu (2006) J Pharm Sci 96 (6) 1258
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Allometric scaling of proteins
Mordenti et al (1991), Pharm Res 8, 1351
http://www.elephants.com/sharma_photos.htm
 Established for small and larger molecules
 Assumes conservation of clearance pathway across species
 For monoclonal antibodies this assumption is frequently violated
– Human target may only be shared by primate species
– Single species allometry
– Consider target expression and target mediated clearance
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Scaling capacity-limited binding to
humans
 MUC-18 cell surface





adhesion (melanoma)
Fit parallel linear and
non-linear binding
elimination pathways
Assume Vmax and Km
are predictive of humans
Residual clearance
allometrically scaled
Simulate human PK
profiles
Ignores neutralisation
http://www.abgenix.com/documents/ASCPT2004%20poster.pdf
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Define the right dose
 Large molecules bind to a target at nanomolar
concentrations
– 150kD implies equates to 0.15µg/ml for 50% binding
 That’s about 0.01 mg/kg
 Antibody binding is normally antagonistic
– High binding required to suppress signaling pathways
– 80-90% binding equates to 1 – 2µg for biological effect
 That’s about 0.1 mg/kg
 Guiding simplification
– Starting dose of Kd[nM]/200 [mg/kg] will give about 50% binding
 [Duff pg. 29]
 Scale for smaller proteins according to MWT and Vdss
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Define the right dose
Proposed (and approved)
Dose
(mg/kg)
Cmax
(ug/ml)
AUC
(0-inf)
(ug.h/ml)
Cover
DOSE
Ratio
Cmax
Kd
0.1
2.309
428
500x
0.5
11.55
2142
2
46.2
5
115.5
Ro
Dose
(mg/kg)
Cmax
(ug/ml)
AUC
(0-inf)
(ug.h/ml)
8.2
89%
0.001
0.023
4.28
50000x
0.08
8%
100x
40.9
98%
0.003
0.069
12.8
16667x
0.25
20%
8567
25x
163.8
99%
0.008
0.185
34.2
6250x
0.7
40%
21418
10x
409.5
100%
0.012
0.277
51.4
4167x
1.0
50%
0.025
0.577
107
2000x
2.0
67%
0.05
1.155
214
1000x
4.1
80%
100x lower starting dose and smaller escalations
*Assumes Cmax/Kd is correlated with functional response
Ro ~ (Cmax/Kd)/(1+(Cmax/Kd))
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Suggested (for agonist)
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Cover
DOSE
Ratio
Cmax
Kd
Ro
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*
Understand the population
 ICH guidelines
 Benefit outweighs the risk
– HVTs do not benefit
– Risk must be managed
accordingly
 Mixed populations?
– HVTs (S&T/PK) then
escalate in patients
 Mild patients?
http://www.noaddedsugar.org/images/gordon/crowd.jpg
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– Neither HVTs nor mild
patients may predict eventual
population
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Healthy subjects or patients?
Points to consider
Comments
Expression of target protein
Healthy subjects may not predict safety and tolerability
Safety profile in patients may vary with disease severity
Determination of optimal
biological dose
May only be possible in patients
Presence of co-morbidities
Detection and interpretation of safety signals more difficult
Long half life
Extended follow-up not always feasible in healthy
volunteers
Opportunity for investigating pharmacodynamic activity
Risk assessment
May preclude healthy subjects
Immunogenicity
May limit future choice of therapy
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Not all created equal …
 Intrinsic variability
–
–
–
–
–
–
–
drug-target interaction
type of transduction
drug access at biophase
delivery & input rate
metabolism pheno/genotype
disease & homeostasis
placebo response
 Extrinsic variability
– drug-drug interactions
– interactions with endogenous
substances
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Mixed study population
Bridging dose
Part 1 – Healthy subjects
Safety, tolerability
PK
Part 2 – Patient
Safety, tolerability
PK, PD
Increasing dose
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Design the right study (practice)
 Stronger drive to deliver more information
earlier: MTD with Proof of Pharmacology
– early call on therapeutic index
– define MTD in relevant populations (target expression?)
– early go/no-go decisions
 Fusion designs in Phase I
– combination of study objectives
 Adaptive designs in Phase I
– say how you will decide to do something
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Proof of pharmacology
 Safety signal from known class of compounds





(e.g. cortisol suppression)
Receptor occupancy signal from ex vivo assay
(e.g. CD11B from neutrophils)
Imaging signal (e.g. fMRI or PET studies)
Transcriptomics for evidence of signal transduction
Clinical surrogate signal (e.g. airway conductance)
Clinical signal (e.g., fasting plasma glucose)
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Design the right study: Phase I Fusion designs
Food
Effect
Drug-Drug
Interaction
Single
Dose
Patient
Population
Repeat
Dose
Human
Pharmacology
FTIH
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Safe and well-tolerated?
FTIH study objectives
Part A
 To investigate the safety and tolerability of single escalating doses of
GSK123456 in healthy subjects.
 To characterize the preliminary pharmacokinetics of single escalating
doses of GSK123456 in healthy subjects.
Part B
 To investigate the safety and tolerability of a single oral dose of
GSK123456 in mild to moderate patients
 To characterize the preliminary pharmacodynamics of single and repeat
doses of GSK123456 as assessed by in an appropriate model
 …GSK123456 is safe, well-tolerated, pharmacokinetics, response in
patients…
 Summarise and report results of Part A and justify doses in Part B
 Will we establish a Maximum Tolerated Dose?
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Summary biopharmCEDD FTIH/FTIP studies
Criteria
Syncra®
GSK1
GSK2
GSK4
Indication
Diabetes
Rheumatoid
arthritis
Severe asthma
Neuro-degeneration
Target
GLP-1
Soluble cytokine
Soluble cytokine
Soluble protein
Precedence
Yes
No
Semi
No
Population
HVT
HVT
HVT/Patients
Patients
Design
Parallel 2-dose
adaptive AUCbased escalation
Parallel SD
adaptive follow-up
Parallel SD/RD
Part A/B
Parallel SD/RD Doptimal adaptive
dose escalation on
target inhibition
Escalation
416x
10,000x
10,000x
800x
Proof of
Pharmacology
Fasting glucose
compared to active
control (enabling)
Target binding and
ex vivo LPS
inhibition
Allergen challenge
Target binding and
inhibition
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GSK123456 Pop-PK analysis (0.03 – 1.0 mg/kg)
during ongoing trial
Concentration [ng/ml]
1000000
Population PK analysis ongoing to
predict time to follow-up
100000
10000
1000
100
10
0
7
14
21
28
35
42
Time [days]
Population Mean
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Individual Predictions
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Conduct the study right
Ensure clinical excellence
All FTIH studies
conducted in a
hospital based Unit
Assure staff
training and
experience
Integrated emergency
response system and
access to ITU
Dosing staggered
Interval hrs - days
Determine if additional
measures or clinical
expertise is needed
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Staff and facilities to
handle medical
emergencies
Shared medical
accountability between
site (PI) and sponsor
(medical monitor)
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Summary
 Understand the mechanism
–
Translational medicine plan
 Understand the pharmacology
–
Same principles, different size, High/Low risk molecule?
 Design the right study (theory)
–
Think escalations not doses, start low, end slow
 Define the right dose
–
MABEL, Cmax/Kd, Preclinical PKPD, Allometry
 Understand the population
–
HVTs and/or/then Patients? Target? MTD?
 Design the right study (practice)
–
Fusion designs with Proof of Pharmacology for FIM expected
 Conduct the study right
–
Hospital site, staggered dosing
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Acknowledgements




© Mike Baldwin
GSK biopharmCEDD
GSK riCEDD
Ruth Oliver, CPDM
Colin Dollery, GSK
“Laugh when you can, it’s good medicine” Lord Byron
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