Dr. S. Harinarayana Rao

Transcription

1 Dr. S. Harinarayana Rao Theatre, Indian Habitat Centre, New Delhi July 30 31, 2013

2 Introduction Classification ICH 6 guidelines Innovative methods RCGM and EMEA Challenges Conclusion

3 What is a biopharmaceutical medicine? - A pharmaceutical synthesized by biotechnology. - inherently biological in nature

4 Biotechnology derived pharmaceuticals Hormones Growth Factors Cytokines Others Monoclonal antibody Antibody related products Nucleic acid products FSH, LH, GH, Insulin, insulin analogues PDGF, NGF, IGF1 IFNs, IL, GCSF, EPO Albumin, cloting factors, enzymes Murine, chimeric, humanized, rdna technology Single chain, fragments, fusion protein antigen, modified bacteria or virus, anti idiotype, mimotopes Autologous, allogenic, xenogenic Cell tissue organs Autologous, allogenic, xenogenic J. Sims/ Toxicology letters 120 (2001): 59-66

5 Small molecules Biotech product Structure Simple Complex Stability Stable Less stable Toxicology Unpredictable Predictable Immunogenicity Non immunogenic Highly immunogenic Dosing Daily Intermittent Animal use Species-independent Species-specific Regulatory guidelines Established Emerging Biological drugs are more complex molecules

6 Classified based on mode of action Pharmaceutical effects and toxicity with low species specificity EPO, GCSF, Insulin Pharmaceutical effects and toxicity with high species specificity Rituximab Toxic but no pharmaceutical effect in healthy animals Erbitux High therapeutic efficacy and no toxicity Herceptin

7 EPO Glycoprotein Mortality due to Iron deficiency and excess erythropoisis in all animals Rituximab Erbitux Herceptin chimeric mouse/human monoclonal antibody (mab) a chimeric monoclonal antibody against the human epidermal growth factor receptor (EGFR) humanised monoclonal antibody that binds to the HER2 protein B cell depletion in the peripheral blood, bone marrow and lymphatic tissues in Cynomolgus monkeys Severe skin reactions and deaths in the high dose group. skin lesions included scale formation,erythema, swelling, dermatitis injection-site trauma in the rhesus monkey Species specific toxicity for the monoclonal antibodies

8 Compounds that exhibits pharmaceutical effects and toxicity in healthy animals Main study: toxicology study with Pharmacological endpoints and kinetics Pharmacology study in disease model: eg: neurotrophic, tumor bearing animals

9 Compounds that exhibits toxicity but no pharmaceutical effects Toxicity: Repeated dose toxicology study with TK PK may be included

10 Immunological Anti product antibodies Host cell protein contamination Development of Immune tolerance to DNA vaccines Pharmacological Excessive pharmacological response Unknown receptor binding General Safety Local tolerance Effect of formulation or Excipient

11 Safety concerns for therapeutic Vaccines Immune mediated toxicity Induction of pro inflammatory response Hypersensitivity/anaphylaxis Adjuvant related toxicity Injection site reaction CBER,FDA

12 Safety concerns with cell based therapy Delivery procedure risk Ex vivo manipulation Potential inflammatory response Inappropriate cell proliferation/differentiation Cell migration to non target tissues CBER,FDA

13 Safety concerns for gene therapy products Risk of delivery procedure Vector/Virus bio distribution Viral replication and persistence in non target tissues Inappropriate immune activation Potential for insertional mutations and /oncogenicity CBER,FDA

14 Preclinical Testing of Biotechnology-Derived Pharmaceuticals usage of relevant vs. nonrelevant species usage of animal models of disease immunogenicity testing and its implications genotoxicity chronic toxicity carcinogenicity

15 Administration/Dose Selection* ROA, dosing regimen should mimic proposed clinical use alternative routes/regimens acceptable in some cases attainment of toxic dose & NOAEL desirable multiples of human dose needed to determine adequate safety margins can vary with product class & clinical indication * Sec 3.5

16 Standard toxicology paradigms often not adequate or appropriate Use of relevant species single relevant species with justification limited toxicology in a single nonrelevant species Alternative approaches transgenic animals homologous proteins animal models of disease * Sec 3.3

17 Keliximab is a monoclonal antibody specific to human and Chimpanzee CD4 and does not bind to CD4 from any other old world primates or rodents Chimpanzee, an endangered species is the only non human primate that expresses pharmacological activity HuCD4/Tg ( murine CD4 knockout, human CD4 knock-in) is used for evaluating toxicity studies. HuCD4/Tg mice produced by two transgenic manipulations. First murine Cd4 was knocked out by homologous recombination. These mice were next injected with human CD4 mini gene The first reported use of Tg mice in Toxicity testing of a biotechnology derived product

18 Preclinical studies in HuCD4/Tg mice conducted with keliximab Study Title Doses (mg/kg) Frequency of dosing and route Single dose toxicity 0, 0.3, 3, 10, 30 Once; iv 3-day toxicity 0, 1, 10, 100 Daily x3 ;iv 14-day toxicity study 0, 100 Daily x14;sc 6-month intermittent dose chronic toxicity study Male and female fertility and embryo-fetal development study 0, 30, 100 2/wkx4,then 1/monthx5;iv 0, 30, 100 males 2/wkx7, females 2/wkx8;iv Mouse micronucleus test 0, 5, 50, 500 Daily x2; iv Bugelskil et al. Hum Exp Toxicol 19: :2000

19 S.no MAbs Pharmacologically responsive animal Transgenic mouse 1 Trastuzumab Rhesus TgErbb2 (HER2) 2 Infliximab Chimpanzee Tg197 (htnf-α) 3 Adalimumab Cynomolgus Tg 197 (htnf-α) 4 Rituximab Cynomolgus hcd20/k/g7 5 Bevacizumab Cynomolgus Rho/VEGF 6 Efalizumab Chimpanzee TSG-p53

20 Pro s May reduce uncertainty Helps to conduct study in rodents Con s Not the clinical candidate It needs to be well characterized Comparability during the development process can be challenging Co-development pathway

21 Cost and resources Production capabilities Specificity / similarity of new molecule/animal to clinical candidate Bioanalytical analysis

22 In Vitro studies: Receptor binding studies or cell based assays for establishing comparability of biological activity with innovator. In Vivo studies: At least one repeat dose toxicity of 28 day duration with recovery period in relevant species. comparative nature with reference product. Local tolerance as part of above tox study. If relevant animal species NOT available a) transgenic animals may be used or b)toxicology studies should be done in two species (rodent and non rodent ) as per Schedule Y guidelines Contd

23 Summary (RCGM, DBT) The preclinical studies are designed for comparative evaluation of similar biologic with innovator product The animal model selected for toxicity testing should be pharmacological responsive strain Use of transgenic animal models may be used in case of nonavailability of relevant animal model Dose administration to mimic therapeutic schedule Minimum recommended dose levels are 1X, 2X and 5X with reference product to be tested at 1X Preclinical studies should be conducted at GLP facilities

24 Similar biological medicinal products containing biotechnology-derived proteins as active substance Non-Clinical and Clinical Issues, Feb 2006 Non clinical data : in vitro, in vivo studies (Pharmacodynamic effect, toxicity) Clinical studies :Pharmacokinetic, Pharmacodynamic, Efficacy trials

25 Biological activity in vitro/ in vivo In vivo studies Test system selection Number of animals Dose administration route Immunogenicity Safety pharmacology Pharmacokinetics and Pharmacodynamics Single dose Repeated dose Immunotoxicity Reproductive/ fertility/ embryo fetal and prenatal Development Carcinogenicity Local tolerance

26 Emerging guidelines: We need product specific guidance Require large quantity of therapeutic proteins ( Mabs) for toxicology testing by conventional studies Dose selection Species selection Immunogenicity

27 Relevant animal species Primates are the relevant animal species for monoclonal antibodies. None of the Indian CRO have Cynomolgus monkeys Outsourcing of studies is not cost effective Many CROs do not have experience in maintenance of transgenic animals.

28 General comment The value of in vivo non-clinical studies for the assessment of biosimilars is often limited particularly if studies on the reference product do not show much evidence of toxicity or where neutralizing antibodies are readily formed. Further, species specificity may restrict the available options in terms of suitable species. Source: Unknown

29 Preclinical development of biotech products needs to be a tailor made strategy Conventional non clinical paradigms are not relevant for biotechnology products Safety issues include biological contamination, exaggerated pharmacology and immunogenicity or potential carcinogenicity of growth factors and cell therapy products Guidelines only give a general frame Innovative methods needs to be used

30 References 1. Note for guidance on Preclinical safety evaluation of biotechnology derived pharmaceuticals.cpm/ic/302/95 2. Guidelines for generating preclinical and clinical data for r- DNA based vaccines, diagnostics and other biologicals Department of Biotechnology, Government of India, Guidelines on Similar Biologics: Regulatory requirements for marketing authorization in India, ICH guidelines S6 (R1)-Preclinical safety evaluation of biotechnology derived pharmaceuticals, June 2011

31 Thank you!