1. Human pharmacology for biologicals – First into man studies Daren Austin PhD Clinical Pharmacology Discovery Medicine GlaxoSmithKline

2. 27/04/2007AGAH/Club Phase I Annual Mtg2 London - March 13, 2006

3. 27/04/2007AGAH/Club Phase I Annual Mtg3 London - March 13, 2006

4. 27/04/2007AGAH/Club Phase I Annual Mtg4 Some perspective  Developing new medicines is a collaborative effort –industry, academia and regulatory bodies  FTIH studies are generally very safe –protocols represent a high standard of science and medicine  TGN1412 underscores the importance of translational science, clinical pharmacology and study design for safe drug development  Most antibodies are very safe –At least one marketed antibody has the same cytokine profile as TGN1412

5. 27/04/2007AGAH/Club Phase I Annual Mtg5 A few successes…

6. 27/04/2007AGAH/Club Phase I Annual Mtg6 Applications of therapeutic antibodies Abciximab Basiliximab Daclizumab Efalizumab Natalizumab Palivizumab Adalimumab Bavacizumab Etanercept Infliximab Omalizumab Gemtuzumab ozogamacin Ibritumomab tiuxetan Tositumomab Alefacept CetuximabMuronomab Trastuzumab DESTROY TARGET CELLS ALTER CELL FUNCTION TARGETED DRUG DELIEVRY NEUTRALIZE “TOXINS” IMMUNOTOXICOTHERAPY

7. 27/04/2007AGAH/Club Phase I Annual Mtg7 The wrong way … We’ve got a new wonder drug! … we give it to you and wonder what it will do

8. 27/04/2007AGAH/Club Phase I Annual Mtg8 The right way…Outline  Understand the mechanism  Understand the pharmacology  Design the right study (theory)  Define the right dose  Understand the population  Design the right study (practice)  Conduct the study right www.prairierivers.org

9. 27/04/2007AGAH/Club Phase I Annual Mtg9 Understand the mechanism  Soluble or cell-associated target  Pleiotropy  Redundancy  Potential for biological amplification  Downstream signalling  Tissue expression and homeostasis  Translation plan for human systems

10. 27/04/2007AGAH/Club Phase I Annual Mtg10 Understand the pharmacology Big molecules – small differences? CharacteristicSmall MoleculeAntibody Molecular weight< 700150,000 (300x higher) PotencypM – nM ( agonist/antagonist ) pM – nM (typically antagonists ) ClearanceLinear at low doses, Non- linear at high doses Non-linear at low doses, linear at high doses VolumeWide range, < 1000 L/kg70 ml/kg, 2x plasma Bioavailability0 – 100%, predictable from Phys Chem properties 0% via oral, 30 – 90% via sub-cut PK/PD timeframePD slower than PKPK slower than PD Preclincal NOAELDose limiting, non-specific, off-target binding Exaggerated pharmacology FTIH designMulti-cohort, cross-over design Multi-cohort, parallel group design

11. 27/04/2007AGAH/Club Phase I Annual Mtg11 Understand the pharmacology  Antagonists –possess affinity without activity  acts by blocking a receptor, occupying or inhibiting messenger  Agonists –possess affinity with efficacy,  binds and activates a response via downstream signalling Hence, an agonist activates a receptor, an antagonist binds but doesn’t activate it (i.e., it blocks access of agonist)

12. 27/04/2007AGAH/Club Phase I Annual Mtg12 Design the right study (theory) What dose range? What starting dose? www.pbase.com

13. 27/04/2007AGAH/Club Phase I Annual Mtg13 Dose ranges: are they adequate? Data from 100 GSK FTIH studies Median of 6 dose levels (8 periods) Cumulative escalation is 60x (2–20000x) Distribution is different to industry benchmark # # Buoen et al. (2005) J. Clin Pharm 45 : 1123-1136

14. 27/04/2007AGAH/Club Phase I Annual Mtg14 Design the right study Typical GSK FTIH designs  For small molecules typically five period (incl. placebo) with repeated dose across cohorts and 2-3 fold escalations: –P, X, 2X, 4X, 8X then P, 8X, 16X, 32X, 64X –2 3 x 2 3 = 64-fold –3 x 3 x 2 x 2 x 1.5 x 1.33 = 72-fold  For large molecules typically six period parallel group with log/semi-log decreases –X, 10X, 10X, 3X, 3X, 3X –10 2 x 3 3 = 2700-fold  Overall dose range defined by number of cohorts  Define starting dose to give top dose

15. 27/04/2007AGAH/Club Phase I Annual Mtg15 Exposure ranges for responses  Agonists are very efficient at signalling (80/20)  Antagonists must block most receptors before signal is turned off Desired response Exposure Ratio Shallow Anta- gonistAgonist"Switch" 90% ED90/ED10 421<1 95% ED95/ED5 531<1 99% ED99/ED1 8421 Orders of magnitude for exposure range GOOD (<100x) POSSIBLE (100 – 1000x) IMPOSSIBLE (>1000x)

16. 27/04/2007AGAH/Club Phase I Annual Mtg16 Exposure ranges for responses  Agonists are very efficient at signalling (80/20)  Antagonists must block most receptors before signal is turned off Desired response Exposure Ratio Shallow Anta- gonistAgonist"Switch" 90% ED90/ED10 421<1 95% ED95/ED5 531<1 99% ED99/ED1 8421 Orders of magnitude for exposure range GOOD (<100x) POSSIBLE (100 – 1000x) IMPOSSIBLE (>1000x)

17. 27/04/2007AGAH/Club Phase I Annual Mtg17 Exposure ranges for responses  Agonists are very efficient at signalling (80/20)  Antagonists must block most receptors before signal is turned off Desired response Exposure Ratio Shallow Anta- gonistAgonist"Switch" 90% ED90/ED10 421<1 95% ED95/ED5 531<1 99% ED99/ED1 8421 Orders of magnitude for exposure range GOOD (<100x) POSSIBLE (100 – 1000x) IMPOSSIBLE (>1000x)

18. 27/04/2007AGAH/Club Phase I Annual Mtg18 Define the right dose http://pixelsoap.com/photos/album32/roulette

19. 27/04/2007AGAH/Club Phase I Annual Mtg19 Define the right dose What starting dose? Define No Observable Adverse Effect Level Safety cover for top dose (1 – 5x) Low dose based on enhanced cover (100 – 500x) Low dose based on expected pharmacology For NMEs, low dose will be typically 100x lower based on design arguments

20. 27/04/2007AGAH/Club Phase I Annual Mtg20  Define lowest level of biological activity preclinically  Equivalent to “Minimally effective” Phase IIB dose  Will require downward preclinical dose titration for antibodies Define NOAEL Safety cover for top dose (1 – 5x) Safety cover for low dose (100 – 500x) Low dose based on pharmacology Define MABEL Low dose = Min(MABEL, NOAEL/cover, Binding) Minimally Active Biological Effect Level Define the right dose What starting dose?

21. 27/04/2007AGAH/Club Phase I Annual Mtg21 MABEL based on PD/PD of orthologues  Raptiva™ targets CD11a did not bind to preclinical species  muM17 is an anti-mouse CD11a Mab developed as a surrogate molecule to assess reproductive toxicity in mouse  Mechanistic PK/PD model used to determine dose equivalence to humans Wu (2006) J Pharm Sci 96 (6) 1258

22. 27/04/2007AGAH/Club Phase I Annual Mtg22 PK/PD and orthologues Wu (2006) J Pharm Sci 96 (6) 1258

23. 27/04/2007AGAH/Club Phase I Annual Mtg23 PK/PD and orthologues model validation Wu (2006) J Pharm Sci 96 (6) 1258

24. 27/04/2007AGAH/Club Phase I Annual Mtg24 Allometric scaling of proteins  Established for small and larger molecules  Assumes conservation of clearance pathway across species  For monoclonal antibodies this assumption is frequently violated –Human target may only be shared by primate species –Single species allometry –Consider target expression and target mediated clearance http://www.elephants.com/sharma_photos.htm Mordenti et al (1991), Pharm Res 8, 1351

25. 27/04/2007AGAH/Club Phase I Annual Mtg25 Scaling capacity-limited binding to humans  MUC-18 cell surface adhesion (melanoma)  Fit parallel linear and non-linear binding elimination pathways  Assume Vmax and Km are predictive of humans  Residual clearance allometrically scaled  Simulate human PK profiles  Ignores neutralisation http://www.abgenix.com/documents/ASCPT2004%20poster.pdf

26. 27/04/2007AGAH/Club Phase I Annual Mtg26 Define the right dose  Large molecules bind to a target at nanomolar concentrations –150kD implies equates to 0.15µg/ml for 50% binding  That’s about 0.01 mg/kg  Antibody binding is normally antagonistic –High binding required to suppress signaling pathways –80-90% binding equates to 1 – 2µg for biological effect  That’s about 0.1 mg/kg  Guiding simplification Kd[nM]/200 –Starting dose of Kd[nM]/200 [mg/kg] will give about 50% binding  [Duff pg. 29]  Scale for smaller proteins according to MWT and Vdss

27. 27/04/2007AGAH/Club Phase I Annual Mtg27 Define the right dose Proposed (and approved)Suggested (for agonist) 100x lower starting dose and smaller escalations * Assumes Cmax/Kd is correlated with functional response Ro ~ (Cmax/Kd)/(1+(Cmax/Kd)) * Dose (mg/kg) Cmax (ug/ml) AUC (0-inf) (ug.h/ml) Cover DOSE Ratio Cmax KdRo 0.12.309428500x8.289% 0.511.552142100x40.998% 246.2856725x163.899% 5115.52141810x409.5100% Dose (mg/kg) Cmax (ug/ml) AUC (0-inf) (ug.h/ml) Cover DOSE Ratio Cmax KdRo 0.0010.0234.2850000x0.088% 0.0030.06912.816667x0.2520% 0.0080.18534.26250x0.740% 0.0120.27751.44167x1.050% 0.0250.5771072000x2.067% 0.051.1552141000x4.180%

28. 27/04/2007AGAH/Club Phase I Annual Mtg28 Understand the population  ICH guidelines  Benefit outweighs the risk –HVTs do not benefit –Risk must be managed accordingly  Mixed populations? –HVTs (S&T/PK) then escalate in patients  Mild patients? –Neither HVTs nor mild patients may predict eventual population http://www.noaddedsugar.org/images/gordon/crowd.jpg

29. 27/04/2007AGAH/Club Phase I Annual Mtg29 Healthy subjects or patients? Points to considerComments Expression of target proteinHealthy subjects may not predict safety and tolerability Safety profile in patients may vary with disease severity Determination of optimal biological dose May only be possible in patients Presence of co-morbiditiesDetection and interpretation of safety signals more difficult Long half lifeExtended follow-up not always feasible in healthy volunteers Opportunity for investigating pharmacodynamic activity Risk assessmentMay preclude healthy subjects ImmunogenicityMay limit future choice of therapy

30. 27/04/2007AGAH/Club Phase I Annual Mtg30 Not all created equal …  Intrinsic variability –drug-target interaction –type of transduction –drug access at biophase –delivery & input rate –metabolism pheno/genotype –disease & homeostasis –placebo response  Extrinsic variability –drug-drug interactions –interactions with endogenous substances

31. 27/04/2007AGAH/Club Phase I Annual Mtg31 Part 1 – Healthy subjects Safety, tolerability PK Part 2 – Patient Safety, tolerability PK, PD Increasing dose Bridging dose Mixed study population

32. 27/04/2007AGAH/Club Phase I Annual Mtg32 Design the right study (practice) Proof of Pharmacology  Stronger drive to deliver more information earlier: MTD with Proof of Pharmacology –early call on therapeutic index –define MTD in relevant populations (target expression?) –early go/no-go decisions  Fusion designs in Phase I –combination of study objectives  Adaptive designs in Phase I –say how you will decide to do something

33. 27/04/2007AGAH/Club Phase I Annual Mtg33 Proof of pharmacology  Safety signal  Safety signal from known class of compounds (e.g. cortisol suppression) occupancy signal  Receptor occupancy signal from ex vivo assay (e.g. CD11B from neutrophils)  Imaging signal  Imaging signal (e.g. fMRI or PET studies) signal transduction  Transcriptomics for evidence of signal transduction  Clinical surrogate  Clinical surrogate signal (e.g. airway conductance)  Clinical signal  Clinical signal (e.g., fasting plasma glucose)

34. 27/04/2007AGAH/Club Phase I Annual Mtg34 Design the right study: Phase I Fusion designs FTIH Single Dose Repeat Dose Food Effect Drug-Drug Interaction Patient Population Human Pharmacology

35. 27/04/2007AGAH/Club Phase I Annual Mtg35 Safe and well-tolerated? FTIH study objectives Part A  To investigate the safety and tolerability of single escalating doses of GSK123456 in healthy subjects.  To characterize the preliminary pharmacokinetics of single escalating doses of GSK123456 in healthy subjects. Part B  To investigate the safety and tolerability of a single oral dose of GSK123456 in mild to moderate patients  To characterize the preliminary pharmacodynamics of single and repeat doses of GSK123456 as assessed by in an appropriate model  …GSK123456 is safe, well-tolerated, pharmacokinetics, response in patients…  Summarise and report results of Part A and justify doses in Part B  Will we establish a Maximum Tolerated Dose?

36. 27/04/2007AGAH/Club Phase I Annual Mtg36 Summary biopharmCEDD FTIH/FTIP studies CriteriaSyncra®GSK1GSK2GSK4 IndicationDiabetesRheumatoid arthritis Severe asthmaNeuro-degeneration TargetGLP-1Soluble cytokine Soluble protein PrecedenceYesNoSemiNo PopulationHVT HVT/PatientsPatients DesignParallel 2-dose adaptive AUC- based escalation Parallel SD adaptive follow-up Parallel SD/RD Part A/B Parallel SD/RD D- optimal adaptive dose escalation on target inhibition Escalation416x10,000x 800x Proof of Pharmacology Fasting glucose compared to active control (enabling) Target binding and ex vivo LPS inhibition Allergen challengeTarget binding and inhibition

37. 27/04/2007AGAH/Club Phase I Annual Mtg37 GSK123456 Pop-PK analysis (0.03 – 1.0 mg/kg) during ongoing trial Population PK analysis ongoing to predict time to follow-up

38. 27/04/2007AGAH/Club Phase I Annual Mtg38 Conduct the study right Ensure clinical excellence All FTIH studies conducted in a hospital based Unit Integrated emergency response system and access to ITU Determine if additional measures or clinical expertise is needed Assure staff training and experience Shared medical accountability between site (PI) and sponsor (medical monitor) Dosing staggered Interval hrs - days Staff and facilities to handle medical emergencies

39. 27/04/2007AGAH/Club Phase I Annual Mtg39 Summary  Understand the mechanism –Translational medicine plan  Understand the pharmacology –Same principles, different size, High/Low risk molecule?  Design the right study (theory) –Think escalations not doses, start low, end slow  Define the right dose –MABEL, Cmax/Kd, Preclinical PKPD, Allometry  Understand the population –HVTs and/or/then Patients? Target? MTD?  Design the right study (practice) –Fusion designs with Proof of Pharmacology for FIM expected  Conduct the study right –Hospital site, staggered dosing

40. 27/04/2007AGAH/Club Phase I Annual Mtg40 Acknowledgements  GSK biopharmCEDD  GSK riCEDD  Ruth Oliver, CPDM  Colin Dollery, GSK “Laugh when you can, it’s good medicine” Lord Byron © Mike Baldwin