Expert interview with Susan Galbraith, Senior Vice-President and Head of Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK
Susan joined AstraZeneca in 2010 as Head of Oncology in the Innovative Medicines and Early Development (IMED) Biotech Unit. Since then she has been responsible for transforming the productivity and scientific output from oncology. Five programs have moved into Phase 3 trials, two of which are now approved in many countries around the world. Her team of oncology scientists have published over 40 high impact papers over the last two years.
Susan also co-leads the Cambridge Cancer Centre Onco-Innovation group, connecting Cambridge scientists to the biotech and pharmaceutical companies in the region. She is a non-executive on the Board of Horizon Discovery PLC and on the scientific advisory board of the ICR Cancer Research Centre of Excellence. She also serves on the AACR Finance Committee and the AACR Annual Meeting Scientific Program Committee.
Q. Could you summarise the rationale for the development of selective estrogen receptor degraders (SERD) in breast cancer and their mechanism of action?
Estrogen receptors are expressed in around 70% of breast cancers, and can be a key driver and important therapeutic target. SERDs antagonistically bind to estrogen receptor alpha (ERα) and induces a conformational change that results in the degradation of the receptor. This prevents estrogen receptor mediated signalling and inhibits the growth and survival of estrogen receptor expressing cancer cells.
Q. How has AZD9833 been designed to have enhanced bioavailability?
Poor pharmacokinetic (PK) properties, insolubility and/or short half-life have limited previous oral SERD molecules from once or twice daily oral dosing regimens. AZD9833 overcomes these challenges via optimization of potency and clearance control.
Q. Where will AZD9833 fit into the breast cancer treatment armamentarium?
AZD9833 is a potential medicine that has the potential to be a suitable once-daily oral SERD – improving convenience for breast cancer patients who currently may require regular injections for hormone receptor-positive breast cancer.
Q. What have preclinical and early clinical studies taught us about AZD9833?
The structure, pre-clinical pharmacology and clinical PK data on AZD9833 was shared in a mini symposium at AACR VAM I. These findings showed that AZD9833 is a highly potent degrader and pure antagonist of the ERα, with excellent drug-like properties. AZD9833 also showed greater efficacy than fulvestrant or RAD1901 (elacestrant) in a pre-clinical tumour model with a clinically-relevant mutation in ESR1, the gene for ERα. Finally, the preclinical study shows a desired half-life in human, making it suitable for once-daily oral administration.
Q. What future studies are planned?
AZD9833 is currently in clinical testing for the treatment of estrogen receptor positive (ER+) metastatic breast cancer in the SERENA-1 clinical trial (NCT03616587). We anticipate sharing initial results from SERENA-1 at the virtual ASCO meeting this year. We are also currently investigating AZD9833 in a Phase 2 trial, SERENA-2, as a monotherapy vs fulvestrant.
Support: Commissioned, developed and supported by Touch Medical Media.
Published: 13 May 2020