Pragmatist wrote: MUGMODs wrote: Never really thought much about it before ...
Thanks to all of you for your generous "thumbs up" over the years.
You are very kind !
Thankyou for your previous offer to provide your experience/insights on related technical/scientific issues. Your positive reviews are well deserved. Some issues upon which I have been pondering. Would very much appreciate your thoughts.
1. Re: ATB-346 COX inhibiting properties vs Naproxen. I have seen several graphs showing the impact of NSAIDs wrt COX. Frankly, they all look the same to this novice. Do you have any references showing COX inhibiting properties for varying dosages of Naproxen? My understanding this is generally understood as a threshold issue, over 70% COX inhibition leads to clinically relevant inflammation and pain reduction. Yes you can take too little dose to get pain relief. Does dosage affect the time in which pain relief is attained? I suspect this is important to many sufferers (including me.) How relevant is the H2S contribution to pain relief compared to Naproxen dose? Not completely understood. Could contribute. It's not essential to know the H2S contribution to the MOA, there are lots of drugs on the market where the MOA is just not known, I take one. But if they could figure out how H2S is contributing that would certainly add strength.
2. Is COX 2 inhibition universally recognized as the principal (maybe exclusive) indicator of pain relief? Yes. If so, then would ATB-346 not necessarily inhibit COX-2? In animal studies 346 inhibited COX2 more strongly than naproxen, in human trials they've only reported total Cox inhibition so we don't know for sure in humans but generally on this issue animal results hold up in humans. Is continued COX-2 inhibition then not a precursor to cardio vascular events? Maybe, there is no clear consensus on what causes CV risks, multiple possible mechanisms exist. Vioxx has 10x higher Cox2 specificity than any other nsaid. My amateur guess (based on the mice data) was 346 was below Celebrex in its Cox2 specificity, maybe close to Indomethicin but I'd like the company to be more clear on this. The way I think about this is as a Goldilocks problem. Too much and you get CV risk, too little and you don't get pain control. The problem is just where the sweet spot lies is not understood, what exact properties the drug needs to have in order to lie in the sweet spot is not exactly known, the size of the sweet spot is unclear it's probably quite big. It's probably easier to say when a drug is outside the sweet spot and has serious issues than it is to place it in the sweet spot. The company could reveal more data they probably have but I'm not sure it would help too much. Hopefully it doesn't have a profile like Vioxx, if it did and the company know that they would be obliged to reveal that to the regulators and maybe the trials wouldn't have happened. In my view the best assumption is 346 lies somewhere in the spectrum of other NSAIDs on CV risk, it's probably going to be unlikely they can prove otherwise in Ph3 so if it comes to market it'll probably have the same CV warning as all other NSAIDs. Published papers suggest this is the case. Yeah but other papers suggest other mechanisms, this is not settled science. Has Antibe yet demonstrated the safety of ATB-346 wrt prolongued use? No, this is for Ph3 (not sure in animals maybe) Could not find any info on this.
3. Are there safety concerns of ATE-346 use wrt liver/renal function? Yes, those concerns exist for all drugs, the companies line is 346 is in-line with other Nsaids on this. This gets resolved at Ph3 but some data coming in this trial. Has this been adequately investigated, in your opinion? Won't be adequately answered until the clinical program is finished, that is normal. The answer atm is it's tolerable but the Ph1 snafu probably keeps this a bubbling issue to the end.
4. WOMAN is a subjective assessment of pain. No it's not. Many studies have shown that subjective systems for pain measurement have inherent shortcomings (all tests have limitations, science likes to know those limitations so as to not draw the wrong conclusions. But limitations doesn't mean that a test isn't good for answering all questions. If it's validated to answer certain questions then it's validated) related to how they are interpreted/applied. While WOMAN might be a gold standard, are there not inherent risks in applying a subjective pain measurement system to a trial where there are relatively minor differences in the dosages/placebo being investigated? The risk is the pharma partners or the regulators won't like the WOMAC data. Is there evidence that partners or regulators don't like WOMAC? If it's executed badly then yes they don't like it. If it's performed properly, with all the right statistical analysis then it's a well validated test and they will accept the results. Look at that EMA doc I linked to, they describe WOMAC in there. Are there not inherent shortcomings in the inappropriate implementation of trial protocals, with a devestating impact on share price? Yes bad execution is a very bad thing(See Antibe, Acasti experience). Bad/inconclusive results could be devasting.Yes
The science wrt to ATB-346 safety is impeccable. The observations wrt effectiveness were impressive, but not necessarily conclusive. I suspect that Phase 2 trials will be positive, and share price will rise.
But if ATB-346 is such a slam dunk as many posters have surmised, than why has Big Pharma not already stepped in. What are their concerns? it's not a slam dunk, it's an end of phase2 drug program. Still lots of un-asked questions, uncertainty and risk. You can only remove that with empirical evidence by doing the Ph3 trials. The only thing you can really do atm is look at the questions that have already been asked and how well they were answered. I'm most positive on the outcome of this trial, a number of previous results suggest they should meet their efficacy goal of non-inferiority to Naproxen, safety looks ok atm but is an ongoing worry. Sometimes you look at the long term picture and sometimes you look at the next milestone.
My view is that Antibe is a speculative stock with its associated risks. It has excellent potential, but not quite there yet. Yes it's speculative and high risk, that is inherent in biotech. Again I see this as looking at it as phase 2 drug. The questions they've asked so far have generally come back with positive answers, not so negative as to kill the program, in some cases (gut result) spectacularly positive. The imminent data readout should hopefully further derisk it, it could kill it off though. The horror and the joy of biotech.
I would truly appreciate your unbiased thoughts on the scientifice aspects of this drug My honest opinion Many thanks.