ACE-031 trial data from years back still worth a look, what do you think?

Question

I was reading through older ACE-031 papers the other day, the Phase 1 in postmenopausal women from Acceleron, and it is honestly one of the more interesting myostatin-pathway results I have seen. Single dose, clear lean mass bump on MRI versus placebo, and the mechanism of soaking up multiple ligands at once myostatin, activin, GDF-11 makes sense on paper. I keep wondering why it stalled out for muscular dystrophy when the biology seemed to track. For me, the nosebleeds and gum bleeding they reported are a real flag though. If a decoy receptor is hitting TGF-B family ligands broadly, that vascular signaling is probably not a small side effect to brush off. Compare that to follistatin 344, which is more targeted but has its own short half life and almost no long term human data. YK-11 is a whole different category and I would not lump it in personally. Has anyone followed what happened to the soluble ActRIIB approach after 2017? Curious if there is any newer trial, or if the whole strategy got shelved because of those mucosal side effects.

data_sauna · Accepted Answer

Actually. I only know the older ACE-031 stuff on paper, never tried it myself, but the mucosal bleeding thing you mentioned stood out to me too when I went back through the data a while ago. My read is basically this: when you soak up multiple TGF-B family ligands at once, you are not just blocking myostatin. You are touching angiogenic and vascular signaling, so the nosebleeds are probably a mechanistic warning, not just a random nuisance. That kind of side effect profile is a hard sell for chronic use in a progressive disease where patients already deal with a lot. For the ActRIIB follow-up after 2017, I think Acceleron moved on to different ligand traps luspatercept and sotatercept, both more targeted to EPO signalling and the muscle program basically got shelved. There were some academic groups still working on selective myostatin antibodies, but the decoy receptor approach for muscle growth seemed to die with ACE-031. I could be wrong on some of this though, would love if someone

curiouscaleb · Answer

Yeah the mucosal bleeding thing keeps nagging at me too. A decoy receptor mopping up multiple ligands at once just feels like a lot of off-target risk for something thats meant to be long term, and in muscular dystrophy patients specifically thats a tough trade. You ever come across any of the follow up myostatin antibodies that tried to be more selective, or did most of them hit the same wall?

reid_hrv · Answer

, I think the bigger issue was that the antibodies like domagrozumab and the ones from Pfizer tried to be selective for myostatin only, but in adult muscular dystrophy the lean mass gains did not really translate to functional endpoints on the 6 minute walk. So even with a cleaner safety profile they still hit the wall on clinical benefit. The broad ligand capture at least had a stronger mechanistic rationale for muscle, but yeah, the bleeding is what killed it in practice for me too.

reid_hrv · Answer

Yeah the mucosal bleeding point is exactly what worries me too, and I think your framing is right that it is probably mechanistic, not random. If the decoy is grabbing stuff like BMP-10 and activin along with myostatin, vascular tissue is going to notice. That is why I keep coming back to it being a chronic-use problem, especially in something like DMD where kids are already on a lot. The single-dose lean mass bump looked clean on MRI, but a single dose is not what anyone with muscular dystrophy is signing up for. Did you ever look into the ActRIIB antibody follow-ups, the ones that were supposed to be more selective? I am curious if anyone narrowed the ligand binding enough to drop the bleeding signal, or if it was the same trade-off just dressed up different.

ACE-031 trial data from years back still worth a look, what do you think?

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