The Science

History

Adipo Therapeutics was founded to realize the potential of a novel therapeutic approach of inducing browning of adipose tissues to treat people with type 2 diabetes and obesity. Adipo was founded by Meng Deng, PhD, a faculty fellow of Entrepreneurial Leadership Academy at Purdue University, after he completed NSF I-Corps in December 2016 to validate market niche for his innovation involving development of bioengineered polymeric nanoparticles to induce local browning of white fat through inhibition of Notch signaling, leading to weight loss and improved glucose control in animal models. Adipo has grown to continue the development, testing and commercialization of this technology, licensed through the Purdue Research Foundation Office of Technology Commercialization, as a novel approach to treating diabetes and obesity. Adipo’s efforts are directed by an inspired team of experienced pharmaceutical leaders in diabetes, regulatory affairs, manufacturing, pharmacology, drug development and commercialization.

Adipo Therapy

The proprietary nanoparticle-mediated Notch inhibition therapy is a weekly injection developed to provide the benefits of weight loss and glucose control for obese diabetes patients, a population where the majority of treated patients are not achieving therapeutic goals. The Adipo therapy induces adipose (fat) browning, the transformation of energy-storing white adipocytes to energy-burning brown adipocytes, through inhibition of the Notch signaling pathway. Adipo’s proprietary Notch-inhibiting biodegradable poly(lactide-co-glycolide) (PLGA) nanoparticles are injected directly into adipose tissue, providing localized delivery and sustained intracellular release, to induce adipose browning, reduce weight, and improve glucose control (PCT/US16/58997; US63/055, 410) [1-4]. Proof-of-concept animal studies have been completed, confirming inhibition of Notch signaling through local nanoparticle-based delivery induces browning of white adipocytes, leading to weight loss and improved glucose control in obese mice [3] and in pigs [4]. Adipo has chosen FDA-approved, biodegradable PLGA nanoparticles which are easily broken down and excreted by the body [5]. The Notch signaling pathway, as a highly conserved intercellular communication mechanism, is a promising regulator of metabolism [6-8]. The Adipo therapy has the opportunity to deliver a unique approach to treating T2D, as the first treatment to: induce browning; directly transform fat; lower blood glucose through improved insulin resistance; and decrease weight through increased energy expenditure.

Adipocyte Browning

Adipose (fat) tissue comes in two main types: white adipose tissue (WAT), which is the primary site of energy storage, and brown adipose tissues (BAT), which predominantly function to dissipate energy surplus (lipids) to generate heat, increasing energy expenditure and counteracting obesity [9,10]. The accumulation of the excess, dysfunctional fat (WAT) that characterizes obesity is a major risk factor for many diseases including T2D, cardiovascular disease, hypertension, stroke, arthritis and some types of cancer [11]. However, the presence of brown fat in adult humans is limited, especially in obese subjects. Existing data strongly suggests that BAT likely plays a significant role in the regulation of body weight, and increasing the amount of this tissue could be a safe and effective therapy to limit obesity [12].

Beige adipocytes which are present in WAT are inducible brown-like cells, which can be converted from white adipocytes to brown. Notably, the density and activity of beige adipocytes correlate with leanness in humans [13,14]. Thus, transformation of white adipocytes through browning holds great promise as a new therapeutic strategy to raise energy expenditure and reduce adiposity.

Type 2 Diabetes

Type 2 diabetes (T2D) is a complex metabolic disorder featuring obesity, high blood pressure, and high cholesterol in addition to high blood sugar, leading to an increased risk of macro- and microvascular complications, worsening of quality of life, large burdens on the medical system, and reduced life expectancy. T2DM results from the body’s inability to adequately respond to insulin (insulin resistance), driven largely by obesity [15]. T2DM prevalence in the US is ~ 25.5 million in 2018, with an annual growth rate of over 5% and is the seventh leading cause of death [15]. Nearly 90% of those with T2DM are overweight or obese with a BMI of ≥ 25 [16].

The current leading T2DM treatments are based on mechanistic approaches of improving insulin secretion, reducing weight through reduced caloric intake, and removing sugar directly through the kidneys. Despite the variety of existing treatment options, among adults diagnosed with T2DM, 50% have blood sugars above recommended guidelines (A1c of 7.0 or above), including 33% with an A1c of 10.0 or higher [15]. There are no treatments currently available that act directly on transforming fat composition.

Patent Information

US15/771,312 Polymer-based Therapeutic for Inductive Browning of Fat. PCT version PCT/US16/58997 covers US, China, and EU
US63/055,410 Notch Signaling Inhibitors for Treating Obesity and Metabolic Disorders

References

1. Bi P, Shan T, Liu W, Yue F, Yang X, Liang X-R, Wang J, Li J, Carlesso N, Liu X. Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity. Nat Med. 2014;20(8):911-8.

2. Jiang C, Kuang L, Merkel M, Cano-Vega M, Narayanan N, Yue F, Kuang S, Deng M. Biodegradable polymeric microsphere-based drug delivery for inductive browning of fat. Front Endocrinol (Lausanne). 2015;6:169.

3. Jiang C, Cano-Vega M, Yue F, Kuang L, Narayanan N, Uzunalli G, Merkel M, Kuang S, Deng M. Dibenzazepine-loaded nanoparticles induce local browning of white adipose tissue to counteract obesity. Mol Ther. 2017;25(7):1718-29.

4. Huang D, Narayanan N, Cano-Vega M, Jia Z, Ajuwon K, Kuang S, Deng M: Nanoparticle-mediated inhibition of Notch signaling promotes mitochondrial biogenesis and reduces subcutaneous adipose tissue expansion in pigs. iScience. 2020; 23(6):101167.

5. Huang D, Deng M, Kuang S. Polymeric Carriers for Controlled Drug Delivery in Obesity Treatment. Trends Endocrinol Metab. 2019;30(12):974-89.

6. Bi P, Kuang S. Notch signaling as a novel regulator of metabolism. Trends Endocrinol Metab. 2015;26(5):248-55.

7. Gridley T, Kajimura S, Nat Med. 2014;20(8):811-2.

8. Wong W, Sci Signal. 2014:7(338):ec211.

9. Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature. 2006;444(7121):847-53.

10. Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013;19(10):1252-63.

11. Bray GA, Bellanger T Epidemiology, trends, and morbidities of obesity and the metabolic syndrome. Endocrine. 2006;19:109-117.

12. Seale P, Lazar M. Brown fat in humans: turning up the heat on obesity. Diabetes 2009;58(7):1482-1484.

13. Pfannenberg C, Werner MK, Ripkens S, Stef I, Deckert A, Schmadl M, Reimold M, Häring H-U, Claussen CD, Stefan N. Impact of age on the relationships of brown adipose tissue with sex and adiposity in humans. Diabetes. 2010;59(7):1789-93.

14. Ouellet V, Routhier-Labadie A, Bellemare W, Lakhal-Chaieb L, Turcotte E, Carpentier A, Richard D. Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans. J Clin Endocrinol Metab. 2011;96(1):192-9.

15. CDC. National Diabetes Statistics Report Estimates of Diabetes and Its Burden in the United States. 2020.

16. NIDDK. Diabetes in America, 3rd Edition. 2018.