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Human pharmacology for biologicals – First into man studies

Human pharmacology for biologicals – First into man studies. Daren Austin PhD Clinical Pharmacology Discovery Medicine GlaxoSmithKline. London - March 13, 2006. London - March 13, 2006. Some perspective. Developing new medicines is a collaborative effort

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Human pharmacology for biologicals – First into man studies

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

  2. London - March 13, 2006 AGAH/Club Phase I Annual Mtg

  3. London - March 13, 2006 AGAH/Club Phase I Annual Mtg

  4. 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 AGAH/Club Phase I Annual Mtg

  5. A few successes… AGAH/Club Phase I Annual Mtg

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

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

  8. 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 AGAH/Club Phase I Annual Mtg

  9. 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 AGAH/Club Phase I Annual Mtg

  10. Understand the pharmacologyBig molecules – small differences? AGAH/Club Phase I Annual Mtg

  11. 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) AGAH/Club Phase I Annual Mtg

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

  13. Median of 6 dose levels (8 periods) Cumulative escalation is 60x (2–20000x) Distribution is different to industry benchmark# Dose ranges: are they adequate?Data from 100 GSK FTIH studies # Buoen et al. (2005) J. Clin Pharm45: 1123-1136 AGAH/Club Phase I Annual Mtg

  14. Design the right studyTypical 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 • 23 x 23 = 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 • 102 x 33 = 2700-fold • Overall dose range defined by number of cohorts • Define starting dose to give top dose AGAH/Club Phase I Annual Mtg

  15. Exposure ranges for responses • Agonists are very efficient at signalling (80/20) • Antagonists must block most receptors before signal is turned off AGAH/Club Phase I Annual Mtg

  16. Exposure ranges for responses • Agonists are very efficient at signalling (80/20) • Antagonists must block most receptors before signal is turned off AGAH/Club Phase I Annual Mtg

  17. Exposure ranges for responses • Agonists are very efficient at signalling (80/20) • Antagonists must block most receptors before signal is turned off AGAH/Club Phase I Annual Mtg

  18. Define the right dose http://pixelsoap.com/photos/album32/roulette AGAH/Club Phase I Annual Mtg

  19. Define the right doseWhat 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 AGAH/Club Phase I Annual Mtg

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

  21. 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 AGAH/Club Phase I Annual Mtg

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

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

  24. Allometric scaling of proteins Mordenti et al (1991), Pharm Res 8, 1351 http://www.elephants.com/sharma_photos.htm • 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 AGAH/Club Phase I Annual Mtg

  25. 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 AGAH/Club Phase I Annual Mtg

  26. 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 • 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 AGAH/Club Phase I Annual Mtg

  27. 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)) AGAH/Club Phase I Annual Mtg

  28. 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 AGAH/Club Phase I Annual Mtg

  29. Healthy subjects or patients? AGAH/Club Phase I Annual Mtg

  30. 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 AGAH/Club Phase I Annual Mtg

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

  32. Design the right study (practice) • 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 AGAH/Club Phase I Annual Mtg

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

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

  35. 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 pharmacodynamicsof 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? AGAH/Club Phase I Annual Mtg

  36. Summary biopharmCEDD FTIH/FTIP studies AGAH/Club Phase I Annual Mtg

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

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

  39. 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 AGAH/Club Phase I Annual Mtg

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

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