Matthias Grossmann, MD PhD Principal Consultant Early Phase 2013 PAREXEL International

Transcription

1 Challenges in translating a candidate antibody to clinical development Matthias Grossmann, MD PhD Principal Consultant Early Phase 2013 PAREXEL International

2 Agenda Early clinical development of therapeutic antibodies Introduction Safety aspects Regulatory Guidance Risk Identification and Mitigation PAREXELs experience with therapeutic antibodies Summary 2

3 Introduction What makes therapeutic antibodies unique? The manufacturing process involves living organisms products are variable Difficult to characterize batch-to-batch differences ( similar ) The binding domain fits perfectly into the receptor binds very tight and is cleared by Target Mediated Disposition Almost all safety concerns are related to the pharmacological mechanism exaggerated pharmacology 3

4 Safety Aspects Agonist versus Antagonist Defining the safe starting dose is challenging (MRSD or MABEL?) Immune response Immediate: cytokine storms Intermediate: autoimmunity Delayed: Immunosuppression Organ specific toxicity Primary or secondary pharmacodynamics? 4

5 EMA First In Human Guideline (2007) Definition of high-risk IMP mode of action nature of the target relevance of animal model preclinical relevant species human tissue/cells clinical study population study design starting dose (MABEL) dose escalation monitoring (safety) stopping criteria study site accreditation 5

6 EMEA/CHMP/SWP/294648/2007 6

7 Risk Identification (Document Part 1) 7

8 Risk Mitigation (Document Part 2) 8

9 Risk Identification and Mitigation Joint effort of sponsor and investigator Evaluate risk based on scientific knowledge, experience and preclinical findings Identify major safety issues Mitigate risk by proper planning of safety monitoring and selection of study population Based on relevant regulatory advice EMEA/CHMP/SWP/ /2007 9

10 Challenges The RIM process starts very early in the planning of the FIH study often preclinical safety data is limited not enough data available to calculate starting dose, especially not MABEL But, this allows sponsor and investigator to plan the FIH study jointly preparation of scientific advice meeting with CA preparation and training of site personnel if High Risk IMP needs additional safety precautions 10

11 PAREXEL Early Phase Global Network Baltimore (90) London (50) Berlin (140) Los Angeles (90) Bloemfontein (130) 11

12 Early Phase: Therapeutic Antibody Experience More than 20% of all studies involved biopharmaceuticals Antibody type (since 2008) Chimeric mab 2 Humanised mab 10 human mab 38 Fusion Protein 2 Fragment mab 1 Domain Ab 4 Study populations Healthy subjects (52) Patients (12) Asthma COPD Psoriasis Rheumatoid arthritis Crohn s disease Hemophilia 12

13 PAREXELs Experience: A case study GSK VH Domain Antibody Antagonist of TNF-α Receptor 1 RIM STEP1: High Risk Single-blind, randomised, placebo-controlled dose escalation study in which healthy males (n=28) Single intravenous infusion of , and 0.01 mg/kg All enrolled subjects pre-screened for human anti-vh (HAVH) autoantibody status and prospectively stratified Serum samples from drugnaïve, HAVH-positive volunteers were used to investigate the effect of HAVH/GSK complexes on the activation of TNFR1 and cytokine release in vitro. J Clin Immunol 33(7), 2013:

14 PAREXELs Experience: A case study GSK human anti-vh autoantibodies were detected in approximately 50 % of drug-naïve subjects formation of HAVH autoantibody/gsk complexes activated TNFR1 and caused cytokine release in vitro When GSK was administered, clinical and physiological signs of cytokine release were observed in two HAVH autoantibody-positive subjects following GSK infusion J Clin Immunol 33(7), 2013:

15 Summary mabs are highly specific therapeutics Per se, they are not more critical with regard to safety Translating data from preclinical to clinical can be more complicated Pleiotropic and secondary PD effects may play a larger role than expected, especially for Antibody fragments A proper Risk Identification and Mitigation plan is essential before the First in Human study can be initiated 15

16 Thank you very much for your attention! 16

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