Starpharma and my interpretation, page-66

Paul Secrist Paul Secrist is Director of Oncology Bioscience and had a significant impact on the pre-clinical portfolio this year - serving as the biology lead for two successful candidate drug investment decisions (CDIDs) for AZD5991 (MCL1) and AZD0466 (Bcl2/xL). Paul was the major driver of the overall cell death strategy and has led multiple research collaborations with prominent academic laboratories in this exciting area of drug discovery. In addition, Paul co-leads the small molecule immuno-oncology strategy within AstraZeneca and has been instrumental in building both the pre-clinical portfolio and the rapidly expanding repertoire of immunological capabilities within IMED Oncology.

AZD0466 is a dual BCL2/xL inhibitor with broad pre-clinical activity in a range of haematological malignancies. Delivered as a nanomedicine formulation administered intravenously, it has been designed to improve the therapeutic window for thrombocytopenia, which has prevented agents of this profile delivering their full potential previously. Targeting these pro-survival proteins of the BCL2 family in combination with other mechanisms, offers the potential to increase the fraction of tumour cells that are killed.

PRECLINICAL PIPELINE
AZD4573 / CDK9 AZD5991 / MCL1 AZD0466 / Bcl2/xL AZD1390 / ATM-BBB AZD4785 / KRAS AZD4205 / JAK1 AZD0364 / ERK AZD5153 / BRD4 AZD0156 / ATM AZD4635 / A2aR AZD2811 / AURN AZD8186 / PI3Kβ AZD9496/ SERD olaparib / PARP osimertinib / EGFR acalabrutinib / BTK selumetinib / MEK fulvestrant / ER antagonist

In December we nominated AZD0466 which is a dual Bcl2/xL inhibitor with broad pre-clinical activity in a range of haematologic malignancies. Bcl2 is a clinically validated target with venetoclax being approved by the FDA in 2016 for sub-types of chronic lymphocytic leukaemia (CLL). However our data suggests that venetoclax’s continuous oral dosing is not ideal in maximising cell kill whilst those cells that do survive are often able to exploit Bcl2/xL as a parallel survival mechanism. Consequently AZD0466 has the potential to be a best-in-class agent in this field with a highly-optimised i.v. nanomedicine formulation with a broader Bcl2/xL profile. Previous attempts to develop this dual profile were seriously compromised by on-target toxicities such as thrombocytopenia.

Melinda Merchant Melinda Merchant is a Senior Medical Science Director who serves as lead for the Boston Oncology Therapeutic Medical Unit and represents ECD on the Site Leadership Team. A pediatric oncologist with a PhD in Immunology, her prior expertise in immunotherapy has been valuable in the early clinical development of AZD4635 (A2aR) and implementation of the Phase I First-Time-in-Human trial this year. Her collaborative efforts with IMED and Acerta are reflected in the successful Candidate Drugs AZD5991 (MCL1), AZD0466 (Bcl2/xL), and AZD1390 (ATM-BBB).