Navigating the journey from bench to bedside
By Dr Chua Li Min, Science writer
Image of a healthy lung tissue (left) and a fibrotic lung tissue (right) // Credit: Benjamin Ng
Every once in a while, when Sebastian Schäfer checks his inbox, he finds an email from a patient whose lungs are so scarred that breathing is a struggle—often living halfway across the world—asking for help. Because increased shortness of breath is not the only fear of those diagnosed with lung fibrosis.
“The diagnosis is life threatening as patients can slowly suffocate from all that damage in their lung tissues,” explained Schäfer, an assistant professor with Duke-NUS’ Cardiovascular & Metabolic Disorders Programme.
For most of these enquirers, the antibody drug that Schäfer is helping to develop is the glimmer of hope that could mean the difference between life and death.
And this fervent hope spurs Schäfer and his collaborator Stuart Cook, Tanoto Foundation Professor of Cardiovascular Medicine at Duke-NUS and the National Heart Centre Singapore, in their quest to bring the drug to patients.
“It’s actually quite intense,” said Schäfer. “It’s on your mind all the time.”
Schäfer and Cook’s journey to translate their research findings from the bench to bedside began in 2015 when they first discovered that the signalling molecule interleukin 11 (IL-11) played a central role in scarring, or fibrosis.
And they have come a long way since their breakthrough discovery. In 2017, they founded Enleofen—a start-up company with the goal of developing this molecule into a first-in-class antibody drug for treating the debilitating effects of fibro-inflammatory diseases caused by extensive scarring in affected tissues such as the lung, liver, kidneys, heart and bowel.
Co-founders of Enleofen, Stuart Cook (left) and Sebastian Schäfer (right) during one of their many discussions on their journey from the bench to bedside // Credit: Sebastian Schäfer
Their potential new treatment is but one of a number of exciting ideas from researchers and clinician-scientists at Duke-NUS that were turned into tangible innovations. Other than therapeutics, Duke-NUS scientists have created new diagnostics, medical devices and even digital services—which “help address unmet needs or existing problems in healthcare,” explained Dr David Wang, director of the Centre for Technology and Development (CTeD) at Duke-NUS.
“This can take months or even years,” added Wang, who leads his team in shepherding innovations through CTeD’s doors and out into the world. “Therapeutics like drugs or small molecules usually take much longer because they have to go through extensive pre-clinical development and clinical trials.”
A recipe for innovation
Besides taking time, the journey from the bench to bedside requires patience, grit and—perhaps—a dash of luck. But there is another secret to this recipe.
“It’s very important to be passionate about the problem that you’re trying to solve, because in the hardest periods, that’s actually the bit that will carry you through,” said Associate Professor Derrick Chan from the SingHealth Duke-NUS Academic Medical Centre (AMC), speaking from his own experience as a self-taught innovator. He developed a prototype for a seizure detector that can be used at home, which he hopes will benefit young patients suffering from epilepsy.
Now, as programme director for the AMC’s Clinician-Innovator Development Programme, he encourages innovation throughout the Centre’s 15 academic clinical programmes by organising outreach activities and workshops that impart the technical know-how needed to innovate, while training the next generation of mentors to guide the growing pool of budding clinician-innovators.
“We need people to have that inquiring mind, coupled with the dedication to develop the skills to be good innovators,” said Chan, who is also director of the SingHealth MedTech Office and the lead for culture building and developing human capital at the SingHealth-Duke NUS Academic Medicine Innovation Institute.
As Programme Director of the Clinician-Innovator Development Programme, Associate Professor Derrick Chan encourages innovation within the AMC.
Going in with well-defined objectives is also crucial, shared Schäfer.
“It’s very important that you know what you’re looking for. From the start, Stuart wanted to discover a druggable target in the cells that cause scarring—fibroblasts—which are found in every single tissue in the body,” he recalled.
While others were investigating individual diseases for clues, the duo had searched within fibroblasts, a common thread among these diseases, for answers. And it wasn’t long before they were on to something.
They found that the levels of the IL-11 gene were off the charts in activated fibroblasts, leading to the discovery that IL-11 was the major driving force behind the extensive scarring seen in fibrotic diseases, which is what Enleofen’s technology is based on.
“We’d found something crucial. It was the number one gene that came up in the analysis and a perfect target for an antibody drug that blocks signalling,” explained Schäfer.
What worked in their favour at the time was that their findings were controversial, as most of their peers believed IL-11 to play a protective role instead.
“This meant that what we were saying was novel, and could be patented. So, over the course of the whole project, we filed a lot of patents,” added Schäfer.
With no one hot on their tails, they also had a window of opportunity, enough for Schäfer and the team to conduct the additional experiments necessary to verify and confirm their initial findings.
Taking that first step to commercialisation
Filing patents is something that Senior Research Fellow Dr Anthony Tan from Professor Antonio Bertoletti’s lab at Duke-NUS is also familiar with.
Bertoletti and Tan have been working to develop T-cell therapies for the treatment of liver cancer for more than 15 years. One of the problems they wanted to address was related to the recurrence of hepatitis B-related liver cancer in patients who had received a liver transplant.
Together, they engineered a novel method using a patient’s own T cells that are modified to not only target hepatitis B-related liver cancer cells but also resist to immunosuppressants given to patients after transplantation.
These armoured T-cells then eliminate any cancerous cells still lingering in patients at maximum efficiency without being restricted by immunosuppressants.
“The moment we had in vitro data to show that it was working well, we went to CTeD and said ‘Look there is this technology we developed—do you want to file a patent for it?’,” recalled Tan.
Tan (second from left) and Bertoletti (first from right) with other members of the Bertoletti lab
Initiating this first step is key, according to Wang. “It is hard to commercialise a product if we lose the patentability,” he said. “The patentability of a scientific discovery is severely compromised if an innovation is published or disclosed in the public before a patent is filed. For this reason, we always ask our researchers to submit an invention disclosure to us before publishing so we can kickstart the process of patent evaluation and filing.” This process takes between 30 to 60 days.
After a series of discussions between Tan, Bertoletti and the CTeD team, they concluded that the science underpinning the armoured T-cell method was patentable.
“It took us a couple of meetings to explain the science behind our method before we decided on what could be patented,” added Tan.
Getting support from the ecosystem
Once the scientific discovery is protected by a patent, Wang and his team step in to help researchers explore additional funding opportunities that can help bring the project to the next phase. They also bring in other experts to support the research team in product development.
“For example, we may need to bring in engineers to help develop medical devices, while small molecule development may require the expertise of chemists,” Wang explained.
“It’s a dynamic process and you often go through successive iterations to try to get to the working solution,” added clinician-innovator Derrick Chan.
And within the AMC, researchers and clinician-innovators may also leverage the Bridge Accelerator Programme, offered by the Joint Centre for Technology and Development. The programme, which provides researchers with a gap funding opportunity for collaborative projects within the AMC, began its first run in 2020. Through this accelerator programme, Parakalan and senior manager Dr Erin Teo from SingHealth Intellectual Property were able to reach out to more researchers to help them commercialise their inventions.
But whether it is within Duke-NUS or the wider AMC, “the processes are the same” said Parakalan. “For each project, we look at whether there is potential to develop patentable intellectual property (IP), whether there is an opportunity for commercialisation and what needs to be done to develop the IP to that stage,” he explained.
"Ultimately, we hope to add value to the IP by bringing it to a stage where it’s either more attractive for biopharmaceutical companies to take a license, or to create a start-up company that draws investors."
Which route to take also depends on the number of potential product applications arising from the patent. If only a single product is involved, “licensing to an established company may give the product a better shot at getting to the market in a shorter timeframe,” said Wang, citing recent success stories such as the world’s first surrogate SARS-CoV-2 neutralising antibody test, cPassTM, a rapid T-cell test to track patients’ immunity levels to SARS-CoV-2 and a novel saliva-based antigen rapid test, called the Parallel Amplified Saliva rapid POint-of-caRe Test (PASPORT).
“To accelerate this translation from the bench to bedside, we work closely with our scientists and investors or industry partners to facilitate license and option deals,” said CTeD Associate Director Rishu Srivastava, who helped the team behind cPass commercialise the test in record time.
And when the patent finally makes it to a licensing stage or a commercial endpoint, “you feel happy that you’ve played a part in enabling that process of bringing the scientific discovery from bench to bedside,” reflected Parakalan.
The CTeD team with Parakalan Rangarajan (standing first from left), David Wang (seated in middle) and Rishu Srivastava (seated first from right)
Starting up from scratch
In Schäfer and Cook’s case, as their findings could potentially result in a range of therapeutic products for various fibro-inflammatory diseases, they took the route of creating a start-up company instead.
“It was quite exciting, because as scientists, we all love to try new things, and we have never done a start-up before so, I felt the challenge was super exciting,” shared Schäfer.
Almost immediately, the duo faced the challenge of securing funding. They had to meet with potential investors one by one to get their support and buy in.
“They [investors] want to see everything that helps them to understand the potential of the new findings, including the raw data. No one can explain this any better than the scientists themselves,” said Schäfer.
So for over a year and a half, Schäfer and Cook communicated their discovery and its significance in a way that was understandable even to non-scientists.
“We were really committed to this, because if we didn’t do it, it was probably going to be just a paper and forgotten,” added Schäfer. “In the end, you do it with the patients in mind.”
When they finally met two Singapore-based investors, they had found the partners they were looking for.
“That was the first time we were really aligned with someone,” shared Schäfer.
With their support, Schäfer and Cook became scientific co-founders of Enleofen in 2017. Since then, Enleofen has continued to grow, turning heads with its innovative drug concept that resulted in the young start-up inking a partnership with pharmaceutical giant Boehringer Ingelheim in 2020 to develop these first-in-class therapies for fibrotic diseases such as idiopathic pulmonary fibrosis and nonalcoholic fatty liver disease.
But it was not just Boehringer Ingelheim’s eye that they caught. Enleofen’s patents have been assailed by other pharmaceutical companies.
“The patents draw a lot of attention because competitors want to pursue the same technology,” explained Schäfer.
So far none of the legal attacks were successful and the entire patent portfolio stays intact.
The next step in the development of these anti-IL11 treatments is to launch the first clinical trial, a milestone which will bring the duo closer to seeing the drug out in the market.
“It will be amazing if it works, because if we manage to find something that improves the health of society, that’s how we would immediately give back to people who have supported our research.”