BTB: Modernising Pain Management with 3D Drug Discovery Technology

Pain is a debilitating condition that affects approximately 20 per cent of the global adult population.Over the past few decades, escalating use of opioid therapeutics to manage pain has become a cause of concern in many countries. In Australia, 15.4 million opioid prescriptions were dispensed under the Pharmaceutical Benefits Scheme (PBS) to 3.1 million people between 2016 and 2017. Each day during this period, nearly 150 hospitalisations and 14 emergency department presentations were attributed to opioid harm, and three people died from drug-induced deaths involving opioid use.2

The situation in the US is even more dire, with the opioid crisis causing significant health and socio-economic problems. The latest data estimates that overdose deaths from opioids increased to 75,673 in the 12-month period ending April 2021, up from 56,064 the year before.3

Addiction to pain medication is common

Post-surgical use of opioids is a common source of addiction. Around the world, over 300 million major surgical operations are performed each year4 and approximately six per cent of these opioid-treated patients become addicted to pain medication.

Though pain was once viewed as a necessary side effect of surgery, it is now understood that prompt and effective treatment not only reduces suffering, increases healing, and limits complications, but is essential to the success of the surgical intervention. Failure to adequately manage pain postoperatively is associated with a higher likelihood of developing chronic pain – which, in Australia, was estimated to cost $139 billion in 2018, mostly due to reduced quality of life and productivity losses.5,6

Frustratingly, post-surgical pain is still treated ineffectively for a large percentage of patients, and opioids continue to be administered as standard care despite their negative side effects, such as nausea, vomiting, constipation, dependency, and even respiratory depression. Clearly, there is an urgent need to cultivate more effective postoperative pain-management treatments – both for the purpose of improving patient outcomes and overcoming the opioid crisis.

Establishing alternative pain-relief therapies

Aiming to establish alternative pain-relief therapies, Brisbane-based biotechnology company Vast Bioscience Pty Ltd is using a proprietary technology platform called VAST (Versatile Assembly on Stable Templates) to develop three-dimensional (3D) small molecule sodium channel inhibitors. VAST technology provides a turnkey chemistry solution to access a diverse world of complex 3D drug-like molecules for the systematic discovery of 3D drugs, which deliver superior specificity, selectivity and potency when compared to two dimensional (2D) molecules, and hence a higher chance of safety in the clinic.

One possible target is hNav1.8 – one of the nine Voltage-gated sodium channel (VGSC) subtypes, which plays a critical role in the initiation and propagation of pain signals along nerve fibres. Using VAST technology, Vast Bioscience has developed a Nav1.8 inhibitor that fully reverses pain in an in vivo model of post-surgical pain following oral dosing, outperforming competitor lead molecules in efficacy and safety.

The key challenge when developing hNav1.8 inhibitors lies in obtaining specificity and selectivity while maintaining drug-like properties. Some of the other sodium channel subtypes are critical for heart function or muscle function, and hence selectivity for the hNav1.8 subtype is paramount to obtaining effective and safe pain relief.

BTB program funding supports development of Investigational New Drug candidate

To progress its efforts in this space, Vast Bioscience was awarded $822,451 in matched funding during Round 1 of the BTB program and was supported by BTB venture partner, BioCurate. The project started with a lead molecule that exhibited exceptional efficacy and safety in an in vivo model of post-surgical pain at very low exposure. Through the BTB program, Vast Bioscience set out to optimise this lead molecule to an Investigational New Drug (IND) candidate – ultimately hoping to develop an effective non-opioid treatment for post-surgical pain through selective hNav1.8 inhibition with an excellent safety profile, and with a robust data package suitable for commercialisation.

Over the course of the project, the versatility of the VAST platform was demonstrated, with the optimisation of the five available positions on the lead scaffold. More than 400 3D hNav1.8 inhibitors have now been synthesised, with many having affinity at the target (hNav1.8), while demonstrating high selectivity at related off targets (hNav1.x’s and hERG). This has allowed the team to improve on its original compound, with the new compound demonstrating efficacy in several mouse models. Pharmacokinetic (PK) studies linked the efficacy with low free drug concentration, which was an attractive quality to maintain in a prospective analgesic.

Further top-up funding for commercialisation activities

Vast Bioscience was further awarded $114,000 in top-up funding, which enabled them to carry out critical activities in the commercialisation process. These included engaging a business development manager to drive a professional commercialisation process with several potential partners now in confidential discussions. The funding also enabled the successful completion of scale-up chemistry and formulation experiments to address specific requests from potential partners.

According to Vast Bioscience’s Chief Scientific Officer, Dr Wim Meutermans, the BTB program has enabled the team to take its project through lead optimisation to achieve high specificity and selectivity in its candidate – a critical requirement in the development of safe and effective therapies for severe acute and chronic pain. “VAST is to our knowledge the only well-established drug discovery technology that enables systematic moulding of the shape and function of its 3D molecules, and this is paramount to delivering potent lead molecules of high 3D complexity,” Dr Meutermans said. “In this project, we have been able to produce highly selective VAST compounds by using the unique characteristics of the 3D scaffold, while maintaining drug-like qualities.”

Research progress, achievements and patents

In 2021, more than $1 million was raised to further advance the product, based on the research progress and achievements made during the BTB program. A business development outreach campaign was initiated later that year and commercialisation discussions with several pharma and specialised biotech companies are ongoing. Two new provisional patent applications were lodged in 2021, covering the broad invention of selected VAST molecules as Nav1.8 inhibitors and their application to treat pain. The patents cover new composition of matter discovered in this project, as well as their method of use, and support the commercialisation process.

The successful development of a 3D hNav1.8 inhibitor has the potential to revolutionise how pain is treated in the future. Further to that, success in this project would have a significant impact on Vast Bioscience’s drug discovery opportunities, providing validation of the 3D approach and enabling application in other areas of unmet medical need.