Orforglipron and hepatic first-pass metabolism — anyone have experience?

The manufacturing economics here are worth emphasizing. Current estimates for injectable GLP-1 manufacturing cost:

• Semaglutide: ~$40-80/month (peptide synthesis + formulation + device)
• Tirzepatide: ~$50-100/month (similar)

Estimated manufacturing cost for an oral small molecule like orforglipron: $2-5/month.

Even with typical pharmaceutical markup, this opens the door to dramatically lower pricing. If Lilly prices orforglipron at $400-500/month instead of $1,000+, the volume could more than make up for the per-unit revenue reduction. And it would undercut the compounding pharmacy market significantly.

That manufacturing cost difference is staggering. But let's be real — pharmaceutical companies don't price based on manufacturing cost, they price based on what the market will bear. I wouldn't be surprised if Lilly prices orforglipron at $800-900/month, just slightly below injectables, and pockets the margin difference.

The real price pressure will come when generics/competitors enter the oral GLP-1 space. Pfizer's danuglipron, AZ's oral candidates, etc.

Good thread. One thing to add: the ATTAIN-3 trial is a head-to-head comparison of orforglipron vs. injectable semaglutide 2.4mg. That readout will be incredibly important because it will directly answer the question of how much efficacy you're trading for convenience.

If orforglipron gets within 2-3 percentage points of injectable semaglutide, that's a huge win for the oral formulation. If the gap is larger than 5 percentage points, it becomes a harder sell for patients who prioritize results.

Either way, more options is better for patients. Not everyone needs maximum-potency treatment.

Also worth watching: Lilly has hinted at developing an oral triple agonist as a follow-on to orforglipron. If you can get triple agonism (GLP-1/GIP/GCG) in a pill form with even 70-80% of the efficacy of injectable retatrutide, that's the holy grail. Small molecule, oral, cheap to manufacture, no cold chain.

We're probably 5-7 years away from that, but the direction of travel is clear: the future of obesity pharmacotherapy is oral, not injectable.