Nerve Growth Factor and Diabetic Neuropathic Pain

Neurotrophins have significant potential in treating neuropathic pain. Nerve growth factor (NGF) has been well studied and characterized for its role in neuroprotection. NGF decreases in patients with diabetic neuropathy (Verge et al., Pittenger et al), and initial trials show that it is restored to normal by NB-01.

NGF therapy (rhNGF, Genentech) has shown promising Phase II results in improving pain-related endpoints. However, it was discontinued after Phase III showed no efficacy, potentially due to low dose or concentration of drug (Pittenger and Vinik). 

As a natural product that elevates NGF safely and impacts AGE and inflammation, NB-01 provides a unique therapeutic opportunity to address a largely unmet need in the treatment of neuropathic pain. 

NB-01 for Diabetic Neuropathic Pain — strong preclinical science 

NB-01 is a Phase III-ready drug with a completed U.S. Phase II study for safety and efficacy at 16 sites. In early 2019, NB-01 will be starting a Phase III trial designed to demonstrate pain reduction, safety, and to study disease modification with nerve regeneration.

Phase III clinical study for Diabetic neuropathic pain

With our first patient targeted for Q2 2019, NB-01 will havetwo pivotal trials with double-blind treatment for a duration of 12 weeks with a primary endpoint of improved weekly mean of pain scores using an electronic diary.

NB-02 for Alzheimer’s disease

Alzheimer’s disease (AD) affects about 47 billion people worldwide, and that number is expected to increase to 132 billion by 2050. Additionally, the Alzheimer’s disease market is expected to reach $15 billion USD by 2024 and is a market with substantial unmet need, as symptomatic treatments have limited effectiveness, and no disease-modifying therapy is currently available. Today, four drugs are approved for symptomatic treatment of AD, based on acetylcholinesterase (AChE) inhibition (3 drugs) and NMDA receptor antagonism (1 drug).

NB-02 has shown great promise as a neuroprotective agent in pre-clinical studies providing effects on several levels of the pathogenic pathway, providing a clear rationale for IND submission towards a Phase I study. Specifically, the candidate has demonstrated inhibition of acetyl cholinesterase inhibition, as with the current drugs on the market, but more importantly, has also demonstrated inhibition of amyloid-beta plaque formation and inhibition of Tau phosphorylation – both mechanisms implicated to be potential causes of Alzheimer’s disease.


Poster

A poster on NeuroBo’s second candidate, NB-02, was recently presented at the Society for Neuroscience’s recent conference, Neuroscience 2018, during a session titled, “Alzheimer's Disease and Other Dementias: Therapeutic Strategies: Preclinical Cellular Models.”

This study, conducted out of Massachusetts General Hospital and Harvard Medical School, shows that active properties in NB-02 demonstrated strong preventative effects of amyloid plaque. The study also concluded that NB-02 has great promise as a potential therapeutic for Alzheimer’s disease. 


Publications

Combined Application of UHPLC-QTOF/MS, HPLC-ELSD and 1 H-NMR Spectroscopy for Quality Assessment of DA-9801, A Standardised Dioscorea Extract. Kang KB, Ryu J, Cho Y, Choi SZ, Son M, Sung SH. Phytochem Anal. 2017 May;28(3):185-194. doi: 10.1002/pca.2659. Epub 2016 Dec 1.

Comparison of sensory tests and neuronal quantity of peripheral nerves between streptozotocin (STZ)-induced diabetic rats and paclitaxel (PAC)-treated rats. Jin HY, Lee NY, Ko HA, Lee KA, Park TS. Somatosens Mot Res. 2016 Sep - Dec;33(3-4):186-195. Epub 2016 Oct 18.

P2X1 Receptor-Mediated Ca2+ Influx Triggered by DA-9801 Potentiates Nerve Growth Factor-Induced Neurite Outgrowth. Back MJ, Lee HK, Lee JH, Fu Z, Son MW, Choi SZ, Go HS, Yoo S, Hwang SW, Kim DK. ACS Chem Neurosci. 2016 Nov 16;7(11):1488-1498. Epub 2016 Aug 22.

DA-9801 promotes neurite outgrowth via ERK1/2-CREB pathway in PC12 cells.Won JH, Ahn KH, Back MJ, Ha HC, Jang JM, Kim HH, Choi SZ, Son M, Kim DK. Biol Pharm Bull. 2015;38(2):169-78. doi: 10.1248/bpb.b14-00236. Epub 2014 Dec 5.

Dioscorea Extract (DA-9801) Modulates Markers of Peripheral Neuropathy in Type 2 Diabetic db/db Mice. Moon E, Lee SO, Kang TH, Kim HJ, Choi SZ, Son MW, Kim SY. Biomol Ther (Seoul). 2014 Sep;22(5):445-52. doi: 10.4062/biomolther.2014.051. Epub 2014 Sep 30.

Evaluation of the transporter-mediated herb-drug interaction potential of DA-9801, a standardized dioscorea extract for diabetic neuropathy, in human in vitro and rat in vivo. Song IS, Kong TY, Jeong HU, Kim EN, Kwon SS, Kang HE, Choi SZ, Son M, Lee HS. BMC Complement Altern Med. 2014 Jul 17;14:251. doi: 10.1186/1472-6882-14-251.

The protective effects of DA-9801 (Dioscorea extract) on the peripheral nerves in streptozotocin-induced diabetic rats. Lee KA, Jin HY, Baek HS, Park TS. J Nutr Sci Vitaminol (Tokyo). 2013;59(5):437-46.

Therapeutic Potential of Dioscorea Extract (DA-9801) in Comparison with Alpha Lipoic Acid on the Peripheral Nerves in Experimental Diabetes. Jin HY, Kim SH, Yu HM, Baek HS, Park TS. J Diabetes Res. 2013;2013:631218. doi: 10.1155/2013/631218. Epub 2013 Mar 12.

Evaluation of DA-9801, a new herbal drug for diabetic neuropathy, on metabolism-mediated interaction. Ji HY, Liu KH, Kong TY, Jeong HU, Choi SZ, Son M, Cho YY, Lee HS. Arch Pharm Res. 2013 Jan;36(1):1-5. doi: 10.1007/s12272-013-0014-9.

Novel botanical drug for the treatment of diabetic neuropathy. Choi SZ, Son MW. Arch Pharm Res. 2011 Jun;34(6):865-7. doi: 10.1007/s12272-011-0621-2.

Neurotrophic activity of DA-9801, a mixture extract of Dioscorea japonica Thunb. and Dioscorea nipponica Makino, in vitro. Kim N, Kim SH, Kim YJ, Kim JK, Nam MK, Rhim H, Yoon SK, Choi SZ, Son M, Kim SY, Kuh HJ. J Ethnopharmacol. 2011 Sep 1;137(1):312-9. doi: 10.1016/j.jep.2011.05.032. Epub 2011 May 31.

Novel botanical drug DA-9803 prevents deficits in Alzheimer's mouse models. Alzheimers Res Ther. 2018 Jan 29;10(1):11. doi: 10.1186/s13195-018-0338-2. Pagnier GJ1, Kastanenka KV1, Sohn M2, Choi S2, Choi SH2, Soh H2, Bacskai BJ3.