Ann: Clinical Trial Update, page-27

'Asymptomatic reported events' means a reported adverse event that the patient does not experienced any noticeable symptom from. That is, the patient does not feel tired, sick, pain, etc relating to the adverse event. For example, an abnormal pathology test above/below what is an acceptable threshold (high liver function test, too low platelet count, too low white cell count, significantly elevated troponin - related to cardiac toxicity) or an abnormal ECG finding (relating to cardiac toxicity).

'Adverse event not related to the DEP Dendrimer technology' means there is no concern regarding toxicity of the dendrimer scaffold (DEP platform). They have put the trial on hold to further investigate toxicity possibly relating to the active payload drug - the released AZD4320. I don't think it will relate to interaction with voriconazole as I don't think they have started that part of the study yet.

People who invest in biotech should be aware that there is always the risk that any toxicity concern can result in a hold on the trial (to keep patients safe until it is investigated fully) and this may eventually be followed by abandonment of the trial, for safety's sake. This was always going to be a risk for AZD0466 as it is known to carry a very toxic active agent, AZD4320. The dendrimer platform has clearly reduced its toxicity but there was always the risk that it might not be enough.

We just have to wait for the outcome of the hold and hope that the concerns are thought to be un-founded or not major enough to abandon the trial.

If a DLT (dose-limiting toxicity) is confirmed, it does not necessarily mean the trial will be abandoned. It might mean a step backwards to a lower dose (eg. step back from 5400 to 3600mg if the DLT was at 5400mg ), in which the trial would only continue if efficacy signals have been demonstrated at the 3600mg dose. Or perhaps they could try again but at a lower final dose such as 4000mg?

Unfortunately, we have not been given enough information to do anything but speculate regarding possible outcomes at this time. Beware of over-confident conclusions drawn by others. Don't get me wrong, it is not great news, but we just have to wait and see what happens.

It is very disappointing but does not reflect badly on the overall DEP platform. IMHO, the platform has already effectively been validated by AZD0466 (as well as the other DEP drug trials), as it has allowed DEP version of AZD4320 to have made it this far, despite the significant toxicity it demonstrated when it was tested pre-clinically on its own.

Regards and GLTAH

Gumnut