Safety of antibody drug conjugates

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T-DM1 Post-IND Strategy T-DM1 Genotoxicity Testing Strategy • To assess mutagenicity, conducted reverse bacterial mutation assay on DM1 – results negative • DM1 expected to be aneugenic/clastogenic based on MOA • Presence of increased mitotic figures seen in (all) in vivo toxicity studies evidence for T-DM1 and DM1 as putative genotoxicants • For confirmation, conducting in vivo micronucleus rat study with DM1 Genentech, Inc.
Phase I Target Organs of Toxicity Identified in Toxicology Studies • Total of 24 patients treated 0.3-4.8 mg/Kg in PhI – DLT at 4.8 mg/Kg, rapidly reversible Grade 4 thrombocytopenia – All other clinical findings ≤ Grade 2 (e.g.↑ LFTs, nausea, vomiting, alopecia, and neuropathy) – No cardiac-specific toxicity observed Genentech, Inc.
Page 1 and 2: Safety Assessment of Antibody Drug
Page 3 and 4: An ADC is a Highly Complex Pro-drug
Page 5 and 6: Antibody Drug Conjugate Processing
Page 7 and 8: Designing an ADC Toxicology Program
Page 9 and 10: ADC Pipeline in 2009 Early Developm
Page 11 and 12: T-DM1 Nonclinical Program: Pivotal
Page 13 and 14: Toxicokinetic Assays Serum/plasma c
Page 15 and 16: T-DM1 Clinically Well-Tolerated in
Page 17 and 18: Mild decreases in platelets were tr
Page 19 and 20: Non-reversible axonal degeneration
Page 21 and 22: Summary of Results for T-DM1 Precli
Page 23: T-DM1 Post-IND Strategy T-DM1 Devel
Page 27 and 28: Key Toxicity Messages for T-DM1 •

Safety of antibody drug conjugates

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