Adipotide (FTPP)

Also known as: FTPP, Prohibitin-targeting peptide, Prohibitin-TP01

Evidence: Preclinical

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Overview

Proapoptotic peptidomimetic that binds prohibitin on white-fat blood vessels; 4 weeks of daily dosing cut body weight 7 to 15% in obese rhesus monkeys, with reversible kidney tubule effects.

Adipotide is CKGGRAKDC, a peptide found by in vivo phage display to home to white-fat vasculature through prohibitin, joined to the proapoptotic D-amino-acid motif (KLAKLAK)2 (Kolonin 2004; Ellerby 1999). In obese mice the conjugate ablated white fat and reversed obesity (Kolonin 2004). In obese rhesus monkeys, 0.43 mg/kg daily for 4 weeks reduced weight 7.4 to 14.7%, cut fat on MRI and DXA, and improved insulin resistance, with predictable, reversible changes in kidney proximal tubule function (Barnhart 2011). A comment argued the monkey weight loss may reflect lower food intake rather than fat-vessel ablation (Criscione 2012). In mice it improved glucose tolerance within days (Kim 2012). A phase 1 trial in men with prostate cancer and obesity enrolled 4 patients and was terminated.

Benefits

Fat-mass reduction and reversal of obesity (mouse), 7 to 15% weight loss and improved insulin resistance (obese rhesus monkeys, 4 weeks), weight-independent improvement in glucose tolerance (obese mice); no human efficacy data

Dosing reference

Research dose: 0.1 to 0.5 mg daily (community range); the human phase 1 started at 0.03 mg/kg daily and primates received 0.25 to 0.75 mg/kg daily
Range: 100 to 500 mcg, 1x daily
Reconstitution: 2 mL bacteriostatic water
Common vial sizes: 10 mg

Subcutaneous, once daily in all published work. Primate studies: 0.43 mg/kg daily for 28 days in obese rhesus monkeys, 0.25 to 0.75 mg/kg in the lean-monkey toxicology study (Barnhart 2011). Phase 1: 0.03 mg/kg daily for 28 days as a starting dose (NCT01262664). No completed human dosing study.

Mechanism

Adipotide has two domains. CKGGRAKDC binds prohibitin, which Kolonin 2004 established as a marker on the endothelium of white-fat blood vessels. The D-(KLAKLAK)2 motif disrupts mitochondrial membranes once internalised, triggering apoptosis (Ellerby 1999). Targeted apoptosis of fat vasculature leads to resorption of white fat (Kolonin 2004; Barnhart 2011). Reduced food intake may also contribute (Criscione 2012). Renal effects are attributed to proximal tubule exposure; the paper describes them as predictable and reversible (Barnhart 2011).

Evidence

Preclinical: animal or in vitro data only

Targeting a proapoptotic peptide to prohibitin on fat vasculature ablated white fat and reversed obesity in mice (Kolonin et al., 2004)
0.43 mg/kg subcutaneously daily for 4 weeks reduced body weight 7.4 to 14.7% in 10 obese rhesus monkeys versus +1.0 to -3.5% in 5 controls, and improved insulin resistance (Barnhart et al., 2011)
Renal proximal tubule changes were dose-dependent and reversible; creatinine rose at 0.75 mg/kg in lean monkeys (Barnhart et al., 2011)
Disputed: a published comment argued the monkey weight loss may be driven by reduced food intake (Criscione, 2012)
Human-trial status: one phase 1 (prostate cancer with obesity, starting dose 0.03 mg/kg daily) enrolled 4 patients and was terminated at the investigator's request; no results published (NCT01262664)

References

Side effects

No published human safety data; the only human trial enrolled 4 patients and posted no results. In monkeys, kidney proximal tubule function changed in a dose-dependent, reversible way: creatinine rose at 0.75 mg/kg/day and sporadically in 2 animals at 0.43 mg/kg/day, with slight residual creatinine and urine glucose elevation in one monkey per study after recovery (Barnhart 2011). Single doses up to 100 mg/kg were not lethal in monkeys. Dehydration and reduced appetite are commonly reported (anecdotal).

Storage

Storage: Refrigerate 2-8°C (36-46°F); general lyophilised-peptide guidance, no compound-specific CoA located
Lyophilized: 2+ years at room temp, 3+ years refrigerated
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: Not published in any species; primate studies dosed once daily subcutaneously (Barnhart 2011)
Bioavailability: Not reported. Primate efficacy studies used subcutaneous injection (Barnhart 2011); the human phase 1 used subcutaneous dosing
Molecular weight: 2557.2 Da
Sequence: CKGGRAKDCGG[D-KLAKLAKKLAKLAK]