dual agonist — 21 things I got wrong before I got it right
dual agonist — 21 things I got wrong before I got it right, and I am aware this is a minority view on this board.
What this compound is actually being developed for, since the boards treat it as a weight-loss molecule with a footnote.
It is a dual GLP-1 and glucagon receptor agonist, and the glucagon arm links to hepatic fat and energy expenditure. The headline programme is metabolic liver disease, with endpoints scored on biopsy rather than on a scale.
That matters for how the data should be read. A histological response rate in a biopsy-confirmed population answers a very different question from a mean weight change in an obesity trial, and quoting one in place of the other — which happens in nearly every thread here — is not a comparison.
The endpoint vocabulary, because you cannot read this literature without it.
Resolution of steatohepatitis without worsening of fibrosis and improvement in fibrosis without worsening of steatohepatitis are the two standard composite endpoints, both scored on biopsy by pathologists against a defined system. Liver fat fraction is an imaging surrogate that correlates imperfectly with histology.
A trial can move the surrogate substantially and the histological endpoint modestly. Both results are real; they answer different questions. Anybody quoting a response rate here should say which endpoint it refers to, and most summaries do not.
The honest evidence position, written out so this board does not drift.
Phase 2 data exists in a specific, biopsy-characterised population, with a slow protocol escalation and tolerability tables worth reading in full. Nothing containing this compound is approved by any regulator anywhere. Research-use-only material is not approved for human use.
Independent purity results across this entire site number in the low single figures. That means nobody here — including the people who post most confidently — has a basis for statements about batch-to-batch consistency. If you test something, post it; the log is the only thing that will change that position.
Sceptical readings welcome. The confident ones are the ones I distrust.
best — the order this archive was captured in
read the histology endpoint definitions before quoting a response rate
the hepatic data is what makes this compound different from the others
It is a dual agonist at the GLP-1 and glucagon receptors. The glucagon arm is associated with increased energy expenditure and with effects on hepatic fat, which is why the development programme is oriented towards liver disease.
not approved anywhere, and the boards forget that constantly
Not convinced. Imaging-based fat fraction is not the same as a histological response and the paper is explicit about that.
Right, and the trial titration was slow for reasons that are visible in the tolerability tables.
Spent an evening on the histology scoring system and understood the trial literature far better afterwards.
the titration in the trials was slow and deliberate
glucagon agonism and energy expenditure is the mechanistic thread
Correction: that is the imaging endpoint, not the histological one. The paper reports both and they differ substantially.
Yes — nothing containing this is approved anywhere, which is the first fact and usually the last one mentioned.
Independent result logged. There are almost none for this compound, so it is genuinely valuable.
Which endpoint — histological response, fibrosis improvement, or fat fraction?
Phase 2 in a biopsy-confirmed population is a demanding design: recruitment is slow, the population is specific, and the results do not generalise to people who have not been characterised that way.
biopsy-confirmed is not the same as imaging-suggested