3. Solid tumour development planRC220 Phase 1a/btrial· Bayesian...

3. Solid tumour development plan

RC220 Phase 1a/btrial

· Bayesian dose-escalation design with RC220 in any solid tumour type where anthracyclineuse is indicated (I would assume that most trial physicians will be comfortable recommending breast cancer patients, but it will be interesting to see what other tumour types are eventually enrolled)

· Primary endpoints: safety and RP2D

· Exploratory endpoints: standard (LVEF + GLT) AND Vo2Peak, m6a RNA levels, anticancer efficacy

· Cohort extension in patient subgroups to determine optimal dosing in different combination settings

· Scheduled to start in H2 CY24 and run for approximately 12-24 months pending enrolment numbers, which would suggest a readout in the vicinity of H2 25 to H1 26

· Bisantrenemonotherapy lead-in dosing designed to collect clean PK/PD data on bisantrene

· Fully-fundedwith RAC current cash on hand

Phase 2 Cardioprotection and M6A RNA trial

· Placebo-controlled, double-blinded combination trial

· Focus on breast ca and other solid tumours that show efficacy in Ph 1a/b trial

· Primary endpoints: cardio protection using standard and advanced biomarkers of cardiotoxicity

· Estimated start: H1 26 – H2 26

· Run-time 18-24 months pending enrolment numbers

· Estimated readout: H1 29 – H2 29

· First robustdata on efficacy and cardio protective ability of bisantrene in humans withsolid tumours

· Aiming to be funded by option exercise

· A positiveresult in this trial would be the most valuable validation of bisantrene todate

The rationale anddesign of the Phase 1a/b and Phase 2 trials in solid tumours seems to be wellthought-out and makes sense to me so broadly speaking I’m in favour of thisstrategy. More importantly I’m happy that this development program is takingpriority over AML. The timelines don’t seem to be extended too far beyond whatwe were offered in the August strategic update and the first trial is alreadyfully-funded. Hopefully the options will be enough to cover the P2 trial. Dataread out of the P2 trial at some point in 2029 will position RAC well for apartnership or as an acquisition target.

The use of a Bayesiandesign in this trial is interesting. This method of designing trials is knownas Adaptive Trial Design. There are a huge number of benefits using adaptivetrial designs which I will discuss below. It is a relatively emerging trend indrug development (although has been around for the better part of a decade),and regulators are beginning to acknowledge is acceptability and also thebenefits it has for patients. Perhaps more importantly for us as shareholdersare the ways that it can improve the chances of success for trials.

Adaptive trial designsallow for sponsors to pre-define the way they will respond to the way the trialand the data it is producing is evolving. Think of it as the difference betweenusing a hard copy map to navigate andunfamiliar place vs. an app like Waze. Traditional trial designs are rigid andonce they are set you are bound to continue the trial as designed until it endsor you terminate it, regardless of the insights you glean from interim datareadouts. This is the hardcopy map, which you are stuck with no matter how thetraffic is building up on certain roads, or roadworks and road closures thatthe map can’t detect pop up in your way.

Now let’s look at an adaptivedesign, which is far more like Waze in that it allows you to update yourtrajectory based on continually updating information. The adaptive trial designallows you to alter patient enrolment as more data is gathered in regard toparticular patient subgroups, cancer types, dosages etc. whatever the case maybe. For example, if a lung cancer patient is enrolled that shows reallypromising data, more can be enrolled to further investigate, and vice versa. Now all of these decisions and the correspondingactions that are to be taken in the trial are pre-defined, so it doesn’t impactthe robustness of the trial or increase the risk of bias, but it does allow thetrial to evolve in a way that improves the chances of success. This has beenused for some time now, is accepted by regulators, and is an emerging field indrug development. In terms of cost-effectiveness, it limits the risk of runninga trial to completion with poor results. Another prudent decision bymanagement.