ze vreten hun kas op (deel2):
BIOINVEST JOPAGOyesterday
This is very important news.
Upadacitinib was seen as the main competitor of filgotinib under the JAKs. This is a major blow, and an acknowledgment from Abbvie that safety is only so.
If Filgotinib can maintain its good safety profile at Finch1 + Finch 3, it will become the dominant player on the JAK market and eventually also, given the emerging class of the JAKS, on the entire ignition market.
The fact that the safety of filgotinib is better has been statistically clear for a long time. From the comparison included in the GLPG presentations it is clear, for example, that the amount of serious infections and herpes zoster infections in upa is more than twice as high as in the case of filgo. See this presentation, page 19, also known from the JPM presentation and the New Year's drink:
I have not collected the data about the most common safety problems, such as these infections and herpes zoster infections. I think it is true that these problems are greater with the tested 30mg dose than with the lighter 15mg dose. Apparently the differences are such that the improved effectiveness of the 30mg does not outweigh the worsened safety of this higher dose.
That is not good for upa. Ultimately, it is realistic for Abbvie to withdraw the 30mg dose themselves, instead of being forced by the FDA / EMA, as happened with baricitinib / olumiant from Lilly / Incite.
How are the odds then for approval of only the 15mg dose? Undoubtedly bigger, but this has not yet been done. Given the fact that Abbvie expects an Advisory Committee, which will be looked at critically.
Apart from the fact that upa does have some safety issues around infections, there is of course the PE / DVT's, which already played an important role at the Advisory Committee meeting of baricitinib, and also helped to drain the heavier dose of 4mg. because the numbers of PE / DVTs increased at higher doses (if I remember correctly).
So I would like to see what the PE / DVT cases with upadacitinib are. We already know from the Galapagos comparative sheet (p19, see above) that a rate of 0.7 PE / DVT cases per 100 patient years (py) was measured in the case of upa, while the background rate for RA patients was between 0.3 - 0.8 per 100 is py. So Abbvie was already on the high side of that.
These data came from BALANCE-EXTEND, which is an extension of a phase 2 study similar to Darwin3 for filgotinib. As a reminder, Darwin3 shows a rate of 0.1 per 100py, so much lower than the upa AND the background.But what about the PE / DVT rate of upa in the phase 3 trials, the SELECT trials? I have not been able to find that information so directly, so I gathered as much data as possible from press releases and conference contributions from the various SELECT trials, focusing on the PE / DVT rates.
So for each trial the participants per category (15mg or 30mg) and the number of weeks that were reported to calculate the number of patient years. Then the PE / DVT cases were taken from the small print, to be able to calculate the rate. The result can be seen in the table in the appendix.
Disclaimer: I did my best. Of course there may be errors in the table. I have not found any updates of the SELECT trials with longer treatment duration, but they might be there.
Conclusions from the table are:
On average, for all SELECT trials together, the PE / DVT rate per 100 py is 1.6 for 15 mg and 0.9 for 30 mg.
The 0.9 for the 30mg is slightly higher than the previously known 0.7 from the BALANCE-EXTEND, and is slightly above the RA background rate of 0.8.
The 1.6 for the 15mg is still considerably higher, and will for example cause major problems for Abbvie at this dose.
This high rate comes despite the lack of DVT / PEs at 15mg of SELECT-EARLY and SELECT-NEXT. With SELECT-MONO and SELECT-COMPARE, 1 resp. 2 cases at the 15mg dose for increased rates. The real problem case was SELECT-BEYOND (the counterpart of Finch 2), with no less than 5 cases: 4 PEs, with one of those 4 patients also a DVT. (And also 2 PEs at the 30mg dose).
So remarkably enough, SELECT trials have the most DVT / PE cases in the 15mg group, and the omission of the 30mg dose therefore makes no sense, on the contrary. Based on the overall picture, Abbvie can not therefore claim that the number of DVT / PEs at upa 15mg corresponds to the background rate for RA patients.
Unless of course they come up with all sorts of statistical tricks. And / or those 5 cases were really a random coincidence.
In any case, it seems to me that if permission for the 15mg upa dose is added, there will also be a black box warning here, just as with baricitinib,
A black box warning is the strictest warning in the labeling of prescription drugs or drug products by the Food and Drug Administration (FDA) when there is reasonable evidence of an association with the drugIncidentally, I find it funny that Bart Filius very clearly emphasized during the New Year's drink how important it will be !