ACD856 Just Cleared Its First Human Hurdle—And It Looks Extremely Clean
Near-perfect oral bioavailability, 20-hour half-life, zero dose-related side effects—the cleanest Trk PAM we’ve seen yet.
A small-molecule positive allosteric modulator (PAM) of TrkA/TrkB receptors—a compound that binds to a site distinct from the natural ligands (BDNF for TrkB, NGF for TrkA), enhancing their signaling only when they’re present—with near-perfect oral bioavailability and a ~20-hour half-life just posted spotless Phase 1 safety data. That’s the kind of profile people wait years for.
“ACD856 was well tolerated with no treatment-emergent or dose-related adverse events or other safety assessments… exhibited rapid absorption, an almost complete bioavailability and a dose proportional increase in exposure.”
A reader left a comment on my Semax article recently — “ACD-856 may interest you, it’s a TrkA/B/&C PAM.” I bookmarked it and noticed that the first-in-human paper is out. Spoiler: it did not disappoint. (Thanks, Nought.)
What Actually Happened in the Trial
AlzeCure Pharma took zero chances after their previous candidate (ACD855) turned out to have a 68-day half-life in humans instead of the predicted ~4–5 days. So they started ACD856 with a proper Phase 0 intravenous microdose (100 µg) in six healthy guys.
Result: terminal half-life ≈ 19–20 hours, low volume of distribution, low clearance, bi-exponential decline. Exactly the kind of predictable, drug-like kinetics you want to see.
They then ran a textbook single-ascending-dose study: 1 mg → 150 mg oral in healthy volunteers (n = 56 on active, 14 on placebo). Doses were escalated only after safety and PK review. Food effect was tested at 40 mg.
Key pharmacokinetic wins:
Near-100% oral bioavailability
Dose-linear exposure across the entire 150-fold range
T½ ≈ 20 h across all oral doses
Food lowers Cmax by ~40% and delays Tmax by a few hours, but AUC barely budges → you can take it with or without food and still get essentially the same total exposure
Negligible renal clearance (basically all metabolic/hepatic)
Safety was boring in the best way possible. No serious AEs, no dose-related trends in adverse events, vital signs, ECG, labs, or stool frequency (they specifically watched for the GI issues seen with direct neurotrophin mimetics). Even at 150 mg—roughly the top of the predicted therapeutic range—nothing interesting happened.
The only “interesting” here means “bad.”
Why This Actually Matters for the Rest of Us
Most nootropic or pro-cognitive compounds that hit Trk receptors directly (or massively upregulate BDNF/NGF) come with baggage: pain, weight loss, GI distress, injection-site reactions, etc. ACD856 is a positive allosteric modulator, so it only amplifies the natural ligand signal when and where BDNF or NGF is actually being released. That’s theoretically a much cleaner way to get the benefits without the side-effect storm.
Preclinical data already showed single-digit nanomolar potency, robust pro-cognitive effects in aged animals, and antidepressant-like activity in forced-swim. Now the human PK says it will be doseable once or twice daily with predictable exposure. That combination is rare.
If you’ve ever used Semax, Selank, dihexa, NSI-189, P21, or any of the other BDNF-upregulating peptides or small molecules, you know how frustrating the PK can be (short half-lives, nasal-only, variable response). A clean oral compound that actually hits the same pathway at physiological levels is legitimately exciting.
What Comes Next
AlzeCure has already started a MAD (multiple-ascending-dose) study and they’re planning Phase II in Alzheimer’s patients in 2025. The company has repeatedly said depression and other cognitive disorders are also in scope, so we’ll likely see additional indications.
The real test will be efficacy in impaired populations—healthy volunteers don’t tell you if something actually improves memory or mood—but everything that could go wrong already went right: safety, tolerability, human half-life prediction, bioavailability, dose proportionality. That de-risks a shocking amount of the program.
The Realistic Caveats (Because Someone Has to Say It)
Single-dose only, healthy subjects only—we still need the 28-day MAD data.
No biomarker readouts (BDNF levels, EEG, etc.) were reported here.
No cognition testing in this study—that will come later.
Company-sponsored, small n, standard stuff.
Still, this is about as clean a Phase 1 package as you will ever see for a CNS-active compound targeting neurotrophin signaling.
If the multiple-dose study looks anything like this one, ACD856 will shoot straight to the top of the most-watched early-stage nootropics list.
One Last Thing
I’ve got this one on the highest-priority watchlist now. When a reader drops a random compound name in a comment and the first human data turns out this good… you pay attention.
Explore the Full Study
Nilsson, B., Bylund, J., Halldin, M.M. et al. ACD856, a novel positive allosteric modulator of Trk receptors, single ascending doses in healthy subjects: Safety and pharmacokinetics. Eur J Clin Pharmacol 80, 717–727 (2024). https://doi.org/10.1007/s00228-024-03645-1
You work quickly!
Eagerly awaiting the results of cognitive testing on both healthy and impaired subjects. Hopefully the impact turns out generally positive and more than marginal, lol.
I think there’re a few US-based vendors offering it atm, might give it a go and let you know how the n=1 turns out.