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27/11/2014

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AGAH WORKSHOP Critical Aspects of Integrated Drug Development -Expect the Unexpected!28. - 29. November 2014, Munich

Non-Clinical Development of Oncology MedicationsElisabeth (Lisa) Koch, DVM, PhD, DABT

PreClinical Safety (PCS) Consultants Ltd

PCS – The Integrated Drug Development Company

Non-clinical development

Clinical developmentPre-clinical development

CTA

Drug Development

■ Manufacturing ■ Pharmacology ■ PK/ADME ■ Toxicology ■ Regulatory

AGAH Workshop Expect the Unexpected 2014 2

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Biologics in Development – by Therapeutic Category

Source: Report from pharmaceutical research and manufacturers of America www.phrma.org

Small molecules are still in the majority

338 biologics in development in the US (2013 data)

Total of 771 oncology drugs in clinical development or awaiting FDA review (2014 data)


Shift from Chemotherapy to Targeted Therapies

Chemotherapies: target any quickly dividing cells such as cancer cells, but also quickly dividing normal cells such as gastrointestinal cells and hair roots

Targeted therapies: target specific molecules that are critical in the biochemical pathways used by cancer cells to grow, divide, and metastasize


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The Hope

Chemotherapy: unspecific, low efficacy, high

toxicity

Targeted therapy:

specific, more effective, less

toxic


Types of Targeted Therapies (1)

Hormone therapies e.g. Tamoxifen for estrogen receptor positive breast cancer

Signal transduction inhibitors e.g. Glivec (imatinib) for chronic myeloid leukemia e.g. Tarceva (erlotinib) for NSCLC e.g. Erbitux (cetuximab) for colorectal cancer

Monoclonal antibodies that deliver toxic molecules (ADC) Kadcyla (ado-trastuzumab + emtansine): for HER-2 positive

breast cancer Adcetris (brentuximab + vedotin): for Hodgkin lymphoma and

anaplastic large cell lymphoma


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Types of Targeted Therapies (2)

Angiogenesis inhibitors e.g. Avastin (bevacizumab) for renal cell carcinoma

Immunotherapies Provenge (sipuleucel-T) for men with metastatic prostate

cancer

Cancer vaccines Hepatitis B virus to prevent liver cancer Human papillomavirus to prevent cervical cancer

Gene therapies Gene expression modulators


Applicable Guidance Documents

Nonclinical evaluation for anticancer pharmaceuticals (ICH S9) Patients with advanced disease

Higher acceptability for toxicities of new therapies

Nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals (ICH M3 (R2)) Adjuvant therapy or healthy volunteers

Risk/benefit ratio is lower

Lower acceptability for toxicities in this healthier patient population

Preclinical safety evaluation of biotechnology-derived pharmaceuticals S6 (R1)


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Pharmacology

Identification of pathways

Screening compounds

Lead optimization

Identification of biomarkers


Signaling Pathways

For more information: O. Dreesen and AH Brivanlous, signaling pathways in cancer and embryonic stem cells, Stem Cell Rev. 2007, 3:7-17

Signaling pathways can be overexpressed in cancer cells

Signaling pathways can cross talk

If one signaling pathways is blocked by an anti-cancer agent other pathways may get turned on

Signaling pathways in cancer cells are also present in normal cells


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Screening of Compounds

In vitro• Biochemical assays• Cellular systems (proliferation, apoptosis, death, target inhibition, ……)

In vivo• Transplantation models • GEM (genetically engineered models)• Carcinogen-induced models• Spontaneous• Metastasis models


Pharmacokinetics and Metabolism

Limited pharmacokinetic parameters :•Peak plasma/serum levels•Area under the concentration curve (AUC)

•Half-life

Information on distribution, metabolism, and excretion should be

generated in parallel with clinical development


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Pharmacokinetic/Metabolism

Biologics

•No metabolism work

•Analytical methods for biologic drug

•Analytical method for anti-drug antibodies

Small molecules

•Extensive metabolism work

•Analytical assays to measure parent drug concentration

• Possible analytical assays to follow metabolites

•Distribution studies• Elimination studies


Toxicology

General toxicology

Genetic toxicology

Carcinogenesis

Reproductive toxicology

Immunotoxicology

Photo toxicology


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General toxicology

Toxicology studies to determine a no observed adverse effect level (NOAEL) or no effect level (NOEL) are not needed

The potential to recover from toxicity should be evaluated, however demonstration of complete recovery is not considered essential

The clinical schedule should be evaluated in toxicology studies


Common Schedules and Duration

Clinical Schedule Example of non-clinical treatment durations for general toxicity studies prior to Phase I

Once every 3-4 weeks Single doseDaily for 5-7 days, alternating weeks

Daily for 5-7 days, alternating weeks (2-dose cycles)

Two or three times a week Two or three times a week for 4 weeks

Daily Daily for 4 weeksWeekly One a week for 4-5 doses


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Determination of Clinical Schedule

Clinical schedulePK profile PD profile

Schedule in toxicology studies can be more frequent than in the clinic

Recovery from toxicity


Selection of Toxicity Species

Small Molecules

• One rodent (rat) and one non-rodent species (usually dog or monkey) needed

• Non-rodent species usually selected based on in vitro cross species metabolism data

Biologics

Need pharmacological relevant species

• homology of the target• target binding affinities• receptor-ligand occupancy• functional activity

Never do a study in a non-relevant species!


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Dose Selection for Toxicology Studies

Small Molecule

• Based on dose-range finding studies

• Establish the maximum tolerated dose

Biologics

The high dose is the highest of the two below:• a dose that provides the

maximum intended pharmacological effect in the preclinical species

• a dose that provides approximately 10-fold exposure multiple over the maximum exposure to be achieved in the clinic

Toxicity driven by unknown endpoints

Pharmacology driven by known endpoints


Duration of General Toxicology Studies to Support Clinical Development

Non-Oncology

• General toxicity studies of equal or longer duration needed to support clinical trials

Oncology

• Treatment can continue according to the patient’s response and can continue beyond the duration of the completed toxicology studies

• Highest dose or exposure tested in the nonclinical studies does not limit the highest dose in cancer patients

• Non-clinical data to support Phase 1 are sufficient for moving into Phase 2

• 3-month toxicology studies needed prior to Phase 3 trials


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Compassionate Use

Expanded access of an investigational drug outside of a

clinical study

Expanded access of an investigational drug outside of a

clinical study

FDA regulations allows access on a case-by-case basis

FDA regulations allows access on a case-by-case basis

Patient must have a serious or immediately life-threatening disease

Patient must have a serious or immediately life-threatening disease

Companies cannot use reports of success but have to monitor safety

and report side effects

Companies cannot use reports of success but have to monitor safety

and report side effects


Compassionate Use (cont.)

Glivec was tested in 2500 people in clinical studies, but Novartis supplied the drug to 5000 additional patients und der compassionate use provision

Following a report of the clinical trial results of Glivec in a New York television station Novartis received 8000 phone calls in one hour

Source: USA today 2001


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Genotoxicity and Carcinogenicity

Non-oncology

Genotoxicity studies needed prior to FIH

Carcinogenicity studies needed for

drugs intended to be used for at least 6

month

Oncology

Genotoxicity studies are not needed for

clinical development, but to support

marketing

Carcinogenicity studies are not

needed for compounds to treat

patients with advanced cancer


Combining Oncology Therapies

When given alone the cancer find ways to overcome the anticancer effect

When given alone the cancer find ways to overcome the anticancer effect

If one signaling pathway is blocked the tumor activates another

If one signaling pathway is blocked the tumor activates another

Combining multiple selective inhibitors

Designing compounds that inhibit multiple pathways


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Nonclinical Evaluations of Combinations

Approved compound + new drug

Each compound should be studied individually in toxicology studies

Data to support the rationale for a combination should be provided

If toxicity profile has been characterized in humans, a nonclinical study evaluating the combination is not needed


LysosomeCancer

cell

Antigen receptor

Monoklonalantibody

Linker

Antibody Drug Conjugates

Cytotoxic agent

• Kadcyla (ado-trastuzumab + emtansine): for HER-2 positive breast cancer

• Adcetris (brentuximab + vedotin): for Hodgkin lymphoma and anaplastic large cell lymphoma


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Determination of Starting Dose

Dose should have pharmacological effects and be reasonably safe

For small molecules interspecies scaling of the animal dose to an equivalent human dose is usually based on body surface area

For biopharmaceuticals the minimally anticipated biologic effect level (MABEL) should be considered


Starting Dose for Non-Oncology Small Molecule Compounds


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Determination of Starting Dose for Small Molecule Oncology Compound


NO

Is 1/10th of the STD10 of rodents severely toxic to non-rodents?

Determine dose severely toxic to 10% of rodents (STD10) and convert to mg/m2

YES

Starting dose Take 1/6 as starting dose

Determine non-rodent HNSTD

Example for Starting Dose Calculation

RAT

1/10 of STD10 = 60 mg/m2 phase 1 starting dose

Dose mg/kg

Dose mg/m2

Findings Effect Level

10 60 ↓ WBCC NOAEL

30 180 ↓ WBCC, histopathology lesions with tendency of recovery

MTD

100 600 All of the above + 1 animal sacrificed moribund

STD10

DOG

Dose mg/kg

Dose mg/m2

Findings Effect Level

1 20 ↓ WBCC NOAEL

3 60 ↓ WBCC, histopathology lesions with tendency of recovery

MTD

10 200 All of the above + 1 animal sacrificed moribund

ToxicDose

RA

TD

OG

1/10 of STD10 = 60 mg/m2 phase 1 starting dose


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Examples of 6 Escalation Steps

Step Dose mg/m2 % increase (modifiedFibonacci sequence)

1 60 100%2 120 67%3 200 50%4 300 40%5 420 30%6 550

21 phase 1 trials in the US between 1992-2008 more than half needed 6 or more dose escalation steps (Tourneau et all 2009)

Among 21 phase 1 trials in the US between 1992-2008 more than half needed 6 or more dose escalation steps (Tourneau et all 2009)


Identification of biomarkers


Biomarkers to detect disease

Biomarkers for toxicity

Biomarkers to monitor activity

Biomarkers to select patients

•Blood pressure as a measure for cardiovascular health

•Blood glucose to detect diabetes

•Liver enzymes for the evaluation of liver function

•Cardiac troponin T (cTnT) to assess myocardial damage

•Target inhibition in tumor biopsies

•Skin rash as surrogate biomarker for EGFR inhibition

•HER-2 receptor: 20-30% of breast cancers have this receptor and may respond to Herceptin (trastuzumab)

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inhibition of target in mouse tumor and/or surrogate (e.g. PBMC, skin)

target inhibition in surrogate (e.g. PBMCs, skin) at tolerated

doses in toxicity study

inhibition of target in in vitro assays

inhibition of target in tumor biopsies and/or surrogates

(e.g. PBMCs, skin)

Biomarker through Development


Biomarker Example

AEE788: combined EGFR and VEGFR pathway inhibitor from Novartis In vitro

EGFR/ErbB-1: IC50 of 0.11µM HER2/ErbB-2: IC50 of 0.22µM VEGF-2/KDR: IC50 of 0.96µM

Phase 1 primary endpoint: MTD based on DLTs tumor biopsies 2 skin biopsies, before and after treatment. Second biopsy overlapping the wound

from the first biopsy to assess VEGF pathway inhibition. p-EGFR inhibition (IC50): 0.033µM in skin and 0.0125µM in tumor no inhibition of p-VEGFR-2 and cyclin D1 in tumor tissue at tolerated doses

Novartis concluded that AEE788 would provide no additional benefit from currently available EGRF and VEGF inhibitors and terminated further development

Source: Baselga et all. Clin Cancer Research 2012


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For more information: David Thomas, inside bio industry analysis, www.biotech-now.org

Overall Phase 1 to FDA approval success

rate (2004-2011)

6.7 % for oncology12.1 % for all other therapeutic areas

combined

Success Rates During Clinical Development


What Drug for Which Patient?

Medication Patient SubpopulationTarceva (erlotinib) NSCLC with EGFR exon 19 deletions or

exon 21 substitution mutations (10% USA, 50% Asia)

Herceptin (tratuzumab) HER-2 overexpressing breast cancer (20-30%)

Zelboraf (vemurafenib) BRAF V600E mutation melanoma (50%)

Erbitux (cetuximab) K-Ras mutation negative, EGFR expressing (60%) colorectal cancer


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Are Targeted Therapies Less Toxic?


Examples of Toxicities for some Targeted Therapies

• hyperglycemia• skin rash• pneumonitis

mTorinhibition

• fluid retention• mucositis• cardiac conduction abnormalities

MET inhibition

• vision changes• hypophosphatemia• neutropenis

ALK inhibition

More information: Dy, G. K. and Adjei, A. A. (2013), Understanding, recognizing, and managing toxicities of targeted anticancer therapies. Cancer Journal for Clinicians, 63: 249–279

Targeted therapies have a wide range of side effects


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Toxicities of targeted therapies

• Target promoting cancer cell growth is also needed for normal cell function

On target toxicity or

mechanism based

toxicities

• Due to activity on multiple pathways

• Due to other unknown activity

Off target toxicity


Targeted Therapies with Cardiotoxicity

Target HER2 EGFR Bcr-Abl

PDGF KIT Raf VEGF RET FLT3

Herceptin (trastuzumab)

x

Tykerb(lapatinib)

x x

Glivec(imatinib

x x x

Tasigna(nilotinib)

x x x

Nexavar(sorafenib)

x x x x x x

Sutent(sunitinib)

x x x x


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Limitations of Toxicity Studies

Number of animals 20 sex/group for rodents

4 sex/group for dogs or monkeys

Conduct animal studies at high doses to compensate for lower number of animals

Do not treat toxicities caused by the drug under investigation

Some “minor” side effects are more serious in animals than in human e.g diarrhea, loss of appetite

May not be able to test high enough doses for oncology compounds


Are Targeted Therapies More Effective?

5-year survival rate

•all types of cancer: 49% in mid 1970’s to 68% from 2002-2008

•CML: from 31% to 89% post Glivec

20% decline in cancer death in the US since the early 1990’s


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Therapy Indication PFS* or TTP# (∆ month)

OS+

(∆ month)Sutent Renal cell cancer 25.3 5.0

Herceptin+Paclitaxel HER-2+ breast cancer

4.7 3.7

Tykerb+Capecitabin HER-2+ breastcancer

2.1 2.3

Avastin+INF-α Renal cell cancer 4.8 2.0

Tarceva Non small celllung cancer

5.2 3.4

Phase 3 Results of Targeted Therapies

* = Progression free survival # = Time to progression+ = Overall survival


Thank you for your attention!


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How to contact us:PreClinical Safety (PCS) Consultants LtdNauenstrasse 63A

CH-4052 Basel

Switzerland

Website: www.pcsconsultants.com

Elisabeth (Lisa) Koch, DVM, PhD, DABTTel: +1 303 325 5574

e-mail: [email protected]

PreClinical Safety (PCS) Consultants Ltd

PCS – The Integrated Drug Development Company

Abbreviations


ADC = antibody drug conjugate

BLA = biological license application

CHF = congestive heart failure

CNS = central nervous system

CTA = clinical trial application

DLT = dose limiting toxicity

ECG = electrocardiogram

EGFR = endothelial growth factor receptor

VEGFR = vascular endothelial growth factor receptor

FDA = food and drug administration

FIH = first in human

HED = human equivalent dose

HNSTD = highest non severely toxic dose

IND = investigational new drug

ICH = international conference on harmonization

LVEF = left ventricular ejection fraction

L = linker

MABEL = minimally anticipated effect level

NOAEL = no observed adverse effect level

NOEL = no observed effect level

MTD = maximum tolerated dose

NDA = new drug application

NSCLC = non-small cell lung cancer

PK = pharmacokinetic

PD = pharmacodynamic

OS = overall survival

PFS = progression free survival

STD = severely toxic dose

TTP = time to progression

WBCC = white blood cell count

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