In this month’s issue of PME, we take a look at Enterprise Therapeutics and talk to CEO Dr John Ford about the company’s technologies and the obstacles it faces in the biotech sector.
Enterprise Therapeutics is discovering and developing new therapies that target the underlying mechanisms of mucus congestion in the lungs, one of the main causes of difficulty in breathing and increased risk of infection in respiratory diseases such as cystic fibrosis (CF) and COPD.
Our novel muco-regulatory therapies target ion channels TMEM16A and ENaC to increase the hydration and clearance of mucus. Our researchers have also identified novel targets and compounds that reduce mucus production, an approach that complements mucus hydration therapies. In a recent paper, Enterprise provided the first pre-clinical proof of principle for TMEM16A potentiation, increasing epithelial fluid secretion in cells from CF patients and mucus clearance in vivo.
Enterprise’s management team has significant expertise in drug discovery, drug development, respiratory biology and ion channel pharmacology. In April 2018 we closed an oversubscribed Series B funding round, and in October 2019 funding was awarded from the Cystic Fibrosis Foundation to advance TMEM16A through to clinical proof of concept in CF.
How is the company advancing research in respiratory disease?
In healthy lungs, mucus lining the airways consists mainly of water (97% fluid, 3% solids), enabling it to capture and remove the harmful agents inhaled with every breath. In many respiratory diseases, however, the mucus becomes thick and sticky, with the solids rising to >10%. This is due to an increase in the amount of mucus and/or a lack of fluid available to hydrate the mucus. The mucus can then no longer be moved, so harmful bacteria and viruses are no longer removed, leading to severe infections and inflammation. In severe situations the mucus actually forms plugs which block the airways and significantly reduce lung function.
Our main therapeutic strategy is to modulate ion channel proteins that control the amount of water in the airways, thereby increasing the amount of fluid available to hydrate the mucus, making it runnier so it can move and be cleared. Enterprise has a first-in-class TMEM16A potentiator (ETD002) and a novel ENaC blocker (ETD001), both entering clinical trials in early 2020.
What makes the company stand out?
CF is caused by loss of function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel, and is estimated to affect >80,000 patients globally. CFTR modulators, which restore anion conductance to CFTR, have been recently introduced and deliver impressive clinical benefits to many CF patients with the most common CFTR mutations. Although CFTR modulators have clinically validated the concept of restoring mucus hydration, they are not available for all CF patients. This is the result of patients with less common CFTR mutations not being suitable, and a number of patients with the most common mutations either failing to respond effectively or unable to tolerate the modulators.
Enterprise’s therapeutic strategies offer novel, non-CFTR mediated approaches and are applicable to all CF patients. The company envisages that its drugs will be effective as monotherapies and in combination with other CF therapies including CFTR modulators. In addition, we have the opportunity to evaluate the clinical efficacy of our drugs in other muco-obstructive lung diseases such as COPD, severe asthma, bronchiectasis and primary ciliary dyskinesia.
What are the R&D obstacles that the company is currently facing?
Our programmes have moved through the research phase relatively rapidly and we are striving to get our therapies to the patients that need them as fast as possible. Identifying and recruiting CF patients into our clinical studies in 2021 is key and we are actively working with the Cystic Fibrosis Trust and Foundation to get this achieved rapidly and effectively. We will also obviously have to plan all of our clinical studies, including healthy volunteer phase 1 studies, very carefully with respect to the COVID-19 pandemic.
What are the practical business issues that the company is facing?
We tend to experience the same challenges that all small biotech companies do – how do we ensure our therapies have the best chance of making it through to registration against a backdrop of the huge costs required to get them to that point? We are fortunate that Enterprise is well positioned and funded by a combination of private investors and the Cystic Fibrosis Foundation to answer the immediate question: do our therapies work in a small group of patients? Planning for success, our main question is, do we continue to build the company as we approach later-stage clinical trials, or form a strategic partnership with a pharmaceutical company?
What impact is Brexit having on its business?
Due to the strong financing we have already completed, and moving into the clinic, we are less vulnerable compared to other early-stage companies. However, it remains to be seen what effects Brexit may have on future fundraising opportunities for the UK biotech industry. Personally, I am optimistic that the impact will be minimal, as investors nowadays have a strong international base and are looking for quality executive teams and projects regardless of the country of origin.
However, the short-term uncertainty caused by Brexit makes planning more difficult and therefore introduces perceived risks in terms of costs, access to markets, protection of intellectual property and access to skilled employees, for example. In Enterprise’s case, as we operate a semi-virtual model with the majority of R&D outsourced, this means we keep a watchful eye on the operations of our suppliers and partners and the impact Brexit may have on their businesses, rather than it having a direct effect internally
