training course oncology nonclinical development …

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




MISSION OF NONCLINICAL DRUG DEVELOPMENT

Desired Effects Undesired Effects

Benefit Risk

4




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




NONCLINICAL GUIDELINES

•ICH

•EMA

•FDA

6




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




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




• 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




• 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




• 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




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




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




FDA (J. DeGeorge et al., 1998)

14




GUIDE FOR STARTING DOSE SELECTION

15




16




ICH S9

17




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




ICH S9 - SCHEDULE OF NONCLINICAL STUDIES RELATIVE TO PROPOSED PHASE 1 TRIAL

19




• 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




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




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




ICH S9 – Q&A 2018

23




ICH S9 – Q&A 2018

24




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




ICH S6(R1) – BIOTECHNOLOGY-DERIVED PHARMACEUTICALS

26




• 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




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




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




• 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




• 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




CD28 superagonist Ab TGN1412

Life-threatening conditions

in FIH trial

THE TEGENERO INCIDENT IN 2006

32




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




• 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




NONCLINICAL GUIDELINES AND PAPERS

35




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




BITE® ANTIBODY CONSTRUCT IN VITRO DEMONSTRATION OF REDIRECTED LYSIS

37




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




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




HEME TARGET BITE®-INDUCED HUMAN T CELL ACTIVATION IN VITRO

40




• 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




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




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




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




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




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




• 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




– 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




GROUP EXERCISE

49




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




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




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




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




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

training course oncology nonclinical development …

Documents