Adipotide

Human data: one terminated phase 1 trial, no published results

The only registered human study of this compound class is a first-in-human phase 1 trial at the University of Texas MD Anderson Cancer Center, listed as "A First-in-Man, Phase I Evaluation of A Single Cycle of Prohibitin Targeting Peptide 1 in Patients With Metastatic Prostate Cancer and Obesity" (ClinicalTrials.gov NCT01262664). The drug is recorded as Prohibitin-TP01 and the registry describes it as designed to destroy white fat, with the rationale that fat produces substances that can promote prostate cancer growth. Eligible men had metastatic or otherwise incurable prostate cancer, a body mass index above 30, and at least six months of androgen deprivation therapy. The design was a dose escalation with up to five dose levels and three participants per level, each receiving a daily subcutaneous injection for 28 days. The two primary endpoints were an acceptable dose and biologic activity, the latter defined as a 10% loss of baseline body weight by the end of the 28-day dosing period.

The trial did not deliver that. The registry records a start date of 24 May 2012, an enrollment of 4 participants against the planned 39, termination with the reason given as "Terminated per PI's request", and a completion date of 2 January 2019. No results have been posted. Nothing is published about what those four men experienced, so there is no human efficacy or safety result for adipotide to report.

Two features of the protocol are worth noting because they show how seriously the kidney signal was taken. Entry required a 24-hour urine collection with less than 2,000 mg of protein, and participants had to agree to avoid non-steroidal anti-inflammatory drugs, intravenous vancomycin, aminoglycosides and other potently nephrotoxic drugs from consent until 30 days after the last dose, with low-dose aspirin the only exception (ClinicalTrials.gov NCT01262664).

Rhesus monkeys, dose finding: 4 animals

The primate work is the strongest evidence that exists. In a dose-finding study, four spontaneously obese female rhesus macaques aged 9 to 13 years, with body mass index from 34 to 45, were split two and two: two received daily subcutaneous adipotide at 0.10, 0.25, 0.43 and 0.75 mg/kg, escalated every two weeks over 63 consecutive days, and two received saline. After nine weeks the two treated animals had lost 1.8 kg (15.4%) and 2.1 kg (20.4%) of body weight; body mass index fell 17.1% and 20.4%, and abdominal circumference fell 6.5 cm (13.1%) and 9.0 cm (14.2%). Weight, body mass index and abdominal circumference did not change in the saline controls. On an intravenous glucose tolerance test three days after the last dose, the area under the insulin curve had fallen 61.4% and 63.5% in the two treated animals (PMID: 22072637).

Rhesus monkeys, fixed dose: 15 animals

The same group then gave 0.43 mg/kg daily for 28 days to 10 obese rhesus macaques against 5 saline controls, with a four-week recovery period. Treated animals lost 7.4% to 14.7% of pretreatment body weight while controls changed by +1.0% to -3.5%. Body mass index fell 3.7% to 17.3% in treated animals. Abdominal circumference fell 6.5% to 14.3% in 9 of the 10 treated animals, with one animal gaining 2%. Weight, body mass index and abdominal circumference kept falling for three more weeks after dosing stopped. By dual-energy x-ray absorptiometry, total body fat fell by an average of 38.7% in treated animals against 14.8% in controls. By magnetic resonance imaging, abdominal white adipose tissue volume fell 17.5% by the end of treatment and 27.0% by the end of recovery. The area under the insulin curve fell 36.2% on average (p = 0.019) and the insulinogenic index fell 48.5% in treated animals while rising 33.8% in controls (p = 0.006). Serum lipid profiles stayed normal throughout and free fatty acids trended down rather than up (PMID: 22072637).

Rhesus monkeys, toxicology in lean animals: 20 animals, 15 of them dosed

A separate study under Good Laboratory Practice conditions gave lean rhesus macaques 0.25, 0.43 or 0.75 mg/kg daily for 28 days against saline. Animals at 0.25 and 0.43 mg/kg did not lose weight; the highest-dose group held their weight or lost a little. That result is the basis for the authors' suggestion that the mechanism is obesity-specific in primates. On necropsy 24 hours after the last dose, kidney lesions were present and dose-dependent, and absent in controls: minimal to mild at the low dose, minimal to mild in most middle-dose animals, and minimal to moderate at the high dose, classified as degenerative or necrotic (single-cell necrosis) and as reactive or regenerative. After the four-week recovery, minimal tubular degeneration remained in one middle-dose animal and two high-dose animals. Serum creatinine rose in a dose-dependent way above 0.25 mg/kg without a matching rise in blood urea nitrogen, serum phosphorus and potassium fell, and urine showed glucosuria, proteinuria and more transitional or renal epithelial cells. Most of these changes reversed within 28 days of stopping (PMID: 22072637).

Other Old World monkeys

The same report describes safety work in 52 cynomolgus macaques for this class of targeted D(KLAKLAK)2 compounds, and states that single doses of adipotide up to 100 mg/kg, roughly 133 times the therapeutic dose, were not lethal. A small uncontrolled pilot in two baboons produced a similar magnitude of weight loss over 12 weeks of daily subcutaneous dosing (PMID: 22072637).

Mice

The founding study is in mice. In vivo phage display isolated the CKGGRAKDC motif that homes to white fat vasculature, the motif was shown to associate with prohibitin, and targeting a proapoptotic peptide to prohibitin in the adipose vasculature ablated white fat. The authors described resorption of established white adipose tissue, normalisation of metabolism, and rapid reversal of obesity without detectable adverse effects, and noted that prohibitin is also expressed in the blood vessels of human white fat (PMID: 15133506). The later primate paper quantifies the mouse result as about 30% weight reduction in obese mice over four weeks (PMID: 22072637).

A second mouse study looked at glucose rather than weight. In obese mice on a high-fat diet, the proapoptotic peptide improved glucose tolerance within two to three days in a way that was independent of weight and of food intake, with a pair-fed comparison group; serum insulin and triglycerides fell, fatty acid and acylcarnitine profiles differed from both vehicle and pair-fed controls, and adipose tissue microarrays showed reversal of high-fat-diet changes in pathways for mitochondrial function, oxidative phosphorylation and branched-chain amino acid degradation (PMID: 22733798).

Reformulated versions in mice

Prohibitin-targeted nanoparticles carrying the D(KLAKLAK)2 peptide reduced body weight in diet-induced obese mice, with the particles accumulating in both adipose vessels and angiogenic clusters of obese fat; the authors reported that unmodified PEGylated particles also reached those clusters, so the delivery was part passive and part receptor-driven (PMID: 22982237). A follow-up compared the nanoparticle against the adipotide bioconjugate directly and reported that a low dose of the nanoparticle, but not the bioconjugate, reduced body weight, serum leptin and ectopic fat in liver and muscle with no detectable hepatotoxicity (PMID: 23871959). A 2025 paper reported a mixed-chirality prohibitin peptide, PTP-r, built by substituting D-arginine into prohibitin-TP01, which reduced body weight in diet-induced obese mice and which the authors attribute to mitochondrial uncoupling (PMID: 40591817). A 2026 study loaded prohibitin-targeted nanovesicles with a microRNA and resveratrol combination and reported effects on adipogenic and metabolic markers in high-fat obese mice (PMID: 42849641).

Cell culture

Gold nanoparticles carrying both the adipose-homing and the proapoptotic peptide were more antiproliferative against cell lines expressing the prohibitin receptor than against those that did not, and killed by apoptosis, which is consistent with receptor-mediated selectivity in vitro (PMID: 28635372).

What the evidence does not contain

There is no published human efficacy result, no published human safety result, no published human pharmacokinetic result, and no completed human trial of adipotide. There is no randomised trial in any species. The primate efficacy work rests on 2 treated animals in the dose-finding study and 10 in the fixed-dose study, all at one centre, all reported in a single 2011 paper (PMID: 22072637). The paper gives the sex of the animals only for the dose-finding cohort and the two baboons, which were female. The weight loss and the kidney findings in monkeys came from the same dose range.

There is no published human safety data for adipotide. The only registered human trial enrolled 4 of a planned 39 participants, was terminated, and has no posted results (ClinicalTrials.gov NCT01262664). Everything below is from monkeys, mice or cell culture.

Kidney injury is the dose-limiting finding in monkeys. In a Good Laboratory Practice toxicology study in lean rhesus macaques given 0.25, 0.43 or 0.75 mg/kg daily for 28 days, kidney lesions were present at necropsy in a dose-dependent pattern and absent in controls: minimal to mild at the low dose, minimal to mild in most middle-dose animals, and minimal to moderate at the high dose. The lesions were classified as degenerative or necrotic (single-cell necrosis) and as reactive or regenerative. After four weeks off the drug, minimal tubular degeneration was still present in one middle-dose animal and two high-dose animals. The authors summarised the primary side effect as relatively mild, predictable and reversible renal injury with altered tubular function (PMID: 22072637).

Laboratory changes in monkeys. Serum creatinine rose in a slight to moderate, dose-dependent way at doses above 0.25 mg/kg, without a matching rise in blood urea nitrogen. Serum phosphorus and serum potassium fell in a time- and dose-dependent way. Urine showed mild to marked glucosuria, mild to moderate proteinuria, and a slight to mild increase in transitional or renal epithelial cells. Treated monkeys produced more urine and mild dehydration was noted at the highest doses. Most of these changes reversed within 28 days of stopping, with slight residual creatinine and urinary glucose elevation in one treated animal per study at the end of recovery (PMID: 22072637).

Food intake and the nausea question. Monkeys on adipotide stayed alert and active, interacted normally with handlers, and showed no overt nausea, vomiting or food aversion, but the number of chow biscuits they ate fell in proportion to dose and to weight lost. The authors stated that mild nausea could not be completely ruled out as a contributor (PMID: 22072637). A published comment argued that the weight loss may reflect a direct effect on food consumption rather than vascular ablation, and the authors replied in the same issue (PMID: 22539771).

What was looked for and not found in monkeys. Lipid profiles stayed normal and free fatty acids trended downward rather than upward during treatment. Abnormal lipid accumulation, including hepatic steatosis, was not seen in any monkey that received adipotide. The authors also reasoned against increased faecal fat loss, since the oily stool and incontinence seen with fat absorption inhibitors did not occur, though faecal lipids were not measured (PMID: 22072637).

Acute lethality in monkeys. In safety work across 52 cynomolgus macaques for this class of compounds, single doses of adipotide up to 100 mg/kg, about 133 times the therapeutic dose, did not cause death (PMID: 22072637).

Mice. The original mouse report described obesity reversal without detectable adverse effects (PMID: 15133506). That is a 2004 statement about a mouse experiment, not a safety conclusion for any other species.

The killer half is cytotoxic by design. D(KLAKLAK)2 on its own kills fungal cells through mitochondrial injury with reactive oxygen species accumulation and caspase-like activity (PMID: 24098573) and disrupts bacterial membranes with loss of membrane potential (PMID: 23345420). Whatever selectivity adipotide has comes from the homing motif, not from the toxic one.