20AA Discontinued Clinical Development
Adipotide (FTPP)
A chimeric peptidomimetic that destroys the blood supply of white adipose tissue via prohibitin-targeted apoptosis; produced dramatic fat loss in primates but was discontinued in Phase I due to irreversible nephrotoxicity in humans.
In Plain English:
Adipotide works like a heat-seeking missile for fat tissue blood vessels. It has two parts fused together: a homing sequence (CKGGRAKDC) that locks onto a protein called prohibitin exclusively expressed on the inner surface of blood vessels feeding white fat, and a killer sequence (D(KLAKLAK)₂) that punches holes in mitochondrial membranes once it gets inside those cells. Without a blood supply, the fat cells starve and die. In obese rhesus monkeys, a 28-day course caused 7–15% body weight loss and a 36% drop in insulin area-under-curve. A Phase I trial in prostate cancer patients (NCT01262664) was started by Arrowhead Pharmaceuticals in 2012 and permanently discontinued by 2019 because the gap between an effective dose and a kidney-damaging dose was too narrow. No efficacy data from that trial was ever published. The peptide has no approved use and remains a research chemical.
Research Maturity
Discontinued Clinical Development (24 PubMed results; only animal data — Phase I human trial terminated without publication+ Studies)
Focus
Metabolic Health
Obesity & Weight
Origin
Discovered via in-vivo phage display random peptide library screening by Kolonin et al. at MD Anderson Cancer Center (2004). The prohibitin-binding motif CKGGRAKDC was fused to the proapoptotic sequence D(KLAKLAK)₂ to create the bipartite peptidomimetic. Licensed to Arrowhead Research Corporation (now Arrowhead Pharmaceuticals) for clinical development. Also known as FTPP (Fat-Targeted Proapoptotic Peptide), prohibitin-targeting peptide 1 (PTP1), and commercially as Adipotide®.
Mechanism
Adipotide operates in three sequential steps. Step 1 — Homing: the cyclic disulfide-bridged N-terminal sequence CKGGRAKDC binds with high affinity to prohibitin-1 (PHB1) and annexin A2 (ANXA2) co-expressed on the luminal surface of endothelial cells specifically within white adipose tissue vasculature; prohibitin expression is upregulated in obese adipose endothelium, explaining selectivity. Step 2 — Internalization: receptor-mediated endocytosis internalizes the full chimeric peptide into the endothelial cell. Step 3 — Mitochondrial disruption: the C-terminal amphipathic D-amino acid proapoptotic sequence D(KLAKLAK)₂ inserts into and disrupts mitochondrial outer membrane integrity, triggering cytochrome c release and caspase-dependent intrinsic apoptosis. Endothelial cell death causes vascular regression; downstream adipocytes undergo secondary ischemic apoptosis due to nutrient deprivation. Secondary effects include leptin-independent reduction in food intake (appetite suppression independent of circulating leptin or hypothalamic POMC expression, observed in ~76% of body mass loss attributed to caloric reduction), modest free fatty acid reduction, improved adiponectin-to-resistin ratio, and restored insulin sensitivity before adipocyte shrinkage completes. The D-amino acid configuration of the proapoptotic domain confers protease resistance.
Outcome
In diet-induced obese mice (4-week IP protocol at 1 mg/kg/day): ~30% total body weight reduction, complete reversal of diet-induced obesity, leptin-independent reduction in food intake (76% of weight loss attributable to caloric restriction). In obese rhesus macaques (0.43 mg/kg/day SC, 28 days): 7.4–14.7% body weight reduction, 3.7–17.3% BMI reduction, 38.7% total body fat reduction (vs 14.8% controls), 36.2% decrease in insulin AUC, 48.5% improvement in insulinogenic index. MRI and DEXA imaging confirmed selective white adipose tissue reduction. Lean animals showed no weight loss at therapeutic doses. In a nanoparticle-reformulated version (KLA-PTNP, 2013): superior fat reduction in obese mice with simultaneous reduction of ectopic liver and muscle fat, elevated serum adiponectin, no hepatotoxicity. Human Phase I (NCT01262664, castrate-resistant prostate cancer): trial terminated; no efficacy data published; nephrotoxicity deemed unacceptable.
