You have got it right
@marianman. While each patient is their own control and we are only looking at the difference between before and after, we can tell we are having an effect even without a formal control group through three ways:
1. Dose response curve. Since the Phase 1a we will have an increasing concentration of bisantrene on a constant background of anthracycline then we should see an improving cardioprotection effect as we move from a sub-optimal initial dose to the optimal dose level of bisantrene.
2. Comparison to historical VO2Peak data. The Baker Institute and other research groups have a large amount of clinical data on the VO2Peak response to anthracyclines. This data can be used to construct what is a called a synthetic control arm similar to what we were going to do with the non-interventional trial that was cancelled.
3. Subclinical conventional oncology cardiac markers. The techniques for detecting heart damage that are currently used in oncology are now sensitive enough to see the damage, the issue has always been what is their relevance to the patient. If you use one of the newer techniques you can see cardiac damage in more than 30% of patients (see the quote from Tom Nelian in the strategy deck), the issue has always been what does this mean to the patient. While not useful for convincing a regulator to approve your drug (they care about outcomes that are relevant to the patient), these techniques are very useful for knowing if bisantrene is working as a cardioprotective drug.
The 7 day lead in single agent dosing gives us a huge amount of valuable data. Firstly, it gives us the human PK/PD data the regulators all demand. Secondly, it gives us direct on cancer efficacy data for bisantrene via changes in the levels of tumour DNA that can be detected in the blood 24 hours after treatment. Finally, it gives us human data on the effects of low dose bisantrene dosing on the m6A RNA system. It really is amazing what we can get out of doing this simple lead in study.
While we do expect that bisantrene will improve the overall tumour response to anthracycline treatment this is not likely to be statistically detectable from the Phase 1 trial. We are going to have to wait for the Phase 2 or later trials to gather than data. This is the whole reason for the zig-zag approach - get what we can prove early and leave what requires more patients for later.
(20min delay)