Phase 2 24.2% vs Phase 3 28.7% — what explains the gap?

The 24.2% was efficacy estimand, not treatment policy. That alone can explain a chunk of the Phase 3 headline gap.

Exactly. Company Phase 3 numbers are not peer-reviewed, so I’m not treating 28.7% as settled. NCT05882045 with 1,946 enrolled is huge though.

Could the glucagon arm explain part of that gap?

Maybe. I saw a small REE bump in my own tracking around week 20, but DEXA scan noise is real. Did yours use same machine?

Same machine, same tech. Lean mass dropped some, but fat mass dropped way more. Total weight isn't the whole story.

Trial estimands are boring until you try to compare across programs. Phase 2 and Phase 3 rarely use identical washout or rescue rules.

The glucagon piece is interesting but overused as an explanation. More energy expenditure doesn't automatically mean more net fat loss if compensatory eating or nausea changes intake.

Without pair-feeding or metabolic chamber data, I’d keep it as a hypothesis. The 24.2% to 28.7% jump could also be better titration and longer exposure.

Nausea absolutely changes intake. Protein goals go out the window for a stretch when that's going on. That confounds any neat REE story.

Lean mass usually tracks protein and resistance training, right?

Agreed, but the trials didn't all report lean mass. If you're comparing 24.2 vs 28.7, you're comparing totla weight, not quality.

I pulled the CTgov entries for NCT05931367 and NCT06039826. They're completed but no headline results in the raw data. That makes cross-trial graphing mostly guesswork until full papers drop. The knee OA trial with 445 enrolled is the one I want to see for body comp and function.

Until peer review, I’m treating 28.7% as a ceiling from company-reported trials, not a normal expectation. The Phase 2 24.2% is the cleaner anchor.

Apples to oranges — 48 weeks against 68. Everyone plateaus after month 10, so it's a stopped clock vs a running one.

Your sheet's biggest confounder is probably the estimand, not the glucagon. Efficacy estimand backfills what dropouts 'would have' lost, which sounds conservative but actually flatters the drug if the people who quit were the ones feeling awful at week 12.

Company phase 3 topline is the best of four trials, so 28.7% is a max, not a mean. I tracked mine weekly for 60 weeks and the boring truth was the last 15% of my loss took the last 25 weeks.

Weird part: my biggest whoosh came in weeks 34 to 38, after I'd already stopped losing per the trendline, so any 48-week snapshot would have undersold me by two or three points. Different cutoff dates alone can move this 3-4%.

The glucagon basal-energy bump is the least of it — my resting metabolic test barely moved, my step count moved a lot.

Baseline BMI is the angle I'd add, because percent loss scales with starting size. Phase 2's cohort was a narrower BMI band at fewer sites; the phase 3 program sprawled across more regions with higher mean starting weights, and someone at 240 lbs sheds a bigger percentage for the same absolute pounds than someone at 190.

My own numbers: I started at 218 and dropped my first 20 lbs in 11 weeks, but the same 20 lbs later on took 19 weeks. So a heavier enrollment pool alone can inflate the percentage without anyone tolerating anything better.

Also enrollment isn't the analysis set — 1,946 can shrink a lot by the time you hit the estimand, and that's before four trials get pooled into one 'up to' headline.

Check the week counts before you check anything else — the Phase 3 readout is at 80 weeks, your Phase 2 number is 48, and that curve wasn't flat when it stopped. Boring answer, I know, but I watched the same thing on my own chart: 9% down at week 24, 14% at 48, 17.5% by week 72, so the last stretch was crawling at roughly 0.1% a week and still handed me 3.5 extra points.

If the Phase 3 tail behaves anything like that, the 4.5 point "gap" is mostly just more calendar, and estimand and dropout are nibbling at the margins rather than driving it.

Honestly, the first number I’d put in that sheet is “up to 28.7% across four trials” — that’s a max, not a pooled mean, so comparing it to a single Phase 2 efficacy estimand is already apples-to-oranges; if one trial carried the 28.7 and the other three sat closer to 24–25, the gap mostly evaporates. I’ve been weighing daily for 14 months and tracking waist, and my monthly average can swing 1.5–3 lb from sodium and sleep alone while my waist barely moves, which is why I’d expect site-level visit timing and hydration to chew up a point or two across a bigger Phase 3.

Contrarian take: I actually trust the 24.2% more right now, because a peer-reviewed single-trial efficacy number is a cleaner thing than a press-release “up to” across four trials.

The placebo arms are the first thing I’d pull—if Phase 2 placebo lost around 2% and the Phase 3 placebos lost 3–4% because of more frequent visits, dietitian check-ins, or step goals, that alone can explain a chunk of the 24.2 vs 28.7 gap without the drug doing anything different. Counterintuitive, but better background weight loss in Phase 3 makes the active raw percentage look bigger too, since you’re stacking the same drug effect on top of a higher floor; I see that in my own sheet where a 10k-step week drops my 7-day average about 1.5 lbs even when I change nothing else.

So before chasing the mechanism stuff, I’d ask what the placebo-arm losses were in those four trials and whether the lifestyle support was identical to Phase 2.