Control Strategies for Small Molecule Components of Antibody-Drug Conjugates

Control Strategies for Small Molecule Components of Antibody-Drug Conjugates Nathan C. Ihle, PhD Executive Director, Process Chemistry Seattle Genetics, Inc WCBP 2012 Antibody-Drug Conjugates: Balancing Large and Small Molecule Control Strategies from Development to Commercialization 23Jan2012 San Francisco, CA

Seattle Genetics Company Overview Biotechnology company focused on monoclonal antibody-based therapies for cancer ADCETRIS (brentuximab vedotin) granted accelerated approval for 2 indications by the FDA in August 2011 Leader in next-generation antibody-drug conjugate (ADC) technology Robust ADC development pp pipeline Founded in 1998 Located in Bothell, just north of Seattle Publicly traded (Nasdaq: SGEN) ~500 employees Lead ADC programs Brentuximab vedotin (SGN-35) SGN-75 ASG-5ME ASG-22ME 2 Non-Confidential

ADCETRIS (Brentuximab Vedotin) ADC directed to CD30 Granted accelerated FDA approval in August 2011 for two indications Broad clinical development program to evaluate use in earlier lines of Hodgkin lymphoma and systemic ALCL and other CD30-positive malignancies Corporate-sponsored trials Investigator-sponsored trials Millennium MAA submission accepted by EMA in June 2011 Seattle Genetics regulatory application to Canadian Health authorities planned for first half of 2012 Relapsed HL and systemic ALCL 3 Non-Confidential

Antibody-Drug Conjugate (ADC) Mechanism of Action 4 Non-Confidential

Brentuximab Vedotin Structure Antibody Linker cac10 anti-cd30 antibody Attachment group Protease- cleavage site Drug MMAE cytotoxic agent cac10: chimeric IgG1κ monoclonal antibody Linker: chemically stable MMAE: synthetic small molecule 5 Non-Confidential

Brentuximab Vedotin Manufacture cac10 (Intermediate) t SGD-1006 (Intermediate) Bulk Drug Substance Drug Product cac10 and SGD-1006 classified as cgmp intermediates Each with dedicated 3.2.S section 6 Non-Confidential

Quality Definitions Control Strategy: A planned set of controls, derived from current product and process understanding d that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. (ICH Q10) ) Begins with an assessment of quality attributes to identify Critical Quality Attributes (CQAs) Critical Quality Attribute: A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. (ICH Q8(R2)) Emphasis on attributes that impact safety and/or efficacy 7 Non-Confidential

Quality Attributes for an ADC Universal quality attributes Potency Purity Microbiological attributes Attributes typically associated with antibody products Charge variants Aggregates Host cell protein Attributes typically associated with small molecules Chiral purity Residual solvents Attributes unique to ADCs Drug-to-antibody molar ratio (MR D ) Free drug-related impurities 8 Non-Confidential

Quality Attributes for an ADC Universal quality attributes Potency Purity Microbiological attributes Attributes typically associated with antibody products Charge variants Aggregates Host cell protein Attributes typically associated with small molecules Chiral purity Residual solvents Attributes unique to ADCs Drug-to-antibody molar ratio (MR D ) Free drug-related impurities 9 Non-Confidential

Quality Attribute: Stereochemical Purity of Conjugated Small Molecule ADC attributes where effect might be observed Cytotoxicity Drug-directed Western blot CD AAA Peptide map Relying on control by testing ADC is not optimum Many tests are influenced by multiple attributes Stereochemistry t is established early in process Process understanding teaches us that once established, stereochemistry does not change Conjugation makes differences harder to detect Limitation of analytical methods Control stereochemical purity early, during manufacture of the small molecule 10 Non-Confidential

Quality Attribute: Stereochemical Purity of Conjugated Small Molecule 13 Stereocenters t 2 13 stereoisomers possible 8192 diastereomers (1 or more stereocenters inverted) 11 Non-Confidential

Quality Attribute: Stereochemical Purity of SGD-1006 12 Stereocenters 2 12 stereoisomers possible 1 enantiomer (mirror image, all stereocenters inverted) 4095 diastereomers (1 or more stereocenters inverted) 12 Non-Confidential

Manufacture of SGD-1006 Produced by chemical manufacturing process Convergent chemical process Defined regulatory starting materials Assembled in multiple stages Isolated intermediates SGD-1006 manufactured and released as GMP intermediate 13 Non-Confidential

Quality Attribute: Enantiomeric Purity of Conjugated Small Molecule Proper enantiomer required for cytotoxicity Therefore, a CQA for SGD-1006 - vs - 14 Non-Confidential

Enantiomeric Control of (1S,2R)-(+)-Norephedrine - vs - 15 Non-Confidential

Enantiomeric Control of (1S,2R)-(+)-Norephedrine - vs - Specification includes Chiral HPLC method Limit on (1R,2S)-(-)-norephedrine Similar approach applied to all starting materials Starting material controls provide the control of the CQAs enantiomeric purity of SGD-1006, and enantiomeric purity of conjugated small molecule 16 Non-Confidential

Quality Attribute: Stereochemical Purity of Conjugated Small Molecule Diastereomeric Purity a CQA Most isomers will have diminished cytotoxicity impact is potency Controls to consider Starting materials Wrong enantiomer or diastereomer of starting material will result in production of diastereomers which may carry forward to SGD-1006 and ADC Process controls Some stereocenters may be sensitive to some reaction conditions 17 Non-Confidential

Quality Attribute: Diastereomeric Purity of Conjugated Small Molecule Proper diastereomer required for cytotoxicity Therefore, a CQA for SGD-1006 - vs - 18 Non-Confidential

Diastereomeric Control of (1S,2R)-(+)-Norephedrine HO H 2 N (1S,2R)-(+)- Norephedrine - vs - HO H 2 N (1R,2R)-(-)- Norpseudoephedrine 19 Non-Confidential

Diastereomeric Control of (1S,2R)-(+)-Norephedrine HO H 2 N (1S,2R)-(+)- Norephedrine - vs - HO H 2 N (1R,2R)-(-)- Norpseudoephedrine Specification includes 2 nd HPLC method Limit on (1R,2R)-(-)-norpseudoephedrine 20 Non-Confidential

Quality Attribute: Diastereomeric Purity of Conjugated Small Molecule Are additional controls for benzylic alcohol stereochemistry required? Is stereochemistry t stable? If unstable, what process parameters are important to control to control this attribute? Does process clear diastereomers? Are analytical methods capable of measuring diastereomers? Process understanding is key Origin and fate of impurities 21 Non-Confidential

Quality Attribute: Diastereomeric Purity of Conjugated Small Molecule Additional controls for benzylic alcohol stereochemistry Process design Include steps designed d to remove undesirable isomers Process understanding Investigate and understand origin of isomer during manufacture and demonstrated ability of steps to clear it Process parameter controls Exposure of in-process materials to acidic conditions scrambles stereochemistry Implement process parameter controls to assure operation within acceptable operating range (AOR) Non-critical process parameter, because normal operating range (NOR) much narrower than proven AOR Intermediate specifications Test methods and established limits for this isomer in isolated intermediates Release specification Test method, and limits for this isomer in the release of SGD-1006 22 Non-Confidential

Quality Attribute: Diastereomeric Purity of Conjugated Small Molecule SGD-1006 Diastereomer Suitable control demonstrated via process validation 23 Non-Confidential

Other Quality Attributes of SGD-1006 Critical Quality Attributes Impact a CQA of the drug product Non-Critical Quality Attributes Indicator of process performance, but do not impact a CQA of the drug product E.g. residual solvents 24 Non-Confidential

Quality Attribute: Residual Solvents in SGD-1006 Residual Solvents a Non-Critical Quality Attribute Solvent residues from SGD-1006 manufacturing process Manufacturing experience demonstrates levels below ICH limits, so no toxicity concerns Additional processing provides further clearance Therefore a Non-Critical Quality Attribute However, residual solvents is an indicator of process performance, therefore important to monitor and control Controls Process design Process understanding Process parameters In-process testing Release testing Suitable control demonstrated via process validation 25 Non-Confidential

Conclusions Control strategy for ADCs relies on assessment of quality attributes of the final drug product, and process understanding Each quality attribute assessed for possible control Many controls impact multiple quality attributes Control strategy for attributes associated with the conjugated small molecule relies mostly on controls applied prior to conjugation Many small molecule quality attributes and associated controls are non-critical Control of regulatory starting materials is one of the most important aspects of the control strategy 26 Non-Confidential

Acknowledgements Seattle Genetics Staff Process Sciences Department Technical Operations Department 27 Non-Confidential