flosz schreef op 25 juni 2015 23:47:
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Comment 1:
www.ozgurogut.com/thoughts/2015/6/25/... Thanks for sharing your thoughts so clearly. In essence you say that the truly stunning animal results of S100A1 bare no relevance to any category of human CHF. I find that heart (!?) to believe. In my opinion it's all be about selection of the relevant subcategory of humans. Aldag mentioned one important factor to consider for a lot gene herapy clinical trials: the trial can only be run in the worst category of patients (e.g. Parkinson or CHF for that matter), while an effect can maybe be better seen if GT were applied early in the disease.
My solution: do an orientational phase 1 in different categories of CHF patients and see where you pick up a signal and develop it from there. That might be a way around the risk that you point out. Because indeed: CHF is a mixed bag and and S100A will probably not work in all.
Comment2=reply comment 1
It does sound harsh doesn't it? After brushing aside Celladon's human data in CUPID-1 as a fluke, I'm not too shy about ignoring preclinical data from animal HF models.
But in seriousness, I think preclinical data are necessary to analyze more because they're predictive for failure rather than for success. If I'm to value Uniqure's animal data so highly and accept them as indications for future clinical success, I would have had to do it with dozens and dozens of prior programs that showed similar preclinical success but failed in the clinic. Development history suggests that there are many reasons to be skeptical or, at the least, very guarded about the relevance and reliability of these models. Uniqure may prove the exception, and their technical achievement is to be lauded. But right now their data package is tracking similarly to other efforts that failed in the clinic.
My general view is that manipulating single intracellular proteins in the heart is, by and large, a losing proposition. I think it can work if you start playing with cell cycle related proteins, but not ones that are generally accessory proteins such as S100A1.
Finally, I agree with your comment regarding earlier treatment. For the sake of brevity, I did not write it up but I think it is the implied message from the post. However, the clinical setting is what it is, and Uniqure faces the same challenge as everyone else in this regard. I think the most apt clinical situation is early treatment of people with confirmed familial cardiomyopathy gene mutations. In that circumstance, you have a defined population and, depending on the severity of the specific mutation, a strong clinical rationale to treat early. This is likely a direction they'll pursue with Bristol-Myers.
I appreciate your comment.