Candidate Drug Proposes a Botanical Solution to Neuropathic Pain
Industry Insight Oct 31, 2018 | by Ruairi J Mackenzie, Science Writer for Technology Networks
Dioscorea japonica, extracts of which are used in NeuroBo's candidate drug NB-01. Credit: harum.koh via Flickr under CC BY-SA 2.0 https://creativecommons.org/licenses/by-sa/2.0/
NeuroBo Pharmaceuticals is a Boston-based pharma aiming to develop solutions for neurodegenerative diseases. Their first lead candidate, NB-01, is positioned as a potential treatment for diabetic neuropathic pain, which is estimated to occur in 25% of diabetes mellitus patients. The candidate, which in 2018 will move into a phase III clinical trial, uses extracts of two species of the plant genus Dioscorea, which has been used in traditional medicine for centuries, but has not been subject to systematic study until now.
We caught up with NeuroBo’s Chief Medical Officer Mark Versavel, MD, PhD, MBA, and Senior Vice President of Business Development Nandan Padukone, PhD, MBA to find out why NeuroBo are targeting neuropathic pain, and how their subsequent candidate looks to tackle one of the biggest challenges in neurodegenerative disease: Alzheimer’s disease.
Ruairi Mackenzie (RM): Why have NeuroBo targeted diabetic neuropathic pain with your lead candidate NB-01? What is its mechanism of action?
Mark Versavel (MV): Treatment of neuropathic pain, and particularly of diabetic neuropathy which affects 50-60% of patients with diabetes, remains an unmet need. The approved drugs today alleviate pain symptoms and have a range of side effects, and do not address underlying nerve damage as the cause of disease
We are positioning NB-01 for neuropathic pain because it alleviates pain symptom, has an excellent safety profile, and additionally, could address nerve growth from its action on the neural growth factor (NGF). Extensive preclinical work has shown that NB-01 can elevate NGF, increase nerve growth, has anti-inflammatory properties and reduces glycosylation end-products. Each of these mechanisms can contribute to nerve damage in patients with diabetes and to the pain resulting from this. Positive proof of concept has been demonstrated in a Phase 2 study that was conducted in the US, justifying confirmation in larger Phase 3 trials.
RM: NeuroBo uses natural product-based therapies. Is this a unique approach within the neuropharmaceutical industry? Can you point to other success stories using natural product-based therapies within this industry?
Nandan Padukone (NP): NeuroBo utilizes knowledge of known plant-based sources which have had beneficial effects on pain management and cognitive effects to create a novel drug treatment approach. The FDA has a well-established path for approval of botanical drugs for the last 15 years, since 2003, and has received over 600 IND applications through this path. The FDA has approved two drugs (Veregen and Fulyzaq) and remains enthusiastic and supportive on helping advance drug development though this process. NeuroBo has an experienced regulatory team and has adhered stringently to the requirements of raw material controls, CMC protocols, GMP manufacturing of drug product, and quality control. The team will work closely with the FDA to meet its guidance requirements towards a new drug application (NDA).
RM: NB-01 uses Dioscorea extract as its active ingredient. What can you tell us about Dioscorea and how its potential for neuropathic treatment came to be considered?
MV: Dioscorea has been extensively used in traditional Chinese medicine for various conditions but no systematic studies have been conducted historically towards drug development. Scientists of Dong-A (a Korean pharmaceutical) found that Dioscorea extracts alleviate pain and increase the release of NGF that can potentially help with nerve growth. They demonstrated that there is a synergy between extracts from two different Dioscorea species towards NGF release and developed an optimal combination as a drug formulation. They also showed characterization of additional mechanisms of action against inflammation and glycation end-products (see above, Q1) that are relevant for treatment of diabetic neuropathic pain.
RM: What, in your opinion, are the biggest barriers to developing treatment for neuropathic and neurological disease?
MV: Today, drugs that are approved for these indications address symptoms of the disease and have adverse effects but are mechanistically not designed to address underlying mechanism(s) of the disease. Our drug approach is designed for a product profile that potentially addresses all three needs.
Demonstration of a disease modifying effect in neurodegeneration is difficult due to variability of progression, difficulties of standardizing measures of nerve function, non-linearity of disease progression (small nerve fibers initially, later also larger fibers involved). Large studies of long treatment duration (2 years or more) are needed for demonstration of a treatment effect.
On the other hand, trials in neuropathic pain can be conducted with a treatment duration of 12 weeks. Sample sizes in these trials are smaller, but many trials have failed due to high placebo response. NeuroBo has opted for a large sample size of 239 per treatment group to minimize the risk of a false negative trial, and is taking extensive measures to minimize placebo response: patient selection based on baseline pain scores using a paradigm that is not disclosed to investigators or patients; monitoring of treatment compliance using a face-recognition app; careful site selection and training of sites not to induce treatment expectations for trial participants.
RM: NB-02, a second NeuroBo treatment, is taking aim at Alzheimer’s disease. What can you tell us about this therapy?
NP: NB-02 utilizes the same principles of deriving the best pharmaceutical effects of two herbal species, combined synergistically, to enhance cognitive effects and develop a treatment for Alzheimer’s disease (AD). AD is increasing in incidence worldwide with an aging population and is currently treated with drugs that address symptoms of cognitive decline but do not address the underlying disease. NB-02 has been extensively characterized in preclinical models and will be ready for an investigational new drug (IND) submission early 2019 with the FDA. The drug 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 AD. These data, in addition to further effects on nerve growth through elevation of NGF may potentially provide a new drug that alleviates symptoms of cognitive decline, is safe and tolerable, and addresses potential underlying mechanisms as a disease-modifying therapy.
Mark Versavel and Nandan Padukone were speaking to Ruairi J Mackenzie, Science Writer for Technology Networks