By special request from G1945V over on Stockhouse regarding apabetalone and FSHD. Some good links that G1945 provided in posts over on SH. 

"ACE-083 is a locally-acting protein therapeutic consisting of modified form of human follistatin that binds GDF8 (myostatin) plus other negative regulators of skeletal muscle in the TGF-β superfamily"

Basically, ACE-083 is locally injected into the affected muscles, where ACE-083 binds to and traps GDF8, GDF11, activins, which are ligands of the TGF-β superfamily that typically bind to and activate the ActRII Receptor Complex. Activation of ActRII Receptor Complex inhibits muscle growth via Smad2/3 signaling. So ACE-083 is basically sequestering/trapping these ligands and attenuating this Smad2/3 signaling cascade.

Sounds like it is promising and could work. However, if it has to be admistered by local injection into each affected muscle every three weeks, how practical is this for systemic relief of FSHD symptoms and for long-term use? A daily, oral therapy would have many advantages to multiple, routine injections.

My biggest question is, how much apabetalone reaches the muscle tissue via oral dosing? Resverlogix has hyped up the effects in liver, kidney and vasculature, as well as brain (though this may be an indirect effect of apabetalone). Not sure how much orally administered apabetalone reaches the muscle. They may need to optimize a different drug delivery method for apabetalone to increase the muscle exposure. The previous study connecting BET inhibitors to potential FSHD therapy was using patient derived skeletal muscle cell cultures. Cell culture is easy to get drug exposure. Not as easy with oral dosing.

BearDownAZ