RE:RE:RE:RE:RE:RE:Fireside Chat on August 10I thought Christian made it very clear that the 33 week patient did not come off the trial due to side-effects. Also, this patient apparently spanned quite a variety fo doses from 60mg to at least 360mg, if I recall correctly.
qwerty22 wrote: It's a great data point (or 11 data points if you prefer). It doesn't say anywhere in the written stuff that she didn't have SAEs, I can't remember if they said that in the CC. We know from Juniper that this trial placed a heavy burden on patients but getting back to normal might also involve turning your back on adverse events.
I'm still struck by the average of 8 previous treatments. It suggests people who have been going through this process a long time and are likely very sick. I can imagine people dropping out for all sorts of non-drug related problems. Which I think is what Juniper described for his wife. Those patients need to be accounted for which could make the whole safety data set very messy. I can see this as being a good reason for THTX not wanting to dig too deep into this just yet.
I tend to nit-pick. I want to know everything. I can also accept they aren't ready to publically report everything. Clearly something happened around the 420 dose but the smooth transition from 1a to 1b after recruiting the final 6 patient should probably also be taken into account. Maybe there is more to reveal but maybe it's manageable?
SPCEO1 wrote: All good points to consider but what do you think about the patient who went for 33 weeks and only came off the trial because they wanted to return to "normal life"?
qwerty22 wrote: I think Christian did much more to set expectations. I remember him breaking down the recruitment process to justify the timeline. But I guess he works for Paul.
I don't have much expectation of biotech updating timelines etc. my experience is they leave it to the last possible moment (or beyond that). Let's say something went awry. They are very unlikely to issue updates until the whole process is worked through and they have some clarity on the path forward. So waiting until they can say "6 more patients at the 300 dose" would make sense to me. Obviously we don't know how long they sat on that info. It seems to me 6 more might be something of a departure from the normal process (I'd expect 3 to add to the previous 3). If that is true then it probably came from discussions with the fda which we can easily imagine contributed to a slowed down process.
Anyway I asked one of the questions at the last CC about where the 420 SAEs came from if only small amounts of the drug was degrading. Christian was quite open in identifying some cell types (nerves) as expressing Sortilin and presumably taking up the PDC. From my reading cells derived from epithelial type cells can also contain Sortilin. There are cells in the eye like this and we know one of the SAEs was an eye problem. It could be possible they began to put together a theory of where the SAEs were coming from. Observing some SAEs is one thing, having a theory as to why seems to me to activate a more cautious approach. Not necessarily that clinically it's more important (an SAE is an SAE) but human psychology kicks in to activate the health and safety officer in all of us.
I'm still worried about their reporting of the SAEs/AEs at the 300 dose. They've only ever talked about DLTs which cover only the first dose each patient receives. All the other doses remain a mystery. It's hard to imagine a whole bunch of SAEs airing in a relatively few 420 doses and then imagine 300 as being 'clean'. There's some scenarios I've convinced myself are possible to allow this but combining a challenging safety profile at 420 with what I consider ongoing opacity about exactly what's happening at 300 tends to make me think there's stuff on the safety side we still need to know. What we do know is the trial is ongoing so it hasn't stopped that.
Just generally speaking safety seems like a strong candidate for slower, more cautious progress.
SPCEO1 wrote: Some thoughts on your comments:
1.) The timelines the company originally gave were way off the mark for 1a. That is just a fact and the company did not do a very good job of updating the market in a timely manner about the delays.
2.) The whole point of a phase 1a dose escalation trial is to push the dosage levels up to the point where you have side-effects. So, that is the plan from the get go - find just how far you can push it. Also, mice cannot talk, so they have a hard time reporting on some side-effects!
3.) I don't think we really know what delayed the phase 1a. Since the goal is to find a dose that causes problems and then step back to a lower dose, that should not have caused any delay. Maybe one day we will know what caused the delay but my best guess is a debate about whether the problems at the 420mg level were big enough and constant enough across patients to stop there.
4.) Not that I have any standing on this subject, but your spelling really falls apart when you reply to JFM, reflecting your long term animosity for him getting the best of you. He made a simple and factual point about the really bad predictions Paul made about the time it would take to complete the phase 1a and you responded with a whole bunch of other heated, mis-spelled stuff.
As Rodney King once famously asked in the midst of rioting in Los Angeles - "Can't we all just get along?"