Evaluation of Carcinogenic Risk for Biotechnology-Derived Therapeutics

1. Nor Cal SOT Evaluation of Carcinogenic Risk for Biotechnology-Derived Therapeutics Tom Gelzleichter September 27th, 2012

2. Topics • 1. Limitations on utility of standard rodent bioassays for biologics • 2. Historical approaches for risk assessment of biologics • 3. 2011 revisions to ICH S6 • 4. Examples of revised approach • 5. How will these changes impact risk communication?

3. Main Objective of Carcinogenesis Testing for Pharmaceuticals A product-specific assessment of carcinogenic potential is used to communicate risk and provide input to the risk management plan along with labeling proposals, clinical monitoring, post-marketing surveillance

4. 2 year bioassays in general have limited utility for all chemical classes • Interpretation difficult due to: • Lack of known negative controls (IARC only classifies one chemical as probably not carcinogenic in humans) • Susceptibility determined by genotype, sex and test conditions • Examples: cigarette smoke, arsenic, benzene were challenging to find rodent models that gave positive results • Lack of concordance across sexes, species (rarely are tumors found in all 4 genotypes i,.e., rat/mouse/M/F) • Inter-rodent predictivity (rat:mouse) 70-75% • Validation efforts have been heavily skewed towards certain chemical classes (plus, nearly all have been genotoxicants) • Poor concordance for immunotoxicants, some hormones • Poor reproducibility (only 57% concordance when repeated) • Positivity rate is extremely high • In NTP studies, 68% of tested chemicals are positive in at least one of the 4 genotypes • 40% of marketed pharmaceuticals and food additives are positive

5. Why are Chronic Rodent Bioassays Still Used? • Most known human carcinogens are positive in at least one of the 4 genotypes tested, when evaluated at MTD • Only 5-10% of positives are strictly rodent carcinogens • i.e, has some positive predictive value • However, rate of false positives poorly understood • Limitations of the assay limit the utility • Typically used to inform label, informed consent • Rarely will regulatory agencies use this data in isolation for decision-making

6. What About Biologics? Limitations in data interpretation and lack of validation limit utility • Rarely are long term studies in rodents feasible for biologics due to antigenicity concerns or lack of binding • Lack of validation data • Limited data for nongenotoxic carcinogens • Virtually no validation efforts with large molecules (e.g., Tg-AC transgenic model) • Known lack of concordance for immunosuppressive agents, many hormones • Surrogate molecules: Discouraged given difficulties in verifying that surrogate accurately reflects the biology of clinical candidate • Other data: • Data from in class or related drugs • Transgenic/ko • Xenograft studies

7. Challenges with NongenotoxicDrugs: What We’ve Learned From Risk Evaluation of Immunosuppressive Agents

8. Human Neoplasms Associated with 13 Immunosuppressive Drugs Source: Bugelski et al.(2010) Int. J. Toxicol. 29(5) 435-66

9. Two year bioassay results for immunosuppresive drugs • Of the 5 positives, 4 are known genotoxicants • Poor concordance with known human risks • Only 2 correctly predict specific tumor risks

10. ICH Guidance for Biologics (Original ICH S6, 1997) • Standard carc bioassays are generally inappropriate for biotech drugs • When there is a concern, “a variety of approaches may be considered to evaluate risk” • In case where product is biologically active and nonimmunogenic and other studies have not provided sufficient information to assess risk, then consider a singe rodent bioassay

11. For Products that Support or Induce Proliferation (ICH S6, 1997) Yes No • In vitro evaluations may be sufficient • Further studies in relevant model • Incorporate sensitive indices of proliferation into chronic studies • If biologically active and nonimmunogenicconsiderlong term assay Evaluate/review receptor expression in malignant and normal cells Is there evidence that can stimulate growth of normal or malignant cells? Cause for concern?

12. Answer: In reality, very few chronic studies have been conducted that have actually impacted product labels Question: Given the limitations of chronic bioassays and ICH guidance, what type of carc studies have been conducted for biologics?

13. 32 FDA-Licensed MAb’s to date: Two sponsors have conducted preclinical studies that impacted label • Two Sponsors conducted trials that impacted label • One label impacted by published literature reports (ustekinumab)

14. Label Claims for Non-MAb Therapeutics

15. New ICH S6 Revision (ICH S6 R1, June 2011) To better inform risk, a new paradigm has been implemented by ICH When an assessment is warranted (i.e., chronic dosing, appropriate patient population, etc.) a weight of evidence approach is now advocated More emphasis on post-marketing surveillance

16. What Can this Include? • Assessment of risk based on published literature and internal data • Clinical • Market surveillance • Human epidemiology • Genetic diseases • Polymorphisms • Class effects • Mechanistic data • Is there impact on pathways known to be associated with malignancy risk • Immunosuppression, chronic inflammation • Downstream signaling through pathways associated with risk • Transgenic models • KO models • Animal disease models • Xenograft models • In vitro data • Chronic tox data • Alternative data (lifetime phenotyping, labeling for proliferation)

17. Recommendations per ICH S6 R1, 2011 • Cause for concern • Hazard best addressed by product labeling and risk management practices • Sponsor can propose additional studies to mitigate concern • Risk unclear • Consider studies as discussed in ICH S6, 1997) • Risk considered low • Additional rodent bioassays not warranted Outcome of Weight Based Assessment

18. Example: PCSK9 Inhibitor Class • FDA has provided guidance to all sponsors that are targeting PCSK9 (LDL-c lowering therapies) • Recommends a “Thorough Carcinogenicity Assessment” as described in ICH S6 (R1) • Requests that it is submitted early in development program (e.g., EOP2) • Includes formal evaluation of immunosuppressive potential (recommends 12 week study in cynos in combo w/ statin) • Specific interest in NK cell activity, CD8+ T cell cytolyticactivity • Includes evaluation of impact on bile acid synthesis • “…evidence of immunosuppression and/or a sustained increase in bile acid secretion and/or intestinal bile acid load would be disclosed in the label as potential cancer risks”

19. Example: Studies to Mitigate Cause for Concern • GLP-1 analogs and C cell tumors • Rodent bioassays identified increases in C-cell tumors • Follow-up in vitro studies evaluated GLP-1 expression in rodent, monkey and human C cells • GLP-1 expression was much lower in humans, monkeys relative to rodents • GLP-1 agonists stimulated measurable C-cell calcitonin release in rodents but not human or monkey cells • Calcitonin levels evaluated in 5000 patients treated for up to two years with no evidence of increase • Longitudinal studies have not identified causal association between GLP-1 analogs and C cell pathology • However, FDA AERS database supports a potential risk of thyroid cancer with exenatide • Current label (liraglutide): • In mice … a dose-related increase in benign thyroid C-cell adenomas was seen… • In rats … a treatment-related increase in benign thyroid C-cell adenomas was seen… • Human relevance of thyroid C-cell tumors in mice and rats is unknown and could not be determined by clinical studies or nonclinical studies

20. Example: Class Effect Labeling 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A carcinogenicity study was not conducted with belatacept. However, a murine carcinogenicity study was conducted with abatacept (a more active analog in rodents) to determine the carcinogenic potential of CD28 blockade. Weekly subcutaneous injections of 20, 65, or 200 mg per kg of abatacept were associated with increases in the incidence of malignant lymphomas (all doses) and mammary gland tumors….

21. Utility of General Tox Study Results Reddy, deGeorge, et al., 2010. Vet. Path. 47(4) 614-629 • Predictivity of 6- or 12 month general tox studies for 2 yr bioassay (rats) • Histology evaluation (+ = increase in hyperplasia, hypertrophy, and atypical cellular foci (e.g., multinucleated cells, dysplasia, etc.) • 2 yr rat bioassay (+ = increase in significant increase in tumors) • 80 pharmacuticals evaluated (all FDA approved, sufficient rat data available for eval) • 30 rat carcinogens, 50 noncarcinogens • Positive predictivity: 63% • Negative predictivity: 88% • False negatives: 6%

22. Where is carcinogenic risk communicated currently in label? • Boxed warning • Section 5: Warnings and Precautions • “Immunosuppression” or “Malignancies” • Section 6: Adverse Events • “Malignancies” • Section13: Nonclinical Toxicology 13.1 …carcinogenesis • “…must state whether long term studies in animals have been performed to evaluate the carcinogenic potential and, if so, the species and results” • “…any precautionary statement on these topics must include practical, relevant advice to the prescriber on the significance of these animal findings. • Human data suggesting that the drug may be carcinogenic … as described in the ‘Warning and Precautions’ section, must not be included in this subsection of the labeling.” • Section17: Patient Counseling Information Source: Dan Mellon, FDA SOT 2012 Presentation.

23. Posited Strategy for Labeling Revisions (Proposed for SOT Discussion Only: Not Formal FDA Position)

26. Bottom Line: Changes in risk communication in not only product labels but informed consent documents, investigator brochures, etc. are anticipated but regulatory agencies have yet to address what these changes will look like

27. Summary • Historically, classical lifetime rodent bioassays have had limited utility for malignancy risk assessment for biologics and have had little impact on informing product labels • ICH has implemented new paradigm: Weight based assessment that incorporates clinical, preclinical and mechanistic data • It remains to be seen how these risk assessments will be communicated in product labels

28. Thank You Slide Credits: Dan Mellon(FDA) Heather Taylor (Genentech) © 2009, Genentech / Proprietary information – Please do not copy, distribute or use without prior written consent.