RE:RE:RE:RE:RE:RE:Keep this in mind LONGs ... It was not my intent to get into a long discussion...more to point out that the AME LTEs were much higher than those previously experienced during trials and that chronic likely has been relegated to the back burner for valid reasons.
You can find the following quote in Section 5.3 Hepatotoxicity of the prescribing information for most NSAIDs, and in many other sources (e.g., Therapeutic Class Review: nonsteroidal anti-inflammatory drugs (NSAIDs) Jan 25, 2016):
"Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials."
Lower elevations of LTEs were found in many more subjects during these trials, as you have stated. What is concerning here is the magnitude and the frequency of the AME LTEs given that it was a short study with low dose. 100mg Oten has approx one third of the naproxen that is contained in a single Aleve pill that you can purchase OTC. I believe that the FDA would consider this as a non-trivial signal for the potential for severe Drug Induced Liver Injury (DILI), notwithstanding the absence of elevated bilirubin. (For the FDA'a perspective on liver issues during clinical trials, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation is an excellent read)
Oten chronic is not included in the pipeline as presented in the deck. I believe it is only mentioned once, and that is in the context of post operative pain. If you have an explanation for this I would appreciate hearing it.
I know that physicians routinely prescribe drugs off label for other indications. I don't believe they frequently exceed an approved dosing regimen. Perhaps the Docs on this board have an opinion.
It is believed that a drug must be taken with a minimum dose threshold before the liver is affected, therefore, a safe dosage regimen probably exists. The issue here is whether that dose will show efficacy. Dan believes that exogenous H2S down regulates endogenous H2S production which leads to oxidative stress in the liver. If true, then it could be difficult to find an effective dose regimen in a lab without a functioning liver. More important is the risk associated with an expensive, long term PH 3 trial. One can imagine how managemment would be crucified if it went down this road and failed several months into the trial.
Naproxcinod is discussed in the minutes of the FDA Special Advisory Committee for the drug which took place a dozen years ago (hard to find now with the reschuffle of the FDA archives). It is a brick, but is an interesting read. Worth looking for it if you have the time. I should add that the FDA's concern with the media coverage was only one of the reasons for the additional CV study. The other was that NicOx did not follow established measuring protocals.
I'm placing my near term bets with acute. ATE recently submitted a new dosing regimen patent for Oten acute. Case law as evolved. A new dosing regimen by itself (chronic) is no longer considered patentable material in Canada and in other jurisdictions. A new medical use for a drug (acute) can be patentable material. ATE's lawyers are optimisitic that the patent will be approved (according to Dan). An additional 20 year IP protection could add considerable value to Oten during discussions with big pharma.