Amycretin: A 24% Weight Figure, and the Trial It Came From

Two receptors, one drug: amycretin was built to hit the GLP‑1 target and the amylin target at once, rather than pairing two compounds. In its first substantial trial, once-weekly subcutaneous amycretin at 60 mg produced an estimated mean bodyweight change of −24.3% at week 36, against −1.1% on placebo.^[1] That is a larger figure than anything currently approved. It is also a phase 1b/2a study at one clinical site, with 101 people on the drug, whose primary endpoint was counting adverse events rather than measuring weight.

What the trial was

A randomized, placebo-controlled phase 1b/2a study at a single research center in San Antonio, Texas, in people aged 18 to 55 with a BMI between 27.0 and 39.9. It ran in five parts — a single ascending dose, a dose-escalation arm and three dose-response arms — with treatment durations between 20 and 36 weeks depending on the part. 125 participants were randomized: 101 to amycretin, 24 to placebo.^[1]

The gradient is the most persuasive thing in the table. More drug, more weight lost, in order, with no reversal — that is what a genuine pharmacological effect looks like, and it is harder to produce by accident than a single impressive number. Note that placebo participants gained weight in three of the four parts.

The withdrawals, and what they do and do not mean

The paper records that a large number of participants withdrew, with a high proportion of those discontinuations occurring for reasons unrelated to treatment-emergent adverse events.^[1] That is a meaningfully different situation from a trial where people leave because the drug is intolerable — but it still shrinks the group any endpoint is calculated from, in a study that was not large to begin with.

On tolerability itself, the most common adverse events were gastrointestinal, mostly mild to moderate, and the majority resolved by the end of the study. The authors describe the rates as similar to those seen in early-phase studies of GLP‑1 and amylin agonists generally.^[1]

Why adding amylin is the interesting part

Amylin is a hormone co-secreted with insulin that slows gastric emptying and signals fullness through a different pathway from GLP‑1. Reaching both targets from one compound is an attempt to add effect without simply pushing a GLP‑1 dose higher — which is the approach that runs into the tolerability ceiling visible in every trial of this class.

Whether that theory survives a phase 3 is the open question, and nothing in a 125-person study answers it. For what happened to another promising oral compound whose trial worked while most participants did not finish it, see danuglipron. For the approved oral small molecule, see orforglipron.