AT7687vsHumanin

AT7687 is a long-acting GIP receptor antagonist designed to reduce fat storage rather than suppress appetite — a fundamentally different mechanism from every other obesity drug currently on the market or in late-stage development. The rationale is grounded in human genetics: loss-of-function variants in the GIP receptor are associated with lower body mass index and reduced cardiometabolic risk, suggesting that pharmacologically blocking GIP signalling should reproduce these protective effects.

GIP (glucose-dependent insulinotropic polypeptide) normally functions as a fat-storage signal — released from intestinal K-cells in response to food intake, it instructs adipose tissue to take up and store circulating fatty acids. By blocking the GIP receptor specifically on adipocytes, AT7687 prevents this fat-storage signal from being transmitted, leading to reduced lipid uptake into fat cells and a metabolic shift favouring fat oxidation in muscle and liver. Because the mechanism does not depend on suppressing hunger or slowing gastric emptying, the gastrointestinal side effects that limit GLP-1 drug tolerability are largely absent.

This mechanism is the conceptual mirror of MariTide (which combines GLP-1 agonism with GIP antagonism in a single molecule) — AT7687 isolates the GIP-antagonist component to test whether it can produce meaningful weight loss alone or in future combination with GLP-1 agonists. Antag Therapeutics' first-in-human Phase 1 results in 2026 showed acceptable tolerability with mild GI symptoms, plus reductions in LDL cholesterol and resting heart rate — early signals consistent with the predicted cardiometabolic benefit profile. Phase 2 trials are expected to define the magnitude of weight loss achievable in obese patients.

Humanin is a 24-amino-acid peptide (MAPRGFSCLLLLTSEIDLPVKRRA) encoded within the 16S ribosomal RNA gene of the mitochondrial genome. Its discovery in 2001 was revolutionary — it was the first identified mitochondrial-derived peptide (MDP), challenging the long-held dogma that the mitochondrial genome only encodes 13 oxidative phosphorylation subunits, 22 tRNAs, and 2 rRNAs. Humanin, along with MOTS-C and the SHLP peptides discovered later, established mitochondria as endocrine organelles.

Humanin exerts cytoprotective effects through multiple mechanisms. Extracellularly, it binds to a trimeric receptor complex composed of CNTFR (ciliary neurotrophic factor receptor alpha), WSX-1 (IL-27 receptor alpha), and gp130 (the shared signaling subunit of the IL-6 receptor family). Activation of this complex triggers JAK/STAT3 signaling, which drives expression of anti-apoptotic genes (Bcl-2, Mcl-1) and cell survival programs. Intracellularly, humanin interacts directly with two pro-apoptotic proteins: it binds IGFBP-3, preventing IGFBP-3 from translocating to mitochondria and initiating apoptosis; and it binds BAX (Bcl-2-associated X protein), preventing BAX oligomerization and insertion into the outer mitochondrial membrane — the critical step in the intrinsic (mitochondrial) apoptosis pathway that releases cytochrome c and activates caspases.

Humanin also reduces cellular stress through multiple pathways. It decreases reactive oxygen species (ROS) production by optimizing mitochondrial electron transport chain function. It reduces endoplasmic reticulum (ER) stress by modulating the unfolded protein response (UPR). It improves insulin sensitivity through STAT3-mediated effects on hypothalamic signaling and peripheral insulin receptor substrate phosphorylation. Circulating humanin levels decline with age (approximately 40% reduction between youth and old age) and are inversely correlated with markers of age-related disease, suggesting that humanin decline contributes to the increased cellular vulnerability and apoptosis susceptibility seen in aging. Its most potent synthetic analogue, HNG (S14G-humanin), has a glycine-for-serine substitution at position 14 that increases cytoprotective potency approximately 1,000-fold.