Drug Development

Portfolio: I read with interest your work on anti-Zika drug. Tell us what prompted you to embark on the research that would lead to the development of this particular drug? What initial challenges did you face in this endeavor, and how did you manage these challenges?

Dr. Yok Hian Chionh: When I came back to Singapore, I was very fortunate to be in the right place, at the right time, and with the right ideas. I was introduced to Dr. Ram Sasisekharan from MIT, a veteran in biologics development, and Dr. Ooi Eng Eong from Duke-NUS Medical School, one of the world’s leading experts in flavivirus infections.

Essentially, we were all asking a similar question – why can’t we accelerate the process of bringing to market treatments that can be used during emergencies, especially for Singapore – the epicenter of both tropical infections and global outbreaks due to its position as a travel and transportation hub.

We wanted to establish a company that could tap into existing knowledge and regulatory support to address health crises with rapid but effective solutions. This need had hitherto been unmet, and was often thought to be just the way things were. This simply did not make sense.

Let me just point out that by the time this article goes to print, more than 200 people in Singapore would have contracted Zika – since the outbreak started in Brazil in 2015 – and that is just a negligible fraction of the ~1.5 million of infected individuals worldwide. Now imagine if a cure had been available within months of the outbreak in Brazil, how many lives we could had changed for the better? A sad fact is that infections still cause 20 million deaths and cost US$20 billion each year.

What were the results of your efforts? Have your findings, for instance, been acquired by a laboratory or a pharmaceutical company to turn into accessible drugs?

I consider myself fortunate enough to work with these visionaries to establish Tychan, a Singapore-based, clinical-stage biotechnology company, that is actively addressing this problem head-on by bringing life-saving treatments for emerging infections to those in need through accelerated drug development. To put it simply, Tychan’s raison d'être is to rapidly develop therapeutic solutions against emerging viruses.

Tychan has established a toolkit of platform technologies to rapidly bring promising therapeutics from bench-to-bedside using integrated analytics, accelerated bio-manufacturing, progressive clinical trial design and evidence-based regulatory frameworks. We now work in a coordinated effort with regulatory authorities to accelerate the translation from non-clinical studies to clinical trials for emerging pathogens.

As a drug developer, I am helping to bring a single dose anti-Zika therapeutic from bench-to-bedside. I believe that the war against infections can be won if we proactively create systems that rapidly design cures, respond to, and treat patients during outbreaks.

You are considered a maverick because of your exploration of radically different science-based regulatory frameworks that can expedite regulatory approvals of therapeutics while meeting the stringent safety and efficacy requirements that are in place today…

Personally, I get excited when I see the components come together – how they fit and interact. As an academic, I learned how to look at huge amounts of data and see patterns in the way each part is organized. This ability had enable me to make a difference. Sometimes it is mind-boggling to see a system give rise to emergent properties that go beyond the sum of its parts.

We had no one to show us a different approach to drug development. Manufacturers and contract research organizations would ask us, “Are you sure you want to take this risk”. We answered, “Yes we do, or we won’t make the timeline”. It became a study of individual wisdom, quantitative measurements, regulatory science and risk management; taking each apart, reassembling schedules and processes and moving them forward.

When we measure individual processes well, the data will speak for itself. After analysis, we take a step back, look at the whole system, and ask, ‘How can we make it better’. That is when we disrupt it with the goal of producing a product of equivalent quality or better – with the data to back it up. So far, the regulators in Singapore are receptive to this new approach. This is the way we can make drugs available quickly and provide it to those who needs it.

Is there a long road between the drug laboratory and the pharmacy? How long does a patient who is suffering from a rare condition or a disease outbreak typically wait for an effective treatment and medication? What can be done to shorten that distance between outbreak and cure?

It’s always an uphill battle to challenge the current paradigms and the general assumptions that had since became common knowledge for the field. Every system has its limitations, and if the current one does not meet our needs, let’s create one that does. There is a need in many fields that require changes to the way we bring things forward. The way we bring drugs to market is no different.

In conventional drug development, the pre-clinical development costs at least US$100 million and takes three to five years, depending on the complexities involved. Another US$1 billion spent on clinical trials lasting three to five years again. We found a way to disrupt this process using integrated analytics – that is, if we measure certain procedures often and frequently enough we can model, predict and expedite the process. In the case of our anti-Zika virus drug, we got the development time down to nine months and we did so with less than US$20 million and within six months. Similarly, we plan to bring to cost of clinical trials – both in terms of time and money – down.

To give you a concrete example, to bring our anti-Zika therapeutic to patients quickly, we made heavy use computational methods in drug design. We know precisely how we wanted to produce to work and thus working backwards; we looked at what had worked previously, and use analysis to determine what the final drug should look like.

All that remains is to make it and test it out. On the other hand, to accelerate manufacturing, we define a desired target product profile early on, and used consensus processes and convergent analytics to measure the product parameters without developing new assays. Therefore, during infectious disease outbreaks, we will go straight to rational product design, accelerate manufacturing using pre-determined processes, then use innovative regulatory paths to quickly move a therapeutic to clinical trials.

A caveat. In our field, it’s easy to get lost in the minutiae. Thus, we take a deliberate stand to look at the process and determine how we can improve on it to meet the criteria during – not after the development process – and not simply check the necessary boxes.

I don’t mind saying that for our first product, we failed our self-imposed six-month timeline. It took nine months to get our anti-Zika virus therapeutic to clinical trials. But there are more potential epidemics out there and we are working to get the process from drug design to human trials shortened from months to weeks. We use evidence-based approaches to map product to process and build these datasets into networks. At this moment, we are getting a head start with the drugs in our pipeline, two of which are showing a lot of promise.

It was reported that you have "discovered fundamental properties of genetic coding that enables pathogens to survive hostile environments” – how would you explain it and its implications to a layman?

I am honored to have made some contributions to the exciting new field of epitranscriptomics. This was my area of research for my PhD under the Singapore MIT Alliance for research and technology (SMART). It came to your attention because that work was well received, and I was selected as an Innovator Under 35 for 2018 by the MIT Technology Review. (An interesting side note: epitranscriptomics was one of the topics presented at the EmTech Asia conference in Singapore last month.)

To give you a summary, I investigated the missing links in molecular biology: why genes are coded in peculiar ways, and why are there more than four basic bases – alphabets if you will – in ribonucleic acids (RNA).

The genes in the genome can be thought of as an instruction manual for how things are made. But genetic information alone does not tell one how much of the gene’s product to make, or how when to make them.

For instance, if you tell me to jump, I’ll ask how high, and when. I wanted to see if there was a code within the genetic code, a certain cadence, or usage of words. And I found that RNAs are biochemically modified to decode the primary message at different efficiencies under different conditions. In other words, I took a very deep dive into the alphabet soup of RNA chemistry and figured out how they came together as a biological system.

Next, I went on to test my ideas on the bacteria causing tuberculosis (TB). As it turns out these bacteria use the epitranscriptomic program I described to control how they survive in humans. By tweaking the programming, I showed that it is possible to kill drug resistant bacteria under conditions that they would normally survive.

What can you tell us about the anti-Zika drug that you’ve designed?

If a pregnant woman contracts Zika, the infection can result in congenital infection, causing the malformation and stunted growth of multiple organs and especially the brain in the fetus. A recent study estimated that the absolute risk of microcephaly in babies from mothers who acquired antenatal ZIKV infection is as high as 17.1 per cent in some parts of Brazil. With no approved vaccine, there is an urgent need for a safe therapy to reduce viral spread and reduce the risk of congenital infection and Guillain Barré syndrome.

Zika virus (ZIKV) has emerged to become a cause of major health concern throughout many parts of the tropical world. ZIKV is a single-stranded RNA virus in the genus Flavivirus, thus phylogenetically related to Dengue, West Nile, Yellow Fever and Japanese encephalitis viruses. The surface-exposed envelope (E) protein is the mediator of host cell attachment and viral entry, and the predominant target for prophylactic and therapeutic antibody treatments for Flaviviruses.

This flavivirus is transmitted by the same Aedes mosquitoes that spread the closely related dengue virus (DENV), and hence ZIKV has the potential to be as widely distributed as DENV globally. This possibility is emphatically underscored by the first documented outbreak of Zika in Singapore in 2016 and emergence of numerous clusters of cases in 2017, despite Singapore’s extensive vector control program.

In most instances, Zika is a mild, self-limiting viral infection, and symptoms only arise in ~20% of infected individuals and include fever, skin rash, conjunctivitis, and muscle and joint pain lasting two to seven days. However, epidemiological observations now reveal a strong link between infection of pregnant women and severe neurological complications, including microcephaly, in the developing fetus.

In rare instances, infection in otherwise healthy adults can develop neurological complications in the form of Guillain-Barré syndrome. This post-infection sequelae result in ascending paralysis that, in some cases, can be life threatening if it involves the respiratory muscles.

The drug we, as in the Tychan team developed, is Tyzivumab, a monoclonal antibody that has been developed for the treatment of Zika infected patients. At this point in time, all our data indicate that a single dose will be sufficient to successfully treat Zika infections in patients. This single-dose treatment will be tested in healthy volunteers in starting February this year, making this the most advanced Zika biologic program anywhere in the world.

Give us an idea of what your next projects are going to be. What theories and hypotheses support your research? How will they benefit the man on the street?

We can cure a lot of things now – the science is there but they not getting to the people because of the barriers that are in place. These barriers had been put in place for good reasons but should be contextualized under emergencies. Many researchers who learned of these barriers often have them set in stone. So, our aim is to continue disrupting the drug development cycle, making it really compact, making clinical trials much easier, all in order to get the right drugs to the people when need it.

We aim to understand the science and create our own playground to move things together in the most advantageous way possible. It is our job to move drug development forward as a whole. There is no one scientific theory or model that we subscribe to. We prefer to let the researchers what they do best and let the data drive our solutions, so while we may patent the product itself and we are constantly looking at making the entire process - from design to manufacturing to clinical trials - more efficient.

For humanitarian reasons, we are actively looking to design anti-infectives, develop them in our new system while constantly improve on it. We foresee a future where it becomes feasible for drug developers to make the necessary drug to address any disease out there. That’s our vision. To make an infectious disease epidemic a minor nuisance rather than a major health crisis. That’s how we what we are doing now will benefit the man on the street.

I’m glad to be on a team that shares this vision. That’s what I love about the team I’m working with right now. This allows me to come to work every day and move things along with passion. Moreover, when we explain this vision to others, people love it. Hence, there’s a good chance of us succeeding in creating new systems to deliver life-changing treatments to patients within weeks and not months or years.