Ann: Updated Strategy and Investor Presentation, page-247

Apologies if this has already been posted. But I took some time today to read the study cited in the updated strategy presentation, from the work at the Baker Institute regarding VO2Peak as a biomarker for cardiotoxicity in chemotherapy patients.

Link to the full-text article: https://academic.oup.com/ehjcimaging/article/22/4/451/6128915?login=false

Here is a summary of some of the key points that I thought were pertinent.

· LVEF is the current standard of care for evaluating cancer-treatment induced cardiotoxicity

· Emergence of heart failure with preserved LVEF as an important sub-type in cancer survivors suggests that reliance on LVEF overlooks this substantial sub-population of cancer survivors

· LVEF cut off points that are internationally recognised show little relationship with HF risk, clinical outcomes and quality of life

· Functional capacity is another potential marker of cardiac dysfunction, and is strongly associated with incident HF and all cause mortality. VO2 Peak therefore may be a sensitive means of detecting cardiotoxicity and evaluating long-term HF risk

· VO2peaks < 18 mL/kg/min is termed functional disability and is associated with a 7 to 9 fold increased risk of HF

· The American Heart Association has endorsed the measurement of functional disability as an important clinical endpoint

Trial Participants

· Participants eligible if they had been treated with anthracyclines, BTK inhibitors (ibrutinib, acalabrutinib, zanbrutinib), stem cell therapy and androgen deprivation therapy

· 58% of patients had received anthracyclines, 19% BTK inhibitors, 26% stem cell therapy and 14% androgen deprivation therapy

Results

· Functional capacity was markedly reduced at follow-up, with a 7.6% reduction in VO2Peak (p=0.016)

· The number of patients who met criteria for functional disability almost doubled

· 43% of patients experienced a clinically significant reduction in VO2 peak, conversely only negligible changes in LVEF and GLS could be measured and these showed little changes in functional capacity

· The mean 7% reduction in 4 months of treatment approximates the decline in function that would be expected in 7 years of ageing

· These declines were most apparent in patients who received anthracycline therapy

· These findings demonstrate a specificity for Vo2Peak as a measure of cardiotoxicity

Other Key Points

· Significant but negligible reductions in LVEF and GLS were detected, although the changes were rarely sufficient to be considered clinically significant

· Under the current standard of care, most decision making is based around changes in LVEF

· Despite a significant proportion of patients experiencing meaningful functional decline, only 4% of patients overall me the LVEF criteria suggestive of cardiotoxicity

· Decline in VO2Peak was almost identical in those that did and did not have a significant reduction in LVEF suggesting that LVEF is insensitive to all but marked systolic dysfunction and also functional decline

· The same can be said for GLT

· The study concludes that LVEF and GLT may provide false reassurance of low HF and CV mortality risk by missing significant reductions in VO2Peak and functional disability