Biotech Values

[iwfal]

ISIS FXI-Rx paper released -

http://www.nejm.org/doi/full/10.1056/NEJMoa1405760?query=featured_home&;

RESULTS
Around the time of surgery, the mean (±SE) factor XI levels were 0.38±0.01 units per milliliter in the 200-mg FXI-ASO group, 0.20±0.01 units per milliliter in the 300-mg FXI-ASO group, and 0.93±0.02 units per milliliter in the enoxaparin group. The primary efficacy outcome occurred in 36 of 134 patients (27%) who received the 200-mg dose of FXI-ASO and in 3 of 71 patients (4%) who received the 300-mg dose of FXI-ASO, as compared with 21 of 69 patients (30%) who received enoxaparin. The 200-mg regimen was noninferior, and the 300-mg regimen was superior, to enoxaparin (P<0.001). Bleeding occurred in 3%, 3%, and 8% of the patients in the three study groups, respectively.

Forbes critique:

New Drug From Isis Breaks Important Ground But Unlikely To Dent The Market

It's an odd critique - the title ("important ground ... unlikely to dent the market") implies the primary critique was that although the results look reasonably real (important ground) the results aren't clinically useful (unlikely to dent market). But the arguments within the paper are almost entirely unrelated to the title. And many are just silly. E.g. I particularly like the

"80% power for a noninferiority trial might be acceptable for a phase 2 trial, but it is not for a phase 3 trial."

because it is the equally incorrect inverse of what bioscam companies say when their trial isn't successful on a secondary (how the trial was powered matters little once you have data - what matters is whether the endpoint was changed. And it wasn't in this case.)

But there were others as well - e.g.

The risk reduction in this trial was primarily driven by asymptomatic distal thrombosis diagnosed on venography which is rarely used in clinical practice, thereby raising questions about its clinical relevance.

The endpoint was the same as for Xarelto in one (all? haven't had time to check) of their pivotal trials. Yes, since it was a small trial (i.e. a phase 2) it was never going to see stat sig pulmonary embolism. But it is misleading to cast it as somehow incorrect to use venography.

Etc - really there are many boilerplate objections you could make to a small phase 2 or inherently open label trial. And the paper makes many of them as if they were somehow unique to this trial and they are adding information. E.g. You could have made very similar objections to the first ALK trial or the first BRAF trial.

The only real objection made in line with the title was the note that it is inconvenient since it requires treatment to start weeks in advance. Certainly true - but if(!) the therapeutic index comes anywhere close to holding up pretty much guaranteed everyone would use it for scheduled arthroplasty. Too much hospital $ and patient risk and lawsuit risk not to use it.

BTW - I don't blame the author. I think this is about a group think within KOL community that just can't wrap their head around the possibility that it could be that much better. (BTW - i think the quote from Weiss (the KOL) is actually fair. That, combined with the fact that the paper did appear in the NEJM, says there is at least a little countercurrent)