James G. Farrelly, Ph.D. Pharmacology Team Leader

1. James G. Farrelly, Ph.D.Pharmacology Team Leader Division of Antiviral Drug Products Center for Drug Evaluation and Research Food and Drug Administration

2. Entecavir Genetic Toxicity • Entecavir is a nucleoside analog, a member of a class of molecules expected to be genetically toxic • Mode of action is consistent with its being a mutagen or a clastogen • Not an obligate chain terminator • It halts DNA synthesis after the addition of a few bases into the growing chain • It is clastogenic in vitro in a human lymphocyte assay • It is negative in the Ames assay and in a number of in vitro and in vivo genetic toxicology assays. • It is negative in the SHE-cell transformation assay

3. Genetic toxicity • Adefovir • Mutagenic in vitro • Induced chromosomal aberrations in vitro • Lamivudine • Mutagenic in two in vitro assays • Interferon • Not a genetic toxin

4. Male Rat Tumor Data

5. Female Rat Tumor Data

6. Male Mouse Tumor Data

7. Female Mouse Tumor Data

8. Carcinogenicity Studies • Interferon • No carcinogenicity studies carried out • Adefovir • Negative for carcinogenicity • Exposures in studies 10-fold for mice and 4-fold for rats • Lamivudine • Negative for carcinogenicity • Exposure in studies 34-fold in mice and 200-fold in rats

9. Carcinogenicity Assessment Committee • CAC founded in the late 1980’s • Founded to examine carcinogenicity protocols • Also interprets the outcome of carcinogenicity studies • Ensures that the assessment of protocols and studies will be consistent among review divisions • Two committees exist, an Executive CAC and a Full CAC

10. Executive CAC • Consists of four members • The Associate Director for the Center • A permanent carcinogenicity expert • Supervisor from the presenting division • A second Pharmacology Supervisor • The Exec CAC meets every Tuesday and reviews from one to four protocols or carcinogenicity studies

11. Full CAC • Reviews studies when the Exec CAC cannot agree or when a drug sponsor makes a request • Consists of • The Associate Director of the Center • The three associate Directors for the Offices • The individual Pharmacology Supervisors for the Divisions • The Full CAC meets very infrequently

12. Full CAC Voting • Does the CAC agree that the lung tumors in mice are relevant to human safety evaluation? • Yes – 16 No/Probably not – 2 Don’t know – 2 • Does the CAC agree that (1) the liver tumors in male mice and (2) the vascular tumors in female mice are relevant to human safety evaluation? • Yes – 17 No – 3 • Does the CAC agree that (1) hepatocellular adenomas and carcinomas in female rats, (2) the skin fibromas in female rats and (3) the brain gliomas in male and female rats are relevant to human safety evaluation? • Yes – 17 No - 3

13. Summary • Entecavir is a nucleoside analog which is a genetic toxin • Entecavir is carcinogenic in male and female rats and mice • Most of the tumors arise at high exposures in the animal studies • The carcinogenic effect is relevant to the human safety evaluation • Animal findings need to be balanced with the positive outcomes in the clinical trials and the nature of the disease