This gets cited here weekly, usually second-hand, so it is worth setting out what it does and does not establish.
Orforglipron is a small molecule rather than a peptide, which is the whole point: no SNAC absorption enhancer, no fasting window, no cold chain, and oral bioavailability in the tens of percent instead of around one. Phase 2 put it near 14.7% weight loss at 36 weeks on the top dose with a side-effect profile that looks like the injectables.
Where I think it is weakest: the completion rate deserves as much attention as the headline, because a large effect among those who finished is a different claim from a large effect among those enrolled.
What would genuinely help is knowing whether a non-peptide oral agonist can match injectable exposure in practice, or whether the convenience is bought with a lower ceiling. Tell me what I have not thought of.
TrialNerd_Beth said:Orforglipron is a small molecule rather than a peptide, which is the whole point: no SNAC absorption enhancer, no fasting window, no cold chain, and…
Agreed, and subgroup analyses deserve particular suspicion. With enough subgroups something is significant by chance, and pre-registered subgroups are a different animal from ones found afterwards.
TrialNerd_Beth said:Orforglipron is a small molecule rather than a peptide, which is the whole point: no SNAC absorption enhancer, no fasting window, no cold chain, and…
Pushing back on TrialNerd_Beth here. Small molecule does not automatically mean cheap. Price is set by what the market will bear and by patent life, not by cost of goods, and I would not assume the savings reach patients.
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View ResultsShort answer first, then the reasoning. The manufacturing argument is the underrated one. Peptide synthesis capacity has been the binding constraint on this entire class, and a small molecule is made in ordinary chemical plants. If it holds up in phase 3, the supply and price picture changes more than the efficacy picture does.
Dr.NateNeph said:Agreed, and subgroup analyses deserve particular suspicion.
Adding a me-too, because a thread of one person's experience is not much use. Posting only so the count is not one.