Post on 02-Aug-2022
29 NOVEMBER 2018
BENNO RATTEL
TRAINING COURSE ONCOLOGY NONCLINICAL DEVELOPMENT OF ANTICANCER DRUGS
2
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
CONFLICT OF INTEREST STATEMENT
I am an employee and stock holder of Amgen
3
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
MISSION OF NONCLINICAL DRUG DEVELOPMENT
Desired Effects Undesired Effects
Benefit Risk
4
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
THERAPEUTIC INDEX
Dose or Exposure
10 100 1000 10000
Eff
ec
t
%
0
20
40
60
80
100
Therapeutic
Range
Toxic
Range
Therapeutic
Index
ED50 TD50
5
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
NONCLINICAL GUIDELINES
•ICH
•EMA
•FDA
6
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
FIH SAFE STARTING DOSE NON-LIFE-THREATENING INDICATION
Dose or Exposure
10 100 1000 10000
Eff
ec
t
%
0
20
40
60
80
100
Therapeutic
Range
Toxic
Range
NOAEL (no observed adverse effect level)
Therapeutic
Index
ED50
Safe Starting Dose
7
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
NONCLINICAL DEVELOPMENT OF ANTICANCER DRUGS FOR PATIENTS WITH ADVANCED DISEASE
• Anticancer drugs can be small molecules and/or biologics.
• They are often used to treat life-threatening malignancies.
• Adverse effects of therapy are often less threatening to a patient
than the disease they are suffering from.
• Most early trials are performed in the patient population, NOT
healthy volunteer subjects.
• Nonclinical testing of oncology drugs for patients with life-
threatening disease therefore differs from non-oncology drugs.
8
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
• Demonstration of pharmacological activity is the first step in the
development of any new small molecule or biologic
• However, efficacy from nonclinical studies may not dependably
predict clinical efficacy
Heterogeneity of disease
Interspecies differences in ADME, target receptor distribution
Role of immune system, etc.
PHARMACODYNAMIC PROPERTIES
9
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
• Data from nonclinical pharmacology studies are used for:
– Understanding the effects at molecular level
• Interaction of molecule with target receptor, tissue, or organ
• Signaling pathways
• Receptor specificity
• Resistance mechanisms
– Identification and evaluation of biomarkers
– Justification for drug combinations
– Relevant species selection for further in vivo testing
– Demonstration of in vivo activity
• Healthy animal model or human tumor xenograft models
• Assessment of best route of administration and appropriate schedule (daily, weekly, q 3 weeks)
• Correlation PD effects with exposure
PHARMACODYNAMIC PROPERTIES
10
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
• Identify effects on vital functions, potential target-organ
toxicity and whether such toxicity is reversible.
• Identify DLT (dose-limiting toxicity).
• Relate the effects to drug exposure and „treatment cycles“ to
support dose-escalation in Phase I and duration of therapy.
• Establish the MTD (maximal tolerated dose) or HNSTD (highest
non-severe toxic dose level) to define the initial safe starting
dose in Phase I trials.
• Identify safety parameters for clinical monitoring.
NONCLINICAL SAFETY EVALUATION OF ANTICANCERMEDICINAL PRODUCTS
11
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
MTD (HNSTD), CANCER INDICATION
Dose or Exposure
10 100 1000 10000
Eff
ec
t
%
0
20
40
60
80
100
Therapeutic
RangeToxic
Range
MTD
Therapeutic
Index
ED90
Selected dose levels
Optimal selection of
dose levels
12
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
MTD (HNSTD), CANCER INDICATION (REALITY)
Dose or Exposure
10 100 1000 10000
Eff
ec
t
%
0
20
40
60
80
100
Therapeutic
Range
Overlaps
with Toxicity
MTD
EC90
Therapeutic
Index
13
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
FDA (J. DeGeorge et al., 1998)
14
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
GUIDE FOR STARTING DOSE SELECTION
15
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
16
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
ICH S9
17
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
ICH S9 – SAFE STARTING DOSE
• Set a start dose at 1/10 the Severely Toxic Dose in 10% of
the animals (STD 10) in rodents.
• If the non-rodent is the most appropriate species, then 1/6
the Highest Non-Severely Toxic Dose (HNSTD) is
considered an appropriate starting dose.
➢ The HNSTD is defined as the highest dose level that does
not produce evidence of lethality, life-threatening
toxicities or irreversible findings.
18
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
ICH S9 - SCHEDULE OF NONCLINICAL STUDIES RELATIVE TO PROPOSED PHASE 1 TRIAL
19
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
• The nonclinical data to support Phase I and the clinical Phase I
data would normally be sufficient for moving to Phase II and into
second or first line therapy in patients with advanced cancer.
• Results from 3-month toxicity studies following the intended
clinical schedule should be provided prior to initiating Phase III
studies.
ICH S9 – TOXICITY STUDIES TO SUPPORT CONTINUED CLINICAL DEVELOPMENT
20
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
COMBINATION OF DRUGS
• Toxicology studies of the combination may not be necessary for
patients with advanced disease, if all components of the
combination are well studied individually.
• Information from pharmacology studies may be useful to
assess whether an additional toxicology study is necessary.
21
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
REPRODUCTION TOXICITY
• An embryofetal toxicology assessment is conducted to
communicate potential risk for the developing embryo or fetus to
patients who are or might become pregnant.
• Should be available when the marketing application is submitted,
but are not considered essential to support clinical trials intended
for the treatment of patients with advanced cancer.
• Are also not considered essential for the purpose of marketing
applications for pharmaceuticals that are genotoxic and target
rapidly dividing cells (e.g., crypt cells, bone marrow) or belong to a
class that has been well characterized as causing developmental
toxicity.
22
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
ICH S9 – Q&A 2018
23
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
ICH S9 – Q&A 2018
24
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
GLP
• Conduct pivotal studies according to Good Laboratory Practices (GLPs)
• If not conducted according to GLP, need to explain study deviations from GLP and discuss their impact on study outcome
25
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
ICH S6(R1) – BIOTECHNOLOGY-DERIVED PHARMACEUTICALS
26
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
• ICH S6 applies to products derived from characterized cells
through the use of a variety of expression systems including
bacteria, yeast, insect, plant, and mammalian cells.
• The active substances include proteins and peptides, their
derivatives and products of which they are components; they
could be derived from cell cultures or produced using
recombinant DNA technology including production by transgenic
plants and animals.
WHAT IS A BIOLOGICAL PRODUCT?
27
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
SIMILARITIESBIOLOGICS AND SMALL MOLECULES
• For Biopharmaceuticals and Small Molecules:
✓ Identify an initial safe dose and appropriate dose
escalation schemes in humans
✓ Identify potential target organs for toxicity and for
the reversibility of toxicities
✓ Identify safety parameters for clinical monitoring
28
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
DIFFERENCESBIOLOGICS AND SMALL MOLECULES
Small Molecules• Toxicity and MTD
• Metabolized and metabolism used to
select species
• Rodent and non-rodent toxicity studies
• Genetic toxicity studies
• Non-immunogenic
• Short-acting requiring chronic
daily dosing
• Linear dose-response curve
• Oral route, complex formulations
Biopharmaceuticals
• Unique molecules; “case by case” approach
• Exaggerated activity
• Pharmacology used to select species
• Single species common
• Degraded
• Immunogenic
• Long-acting leading to intermittent dosing
• Bell-shaped dose-response curve
• Parenteral route
29
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
• Similar expression of target receptor /epitope and similar tissue cross-
reactivity profile to human tissue
• Tested molecule is pharmacologically active in the tox species
• “Safety evaluation programs should normally include two relevant
species. However, in certain justifiable cases, one relevant species may
suffice (e.g., when only one relevant species can be identified or where
the biological activity of the biopharmaceutical is well understood).”
➢ “Toxicity studies in non-relevant species may be misleading and are
discouraged.”
RELEVANT SPECIES
30
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
• Characterize anti-drug antibody responses:
Titer
Frequency
Neutralizing or non-neutralizing
Any corresponding effects (e.g. PD, PK, adverse events,
complement activation, immune complex formation)
• Induction of antibody formation in animals is not predictive for humans.
• Severe anaphylactic responses to recombinant proteins are rare in
humans.
IMMUNOGENICITY
31
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
CD28 superagonist Ab TGN1412
Life-threatening conditions
in FIH trial
THE TEGENERO INCIDENT IN 2006
32
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
MABEL APPROACH FOR THE SELECTION OF A SAFE FIH DOSE
• In response to the TGN1412 incident, the EMEA „Guideline on
Strategies to Identify and Mitigate Risks for First-In-Human
Clinical Trials with Investigational Medicinal Products” was
issued in 2007
• MABEL = Minimal Anticipated Biological Effect Level
– MABEL is the dose/exposure that results in minimal pharmacodynamic (PD)
effects in human
– MABEL was coined to understand lowest animal dose or concentration required
to produce pharmacological activity in vivo and/or in vitro in the animal/human
system
– Minimal PD could be a biological effect (e.g. cytotoxicty, T cell activation) or
receptor occupancy of blood-based cell surface targets
33
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
• Estimate the clinical starting dose for FIH study is based on both toxicology AND pharmacology
Dose or Exposure
10 100 1000 10000
Effect
0
20
40
60
80
100
Therapeutic
Range
MTD
MABEL
NOAEL
MABEL APPROACH FOR THE SELECTION OF A SAFE FIH DOSE
Toxic
Range
EC10
34
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
NONCLINICAL GUIDELINES AND PAPERS
35
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
CASE STUDY: BITE® ANTIBODY CONSTRUCTSPRINCIPLES OF MODE OF ACTION
Redirected
Lysis
Tumor Cell
T Cell
CD3
CD25/CD69
T Cell
Activation
Anti-Tumor Associated
Antigen Antibody
VH
VL
Anti-CD3
Antibody
VH
VL Proliferation
of T Cells
Apoptosis
scFv
scFv
Serial Lysis
Tumor Cells
Cytolytic
synapse
T cell
Tumor
cell
36
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
BITE® ANTIBODY CONSTRUCT IN VITRO DEMONSTRATION OF REDIRECTED LYSIS
37
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
HEME TARGET BITE®-INDUCED DOSE- AND TIME-DEPENDENT REDIRECTED LYSIS IN VITRO
0
2 0
4 0
6 0
8 0
1 0 0
1 0 -4 1 0 -2 1 0 0 1 0 2 1 0 4 1 0 6
M M .1R
A M G 4 2 0 [p g /m L ]
Cy
toto
xic
ity
[%
]
A
6 h
1 6 h
2 4 h
4 8 h
7 2 h
0
M M .1R
T im e [h ]
Ly
sis
[%
]
EC
50
[pg
/mL
]
0
2 0
4 0
6 0
8 0
1 0 0
0
2 0
4 0
6 0
8 0
1 0 0
L y s is [% ]
E C 5 0 [n g /m L ]
6 1 6 2 4 4 8 7 2
B
BiTE
38
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
HEME TARGET BITE®-MEDIATED COMPLETE ELIMINATION OF AML CELLS FROM A PATIENT WITH REFRACTORY AML
Time-dependent expansion of effector T-cells
control BiTE
CD33
day 0
day 4
day 20
mu
CD
29
Krupka et al., Blood, 2014, 123(3):356-65
Control
BiTE
T Cells
39
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
HEME TARGET BITE®-INDUCED HUMAN T CELL ACTIVATION IN VITRO
40
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
• Lineages affected depends on target expression
• Occasional infections can occur
HEME TARGET BiTE® ANTIBODY CONSTRUCTS CAN RESULT IN CELL DEPLETION IN PERIPHERAL BLOOD, LYMPHOID SYSTEM AND BONE MARROW
0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2
0
5 0 0
1 0 0 0
1 5 0 0
T im e (D a y s )
B c
ell
(c
ou
nts
/L
)
1 0 0 1
1 0 0 2
1 0 0 3
2 5 0 1
2 5 0 2
2 5 0 3
3 5 0 1
3 5 0 2
3 5 0 3
P re
Peripheral Blood Tissue/Tonsil
Animal 2501
CD20 IHC
Control
0
Bone Marrow
41
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
TUMOR-ASSOCIATED ANTIGEN-SPECIFIC TISSUE EFFECTSCORRELATE WITH TISSUE EXPRESSION
Necrosis of parietal epithelium of Bowman’s Capsule,
degeneration/necrosis of renal tubular epithelium
IHC in Normal
Cyno Kidney
IHC in normal
Human Kidney
IHC
in Normal
Human Skin
Skin Reaction
Necrotic inflammation
42
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
PK
EC50 0.25 ng/mL
Peripheral Blood
EC90 0.7 ng/mL
PHARMACOKINETICS AND PHARMACODYNAMIC OF A BITE® ANTIBODY CONSTRUCT IN NHP
PD
43
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
SAFE CLINICAL STARTING DOSE OF BITE® ANTIBODY CONSTRUCT ISBASED ON IN VITRO MABEL
• FIH Starting dose calculated based on MABEL and PK modeling
0
2 0
4 0
6 0
8 0
1 0 0
1 0-1
1 00
1 01
1 02
1 03
1 04
A M G 3 3 0 [p g /m L ]
Bio
ac
tiv
ity
[%
]
0
0
5
1 0
1 5
Bio
ac
tiv
ity
EC
xx
[p
g/m
L]
Predicted Human Concentration-Time Profiles
BiTE® Antibody Construct
44
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
United States:
On December 3, 2014, the U.S. Food and Drug Administration granted accelerated approval for blinatumomab
(BLINCYTO®, Amgen Inc.) for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell
precursor acute lymphoblastic leukemia (R/R ALL).
On July 11, 2017, the U.S. Food and Drug Administration approved blinatumomab (BLINCYTO®, Amgen Inc.) for
the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children.
On March 29, 2018, the U.S. Food and Drug Administration granted accelerated approval to BLINCYTO®
(blinatumomab) to treat adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) who are in
remission but still have minimal residual disease (MRD).
European Union:
On November 23, 2015, the European Commission granted conditional marketing authorization for
BLINCYTO®▼ (blinatumomab) for the treatment of adults with Philadelphia chromosome-negative (Ph–) relapsed
or refractory B-precursor acute lymphoblastic leukemia (ALL).
On June 18, 2018, the European Commission granted full marketing authorization for BLINCYTO®▼
(blinatumomab) based on the overall survival (OS) data from the Phase 3 TOWER study in adult patients with
Philadelphia chromosome-negative (Ph–) relapsed or refractory B-cell precursor acute lymphoblastic leukemia
(ALL).
On Aug 29, 2018, the European Commission approved an expanded indication for BLINCYTO®▼ (blinatumomab)
as monotherapy for the treatment of pediatric patients aged one year or older with Philadelphia chromosome-
negative relapsed or refractory CD19 positive B-cell precursor acute lymphoblastic leukemia (ALL), which is
refractory or in relapse after receiving at least 2 prior therapies or in relapse after receiving prior allogenic
hematopoietic stem cell transplantation
BLINCYTO® THE FIRST APPROVED T CELL ENGAGING ANTIBODY
▼This medicinal product is subject to additional monitoring.
All suspected adverse reactions should be reported.
45
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
Hematologic
MalignanciesSolid Tumors
LeukemiaAMG 701*
BCMA
Multiple
Myeloma
Preclinical Clinical
Short-Acting BiTE® Format
Half-Life–Extended BiTE® Format
AMG 673*
CD33
Leukemia
Melanoma
AMG 330*
CD33
Leukemia
AMG 420*
BCMA
Multiple
Myeloma
BLINCYTO®†
CD19
Lymphoma
AMG 757*
DLL3
Small Cell
Lung Cancer
AMG 596*
EGFRvIII
Brain
Prostate
OVERVIEW OF BITE® ANTIBODY CONSTRUCTS IN FORMAL DEVELOPMENT PROGRAMS
*Phase 1 development; †Phase 2 development; **Not yet enrolling patients
EGFRvIII, epidermal growth factor receptor variant III
Multiple
Indications AMG 562**
CD19
Lymphoma
46
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
• Animal studies really only give you a “best guess” of what to
expect:
– no animal model is 100% predictive of response in man
– sometimes animal studies can give a false sense of security
– however, these models may be useful in evaluation of
pathogenesis of potential toxicities
➢ Employ careful design and judicious use of animals!
TAKE-HOME MESSAGES
47
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
– Pharmacology/PK = Scientific Rationale, MoA
MABEL
– PK = ADME
PK/PD
– Toxicology = Safe FIH Starting Dose
Characterization of potential toxicity
Recommendation for safety
monitoring in the clinic
TAKE-HOME MESSAGES
48
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
GROUP EXERCISE
49
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
CALCULATE THE STARTING DOSE IN A 60KG PATIENT
Rat
(mg/kg)
Dog
(mg/kg)
NOAEL 2 1
HNSTD 20 10
STD10 80 30
• Dog is relevant species
• Calculate for Cancer patient versus Healthy volunteer
50
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
FIH STARTING DOSE
Patients (ICH S9): 1/10th rodent STD10 is 48 mg/m2
Dog is considered more appropriate species
HNSTD in dogs is: 200 mg/m2
Human start dose = 33 mg/m2 = 0.9 mg/kg = 54 mg/patient
Patients (CPMP): Caveat: only dog is relevant species!
1/10th Rodent MTD is 48 mg/m2
Human start dose = 1.3 mg/kg = 78 mg/patient
Healthy Volunteers: NOAEL is 12 mg/m2 in rat and 20 mg/m2 in dog
(ICH M3R2) Safety factor is ordinarily 10 fold
Human start dose = 2 mg/m2 = 0.05 mg/kg = 3 mg/patient
51
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
Toxicology
• NOAEL Cyno: 50 mg/kg
• HNSTD Cyno: 150 mg/kg
Pharmacology
• Minimally effective in vitro pharmacological effect: 0.1 g/mL
• 10% receptor occupancy: 0.033 g/mL
CALCULATE THE STARTING DOSE IN A 60KG PATIENTIMMUNE ACTIVATING ANTICANCER DRUG
52
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
Toxicology
• Is cyno a relevant species?
• NOAEL in Cyno: 50.0 mg/kg = 600 mg/m2
• HED: 600 mg/m2 : 37 = 16.0 mg/kg
adjust for inter-species differences in affinity / potency (not done)
• Apply >10-fold safety factor 1.6 mg/kg
• Increased to 160-fold: 0.1 mg/kg
CASE STUDY TGN1412
53
Provided Nov 29, 2018, as part of an oral presentation and is qualified by
such, contains forward-looking statements, actual results may vary
materially; Amgen disclaims any duty to update.
Pharmacology
• MABEL
• Minimally effective in vitro inhibition of T-cell proliferation: 0.1 g/mL ~0.003 mg/kg in man
• Initial 10% CD 28 receptor occupancy ~0.001 mg/kg in man
Maximum Recommended Starting Dose
0.001 mg/kg
CASE STUDY TGN1412: NOAEL VERSUS MABEL