PreClinical Safety (PCS) Consultants Ltd

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1 PreClinical Safety (PCS) Consultants Ltd AGAH WORKSHOP Critical Aspects of Integrated Drug Development - Expect the Unexpected! November 2014, Munich Non-Clinical Development of Oncology Medications Elisabeth (Lisa) Koch, DVM, PhD, DABT PCS The Integrated Drug Development Company Drug Development CTA Pre-clinical development Clinical development Non-clinical development Manufacturing Pharmacology PK/ADME Toxicology Regulatory AGAH Workshop Expect the Unexpected

2 Biologics in Development by Therapeutic Category 338 biologics in development in the US (2013 data) Total of 771 oncology drugs in clinical development or awaiting FDA review (2014 data) Small molecules are still in the majority Source: Report from pharmaceutical research and manufacturers of America AGAH Workshop Expect the Unexpected 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 AGAH Workshop Expect the Unexpected

3 The Hope Chemotherapy: unspecific, low efficacy, high toxicity Targeted therapy: specific, more effective, less toxic AGAH Workshop Expect the Unexpected 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 AGAH Workshop Expect the Unexpected

4 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 AGAH Workshop Expect the Unexpected 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) AGAH Workshop Expect the Unexpected

5 Pharmacology Identification of pathways Screening compounds Lead optimization Identification of biomarkers AGAH Workshop Expect the Unexpected Signaling Pathways Signaling pathways can be overexpressed in cancer cells Signaling pathways can cross talk If one signaling pathways is blocked by an anticancer agent other pathways may get turned on Signaling pathways in cancer cells are also present in normal cells For more information: O. Dreesen and AH Brivanlous, signaling pathways in cancer and embryonic stem cells, Stem Cell Rev. 2007, 3:7-17 AGAH Workshop Expect the Unexpected

6 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 AGAH Workshop Expect the Unexpected 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 AGAH Workshop Expect the Unexpected

7 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 AGAH Workshop Expect the Unexpected Toxicology General toxicology Genetic toxicology Carcinogenesis Reproductive toxicology Immunotoxicology Photo toxicology AGAH Workshop Expect the Unexpected

8 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 AGAH Workshop Expect the Unexpected Common Schedules and Duration Clinical Schedule Once every 3-4 weeks Daily for 5-7 days, alternating weeks Example of non-clinical treatment durations for general toxicity studies prior to Phase I Single dose 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 weeks Weekly One a week for 4-5 doses AGAH Workshop Expect the Unexpected

9 Determination of Clinical Schedule Recovery from toxicity PK profile Clinical schedule PD profile Schedule in toxicology studies can be more frequent than in the clinic AGAH Workshop Expect the Unexpected 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 nonrelevant species! AGAH Workshop Expect the Unexpected

10 Dose Selection for Toxicology Studies Small Molecule Based on dose-range finding studies Establish the maximum tolerated dose Toxicity driven by unknown endpoints 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 Pharmacology driven by known endpoints AGAH Workshop Expect the Unexpected 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 AGAH Workshop Expect the Unexpected

11 Compassionate Use Expanded access of an investigational drug outside of a clinical study FDA regulations allows access on a case-by-case basis 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 AGAH Workshop Expect the Unexpected 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 AGAH Workshop Expect the Unexpected

12 Genotoxicity and Carcinogenicity Nononcology Oncology Genotoxicity studies needed prior to FIH Genotoxicity studies are not needed for clinical development, but to support marketing Carcinogenicity studies needed for drugs intended to be used for at least 6 month Carcinogenicity studies are not needed for compounds to treat patients with advanced cancer AGAH Workshop Expect the Unexpected Combining Oncology Therapies When given alone the cancer find ways to overcome the anticancer effect Combining multiple selective inhibitors If one signaling pathway is blocked the tumor activates another Designing compounds that inhibit multiple pathways AGAH Workshop Expect the Unexpected

13 Nonclinical Evaluations of Combinations 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 Approved compound + new drug AGAH Workshop Expect the Unexpected Antibody Drug Conjugates Lysosome C a n c e r c e l l Antigen receptor Linker Cytotoxic agent Monoklonal antibody Kadcyla (ado-trastuzumab + emtansine): for HER-2 positive breast cancer Adcetris (brentuximab + vedotin): for Hodgkin lymphoma and anaplastic large cell lymphoma AGAH Workshop Expect the Unexpected

14 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 AGAH Workshop Expect the Unexpected Starting Dose for Non-Oncology Small Molecule Compounds AGAH Workshop Expect the Unexpected

15 Determination of Starting Dose for Small Molecule Oncology Compound Determine dose severely toxic to 10% of rodents (STD 10 ) and convert to mg/m2 Is 1/10 th of the STD 10 of rodents severely toxic to non-rodents? NO YES Determine nonrodent HNSTD Starting dose Take 1/6 as starting dose AGAH Workshop Expect the Unexpected Example for Starting Dose Calculation R A T RAT Dose mg/kg Dose mg/m2 Findings Effect Level WBCC NOAEL WBCC, histopathology lesions with MTD tendency of recovery All of the above + 1 animal sacrificed moribund STD 10 1/10 of STD 1/10 of STD 10 = 60 mg/m 10 = 60 mg/m 2 phase 2 phase 1 starting dose 1 starting dose Dose mg/kg Dose mg/m2 Findings Effect Level D O G DOG 1 20 WBCC NOAEL 3 60 WBCC, histopathology lesions with MTD tendency of recovery All of the above + 1 animal sacrificed moribund Toxic Dose AGAH Workshop Expect the Unexpected

16 Examples of 6 Escalation Steps Step Dose mg/m2 % increase (modified Fibonacci sequence) % % % % % Among 21 phase 21 phase 1 trials 1 trials in the in US the between US between more more than half than half needed 6 or 6 more more dose dose escalation steps steps (Tourneau et all et 2009) all 2009) AGAH Workshop Expect the Unexpected Identification of biomarkers Biomarkers to detect disease Biomarkers for toxicity 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 Biomarkers to monitor activity Target inhibition in tumor biopsies Skin rash as surrogate biomarker for EGFR inhibition Biomarkers to select patients HER-2 receptor: 20-30% of breast cancers have this receptor and may respond to Herceptin (trastuzumab) AGAH Workshop Expect the Unexpected

17 Biomarker through Development inhibition of target in in vitro assays 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 tumor biopsies and/or surrogates (e.g. PBMCs, skin) AGAH Workshop Expect the Unexpected Biomarker Example AEE788: combined EGFR and VEGFR pathway inhibitor from Novartis In vitro EGFR/ErbB-1: IC 50 of 0.11µM HER2/ErbB-2: IC 50 of 0.22µM VEGF-2/KDR: IC 50 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 (IC 50 ): 0.033µM in skin and µM 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 AGAH Workshop Expect the Unexpected

18 Success Rates During Clinical Development Overall Phase 1 to FDA approval success rate ( ) 6.7 % for oncology 12.1 % for all other therapeutic areas combined For more information: David Thomas, inside bio industry analysis, AGAH Workshop Expect the Unexpected What Drug for Which Patient? Medication Tarceva (erlotinib) Herceptin (tratuzumab) Zelboraf (vemurafenib) Erbitux (cetuximab) Patient Subpopulation NSCLC with EGFR exon 19 deletions or exon 21 substitution mutations (10% USA, 50% Asia) HER-2 overexpressing breast cancer (20-30%) BRAF V600E mutation melanoma (50%) K-Ras mutation negative, EGFR expressing (60%) colorectal cancer AGAH Workshop Expect the Unexpected

19 Are Targeted Therapies Less Toxic? AGAH Workshop Expect the Unexpected Examples of Toxicities for some Targeted Therapies mtor inhibition MET inhibition ALK inhibition hyperglycemia skin rash pneumonitis fluid retention mucositis cardiac conduction abnormalities vision changes hypophosphatemia neutropenis Targeted therapies have a wide range of side effects More information: Dy, G. K. and Adjei, A. A. (2013), Understanding, recognizing, and managing toxicities of targeted anticancer therapies. Cancer Journal for Clinicians, 63: AGAH Workshop Expect the Unexpected

20 Toxicities of targeted therapies On target toxicity or mechanism based toxicities Target promoting cancer cell growth is also needed for normal cell function Off target toxicity Due to activity on multiple pathways Due to other unknown activity AGAH Workshop Expect the Unexpected Targeted Therapies with Cardiotoxicity Target HER2 EGFR Bcr- Abl PDGF KIT Raf VEGF RET FLT3 Herceptin (trastuzumab) Tykerb (lapatinib) x x x Glivec (imatinib Tasigna (nilotinib) Nexavar (sorafenib) Sutent (sunitinib) x x x x x x x x x x x x x x x x AGAH Workshop Expect the Unexpected

21 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 AGAH Workshop Expect the Unexpected Are Targeted Therapies More Effective? 5-year survival rate all types of cancer: 49% in mid 1970 s to 68% from CML: from 31% to 89% post Glivec 20% decline in cancer death in the US since the early 1990 s AGAH Workshop Expect the Unexpected

22 Phase 3 Results of Targeted Therapies Therapy Indication PFS* or TTP# ( month) OS + ( month) Sutent Renal cell cancer Herceptin+Paclitaxel Tykerb+Capecitabin HER-2 + breast cancer HER-2 + breast cancer Avastin+INF-α Renal cell cancer Tarceva Non small cell lung cancer * = Progression free survival # = Time to progression + = Overall survival AGAH Workshop Expect the Unexpected Thank you for your attention! AGAH Workshop Expect the Unexpected

23 PreClinical Safety (PCS) Consultants Ltd How to contact us: PreClinical Safety (PCS) Consultants Ltd Nauenstrasse 63A CH-4052 Basel Switzerland Website: Elisabeth (Lisa) Koch, DVM, PhD, DABT Tel: 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 AGAH Workshop Expect the Unexpected