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Nor Cal SOT

Evaluation of Carcinogenic Risk for Biotechnology-Derived Therapeutics

Tom GelzleichterSeptember 27th, 2012

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1. Limitations on utility of standard rodent bioassays for biologics2. Historical approaches for risk assessment of biologics3. 2011 revisions to ICH S64. Examples of revised approach5. How will these changes impact risk communication?

Topics

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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

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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

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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

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What About Biologics?

Rarely are long term studies in rodents feasible for biologics due to antigenicity concerns or lack of bindingLack 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

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Challenges with Nongenotoxic Drugs:

What We’ve Learned From Risk Evaluation of Immunosuppressive Agents

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Human Neoplasms Associated with 13 Immunosuppressive Drugs

Type Drugs

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

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Two year bioassay results for immunosuppresive drugs

Drug Rat 2 yr Mouse 2 yr

Abatacept - Lymphomas and mammary tumors (MLV/MMT virus)

Dexamethasone Neg -

Prednisone - Neg

Busulfan - Thymic and ovarian

Cyclophosphamide multiple multiple

Azathioprine Lymphoma and squamous Lymphoma, hemangioendothelioma

Leflunomide Neg Lymphoma and lung

Methotrexate Neg Neg

Mycophenolate Neg Neg

Cyclosporine Neg Neg

Tacrolimus Neg Neg

sirolimus Neg Lymphoma and liver

everolimus Neg Neg

• Of the 5 positives, 4 are known genotoxicants• Poor concordance with known human risks• Only 2 correctly predict specific tumor risks

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ICH Guidance for Biologics (Original ICH S6, 1997)

Standard carc bioassays are generally inappropriate for biotech drugsWhen 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

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For Products that Support or Induce Proliferation (ICH S6, 1997)

Evaluate/review receptor expression in malignant and normal cellsIs 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

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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

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32 FDA-Licensed MAb’s to date: Two sponsors have conducted preclinical studies that impacted label

Generic NameYear Licensed by

FDA Target LT Carc studies on label?Muromonab-CD3 1986 T cell CD3 Receptor no

Abcixumab 1994 inhibition of glycoprotein IIb/IIIa noDaclizumab 1997 IL-2Rα receptor (CD25) noRituximab 1997 CD20 no

Basiliximab 1998 IL-2Rα receptor (CD25) noInfliximab 1998 inhibition of TNF-α signaling no

Palivizumab 1998 an epitope of the RSV F protein noTrastuzumab 1998 ErbB2 noGemtuzumab 2000 CD33 noAlemtuzumab 2001 CD52 noAdalimumab 2002 inhibition of TNF-α signaling noEfalizumab 2002 CD11a no

Ibritumomab 2002 CD20 noTositumomab 2003 CD20 noBevacizumab 2004 VEGF no

Cetuximab 2004 epidermal growth factor receptor noOmalizumab 2004 immunoglobulin E (IgE) no

Natalizumab2006

alpha-4 (α4) integrin,xenograft models of a4+ cell lines: no drug related impact

Panitumumab 2006 epidermal growth factor receptor noRanibizumab 2006 VEGF-A noEculizumab 2007 Complement system protein C5 no

Certolizumab pegol 2008 inhibition of TNF-α signaling noCanakinumab 2009 IL-1β noGolimumab 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]

Ofatumumab2009

CD20

7 month cyno tumorigenicity data included in label - no drug-

related effects noted

Denosumab 2010 RANK Ligand inhibitor noTocilizumab (Atlizumab )

2010Anti- IL-6R no

Belimumab 2011 inihibition of B- cell activating factor noBrentuximab vedotin 2011 CD30 noIpilimumab ( MDX-

101 )2011

blocks CTLA-4 no

• Two Sponsors conducted trials that impacted label

• One label impacted by published literature reports (ustekinumab)

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Label Claims for Non-MAb Therapeutics

Label Claim2 yr studies in one or two species glargine (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 label asparaginase (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,

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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

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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 modelsKO modelsAnimal disease modelsXenograft modelsIn vitro dataChronic tox data

Alternative data (lifetime phenotyping, labeling for proliferation)

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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)

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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”

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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

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Example: Class Effect Labeling

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityA 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….

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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

+ -

+ 25 5

- 15 35

Reddy, deGeorge, et al., 2010. Vet. Path. 47(4) 614-629

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Where is carcinogenic risk communicated currently in label?

Boxed warningSection 5: Warnings and Precautions

– “Immunosuppression” or “Malignancies”

Section 6: Adverse Events – “Malignancies”

Section13: Nonclinical Toxicology13.1 …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.

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

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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

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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

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Thank You

Slide Credits:Dan Mellon(FDA)Heather Taylor (Genentech)