TatdMt

TatdMt: a breakthrough  therapy in suppressing and treating severe obesity

About Program

OBETAT’s lead compound, TatdMt, is being studied as a pharmacological alternative to bariatric surgery for severe obesity. The company plans to complete IND enabling works for US FDA and initiate Phase 1a / 1b studies with TatdMt administered via subcutaneous injection. OBETAT is also developing new compounds suitable for oral administration for use in broader indications as part of its second generation program.

TatdMt was initially developed by Prof Man-Wook Hur,PhD, Medical School of Yonsei University. OBETAT holds exclusive worldwide rights for development and commercialization of TatdMt.

About TatdMt Polypeptide: a breakthrough therapy for severe obesity

TatdMt is a potent, fast acting novel anti-obesity compound with unique dual mechanism of actions of by directly reducing fat mass and by suppressing food intake.

It reduces fat mass and fat cell size by increasing β-oxidation of fatty acids selectively and by increasing total energy expenditure. It also significantly reduces food-intake by activation of the central melanocortin system.

TatdMt is a tiny partial non-infectious fragment of Tat (Trans activator of transcription), a major regulatory protein of HIV ^{9, 10}. TatdMt is a fusion protein that blocks activity of Tat wild type. TatdMt blocks HIV transcription and replication but has strong fat reducing activity of Tat.

TatdMt novel mechanism of actions: Directly reduce fat mass/fat cell size by increasing oxidation of fatty acids and energy expenditure

TatdMt mechanism of action:reduce food intake as well

Efficacy in animal⁸

TatdMt has been administered in obese Lep-/- mouse and rabbits, beagle dog, and also transgenic mice over-expressing TatdMt was prepared to study anti-obesity activity of TatdMt.

Rapid and substantial weight loss

Administration of TatdMt caused severe weight loss (~25%) by reducing fat mass of BAT (brown adipose tissue), WAT (abdominal white adipose tissues) and liver of mice and rabbits. It started to show reduction of fat mass only after 3 SC injections (14 days) and lasted for 5 months (150 days). Daily injection of TatdMt induced a strong anorexic effect and weight reduction starting at day one in rabbit.

Weigth loss largely due to a reduction in fat mass/fat cell size

Intra-abdominal and sccpular fat mass was significantly reduced, while other organ weights remain unchanged. Fat mass and Fat cell size reduced to 1/3-1/4 of the original in the TatdMt treated group. Obesity is defined as having an excessive amount of body fat. Reduction of excess fat mass is the goal of treating obesity.

TatdMt directly attack and reduce fat cells by increasing energy expenditure and burning fat

All animal showed increase in energy expenditure, thermogenesis, oxygen consumption, and physical activity. Significant increase of β-oxidation of fatty acids was observed, particularly in WAT (2.5x), BAT(1.5x) and Liver than control.

Changes in gene expression important in fat and energy metabolism.

WAT tissues were transformed into BAT like tissues morphologically and over-expressed UCP-1, a hall mark of BAT.FAT liver was remarkably turned into red healthy liver.

• The size of adipocytes was drastically reduced
• The size of WAT was nearly the same as that of BAT of untreated
• Cytoplasm of BAT was filled with more mitochondria

TatdMt treated animal showed 25-49% less food-intake than control.

Insulin sensitivity and glucose adsorption remain unchanged after significant weight loss following TatdMt treatment.

TatdMt did not alter glucose homeostasis, despite the reduction in fat mass. 

TatdMt Oral Administration⁸

The oral administration of TatdMt in mice significantly inhibited the body weight gain (-14% vs. placebo), with no changes in blood biochemical parameters. Furthermore, no observable changes in the behavior were observed.

Pre-Clinical Studies

Pharmacokinetics ^4,5,6,8:

Pharmacokinetics of TatdMt was studied in Rats after nasal, s.c., and p.o. administration. The absolute bioavailability was 98.0, 75.8, 87.1% after nasal, s.c., and oral administration, respectively. The absolute bioavailability of TatdMt was 42.8% and 60.5% after p.o. and i.p. administration, respectively in Mice.

Toxicology ^{7, 8}

No toxicity was reported in various toxicology studies: single IP in rat, bacterial reverse mutation, In vitro chromosomal aberration test, single in vivo micronucleus test in mice, and 4 weeks repeated SC toxicity in beagle dog by leading company in accordance with KGLP standards.

CMC studies⁸:

Extensive works were done for characteristics, analytical, pre-formulation and formulation.

References

1. Artificial Zinc Finger Fusions Targeting Sp1-binding Sites and the trans-Activator-responsive Element Potently Repress Transcription and Replication of HIV-1*, YS Lim et al, Vol. 280, No. 22, Issue of June 3, pp. 21545–21552, 2005
2. The Trans-Activator of HIV-1 Transcription Reduces Fat Mass by Increasing Total Energy Expenditure and Decreasing Food-Intake in Mice, JE Kang (Publication in process)
3. U.S. Patent Application No. 13/805,156, December 18,2012 (PCT/KR2009/007769)
4. Pharmacokinetics of GST-TatdMt, a Recombinant Fusion Protein Possessing Potent Anti-obesity Activity, in Mice, BS Shin et al, Arch Pharm Res Vol 30, No 9, 1162-1167, 2007
5. Pharmacokinetics of 125I-GST-TatdMt, a recombinant fusion protein possessing potent anti-obesity activity, after intravenous, nasal, oral, and subcutaneous administration, BS Shin et al, Regulatory Peptides 140 (2007) 74–80
6. Dose-linear pharmacokinetics, tissue distribution, and excretion of a recombinant fusion protein 125I-GST-TatdMt possessing potent anti-obesity activity, BS Shin et al, Regulatory Peptides 129 (2005) 25– 30
7. TatdMt polipeptide toxicology studies (STUDY NO: B04312-B04315, B05581), Biotoxtech Ltd, 2004, Ochang, Korea,
8. Study Report submitted to Korea Ministry of Knowledge and Economics: Preclinical study of potent anti-obesity therapeutic polypeptide (study # M1-0310-60-0000), compiled by Prof. Man-Wook Hur, PhD, Younsei University, March 10,2006, Seoul, Korea.
9. TAT-apoptosis repressor with caspase recruitment domain protein transduction rescues mice from fulminant liver failure, An et al, Hepatology, Volume 56, Issue 2, pages 715–726, August 2012
10. NF-_B activation in hypothalamic POMC neurons is essential in illness- and leptin-induced anorexia, Jang et al, Journal of Biological Chemistry, Volume 285,No13,page 9706-9715, March 2010.