Hi Bedger. Not sure if you wanted a response or not - but I wouldn't say i'm especially informed on the topic. I've just been paying attention on the across the last year or so. Some people who have rocked up lately have fundamentally misinterpreted things. That's maybe natural, but the guy who I let loose on in your post concluded that this was incompetence on the boards behalf, which I wasn't having. That was just plain incorrect.
If I had time, i'd pull together all the dates and announcements to show a timeline...but basically, as you and others who have been around for a few years will know, the timeline goes something like this:
- Company has been using a standardised dosage of 2mg/kg twice weekly throughout SAS, Phase II, EAP....up to a thousand patients dosed. The entire reputation of the treatment and it's efficacy has been created by the use of this dose. There is a huge body of evidence regarding it's efficacy and also safety.
- Then comes the discovery of an adrenal issue in a laboratory rat in one of PARs non-clinical studies. It's a wild anomaly when taken in context, as this AE has never shown up in the thousands of humans, and millions of doses given to animals over the decades. Still, the FDA can't just ignore it. It leads to a conversation where they ask PAR 'is there a lower dose that is also effective?' and if so, can we identify the lowest?
- I doubt PAR would have enjoyed being asked that, but being the accommodative lot they are and not wanting to argue with the agency whom they will be seeking approval from - they say, "ok, before we do Phase III we'll run a pre-lim study to see if there is a lower effective dose. If we find a lower dose with the same efficacy, we'll use that for Phase III". PAR also committed to testing for any adrenal issues from trial patients.
- So the "Dosing Study" is born to satisfy this query. Stage 1 is built into Phase III, which will seek to find if there is a lower effective dose. There was potential upside for PAR. Obviously if a lower dosage produced the same results, they could charge the same for treatments and have lower costs. If a once-weekly dosage was effective it could have significantly improved market adoption (who likes needles? who like 2 trips to the clinic each week for 6 weeks instead of 1? etc).
- Now, the part which seems to be causing confusion (especially amongst those who haven't been following very closely) is that a few dosages were selected - none of which were 2mg/kg twice weekly. Because, simply, they were testing LOWER doses for efficacy. We already knew 2mg/kg twice weekly was efficacious, so there was zero point in including it in the dosing study. With hindsight, it might have been worth including it as a benchmark dosage, just to avoid all this daft confusion at this stage.
- Another thing to say is that this question came up on HotCopper at the time (almost exactly a year ago) and I emailed Simon to ask, specifically, if the 2mg/kg twice-weekly dosage would still be considered for Phase III. He answered 12-months ago that YES, if 2mg/kg twice-weekly proved to be the most effective dose then it would be used. I've posted his email on this forum a couple of times already. 2mg/kg twice-weekly was NEVER off the table. Some people appear to think it was, but it wasn't, those people made an assumption in thinking so. In fact, personally, I think PAR were always privately feeling they would revert to this well-established dosage, or at worst 1.5mg/kg twice-weekly (which Paul pushed as a genuine option in presentations 6 months ago or so).
- Fast forward to the 008 Phase II trials, and the data which is revealed shows PAR clearly that the lower dosages suggested by the FDA are not efficacious, or at least not AS efficacious, or at least not AS efficacious over durations such as 6- and 12-months. We tried it, we tested it, under clinical conditions, and the lower doses were a flop. No good.
- PAR (both Paul and also Donna) were unequivocal in last weeks webinar and this weeks one. We will now proceed to Phase III with the known, reliable, well-established dosage of 2mg/kg twice-weekly. That is the dosage for trial. Study finished, results are clear, we've satisfied the scientific curiosity which led to the study. Done. Dusted. Full steam ahead. We've also (according to Donna), since all of this has been happening, satisfied the FDA that the rat issue was a wild anomaly (although I believe PAR will still test for adrenal-related AEs in the trial participants). Anyway, just listen to the last two webinars again when the dosing issue is mentioned. There is zero equivocation. They have made their decision.
What happens next is HotCopper bros who have either just shown up, have short memories, or just haven't been paying attention start launching in with:
"omg they are changing the dose for Phase III"
Not quite, genius. No dose had yet been selected for Phase III, so how are they changing it? Changing it from what?
"omg they are going to Phase III and they don't even know the best dose yet. The board are incompetent. This is embarassing."
You saw my response to that one.
"omg this trial (008) has failed because the lower doses weren't effective and they've buried this in page 4 of the announcement" (this one's from Twitter and I saw a very patient Oxxa trying to explain to the guy that he was incorrect LOL - but bro was already sure he was a genius who had spotted something no-one else had (that's a pretty standard HotCopper trait as well as Twitter). I don't know where the likes of Oxxa and Mozz get the patience to try to explain to these Dunning-Kruger numpties. Saints. You boys are better humans than me, I just block them.
We've even had one halfwit here who has decided to short a Pharma company who's one asset is entirely hinged on Pain/Function results at Day 56 in a Phase III trial because....get this....no-one was had mentioned statistical significance on a HotCopper thread about a peripheral Phase II trial looking at structural changes at Day 168 via MRI. They don't come much more entertaining than that, but if we drop 10c he'll think he's a genius hahaha.
Anyway, sorry for the long reply. Not even sure you wanted one!
(20min delay)