The NovartisInstituteforTropicalDiseases (NITD) in Singapore discovers and develops novel treatments for major tropical diseases up to proof-of-concept in man. Established in 2002 in a partnership between Novartis and the Singapore Economic Development Board (EDB), NITD focuses on malaria, dengue fever and sleeping sickness – diseases which are collectively responsible for the deaths of hundreds of thousands of people each year. Yet these diseases are also termed "neglected" because few companies in the industry invest in them. Following is an excerpt from a conversation with Thierry Diagana, Head of the Institute; Feng Gu, Associate Director of Preclinical Development; and Francesca Blasco, Director of Drug Metabolism and Pharmacokinetics, about their paths to NITD and their research.
What drew each of you to work for NITD?
Blasco: I have always been fascinated by science, but in particular by drug discovery. I dreamed of developing new medicines when I was very young. That must have been fuelled by watching my mother and grandmother afflicted by a genetic disease for which no therapy is available. It was very hard watching them deteriorate knowing that there was nothing that anyone could do. Working at NITD means a lot to me. I am realizing my childhood dream and contributing to the discovery of medicines that could help many.
Gu: For me, this was my ideal job. After leaving school I studied and worked in Europe and North America, but I was born and raised in China. Life wasn’t easy there and I was really struck by the contrast when I moved to Europe. That experience gave me the desire to do some healthcare volunteering in Asia or Africa, so the opportunity to return to Asia and work in an area where I could have a direct impact on the wellbeing of patients in the developing world was so exciting.
Diagana: It does sound cliché to say we got into science to help patients and make a difference but that is the truth for many scientists. Like Feng and Francesca, my motivation to work in drug discovery stems from childhood. My father is from West Africa and when I visited family there I could see how the healthcare system was struggling to combat the effects of malaria. The desire to do great science to alleviate suffering in the developing world is what brought me to NITD and it’s what keeps me here.
Do you face unique challenges when you work on projects targeting tropical infectious diseases?
Diagana: The development of therapies for these diseases involves a tremendous amount of additional work you would not need to give a moment’s thought to in drug discovery in the developed world; not least trial operational issues. To run a trial in a place where tropical infectious diseases are endemic you often have to start from scratch as the infrastructure is normally not in place. We have to build capability, train people to run diagnostics and the biochemical analysis of blood work, ensure compliance with good clinical processes and bring in the necessary kit and technology.
Economic and social challenges, climate and medical care infrastructure are all factors we have to build into each programme’s target product profile. The majority of people in the endemic regions cannot afford to take time off work so we need to make drugs that are efficacious with a short course of treatment. The drugs must be cheap to produce as many of the patients have little money. The stability of the drug is critical in these regions as we need a formulation that won’t degrade in the heat and high humidity. Finally, since a high proportion of the cases are in infants and children we also need very safe compounds.
Gu: I had underestimated those challenges when I first came to NITD. I visited one of the clinical trial sites of an anti-malarial compound. The site is on the Thai-Myanmar border, along the bank of a river, set in the fields, miles from anywhere. The clinic is not a hospital as such, but a hut with very little of the technology we rely on in hospitals in the developed world. The protocol and sampling times are recorded on a white board. Yet despite the significant infrastructure challenges and all the training that had to be put in place, the operations supporting the trials have been a fantastic success. Everyone involved did a great job in difficult circumstances.
Blasco: The other challenge is that, by their very nature, relatively little is known about neglected infectious diseases. Take dengue fever, for example. Dengue is now endemic in more than 100 countries and the number of cases is rising year on year. Last year, Singapore experienced one of its worst ever outbreaks. Everyone at NITD knows someone who has had the disease, so it is a very present threat for us. Yet, until recently, very little was known about the disease. Before we could find potential drug candidates our initial step was to develop the first tools to begin to understand the disease at the molecular level.
Where do you think NITD is making significant progress in understanding and treating tropical infectious diseases?
Blasco: The progress (July 30 Media Release) of our two anti-malarial candidates in clinical trials is a major milestone, but there is also the potential for similar success in our other disease programs. TB is one of the first diseases we focused on, together with dengue fever. According to the World Health Organization (WHO) more than 50 million people are infected with multidrug-resistant TB. We set out to develop a drug to combat these drug-resistant strains and began by developing tools that are now regarded by many as the standard for identifying potential TB drugs. Several potential candidates have emerged and we have now handed over the drug development work to our research partner, the TB Alliance.
Our focus has now switched from TB to African sleeping sickness. The current therapies for the disease are inadequate. All existing drugs are old and are very challenging to administer without skilled healthcare professionals. We have committed to supporting the WHO achieve its goal of eliminating sleeping sickness by 2020. Our aim is to develop a revolutionary treatment for sleeping sickness in the next five to eight years.
Diagana: My landmark moment was being notified by the physician running the malaria trial in Thailand that the first patient had taken a dose of one of our trial drugs. It had been great to get good results from our in vitro testing, but advancing to human testing was the major milestone. There was an incredible sensation of fulfilment that patients were now receiving experimental drugs that we had discovered and developed in collaboration with our colleagues at the Genomics Institute of the Novartis Research Foundation, the Swiss Tropical and Public Health Institute and The Scripps Research Institute.
We now have two anti-malarials that have succeeded in early proof of concept human trials, and another strong candidate following behind. At the moment there is every indication that these are active against the relapse form of malaria. These could potentially be the first novel therapies for the disease to be launched in many years. There is also the potential to apply our learning from malaria to research of the kinetoplastid parasites that cause diseases such as sleeping sickness.
Gu: We have also made significant progress in dengue fever research. As Francesca mentioned, very little was known about the disease when we launched our programme ten years ago. There were only 4,000 published papers on dengue, no research tools and no treatment for the disease; only supportive care. We reached out to dengue experts in academia and, working in collaboration with them, we spent several early years designing the basic tools. We were the first to elucidate the crystal structures of several viral proteins. We knew that the dengue virus has a complex pathology that is not easily recapitulated by animal models. We still don’t understand the underlying molecular pathology but we are trying to identify the target organ of the virus. Our goal is to deliver a drug candidate in the next three to five years. In fact, that is the picture for each disease area we work in. We have already achieved a breakthrough in malaria research. We want to replicate that success with dengue and sleeping sickness in the next few years. These are exciting times for NITD!
This conversation first appeared in Novartis’ live magazine.