# Presentation: 501876

## Preclinical Development Considerations for Biologics – Phase I Oncology FocusODAC Meeting, March 13, 2006, Rockville, MD.

**Preclinical Development Considerations for Biologics – Phase I Oncology Focus****ODAC Meeting, March 13, 2006, Rockville, MD.**

- James D. Green, Ph.D., DABT
- SVP – Preclinical and Clinical Development
- 	Sciences
- Chairman – BioSafe BIO
- Cambridge, MA

## Background Comments

**Biologic drug development**
**Decades of experience across wide range of product classes**** **
**ICH S6 guidance for preclinical safety evaluation programs and approaches**
**Pharmacology, toxicology, pharmacokinetics, unique considerations**
**Case-by-case approach**
**One program design may not look like another due to product specific issues/concerns**

## Background Comments

**FDA organizers asked that I address differences between preclinical development considerations for biologics compared to small molecules**
**Raise for discussion, how would the above influence a determination of ‘how much preclinical data’ is sufficient to support Phase I trials for a biologic agent**
**Oncology focus**
**Refractory patients**
**Present examples, if possible.**** **
**Provide useful ‘information’**** **

## Presentation Outline

**Unique development issues for biologics**
**Contrast with small molecule drugs**
**Discussion focused on biologic drugs**
**For the committee’s information: **
**Utility of toxicology assessments**
**Utility of pharmacokinetic assessments**
**Unique dose response considerations for Phase I**
**Preclinical development requirements for Phase I**
**Summary**

## Key Messages

**Compared to small molecule drug development programs, there are important differences for biologic drugs that affect program designs and assessment parameters**** **
**Well designed pharmacology, toxicology and pharmacokinetic studies are important to support safe use conditions for human trials with oncology drugs**** **
**Four-week repeat dose toxicology studies with recovery periods should be adequate to support extended treatment of responding and stable disease patients in most cases**
**Case-by-case determination recommended**

## What Are Important Differences?Typical Antibody Construct

**Potent effector**
**molecules, **
**conjugate, and/or**
**glycosylation sites**

**Disulfide bond **

**Tumor-targeting ****regions**

**From:  M. Sanicola, V. Bailly**

**Comments:**
**Non oral ROA**
**Large size**
**  ****complex 3-D**
**  ****structure**
**SAR difficult**
**Variant forms**
**No metabolites**

## What Are Important Differences for Biologics ?

**How the biologic drug is made can affect ‘key product attributes’**
**Product attributes govern:**
**Potency, safety, efficacy**
**Therapeutic ratio and risk estimates**
**Host and process related impurities are related to the production process**

***“******Process = product” at this ***
***stage of development***

## Unique Issues Effecting the Safety Assessment of Biologics

**Immunogenicity complications**
**Duration of repeat-dose treatment in toxicology studies can **_**sometimes**_** be limited**
**Has **_**not**_** been a major complication in preclinical or clinical studies**** **
**Changes in pharmacokinetics**
**Increased or decreased drug clearance**
**Consequent change in dose and potency**** **
**Changes in pharmacologic activity**
**Blocking or neutralizing **
**Hyperpharmacologic response due to extended PK profile**
**Cross reaction to endogenous factor(s)**** **

## Some Important Safety Concerns are Related to Immunogenicity

**Experience to date suggests**
**Anaphylaxis - rare**
**Serum sickness – rare**
**Immune complex disease - rare**
**Changes in immune function status - rare**
**Immune response generated to the biologic - more common**

## General Categories of Immune Response to an Exogenous Biologic

**Categories:**
**Benign**
**Growth hormones and insulins**
**Mixed**
**huMabs, fusion proteins, interferons**
**Auto**
**TPO/PEG, blood factors, EPO (Eprex)**

**Overall, experience to date suggests that immune SAE’s **
**are uncommon and most reactions are clinically “benign”**

## Impact of Cited Differences and Other Unique Issues ?

**Interpret preclinical safety data with prior knowledge of ‘unique’ issues  **
**If preclinical safety assessment is not compromised, they are of no consequence**
**Uncertainties or effects communicated to physician and patient by usual means**
**FDA review, IB, IC**

## Utility of Toxicology Assessments: Generally Accepted Principles

**A range of toxicology responses can be observed dependent upon the properties of the molecule**
**Toxicity is sometimes non-existent, sometimes mild, and occasionally severe**
**Often, toxicity is limited to an extension of known pharmacology; however, severe non-pharmacologic toxicities are sometimes observed**

## Utility of Toxicology Assessments: Generally Accepted Principles

**Duration of toxicology studies needed to support human use is variable**
**Case by case determination**
**Based on planned duration of clinical trials**
**Consider the effects of ‘differences and issues’ previously discussed**
**4 week repeat-dose studies in one or two pharmacologically responsive species with recovery period are typical across many indications for initial INDs**

## Utility of Toxicology Assessments: Generally Accepted Principles

**Many proteins are also “well-conserved” and pharmacologically active across species**
**Rodent models may sometimes be useful**
**NHP are frequently used; sometimes other NR models**
**Single species safety assessments are sometimes scientifically justified**** **
**Often, dosimetry and toxicity profiles established in animal models are directly relevant to humans**

## Clinical Correlations

**IL-1****	****	****+****	****	****+****	****	****+**
**IL-2****	****	****+****	****	****+****	****	****+**
**IL-3****	****	****+/-****	****	****+****	****	****+**
**IL-4****	****	****-****	****	****+****	****	****+**
**IL-5****	****	****+/-****	****	****+****	****	****+**
**IL-6****	****	****+****	****	****+****	****	****+**
**IL-7****	****	****+****	****	****+****	****	****+**
**IL-8****	****	****+****	****	****+****	****	****+**
**IL-9****	****	****-****	****	****	****	****+**
**IFN-g, ******** ****	****-****	****	****[+]****	****	****+**
**TNF****	****	****+****	****	****+****	****	****+**
**G-CSF****	****+****	****	****+****	****	****+**
**GM-CSF****	****+/-****	****	****+****	****	****+**
**EPO****	****	****+****	****	****+****	****	****+**
**TPA****	****	****+****	****	****+****	****	****+****	**
**	****	****	****	****	****	****	**

**Clinical Correlations**

- Modified from Hayes, T.J., 1990

## Utility of Toxicology Assessments: Generally Accepted Principles

**Level of initial toxicologic concern extends beyond pharmacology and immunogenicity**
**Unexpected target organ toxicity and dysfunction**
**Thromboembolic example**

## Hemorrhagic Infarct

**Hemorrhagic Infarct**
**at the margin of the**
** ****left caudal lobe**

## Subacute thrombus

**Subacute thrombus**
** ****within a dissected**
** ****pulmonary artery**

## Occlusive Vasculopathy:

**Occlusive Vasculopathy:**
**mural smooth muscle**
**proliferation resulting**
**in loss of vessel**
**patency**

## Thromboembolic Example

**Unrelated to expected pharmacologic activity**
**Clinically silent in animals**** **
**Observed in animals and in clinical trials**** **
**Underscores relevance of well designed and conducted nonclinical studies to identify relevant human risk factors**

## Utility of Pharmacokinetic Assessments: Generally Accepted Principles

**Clinically relevant disposition profiles can routinely be constructed in pharmacologically responsive animal models**
**Studies employ the clinical route and dosing regimen**
**Studies cover the dose range employed in toxicology studies**

## Utility of Pharmacokinetic Assessments: Generally Accepted Principles

**Therapeutic ratio supported on basis of weight, surface area and exposure extrapolations**
**Interspecies scaling techniques and toxicokinetics are sometimes useful**
**Multiples of projected human dose (exposure)**

***Well-designed pharmacokinetic ***
***studies are important and relevant***

## Non-natural Fusion Construct: Interspecies Scaling 

**Predicts Human Clearance within Two Fold**

## Select examples with direct relevance to dosimetry considerations in Phase I

**Non-linearity**
**Changes in site of injection and ROA**

***Keep  these in mind when ***
***setting dosing conditions***

## Bell Shaped Dose Response Profile

- Ref: Ammann, A, et al, 1990

**Bell Shaped Dose Response Profile**

## Single Dose huMAB PK in Cynomolgus Monkeys

**Comments:**
**LD vs. HD Cl**
**Long exposure**
**Times above **
**TDR**

## huMAB Low Dose CL Example

-     _**Dose (mg/kg)**_** ****	****      **_**CL (ml/min/kg)**_**	****	****0.03****	****	****	**** ****86.9 ******** 1.0**** ****	****0.1****	****	****	**** 7.8 ******** 1.9**** ****	****	****0.3****	****	****	****1.4 ******** 0.4**** ****	****1.0****	****	****	**** 0.6 ******** 0.2**** ****	****	****	****	****3.0 ****	****	****	****0.3 ******** 0.04**

## Factors Affecting Clearance and Half-Life of Antibodies

- R

- FcRn

**Factors Affecting Clearance and Half-Life of Antibodies**

**Apparent high clearance rate at lower doses until receptor saturation occurs**
**Effect of antigen sink**

**FcRn binding  decreases clearance and increases serum half-life**

## Subcutaneous Injection Site

**LEG (F= 0.85)**

**INTRASCAPULAR  (F=0.35)**

- Time (hours)

- 0.10

- 1.00

- 10.00

- 100.00

- 0.00

- 24.00

- 48.00

- 72.00

**h**

**μg/mL**

- Serum Conc (ug/mL)

- Provided by: Drs. Mark Rogge and Jennifer Visich
- Zymogenetics, Inc.

## Reference: Mordenti et al, Pharm Res. 13: 1427,1996

## Can the New Drug Product be Used Safely in Early Clinical Trials?

**Typical biologic development program for a cancer biologic intended for repeat-dose treatment would include:**
**Example: MAB**
**Studies to identify ‘relevant’ species**
**Tissue cross reaction study to ID off target binding sites**
**SD Pharmacokinetic studies in one or more species**
**SD/RD 4 week toxicology studies **_**+**_** recovery is one/two relevant species**
**Total study number: 8-10**
**NB: efficacy, MOA studies also**
**Timeframe:**
**Discovery – 2-3 yrs**
**Preclinical development: 6-12 months.**

## Questions and Issues: Safety

**What does our experience tell us are necessary and reasonable toxicology requirements to support the repeat-dosing of responding patients in Phase I/ll oncology trials?**
**Historically, 4 week repeat-dose studies sufficient for small molecule development programs**
**Historically, 4 week repeat-dose studies have been viewed as sufficient to treat responders for biologics drug development programs (e.g., Rituxan****®****, Herceptin****®****)**
**Recently for biologics, 3 month repeat-dose  toxicology studies are being required to support treatment beyond one month**

## Questions and Issues: Safety

**Are the cited differences between small molecules and biologics of sufficient concern to warrant additional requirements warranted for biologics in all cases? **
**This should not be a mandatory requirement for all biologic drugs for Phase I trials**
**Case by case determination is recommended**
**Agreement with FDA medical and pharmtox reviewers prior to initiation of IND supporting studies**
**Importance of open, early and frequent dialogue with FDA scientists to assure program alignment and avoid unnecessary program delays**

## Summary

**Compared to small molecule drug development programs, there are important differences for biologic drugs that affect program designs and assessment parameters**** **
**Well designed pharmacology, toxicology and pharmacokinetic studies are important to support safe use conditions for human trials with oncology drugs**** **
**Four-week repeat dose toxicology studies with recovery periods should be adequate to support extended treatment of responding and stable disease patients in most cases**
**Case-by-case determination recommended**

## Acknowledgements

**BIO’s BioSafe Expert Nonclinical Safety Assessment Committee Members: **
**Drs. J. Cavagnaro, M. Cosenza, J. Green (Chair), S. Heidel (Vice-chair), C. Horvath, A. Levin, M. Rogge (Sec.), ****R. S****oltys,** **J. Stoudemire, T. Terrell, G. Treacy, G. Warner, P. Working**** **
**Biogen Idec Colleagues: **
**Drs. B. Adelman, J. Clarke, D. Hutto, L. Klunk, M. Li, A. Molina, M. Subramanyan, J. Woodworth, C. TenHoor**** **