Orange re "can't understand why gen 2.5 is not a priority. Suspect there may be some concerns we don't know about."

1.There are a few reasons. With mipo ISIS has no say in the matter. Per the partnership agreement any follow-on drug is completely up to GENZ. When I did become familiar with management's thinking on this in the past they expected GENZ/Sanofi would want the patent to be closer to running out before they'd be interested in the possibility. That's not surprising as that's how big pharma thinks about the economics.

2. Gen 2.5 is not something ISIS is rushing into. The chemistry and thus the characteristics are very different and the plan is to slowly and very deliberately introduce it only when they think it makes sense for a specific drug which to date has only been the STAT 3 drug. They see the transition as playing out over a period of years as they gain more experience and understanding of 2.5. They feel they have that luxury because the later gen 2 drugs are so much better now than the earlier gen 2 drugs. As I've noted, other than mipo every early gen 2 drug is gone mostly by cancellation. Some like PTPB1 are being redone as later gen 2 drugs. I imagine selectively some drugs will be redone as gen2.5 but it hasn't happened yet. I think just to change from early gen 2 to late gen2 has been an unappreciated seismic shift and all the new early stage potential blockbusters are all late gen 2 drugs and we'll see when a second drug joins STAT 3 as a gen2.5.

3. Switching to my personal views I think the issues I've raised about what mipo's place will be in the competitive landscape are important and separate from the patent issues. I doubt Sanofi wants to make any decisions on a follow-on drug until they see how the competitive landscape develops. If it ends up a small niche drug like I'm thinking now and things like PCSK9 dominate beyond HoFH, I doubt they'll want a follow-on mipo, they'll just let the current version do whatever it can. Theoretical issues about why one mechanism may have benefits over another mechanism are fine but the bottom line is if the PCSK9 drugs prove themselves in clinical outcomes trials there may be little need for mipo beyond HoFH given the lack of liver or other issues with the PCSK9 drugs..

Also