Hello Bio, I just moved to the sidelines completely. Don't like our trading pattern, was hoping to move out of the %10-11 range by now. Nice article BTW. Alot of questions seem to be surfacing. GLTY
Response below to the blog article I posted from Marcpw on the IV board. Sounds like a pretty good defense for Mipo. We know that elevations in liver enzymes seen in the MIPO studies are correlated with significant drops in cholesterol levels. (Some individuals have more profound drops then others) The individuals in the study Dirk referred to had loading doses so it makes sense for them to also have elevated liver enzymes. ISIS/GENZ are no longer using loading doses in their trials so the high incidence of reported ALT elevations Dirk refers to in his article should not be seen.
Comments on Dirk's blog post
I've gone over the article now and the PR hat he thought was misleading based on that recent article by Akdim et.al. in JACC so I'll go over the points. Dirk appropriately focuses on the 13 week extended study at 200mg cohort of the dose escalation study which formed the basis for the P3 trials.
One point he raises concerns efficacy. In the PR he notes the mention of a 48% LDL reduction versus the 36% reduction seen in Table 5 of the article. I think this can be explained because it's not an apples on apples comparison. The 36% reduction in the article is a reduction from baseline. In the PR the results are compared to placebo. If one looks at the Flow of Study Patients in Figure 1 of the article we can see that there were only 2 placebo patients in the 13 week 200mg group. The other 15 placebos were allocated to the other dosing cohorts. So it appears that LDL increases in those 2 placebos account for the main part of the discrepancy. As Dirk notes there were also 2 additional patients reported on in the article versus the PR so together with the placebo point this should account for the difference.
Dirk had harsher criticism about the way the safety profile was reported in the PR and in particular the ALT increases. As he noted the PR talks about an "integrated safety analysis" of all trials to that date and does not have the study specific data in the PR. He is particularly bothered by the fact that 5 of the 10 patients had ALT > 3x ULN and his implication is that ISIS presented the PR in a way that diminished or covered up the fact (my words).
I can discuss this in 2 ways. One is perception in terms of did ISIS purposely write the PR in a way to to hide the perception of a safety issue. The other way is to look at the actual clinical importance of the data and whether it is indeed somehow disturbing. I'll discuss the actual significance first as it ties in to the question of whether ISIS was being deceptive.
The first thing that has to be noted is the 200mg cohort got a loading dose. They received a total of 3 200mg doses (given every other day before then being put on the 200mg weekly. So they actually received a relatively massive 800mg in a very short period of time As we know this idea of a loading dose was dropped apparently at some point after this trial. Based on the data we've seen since in 26 week trials I have to think this was a big part of the reason there were 5/10 >3x ULN. Am I bothered by this? I find it pretty irrelevant at this point now that we have 26 week trials in relatively large groups of patients compared to this P2. Did ISIS present the PR in a way to be deceptive? In a way I think that could be true but I think it was also probably the most appropriate thing to do. Since there were no bilirubin increases there wasn't anything urgent to report. However I could see a scenario where once they saw 5/10 patients had significant ALT elevations they made the decision soon after to forget about the loading dose idea. At that point could they have made the decision to downplay the ALT elevations observed in the study because they thought it was partly a loading dose issue? I think the way they presented it combining it with all the other data was probable the best way. But given the totality of the facts could part of their motive have been to bury the 50% of patients with ALT elevations?
I can't read their minds but it's very plausible. Why get yourself all hung up in explaining ALT elevations at a dosing regimen you'll no longer use when the point was to get the dose escalation data to design the P3. So Dirk could have a point there. But it is 3 years later and we know that 50% is in fact not consistent with what we've been seeing now. So I don't care and I think it's irrelevant but if Kurt feels it was somewhat of a deception 3 years ago I can understand his point even if I disagree with it. I know people like to rattle off about it at times but I've never felt Stan is dishonest or deceptive. The bottom line is this 3 year old study adds nothing useful but I suspect the same thing that bugged Dirk bugged ISIS so the loading dose was nixed. IS investor on the IV board.
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