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

2. ©2012, Genentech 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? Topics

3. ©2012, Genentech 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. ©2012, Genentech 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. ©2012, Genentech 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. ©2012, Genentech What About Biologics? 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 Limitations in data interpretation and lack of validation limit utility

7. ©2012, Genentech Challenges with Nongenotoxic Drugs: What We’ve Learned From Risk Evaluation of Immunosuppressive Agents

8. ©2012, Genentech Human Neoplasms Associated with 13 Immunosuppressive Drugs TypeDrugs Lymphoma Dexamethasone, prednisone, busulfan, azathioprine, methotrexate, mycophenolate, cyclosporin A, tacrolimus Squamous Cell Carcinoma Prednisone, busulfan, azathioprine, methotrexate, mycophenolate, cyclosporin A, tacrolimus Kaposi Sarcoma Dexamethasone, prednisone, busulfan, azathioprine, methotrexate, mycophenolate, cyclosporin A Urologic Prednisone, azathioprine, mycophenolate, cyclosporin A, tacrolimus Melanoma mycophenolate Multiple cyclophosphamide Source: Bugelski et al.(2010) Int. J. Toxicol. 29(5) 435-66

9. ©2012, Genentech Two year bioassay results for immunosuppresive drugs DrugRat 2 yrMouse 2 yr Abatacept-Lymphomas and mammary tumors (MLV/MMT virus) DexamethasoneNeg- Prednisone-Neg Busulfan-Thymic and ovarian Cyclophosphamidemultiple AzathioprineLymphoma and squamousLymphoma, hemangioendothelioma LeflunomideNegLymphoma and lung MethotrexateNeg MycophenolateNeg CyclosporineNeg TacrolimusNeg sirolimusNegLymphoma and liver everolimusNeg Of the 5 positives, 4 are known genotoxicants Poor concordance with known human risks Only 2 correctly predict specific tumor risks

10. ©2012, Genentech 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. ©2012, Genentech For Products that Support or Induce Proliferation (ICH S6, 1997) Evaluate/review receptor expression in malignant and normal cells Is there evidence that can stimulate growth of normal or malignant cells? Cause for concern? Further studies in relevant model Incorporate sensitive indices of proliferation into chronic studies If biologically active and nonimmunogenic consider long term assay Yes No In vitro evaluations may be sufficient

12. ©2012, Genentech Question: Given the limitations of chronic bioassays and ICH guidance, what type of carc studies have been conducted for biologics? Answer: In reality, very few chronic studies have been conducted that have actually impacted product labels

13. ©2012, Genentech 32 FDA-Licensed MAb’s to date: Two sponsors have conducted preclinical studies that impacted label Generic Name Year Licensed by FDATargetLT Carc studies on label? Muromonab-CD3 1986T cell CD3 Receptor no Abcixumab1994 inhibition of glycoprotein IIb/IIIa no Daclizumab 1997IL-2Rα receptor (CD25)no Rituximab 1997 CD20 no Basiliximab 1998IL-2Rα receptor (CD25)no Infliximab 1998inhibition of TNF-α signalingno Palivizumab 1998an epitope of the RSV F proteinno Trastuzumab 1998 ErbB2 no Gemtuzumab 2000 CD33 no Alemtuzumab 2001 CD52 no Adalimumab 2002 inhibition of TNF-α signaling no Efalizumab 2002 CD11a no Ibritumomab 2002 CD20 no Tositumomab 2003 CD20 no Bevacizumab 2004 VEGF no Cetuximab 2004 epidermal growth factor receptor no Omalizumab 2004 immunoglobulin E (IgE) no Natalizumab 2006 alpha-4 (α4) integrin, xenograft models of a4+ cell lines: no drug related impact Panitumumab 2006epidermal growth factor receptorno Ranibizumab 2006 VEGF-A no Eculizumab 2007 Complement system protein C5 no Certolizumab pegol2008 inhibition of TNF-α signaling no Canakinumab 2009 IL-1β no Golimumab 2009 TNF-alpha inihibitor no Ustekinumab 2009 anti-IL12/IL23 Decreased host defense to tumors with surrogate; knockout mice susceptible to tumors [Data not from Sponsor-run trials] Ofatumumab 2009 CD20 7 month cyno tumorigenicity data included in label - no drug- related effects noted Denosumab 2010 RANK Ligand inhibitorno Tocilizumab (Atlizumab ) 2010 Anti- IL-6Rno Belimumab 2011 inihibition of B- cell activating factorno Brentuximab vedotin 2011 CD30no Ipilimumab ( MDX- 101 ) 2011 blocks CTLA-4no Two Sponsors conducted trials that impacted label One label impacted by published literature reports (ustekinumab)

14. ©2012, Genentech Label Claims for Non-MAb Therapeutics Label Claim 2 yr studies in one or two speciesglargine (insulin analog), ocreotide (somatostatin analog), teriparatide (parathyroid hormone analog), IGF-1, gonadotropin releasing hormone, exenatide, liraglutide (incretin mimetic), pulmozyme (rhDNAse), abatacept Two year carc studies have not been performed… But tumors ID’ed in chronic tox studies aspart, glusine, and lispro (insulin analogs), calcitonin, pamlinitide (amylin hormone analog), Hypothical risk stated in labelasparaginase (alkylating agent) Two year carc studies in animals have not been performed…. humulin, novolin, lente, ultralente, Exubera, detemir, genotropin, humantrope, norditropin, norIVitropin, nutropin, omnitrope, protropin, siazen, serostim, valtropin, iplex, bioclate, helixate, kogenate, recombinate, reFacto, BeneFIX, ceprotin, aldurazyme, elaprase, naglazyme, fabrazyme, aralast, prolastin, lactaid, arco-lase, cotazym, creon, donnazyme, pancrease, viokase, zymase, adagen octagam, albumarc, albumin, albuminar, albuRx, albutein, flexbumin, buminate, plasbumin, neupogen, neulasta, leukine, neumega, Gonal-F, Follistim, ovidrel, luveris, infergen, roferon-A, Pegasys, Intron A, Peg-Intron, Alferon N, Avonex, rebif, betaseron, actimmune, proleukin, activase, retavase, TNKase, abbokinase, NovoSeven, Xigris, kepivance, regranex, granulex, natrecor, botox, myoblock collagenase, xiaflex, santyl, amphadase, hydase, vitrase, hylenex, oncaspar, elitek, refludan, angiomax, streptase, eminase, antril, kinaret, thioglobulin, fuzeon, somavert, crofab, digifab, ontak,

15. ©2012, Genentech 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. ©2012, Genentech 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. ©2012, Genentech Recommendations per ICH S6 R1, 2011 Outcome of Weight Based Assessment Cause for concern Hazard best addressed by product labeling and risk management practices Sponsor can propose additional studies to mitigate concern Risk considered low Additional rodent bioassays not warranted Risk unclear Consider studies as discussed in ICH S6, 1997)

18. ©2012, Genentech 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 cytolytic activity –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. ©2012, Genentech 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. ©2012, Genentech 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. ©2012, Genentech Utility of General Tox Study Results 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% Chronic Tox (rat) 2 yr Bioassay +- +255 -1535 Reddy, deGeorge, et al., 2010. Vet. Path. 47(4) 614-629

22. ©2012, Genentech 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. ©2012, Genentech Posited Strategy for Labeling Revisions (Proposed for SOT Discussion Only: Not Formal FDA Position)

24. ©2012, Genentech

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. ©2012, Genentech 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. ©2012, Genentech Page 28 © 2009, Genentech / Proprietary information – Please do not copy, distribute or use without prior written consent. Thank You Slide Credits: Dan Mellon(FDA) Heather Taylor (Genentech)