RE:RE:RE:There we are ...Wriggles wrote: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-non-opioid-analgesics-acute-pain-draft-guidance-industry
Fully agree with that. I would add that enhanced dissolution could possibly allow maintenance doses for chronic to be achieved with smaller but more frequent dosing. Chronic is still a risk management issue IMO.
I think that the new formulation solves the poor solubility issue, which is important in an acute pain setting. Perhaps what is more important is that the new formulation provides a second argument for a new Oten Patent (new composition). Extended IP is taking on increasing relevance as the clock ticks IMO. This by itself could justify the change in approach.
There is an interesting discussion paper at link. Well worth a read if you haven't already done so. It gives the FDA's evolving thoughts on acute pain trials, opioid sparing and expedited review. It provides some guidance for selecting primary/secondary endpoints during trials and some considerations when seeking enhanced labeling for opioid sparing. A backdrop for future Oten acute development.
TriumphSpitSix wrote: "Just wish we really understood what "significant dose reduction" meant and how it affects Acute and Chronic drug development. Acute is easy to understand but how the dose reduction affects a Chronic plan is anyone's guess."
Not a doctor or chemist but from reading the NR, I believe it is primarily related to an increase in "bioavailability" i.e., how much of the drug actually enters circulation within the body and is then available to reduce pain, inflammation, etc... Presumably, higher bioavailability would allow them to decrease the doses in both Chronic and Acute applications since more of the drug is actually utilized instead of being flushed out of the body.
Hopefully, lowering the dose would address the "elevated LTEs" which doomed the Ph.2 chronic study.
Maybe they combined it with something else or found a way to treat it to make it more soluble? Dunno, just thinking out loud...
A couple details I can add there folks ...
The key to the improved formulation is in the crystalline structure of 346 - OR shall I say - the processing that reduces the crystalline structure in the new formulation. That's the enhancement.
Significant dose reduction (along with accelerated onset of action) is going to place Acute in the best place possible for us. This is likely as good as it gets for now - just dial it in.
Secondly, on the chronic side, we have three distinct paths to success and hopefully we don't need to go past #1. You already hinted at it ... #1 would be to dial down the chronic dose and hope normal liver function (up/down regulation of H2S) is unaffected. If we can get under the liver's radar, excellent !
Thirdly, both programs (Acute and Chronic) have been moving forward this whole time - though we can't see it - even when it seems chronic was on the back-burner - she was simmering on low.
Finally, thanks for the FDA information, I will have a good look. One thing I know here ... is ... there are two ways to look at the FDA programs ... formal and informal. We are in no rush for the formal (application based) program(s). That can easily come after P2 data is collected. Likely a lot going on informally right now. The FDA needs us as much as we want the programs from them.
As for the markets - they are reacting exactly as you should expect. The markets (in general) have no clue what's going on, they don't like the general conditions out there - and - the fact is - there are no new buyers picking up shares ... yet. Bide your time !!!!
As 2022 was all about deep science - 2023 will likely be all about proving it !!!