Adipotide

Adipotide, also known as FTPP (Fat Targeted Proapoptotic Peptide) or Prohibitin-TP01, is an experimental peptidomimetic compound with the sequence CKGGRAKDC-GG-D(KLAKLAK)2 designed to induce targeted weight loss through vascular disruption of white adipose tissue. The peptide consists of two functional domains: a targeting motif (CKGGRAKDC) that binds to the ANXA2-prohibitin receptor complex expressed on adipose tissue blood vessels, and a proapoptotic domain D(KLAKLAK)2 that disrupts mitochondrial membranes upon cellular internalization. In preclinical studies, adipotide demonstrated remarkable efficacy, inducing 30% weight loss in obese rodents and 11% weight loss in rhesus monkeys over 28 days, accompanied by significant improvements in insulin resistance and glucose tolerance. The mechanism involves selective apoptosis of endothelial cells within white adipose tissue vasculature, causing fat tissue reduction without affecting other organs. Following promising animal data published in Science Translational Medicine (2011), the FDA cleared a Phase 1 clinical trial in 2012 for patients with castrate-resistant prostate cancer. However, this first-in-human trial was discontinued in 2019 for unspecified reasons, with no public release of efficacy or safety data. The primary safety concern identified in animal studies was dose-dependent but reversible renal toxicity. As of 2025, adipotide remains an investigational compound with no approved therapeutic applications, though it continues to be studied in research settings.

Dramatic Weight Loss and Fat Reduction

• Rodent Models: Obese mice and rats exhibited approximately 30% reduction in body weight after 28 days of adipotide exposure, with effects more potent in animals on high-fat diets compared to low-fat diets ^[1][2]
• Primate Studies: Obese female rhesus macaques demonstrated marked decreases in average body weight of 10.6%, with individual variations ranging from 7.4% to 14.7% over 4 weeks of treatment at 0.43 mg/kg daily ^[3]
• Selective Fat Targeting: Dual-energy x-ray absorptiometry (DXA) revealed treated monkeys experienced 38.7% decrease in total body fat versus 14.8% in controls, with both visceral and subcutaneous fat reductions confirmed by MRI ^[3]
• Body Composition: Reductions in body mass index (10.0%) and abdominal circumference (8.4%) were observed in treated primates ^[3]

Insulin Resistance and Glycemic Control

• Rapid Metabolic Improvements: Obese mice displayed significantly improved insulin sensitivity and glucose tolerance after only 2-3 days of treatment, independent of weight loss, demonstrating weight-independent metabolic benefits ^[4]
• Insulin Sensitivity Enhancement: Insulin area-under-curve values decreased 36.2% in treated animals versus controls (p=0.019), indicating considerable reduction in insulin resistance ^[3]
• Insulinogenic Index: The insulinogenic index lowered by 48.5% in treated animals while control groups increased 33.8% (p=0.006) ^[3]
• Adipose Tissue Function: Treatment improved white adipose tissue hormone secretion, plasma lipids, plasma amino acids, and gene expression profiles, suggesting enhanced metabolic function beyond simple mass reduction ^[4]

Appetite and Food Intake Modulation

• Reduced Caloric Intake: Obese mice fed high-fat diets achieved weight equivalent to lean controls, with reduced food intake beginning 8 hours after the second daily administration and persisting throughout treatment ^[2]
• Mechanism Independence: Approximately 76% of weight loss correlated with reduced caloric intake despite paradoxical low-circulating leptin levels and decreased hypothalamic POMC expression ^[2]
• Absence of Illness Signals: Testing for conditioned taste aversion showed the treatment produced no visceral illness effects, distinguishing it from toxin-induced anorexia ^[2]
• Normal Activity Levels: Primates treated at 0.43 mg/kg daily for four weeks exhibited normal activity levels without overt clinical signs of nausea, vomiting, or food aversion ^[3]

Targeted Vascular Disruption

• Selective Adipose Targeting: Adipotide binds specifically to the ANXA2-prohibitin receptor complex expressed on blood vessels supplying white adipose tissue, sparing blood vessels in other organs ^[3][5]
• Endothelial Apoptosis: Treatment induces targeted apoptosis within blood vessels of white adipose tissue, disrupting vascular supply and leading to fat cell death ^[3]
• Dose-Dependent Effects: Vascular disruption and fat reduction demonstrate clear dose-response relationships, with optimal therapeutic dose identified as 0.43 mg/kg via subcutaneous injection ^[3]

Metabolic Parameter Improvements

• Triglyceride Reduction: Serum triglyceride levels decreased significantly in treated animals after 2-3 days ^[4]
• Enhanced Fatty Acid Transport: The PHB/ANX2 complex mediates CD36-dependent fatty acid transport from endothelium into adipocytes, improving metabolic efficiency ^[6]
• Absence of Dyslipidemia: No abnormal lipid accumulation or hepatic steatosis was observed in any treated monkeys ^[3]

Potential Clinical Applications

• Obesity Treatment: Demonstrated efficacy in reversing high-fat diet-induced obesity through targeted adipose tissue reduction ^[1][3]
• Type 2 Diabetes Management: Rapid improvements in glucose tolerance and insulin sensitivity suggest potential therapeutic value for diabetic patients ^[4]
• Cancer Cachexia: Original Phase 1 trial targeted patients with castrate-resistant prostate cancer, exploring whether decreasing white fat could slow cancer progression ^[7]

Primary Safety Concern: Renal Toxicity

• Dose-Dependent Kidney Effects: The primary adverse effect of adipotide is relatively mild, predictable, and reversible renal injury with altered proximal tubular function ^[3][8]
• Serum Markers: Serum creatinine elevation observed at doses exceeding 0.25 mg/kg, while blood urea nitrogen remained unchanged or decreased throughout dosing ^[3]
• Urinary Changes: Mild-to-marked glucosuria, mild-to-moderate proteinuria, and slight-to-mild increases in transitional/renal epithelial cells noted throughout dosing interval ^[3]
• Histopathology: Renal lesions scored minimal to mild in low-dose groups, minimal to mild in middle-dose groups, and minimal to moderate in high-dose groups, consisting of tubular degeneration with single-cell necrosis ^[3]
• Reversibility: Kidney function alterations and histological findings resolved during 28-day recovery periods following treatment discontinuation ^[3][8]
• Electrolyte Imbalances: Decreased serum phosphorus and potassium observed during treatment ^[3]

Additional Adverse Events in Animal Studies

• Dehydration: Mild dehydration observed at highest doses, representing a manageable side effect with proper hydration monitoring ^[3][8]
• Behavioral Observations: Monkeys remained bright and alert throughout studies, interacting normally with caretakers and demonstrating no signs of nausea or food avoidance ^[3]
• No Hepatotoxicity: Abnormal lipid accumulation including hepatic steatosis was not noted in any monkeys receiving adipotide ^[3]

Preclinical Safety Assessments

• High-Dose Toxicity: Dose-dependent toxicity in monkeys receiving single doses up to 100 mg/kg (~133-fold therapeutic dose) did not result in lethality ^[8]
• Multi-Species Testing: Toxicology studies conducted across 20 lean rhesus macaques, 2 baboons, and 52 cynomolgus macaques across various dosage tiers ^[3]
• Standard Toxicity Studies: Animal toxicity evaluations at doses up to 1000 times initial human dose revealed no adverse reactions beyond renal effects ^[3]

Human Clinical Trial Status

• Phase 1 Trial: FDA approved Investigational New Drug Application in January 2012; first patient dosed in July 2012 in a Phase 1 trial at MD Anderson Cancer Center ^[7][9]
• Trial Population: Designed to evaluate single 28-day cycles in patients with castrate-resistant prostate cancer and no standard treatment options ^[7]
• Trial Discontinuation: The first-in-human clinical trial was discontinued in January 2019 for unspecified reasons, with no public release of efficacy or safety data ^[5][10]
• No Published Human Data: No human safety or efficacy results have been published or made publicly available from the discontinued trial ^[10]

Mechanism-Related Safety Considerations

• Selective Targeting: Adipotide's targeting mechanism relies on prohibitin and ANXA2 receptor expression specific to white adipose tissue vasculature, theoretically minimizing off-target effects ^[3][5]
• Apoptotic Pathway: The D(KLAKLAK)2 domain disrupts mitochondrial membranes only after receptor-mediated cellular internalization, providing additional selectivity ^[5]
• Vascular Specificity: The peptide discriminates blood vessels in fat cells from blood vessels throughout the rest of the body, demonstrating high selectivity ^[1]

Regulatory and Development Status

• Investigational Status: Adipotide remains an investigational compound with no approved therapeutic applications as of 2025 ^[5][10]
• Abandoned Development: Clinical development officially discontinued in 2019, classified as an abandoned drug ^[5]
• Research Use Only: Current availability limited to research settings; not FDA-approved for human therapeutic use ^[10]

Unknown Long-Term Effects

• Limited Duration Data: Most animal studies ranged from 4 to 28 days; long-term safety beyond recovery periods remains uncharacterized
• Chronic Dosing: Effects of repeated treatment cycles or extended dosing regimens have not been adequately studied
• Human Applicability: Extrapolation of animal safety data to humans remains uncertain given trial discontinuation without published results

Critical Safety Gaps

• Undisclosed Discontinuation Reasons: The specific reasons for 2019 clinical trial termination remain unspecified, raising concerns about potential unreported safety issues ^[10]
• No Human Safety Data: Absence of published Phase 1 trial results prevents comprehensive human safety assessment
• Kidney Monitoring Requirements: Renal toxicity findings suggest any future human use would require intensive kidney function monitoring and potentially dose limitations

Contraindications and Precautions

• Renal Impairment: Pre-existing kidney disease would likely represent an absolute contraindication given dose-dependent nephrotoxicity
• Hydration Status: Patients would require careful hydration management to mitigate dehydration risks
• Electrolyte Monitoring: Regular assessment of phosphorus and potassium levels necessary during treatment