BIOTECHNOLOGY INDUSTRY ORGANIZATION 1

BIO-Latin America

Regulatory Session

10 September 2014 Rio de Janeiro

Andreas Baumann, Bayer

Rafael Ponce, Amgen

Paul Andrews, Eisai

Frank Brennan, UCB

Tim McLachlan, Novartis

Nonclinical Safety Assessment of Biotherapeutics

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BioSafe Organization and Annual Meetings

BioSafe General Membership

BioSafe Leadership Committee

Special Biologics Work

Group

Pharmacokinetics /

Pharmacodynamics

(PK/PD) Work Group

Mechanism of Action /

Mechanism of Toxicity

Work Group

BioSafe General Membership Meeting (Spring)

BioSafe Europe (Fall)

BioChina , Bio Latin America

BIO International Conference

BioSafe - FDA Liaison Meetings (Yearly) BioSafe –Liaison Meetings with other HA’s (EMA, PMDA, CFDA)

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o To serve as a resource for BIO members and BIO staff by identifying and responding to key scientific and regulatory issues related to the preclinical safety evaluation of biopharmaceutical products.

o We are representatives from pharmacology, pharmacokinetic, toxicology and regulatory departments of large and small biopharmaceutical companies.

We share a common mission

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o Identification of target organs of toxicity and characterization of those toxicities

o Nature of effect, reversibility, translatability (animals-to-humans)

o Inform patient monitoring

o Establish the relationship between safety observations and drug exposure (Cmax and/or AUC)

o Goal of nonclinical safety testing is the identification of:

o Safety margins or therapeutic windows

o Safe starting doses, dose escalation rationale

Nonclinical Safety Assessment of New Therapeutics – View from BIOSafe

Goal: The evaluation and identification of potential human safety issues

through evaluations in predictive model systems

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• These principles are outlined in:

o ICH S6(R1) [Preclinical safety evaluation of biotechnology-derived pharmaceuticals]

o ICH S9 [Nonclinical evaluation for anticancer pharmaceuticals]

o ICH M3(R2) [Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals]

o WHO Guideline on rDNA Products

Nonclinical Safety Assessment of Biotherapeutics – Regulatory Background

Generally, do HA’s in Latin America accept nonclinical

submissions conducted in accordance with these guidances?

Are there routine areas of concern or additional expectations in

Latin America ?

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Goal: The evaluation and identification of potential human safety issues through evaluations in predictive model systems

• Catabolized to ‘building blocks’ (amino acids), not metabolized to other active or reactive molecules.

• Generally, do not cross biological membranes to interact with DNA or other intracellular molecules.

• Highly specific binding properties with few ‘off target’ effects.

• Because of size do not interact with ion channels.

• Only rarely affect metabolizing enzymes.

• Modality (construction) associated with unique biological characteristics.

• The pharmacology of the biologic determines the toxicity profile and the required safety assessment design.

Leads to a ‘case-by-case’ design of the non-clinical program

General safety concerns for biologics are distinct from small molecules

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Non-Clinical Development of Biologics: Defining the Case by Case Approach

Baumann. A. (2009) Nonclinical development of biopharmaceuticals. Drug Discovery

Today (2009) 14, 1112-1122

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Despite diverse modalities and targets, characteristic concerns exist – Are we aligned?

o Nonclinical species selection

o Justification oNumber of species

o Dose extrapolation to humans - PKPD

o Duration of longest general toxicity studies

o Developmental and reproductive toxicity assessment

o Carcinogenicity assessment

o Genotoxicity assessment

o Cardiovascular safety assessment

o Dose selection for toxicity studies

o Tissue cross-reactivity

o Immunotoxicity testing

o Immunogenicity

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• What data support animal species selection for biotherapeutic toxicity studies?

o ‘Pharmacological relevance’ used to justify a species

– Similarity to humans in pharmacologic response (e.g., signaling pathway, target binding, pharmacodynamic activity)

o Species choice will depend on the relevant pharmacology and the assessment tools available

What is similar enough?

Nonclinical species selection

Bussiere JL (2008) Species selection considerations for preclinical toxicology studies for biotherapeutics. Expert Opin Drug Metab Toxicol 4(7):871-7

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• As with small molecules, one each of rodent and non-rodent species, if possible

– Many biotherapeutics are only pharmacologically active in nonhuman primates

o A single nonhuman primate species is sufficient, usually cynomolgus macaque

o Studies in chimpanzee no longer conducted due to ethical and practical issues

– Special case: No suitable species (e.g., target is only expressed with disease, no cross-reactive species)

o Options: Use engineered models, ex vivo tools, ‘paper-based’ argument to create weight-of-evidence argument for patient dosing decisions

Number of species to be studied

Bussiere et al (2009) Alternative strategies for toxicity testing of species-specific biopharmaceuticals. Int J Toxicol. 28(3):230-53.

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PK Support of First in Human Dosing and Beyond

o Predict key PK parameters in man (CL, Vss, bioavailability) Input parameters for exposure estimates

o Estimate exposure (AUC, Cmax) at the starting dose Needed for calculation of safety margins

o Estimate therapeutic exposure (based on PK/PD) Need to estimate efficacious dose range

o Hints for non-linearity / higher variability (Target mediated disposition)

Potential impact on dose steps in SD escalation study

o Give hints for special risks based on biologics modality (e.g. Metabolism, Drug-Drug Interactions, Distribution) Planning of clinical monitoring

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• Does the therapeutic promote tumor formation by non-toxic genetic or epigenetic mechanisms?

Small molecules

o Two year rat carcinogenicity study + six month (transgenic mice) or two year mouse carcinogenicity study

Biotherapeutics

o Carcinogenicity weight-of-evidence ‘assessment’: literature review, in vitro and/or in vivo studies

o Two year rodent studies are generally not appropriate

o Special concerns: Growth factors and immunomodulators

Carcinogenicity assessment

Vahle JL et al. (2010) Carcinogenicity assessments of biotechnology-derived pharmaceuticals: a review of approved molecules and best practice recommendations. Toxicol Pathol. 38(4):522-53 Bugelski PJ et al. (2010) Critical review of preclinical approaches to evaluate the potential of immunosuppressive drugs to influence human neoplasia. Int J Toxicol. 29(5):435-66

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o Approaches to refine use of non-human primates in non-clinical safety testing of biologics and current experience on the use of minipigs as alternative non-rodent species.

o Tissue distribution studies as a useful tool to support pharmacokinetic/pharmacodynamic (PKPD) assessment of biologics, in that they provide valuable mechanistic insights at drug levels at the site of action.

o Mechanisms of nonspecific toxicity of antibody drug conjugates (ADC) and ways to increase the safety margins.

o Although biologics toxicity typically manifests as exaggerated pharmacology there are some reported case studies on unexpected toxicity.

o Specifics of non-clinical development approaches of noncanonical monoclonal antibodies (mAbs),l ike bispecifics and nanobodies.

New Challenges in Non-clinical safety testing of Biologics

Baumann A et al (2014) New Challenges in Non-clinical safety testing of Biologics.

Regulatory Toxicol. & Pharmacol. 69, 226-233