RE:About 2b resultsHipFlex wrote: Hello everyone, I'm new here!
I was wondering if anyone of you knows how similar a rodents or a dogs GI is compared to a humans? I'm also wondering is there a reason that there is a preconception that all NSAIDs cause GI damage? How I'm seeing this is that naproxen and the drugs using the same chemical are a whole different thing from ATB346 and have ulceration as a side effect, so why would ATB346 have the same side effect as them? Seems like apples and oranges even though they are all NSAIDs. They also seem very confident about the results, using words like 'prove', 'demonstrate' etc. Is there something I'm missing here? What backs up the chance that the upcoming results would be negative?
Thanks
Both are important questions imo.
I was wondering if anyone of you knows how similar a rodents or a dogs GI is compared to a humans? I tried looking into the first question. The question I asked was is the rat model of GI damage by NSAIDs directly comparable to humans. I couldnt find any studies that directly set out to answer that question. In one of Wallace's papers they did note that there was some correlations between the level of damage seen in rats to the level in human (ie drugs that tend to be more harmful in humans give more damage in the rat model, the same is true with dosings), but I'd consider that as somewhat anecdotal. So the answer to your question, from my research, is that there is no direct evidence that rats and human guts react to NSAIDs in the same way but experimental use of rats has tended to give comparable results.
I'm also wondering is there a reason that there is a preconception that all NSAIDs cause GI damage? IMO this question closely relates to the first question. All NSAIDs are similar in that they all effect the same pathway in the body, COX, there are some differences though. I once asked my rheumatologist if he thought there would ever be 'safe NSAIDs'. He answered NO. Basically because in part the same mechanism that helps to control inflammatory disease (switching off COX genes) is also the same mechanism that makes the GI tract more prone to damage. He thinks you can't have the good without the bad. Its one of the things that makes ATE-346 a bit of a conundrum. Might be one of the reasons its not seen by the market as the blockbuster. Wallace did show in their rat model paper that.
1) COX was reduced by ATE-346 at the same time as
2) The systemic inflammatory response was surpressed at the same time as
3) The GI tract remained protected
So they did all the right experiments (and more) to try to show that this was a real effect but the conundrum remains. In part you can answer this by saying gut protection is a complex process relying on more than just COX. And so one explanation is that at the same as the NSAID part of ATE-346 switches off COX, the Hydrogen Sulphide part switches on other processes that compensate for this protective loss. Wallace does lay out a number of mechanisms that could be in play but I dont know they have a definitive answer on this. Getting some answers on the mechanism(s) of ATE-346 would be a real bonus, likely make the drug more appealing and maybe cement that blockbuster feel. Its not always necessary to know the mechanism of action of a drug to get it marketed, but it does help to clarify the story and if we had it in this case then, imo, Antibe wouldnt be a $20-30 mil company.
I like a lot about what Wallace and his team have done but there remains alot of unknowns. The present study is important. It does make the answer to your first question less important because we'll have direct human evidence instead of relying on the rat data for GI tract damage. It should also make the uncertainty about your second question less important, we still wont have clarity on 'how it works' to protect the GI tract but we will know 'it does work', in the end that might be all we need to see this thing fly.
Hope that helps