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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
hormonesSurrogate 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 DrugsLymphoma 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 notedDenosumab 2010 RANK Ligand inhibitor noTocilizumab (Atlizumab ) 2010 Anti- IL-6R noBelimumab 2011 inihibition of B- cell activating factor no
Brentuximab 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 dataAlternative 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 ConcernGLP-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 YouSlide Credits:Dan Mellon(FDA)Heather Taylor (Genentech)
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