Phase I studies in non-oncology: Dosing & Designs

1. Phase I studies in non-oncology:Dosing & Designs April 18th 2012 Sharon O’Byrne Senior Medical Director Genentech Research & Early Development

2. Overview of drug development process

3. Pharmacokinetics (PK) & Pharmacodynamics (PD) • PK: What the body does to the drug (exposure-time). • PD: What the drug does to the body (response-time) • PKPD: PD response as a function of drug concentration and time (E-R) Site of action PK Clinical efficacy PD Blood MTC PKPD-Anti-CD11a vs CD11a expression on T-cells TW AUC Tmax

4. Absorption Distribution Metabolism Excretion (ADME) Differences between monoclonal antibodies & small molecules • IV, SC, or IM only, no oral • Distribution limited to blood and interstitial spaces • Large CL capacity • Non-target mediated clearance • Tissue uptake endocytosis/pinocytosis • Lysosomal degradation if not recycled by FcRn (all cells) • Target mediated clearance • Endocytosis of receptor/antibody complex • Clearance of soluble ligand/antibody complex • Slow CL and long half life (days to weeks) • Low dose nonlinear, high dose linear • No excretion of intact mAb • Oral administration preferred • Typically all tissues accessible • Smaller CL capacity • Metabolism (liver; kidney) • Oxidation, conjugation, others • Active parent drug  active metabolite • Parent drug may be safe, metabolite toxic • Fast CL and short half life (hours) • Low dose linear and high dose nonlinear • Biliary and renal excretion (secretion) • Active or passive transporter

5. Objectives of a First-in-Human study • To determine the acute safety profile of a study drug in man • Opportunity to detect a large safety signal • To characterize the pharmacokinetic profile of the study drug • Half-life helps to determine future dosing interval • To determine any pharmacodynamiceffects • Is the study drug acting as expected in humans ? • Helps to determine dose levels • Is there an opportunity to quantify clinical activity ? • Disease Activity Score in Rheumatoid Arthritis • Low Density Lipoprotein in Cardiovascular Disease • Glycosylated Hemoglobin levels in Diabetes Mellitus • Mayo Clinic Score in Ulcerative Colitis

6. First-in-Human studiesGeneral considerations • Assessment of Risk • Related to mechanism of action • Totally novel • Target unstable (TGN1412 – anti-CD28)1 • Concern regarding the class of agent under study • May or may not apply to all therapeutics in the class • Related to target patient population • Acute coronary syndrome • Allergy • Pregnancy • Related to how well pre-clinical toxicology studies (in vitro & in vivo) predict toxicity in humans • Healthy Volunteer population vs Patient population • Focus on safety • (small n) • Conduct some early signal seeking for proof of concept • (expanded n in some cohorts) 1Stebbings et al Curr Opin Biotech 2009, 20:673-677

7. First-in-HumanCalculation of maximum recommended starting dose (MRSD) • Starting dose based on • Pre-clinical safety studies • Large molecules – commonly Cynomologous monkeys • Small molecules – commonly Rodent, Dog • In vitro safety testing in a human cell-based system • Calculation of dose based on • No observed adverse effect level (NOAEL) • Highest dose in pre-clinical studies at which no biologically relevant safety events have occurred • Minimum anticipated biological effect level (MABEL) • Dose at the lowest end of the dose-response curve for biological effect • Estimated from all the in vivo and in vitro data, or what is available • EMEA now recommend use of MABEL for calculation of starting dose for all biologics* Use most appropriate species *http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_063117 *http://www.emea.europa.eu/pdfs/human/swp/2836707enfin.pdf

8. First-in-HumanCalculation of maximum recommended starting dose (MRSD) using NOAEL • Calculate human equivalent dose (HED) of NOAEL from most appropriate species • Human equivalent dose (HED) is calculated using appropriate scaling factors • Based on body surface area (division factor of 3 for cynomolgus monkeys) • Dose of 1.0 mg/kg in monkeys ≅ 0.3 mg/kg in humans • Safety factors should be applied to the HED to ensure a safe starting dose • Safety factor applied depending on risk associated with target • In general safety factor of • At least 10 x should be applied for large molecules • At least 50 x should be applied for small molecules • Recommended starting dose • HED ÷ safety factor = maximum recommended starting dose (MRSD) • Safety factors may also be expressed in terms of • Exposure (AUC) or Concentration (Cmax) • The AUC or Cmax at the NOAEL • Using model simulation to determine dose that will provide human equivalent AUC or Cmax

9. First-in-Human studiesEscalation of dose (amount of increase) • Require sufficient dose separation between doses to determine difference, however, not too large an increase • 2 x increase may be too little • 10 x increase may be too much • Initial dose escalation should be conservative based on knowledge of target • Molecule specific • Commonly used rule is 3 x increase to ensure safe separation of dose levels • Semilog increment • Depending on safety profile the degree of increment can be adjusted • < semilog increment

10. Decision making in clinical trialsTerminology used • Adverse Event • An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP; study drug) or other protocol‑imposed intervention, regardless of attribution • Serious Adverse Event – any AE that is any of the following: • Fatal (i.e., the AE actually causes or leads to death) • Life threatening (i.e., the AE, in the view of the investigator, places the subject at immediate risk of death) • Requires or prolongs inpatient hospitalization • Results in persistent or significant disability/incapacity (i.e., the AE results in substantial disruption of the subject’s ability to conduct normal life functions) • A congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product(s) • Considered a significant medical event by the investigator (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above) • Serious vs Severe • Terms not synonymous • Severity refers to intensity of AE – maybe relatively minor but severe e.g. backache • Seriousness is a Regulatory Authority definition • Refers to seriousness of threat to subject’s life or vital functions

11. Decision making in clinical trialsClassification of severity of adverse event Adverse Event grade of severity • National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v.4)1 • Used in non-oncology for patients with moderate to severe disease • Mild, moderate to severe classification used (see examples in appendix) • In patients with less severe diseases • Healthy volunteers 1http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40

12. First-in-Human studiesDecision making • Dose escalation rules • Define dose limiting toxicities (DLTs) • Adverse events that are pre-determined and defined according to grade of severity • Any study drug related Grade ≥ 3 adverse events occurring within 14 days of study drug administration • Any study drug related Grade ≥ 2 adverse events occurring within 14 days of study drug administration that are considered clinically significant as judged by the Investigator or Internal Safety Monitoring Committee • Specific related to target under study • Risk of neutropenia • Risk of infection • Define the number of DLTs at which dose escalation will stop • Study will cease completely • There will be further evaluation of safety and study will continue • Examples – 1-2 DLTs per cohort • Example of dose escalation rules • If 1 patient experiences a DLT, 5 additional patients will be randomized to the dose level at which the DLT was experienced • Of these 5 additional patients, 4 will receive active drug and 1 will receive placebo in a double‑blinded fashion. If the incidence of DLTs in the entire expanded cohort remains at 1 patient (1 of 8 patients treated with study drug), escalation will proceed to the next dose level • If 2 or more patients experience a DLT, enrollment will be stopped for evaluation of all available safety information

13. Dose Limiting ToxicitiesProbability of detection • The sample size is based on the dose escalation rules • The number of subjects in each cohort should be sufficient to characterize the single‑dose safety and tolerability

14. First-in-HumanSafety monitoring • Recommend dosing of first subjects at least 24 hours apart • First dose cohort • First couple of subjects in each increasing dose cohort • Starting dose route of administration • Intravenous infusion over 1-2 hours for totally novel target, or where there are concerns for safety • Considered safer as infusion can be turned off if AE occurs during infusion • Subcutaneous route can be used if the target is not novel http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078932.pdf

15. First-in-HumanSafety monitoring • Timing of dose escalation (SAD/MAD) • 14 days generally considered acceptable length of time to determine acute toxicity • Single Ascending Dose stage – 14 days after single dose • Multiple Ascending Dose stage – 14 days after second or third dose • Depending on likely toxicity of study drug, this time interval can be adjusted • Duration of follow-up of patients for adverse event monitoring • ~ 5 half-lives for clearance of therapeutic under study • Sponsor’s internal safety monitoring committee • Unblinded to treatment assignment to quickly review any SAEs etc • Treating physician and patient • Blinded to eliminate bias • Serious adverse events, adverse events Grade ≥ 2/3 and all events of special interest • Reported to the Sponsor within 24 hours

16. First-in-Human Study Design Example 1 6:1 Cohort H: 300 mg FD SC (4.0 mg/kg) 6:1 Cohort E: 450 mg (6.0 mg/kg)SC Cohort C: 50 mg (0.67 mg/kg)SC Cohort G:100 mg FD SC (1.3 mg/kg) d14 d14 4:1 4:1 Active:Placebo 6:1 Cohort D: 150 mg (2.0 mg/kg)SC Cohort F: 30 mg FD SC (0.4 mg/kg) 4:1 d14 d14 Cohort B: 15 mg (0.2 mg/kg)SC 4:1 d14 d14 Cohort A: 5 mg (0.07 mg/kg) SC 2:1 Dosing Randomized, Double Blind within Cohort, Placebo-controlled, Dose Escalating Study Await full assessment of safety from SAD Phase Ia – SAD Phase Ib – MAD Main objective of Phase I is to seek an early safety signal Assuming body weight of 75 Kg

17. First-in-Human Study DesignExample 2 Cohort E: 450 mg (6.0 mg/kg)SC Cohort C: 50 mg (0.67 mg/kg)SC 4:1 4:1 6:1 Cohort D: 150 mg (2.0 mg/kg)SC 4:1 d14 d14 Cohort B: 15 mg (0.2 mg/kg)SC 4:1 d14 d14 Cohort A: 5 mg (0.07 mg/kg) SC 2:1 Dosing Randomized, Double Blind within Cohort, Placebo-controlled, Dose Escalating Study Phase Ia – SAD Phase Ib – MAD Cohort H: 300 mg FD SC (4.0 mg/kg) - Real time safety reporting - Cohort E & F start at the same time 6:1 Active: Placebo Cohort G:100 mg FD SC (1.3 mg/kg) D14 from 2nd dose D14 from 2nd dose 6:1 Cohort F: 30 mg FD SC (0.4 mg/kg) Wk 0 Wk 2 Wk 4 • All patients dosed in Cohort A dosed on a separate day • First 2 patients in each subsequent cohort in SAD dosed on separate days Assuming average body weight of 75 Kg

18. First-in-Human Study DesignExample 3 Cohort F: 3.0 SC 4:1 d14 d14 d14 = dosing; IV = intravenous; SC = subcutaneous Randomized, Double Blind within Cohort, Placebo-controlled, Dose Escalating Study Multiple dose stage (MD; Phase Ib) Dosing q4wks: Cohort J: 4.0 IV Single ascending dose stage (SAD; Phase Ia) 4:1 Dose mg/kg Cohort D: 10.0 IV 4:1 Cohort I: 3.0 SC 4:1 Cohort C: 3.0 IV Analysis of PK + clinical safety from SD DE Cohort H: 1.5 SC 4:1 Cohort B: 1.0 IV 4:1 4:1 Cohort G: 0.5 SC Cohort A: 0.3 IV 4:1 Active:Placebo 4:1 Time

19. Appendix

20. Examples of Grading for Adverse EventsSystem based

21. Neonatal Fc receptor for IgG (FcRn) FcRn Recycles IgG Via pH Dependent Binding & Release pH 7.4 pH 6 V. Ghetie & E.S. Ward, Ann. Rev. Immunol. 2000