Replies to post #146369 on Biotech Values

[mcbio]

They suggest there is a dose/response QTc relationship, and that opens up the issue of what these numbers look like at higher doses and the degree of variability in the drug's PK and the issue of possible drug-drug interactions (which were the root cause of all the drugs that were withdrawn for QTc issues).

Personally I think the whole QTc issue with these marginal prolongations is hugely overblown in terms of the actual risk compared with the amount of attention focused on it, but that boat sailed long ago and we have to live with the regime we have. I suspect plenty of currently very widely-used drugs would never have been approved under the current standards - including drugs like Zithromax that are given out like candy today.

Thanks Peter. Does QTc issue generally worsen over time or does it typically stay within whatever the given range is for a drug that causes a prolongation? Per the PR, it doesn't sound like QTc prolongation is a major concern right now for 797 at the intended 400mg dose, though there is still the question about drug-drug interactions and that will presumably still need to be explored even at this lower 400mg dose where there doesn't seem to currently be a serious QTc signal.

[olddogwithnewtrix]

ARRY-797 From a poster on YMB

I posted your response to mcbio

ARRY has already noted that QTc prolongation is higher at higher doses, though below thresholds which would be an automatic FDA red flag. It could be annoying to have to monitor the QTc interval during treatment, but possibly not more annoying than monitoring for addiction / GI bleeding / renal dysfunction.

[pcrutch]

I agree that QT issues are largely overblown.

Here, I think it's not nearly as big of an issue as have been made. Study was at 400 mg BID. I dont believe this to be a class issue with the p38's and their previous 14-day study went up to much higher doses with no QT/cardio issues; also none in their molar extraction studies.

Intracellular Signal Pathways: Potential for Therapies
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033497/

Array Phase 1 PLK/PD study
http://www.arraybiopharma.com/_documents/Publication/PubAttachment402.pdf