[Trial Data] phase 2 biopsy endpoints, and what "resolution" means
Thinking out loud about this: phase 2 biopsy endpoints, and what "resolution" means.
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.
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.
Histological endpoints in this field are scored on biopsy: resolution of steatohepatitis without worsening of fibrosis, or improvement in fibrosis without worsening of steatohepatitis. Both are harder to achieve and to interpret than an imaging surrogate.
That is everything I have. The rest is opinion and I have tried to keep it out.
best — the order this archive was captured in
Independent purity results for this compound are very sparse across the whole site, which means any impression about consistency is built on almost nothing.
Small fix — dual agonist, GLP-1 and glucagon. No GIP arm in this molecule.
the weight numbers are secondary to what this is being developed for
MASH endpoints are histological, which is a much harder bar
independent testing on this compound is very thin
Cosigning on the glucagon arm. It is the mechanistic thread that connects the hepatic and the metabolic effects.
Which phase and which arm are you quoting?
the hepatic data is what makes this compound different from the others
Yes — nothing containing this is approved anywhere, which is the first fact and usually the last one mentioned.
not approved anywhere, and the boards forget that constantly
not approved anywhere, and the boards forget that constantly
dario_boateng is right that biopsy and imaging endpoints are not interchangeable.
I would not read across from the obesity programmes. Different population, different endpoint, different question.
How fast was the escalation in that protocol?
That figure is from the obesity programme, and this thread is about the hepatic one.
That figure is from the obesity programme, and this thread is about the hepatic one.
Agreed — and the endpoint definitions are where the actual claim lives.
fibrosis improvement without worsening steatohepatitis is the phrase to learn
glucagon agonism and energy expenditure is the mechanistic thread
What does the tolerability table say at that dose?
Correction: that is the imaging endpoint, not the histological one. The paper reports both and they differ substantially.
Push back: the evidence here is phase 2, in a specific population, and it does not support a general ranking.
dual GLP-1 and glucagon agonist, and the glucagon arm is the story
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.
Which endpoint — histological response, fibrosis improvement, or fat fraction?
do not import intuitions from the obesity programmes
Has anyone posted an independent purity result for this compound?
Imaging-derived liver fat fraction is a surrogate. It correlates with histology imperfectly, and a trial reporting one is not reporting the other.
- 1Independent purity results for this compound are very sparse across the…8 comments in this branch · started by u/julia_mensa
- 2Yes — nothing containing this is approved anywhere, which is the first fact…7 comments in this branch · started by u/thermal_mass_tom