Collecting this in one place because it comes up every few weeks and the answer is always assembled from scratch. It is about orforglipron, and it is deliberately narrow — everything I am not confident about is marked as such.
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.
The caveat that a daily tablet is a daily adherence decision. Weekly injections have an adherence advantage that gets ignored because injections feel like the harder option.
Phase 2: about 14.7% at 36 weeks on 45mg, GI adverse events broadly in line with the injectables, no food-timing requirement.
The narrow version of the question is 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.
JennaRN 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 ALT falling is not the same as fibrosis improving. Enzymes are a crude proxy; FIB-4 or elastography is what tells you about the thing that matters.
JennaRN 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 JennaRN 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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Browse GL BiochemAnswering the narrow version, because the broad one does not have a single answer. 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.
PurityPaulOR said:Agreed, and ALT falling is not the same as fibrosis improving.
This matches mine closely enough to be worth saying so out loud. I had assumed I was the exception until I read this.