2) That prior program shared and explained the results of the #LBCT data from #AZALEA_TIMI_71 at #AHA23. Lots has happened in the #FXI world since then, so it's time revisit and recap. pic.twitter.com/caxbJHB0ML
— cardio-met (@cardiomet_CE) December 14, 2023
4) This program is intended for #HCPs and is accredited for 0.75 hr CE/#CME. It is supported by an independent educational grant from Anthos Therapeutics. Stay current with the latest #cardiometabolic #MedEd delivered wholly on X right here on @cardiomet_CE.
— cardio-met (@cardiomet_CE) December 14, 2023
6) #AZALEA #TIMI-71 was designed to test the promise of greater safety with #FXI inhibition vs. a routinely used #DOAC in clinical practice, #rivaroxaban, in patients with #AFib. Efficacy of #abelacimab in a different setting–#thromboprophylaxis in #TKR, had already been shown. pic.twitter.com/0gX3XSuFz5
— cardio-met (@cardiomet_CE) December 14, 2023
8) The study initiated Mar 2021 & completed enrollment Dec 2021, w/median duration of treatment >20 mos, & the #DMC rec'd the trial stop early 9/2023 for "substantial reduction" in bleeding and benefit : risk favoring #abelacimab over #rivaroxaban. pic.twitter.com/fVGEg0wUYP
— cardio-met (@cardiomet_CE) December 14, 2023
9b) So it's worth quick reminder here that individuals with congenital #FXI deficiency (most often #Ashkenazi Jews) is associated only very rarely with #bleeding diathesis & is associated with decreased incidence of cardiovascular events and VTE.
— cardio-met (@cardiomet_CE) December 14, 2023
10a) 2⃣ The primary EP of #AZALEA was major or clinically relevant non-major bleeding #CRNMB. And we saw a dramatic reduction in those 🩸endpoints, including almost complete elimination of GI 🩸 – the Achilles heel of the #DOACs. pic.twitter.com/WKFEyBfJzG
— cardio-met (@cardiomet_CE) December 14, 2023
11) 3⃣ #AZALEA_TIMI_71 was a safety study, so all efficacy outcomes were exploratory and limited in number. No stat sig differences were seen in ischemic stroke or all-cause death. A dedicated, larger phase 3 trial (#LILAC_TIMI_76, NCT05712200) is ongoing to evaluate efficacy. pic.twitter.com/x09zy2PorG
— cardio-met (@cardiomet_CE) December 14, 2023
13a) Then the calendar turned to 19NOV23, and it was announced that #OCEANIC_AF(NCT05643573), a Ph 3 study of #FXI inhibitor #asundexian vs #apixaban in pts with #AF at risk for stroke was being stopped early for "inferior efficacy of asundexian versus the control arm." pic.twitter.com/IfVrgPRkd2
— cardio-met (@cardiomet_CE) December 14, 2023
13c) OK let's be clear here. WE DON'T KNOW YET. But the trial sponsor and esteemed PI @manesh_patelMD have promised transparency and all the details. But perhaps we can speculate. pic.twitter.com/CKBlo6JomM
— cardio-met (@cardiomet_CE) December 14, 2023
15) But #AZALEA was not an efficacy study, and #OCEANIC_AF was stopped for "inferior efficacy." So we can't make a comparison there. We do, however, know (or don't know) the following:
— cardio-met (@cardiomet_CE) December 14, 2023
16b) Might better efficacy have been attained with a higher QD dose or with BID dosing such as that for the comparator in #OCEANIC_AF, #apixaban? What do we know about FXI inhibition achieved with asundexian?
— cardio-met (@cardiomet_CE) December 14, 2023
16e) Might higher inhibition driven by ⬆️ dosing have achieved greater efficacy and still be safe? pic.twitter.com/EdxNswAnCW
— cardio-met (@cardiomet_CE) December 14, 2023
17b) With small molecules, #aPTT can also be measured, but as there is no sustained binding of the inhibitor to #FXIa and so unbound factor can't be measured, other assays must also be used.
— cardio-met (@cardiomet_CE) December 14, 2023
17d) . . . using a fluorogenic substrate to measure #FXIa generation after triggering the intrinsic pathway with kaolin without calcium, is used. No explanation for the use of a nonstandard assay has been published, nor are there any known data on the correlation of . . .
— cardio-met (@cardiomet_CE) December 14, 2023
18a) 3⃣ We are talking about the first Ph 3 data on a FXI inhibitor in #AFib. It's important to remember that there are multiple drugs being developed as #FXI/#XIa inhibitors, representing different #MOAs.
— cardio-met (@cardiomet_CE) December 14, 2023
18c) . . . and there is the oral small molecule #milvexian vs apixaban (#LIBREXIA_AF, NCT 05757869). We have no Ph 3 readout yet on milvexian, but the #PK and #PD differences between a daily oral med and a monthly SQ med are certainly well-recognized.
— cardio-met (@cardiomet_CE) December 14, 2023
18e) Or perhaps a different small molecule with different #PK and #PD from #asundexian will yield better efficacy. #LIBREXIA will tell us.
— cardio-met (@cardiomet_CE) December 14, 2023
19b) . . . in a different setting (secondary prevention of non-cardioembolic #stroke or high-risk #TIA within 7d of acute event), with a different comparator (#placebo), and as add-on therapy as most pts will also receive #antiplatelets, which of course ⬆️ bleeding risk.
— cardio-met (@cardiomet_CE) December 14, 2023
20b) Genetic/epidemiologic data support the safety of an "inborn FXI inhibition." Animal studies support pharmacologic #FXI inhibition as safe from a #hemostasis perspective.
— cardio-met (@cardiomet_CE) December 14, 2023
21a) In addition, @CMichaelGibson points out another reason to eagerly await a full report from #OCEANIC_AF: so far we only have info on the primary outcome. Remember #ENGAGE_TIMI_48, 🔓 https://t.co/pYN8xa7ixZ, #edoxaban vs #VKA? 2⃣ doses of edoxaban were studied.
— cardio-met (@cardiomet_CE) December 14, 2023
22) The story is still being written. The most conclusive data that we have so far come from #AZALEA_TIMI_71, which demonstrates remarkable safety of a #FXI inhibitor in #AF against a #DOAC standard. Ph 3 trials are actively enrolling. Watch this space to see what happens!
— cardio-met (@cardiomet_CE) December 14, 2023
23b) It's B. Selective inhibition of FXI impairs the intrinsic or contact pathway that results in pathologic thrombosis without meaningfully impairing hemostasis through the #TF-initiated extrinsic pathway.
— cardio-met (@cardiomet_CE) December 14, 2023
23d) It's B. #Asundexian is a once-daily, oral, small molecule that competitively inhibits #FXIa, while abelacimab is a SQ-injected once monthly monoclonal antibody directed against the catalytic domain of #FXI.
— cardio-met (@cardiomet_CE) December 14, 2023
24) And there we are. Thanks for joining @CMichaelGibson and now please join him in FOLLOWING @cardiomet_ce. Then go pick up your certificate for 0.75hr 🆓 CE/#CME at https://t.co/8Wn0HT7urL!
— cardio-met (@cardiomet_CE) December 14, 2023