pl-88, page-9

WAG,

always good to read your posts on PBT board as well - has been a tough couple of days!!

i have been interested in PGL for a while and watching since 25c - have missed a lot of upside!!

i have some scientific/clinical concerns based on the p2 trial. the most important being that one already hi-lighted r.e. lack of dose-dependent efficacy. is hard to explain that logically/scientifically and i notice the investigators really didn't proffer a reasonable hypothesis either. my other major concern is the safety profile. severe AEs were recorded in 11.62% of 160mg arm compared with 3.25% in placebo. they mention the number 'definitely' related/'possibly' related etc but i know from being involved with trials, these conclusions are very hard to come by and are really educated guesses on behalf of the investigators. The reality is, the trial was randomised and there is a dose-dependent increase in AEs (severe AEs 15.6% in 250mg dose). i think people/investors underestimate safety findings at P2 level - everyone just wants to hear about efficacy but people won't prescribe/take a drug with significant risks unless the benefits are amazing or there is absolutely no other choice (not the case here - none of the included patients would actually know if they will develop HCC recurrence, so the drug is 'optional'. some data backing that up is that the placebo group was 50% free of recurrence, compared to 63% in the 160mg group i.e. without any additional risk, half were free of recurrence!!) [as an aside - am happy with safety profile in IMAGINE].

from an efficacy point of view, i think the most useful outcome they measured was recurrence-free rate which was 63% (160mg) c.f. 50% (placebo), so ARR of drug for 50 weeks = 13%. time to recurrence, IMO, less meaningful - who cares too much if you delay metastases/recurrences by weeks if your ultimate prognosis is unchanged?

with regards to the PATRON trial, it is good that their primary end point is different and is clinically meaningful - disease free survival - much more sound. it is hard to critique too much further without being privy to design details but some improvement i see are that they will be a lot more comprehensive in the exclusion of metastases at inclusion - this was a potential significant confounder in the P2 (i.e. mets not definitively excluded - the drug is much less likely to work if mets already exist - it's aim is to prevent these!).

otherwise is seems similar, other than increasing power etc to better assess efficacy.

long winded - my apologies. in summary, some concerns r.e. efficacy (lack of dose response) and safety (high severe AEs; high rate of administration issues: haemorrhage, irritation etc). still, if disease-free survival is proven, then the AE profile will be acceptable IMO to the clinicians and patients (we put patients through a lot worse in other areas e.g. leukaemia etc).

as usual, this is just my take on it, and only the science - haven't considered how much price has been built in to SP on anticipation etc - could still be a good investment, even if don't see thorough results!!! would be interested to hear your opinion.