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Harnessing Science for the Most Neglected Diseases – A Chat with Charles Mowbray, Ph.D., Head of Drug Discovery, DNDi

By Rich Soll, SVP of Research Service Division at WuXi AppTec (@richsollwx), December 01, 2016

 

“Some of these diseases are rapidly fatal, cause huge loss of life, and have a huge impact on people’s lives. Often these are diseases that have attracted little research and attention and certainly haven’t been the focus of traditional research and development because there’s no profitable market; nobody’s going to get rich from making drugs for neglected diseases.”

In 98 countries around the globe – mainly in Asia, East Africa, South America, and the Mediterranean region –350 million people are at risk of developing leishmaniasis, a potentially fatal disease that is caused by protozoan parasites transmitted through a female sand fly bite. Leishmaniasis, known as a neglected disease, affects the poorest of the poor and has strong links with malnutrition, low-quality housing, and lack of resources. Existing drugs for this disease have serious drawbacks in terms of safety, resistance, stability, and cost.

Developing countries continue to face significant morbidity and mortality rates from such neglected diseases  even though these diseases account for 11% of the global disease burden, of the 850 new therapeutic products approved between 2000 and 2011, only 4% were indicated for neglected diseases.

As head of drug discovery at Drugs for Neglected Diseases initiative (DNDi), Charles Mowbray is leading efforts to develop more effective treatments for neglected diseases such as leishmaniasis that are short course, oral, safe, effective, and low cost.DNDi, a collaborative patients’ needs-driven non-profit drug R&D organization launched in 2003, was set up by key research and health institutions from the public sector in neglected-disease-endemic countries – the Oswaldo Cruz Foundation from Brazil, the Indian Council of Medical Research, the Kenya Medical Research Institute, the Ministry of Health of Malaysia and France’s Institut-Pasteur, with seed funding from Médecins Sans Frontières (MSF)/Doctors Without Borders (MSF’s 1999 Nobel Peace Prize), and WHO–TDR (Special Programme for Research and Training in Tropical Diseases) as a permanent observer.

Mowbray  a trained medicinal chemist who spent 19 years at Pfizer Worldwide Research and Development  joined DNDi in 2011 and lends the organization his vast experience across disease areas, target classes, and medicinal chemistry strategies. He also has a keen understanding of global health issues, and developing innovative scientific, collaboration and fundraising approaches to deliver much-needed novel medicines to patients around the globe.

I recently spoke with Mowbray, who discussed DNDi’s successful combination of innovative science, unique R&D model, global partnerships, and strong advocacy, as well as what motivates him to go to work every day.

Rich Soll: Why did DNDi decide to focus on neglected diseases?

Charles Mowbray: The medical need and the burden are huge and there are very large numbers of people in large portions of the world affected by neglected diseases and neglected tropical diseases, so there’s an urgent need to do something about that. Some of these diseases are rapidly fatal, cause huge loss of life, and have a huge impact on people’s lives. When DNDi was created, we began working on malaria. It was one of the first organizations to put together artemisinin-based combination therapies. Then we added other neglected diseases to our portfolio: sleeping sickness, leishmaniasis, and Chagas disease, and later other parasitic infectious diseases, which had very poor existing treatments. Often, these are diseases that have attracted little research and attention and certainly haven’t been the focus of traditional research and development because there’s no profitable market; nobody’s going to get rich from making drugs for neglected diseases.

Rich Soll: What is DNDi’s role in helping to provide affordable medicines to those who do not have access to them?

Charles Mowbray: DNDi is not just an R&D organization. We think of ourselves as having three core missions. One is obviously the research and development piece, another is advocating for policy change, new models for sustainable research and development, and sustainable access. The third part is about building and strengthening capacity for R&D in the disease endemic countries. I think we are different than some of the other PDPs in that we have a larger mission, and we certainly advocate for new models because we recognize that the traditional pharmaceutical model is broken for these diseases, so we need more alternative approaches.

We’re currently operating some projects which are demonstration projects; we received some seed funding from the WHO and TDR to demonstrate some alternative approaches to research and development. We’re also bringing partners together, both public and private, to develop innovative ways of doing science. For example, we have a Neglected Tropical Diseases Drug Discovery Booster project where five pharmaceutical companies are working together on the same project with us to try to accelerate development of high throughput screening hits that could lead to more lead optimization projects. That’s a collaborative approach where companies are sharing a bit more information with us and even with each other, which is quite unusual.

Rich Soll: I counted about 33 projects in DNDi’s 2016 pipeline, which is very impressive. Can you give some examples from that pipeline and what your strategy has been?

Charles Mowbray: One major focus area is sleeping sickness. When DNDi got involved with first and second stage sleeping sickness, treatments were pretty horrible. We took two existing medicines that didn’t work very well and combined those and came up with a regimen that produced much better efficacy, was much better tolerated, and a step in the right direction. But it’s one of those drugs that requires an infusion, and getting large amounts of sterile water for infusion in remote parts of Africa where sleeping sickness is a problem isn’t easy. You need to build infrastructure, and you need transport to remote areas. So although the treatment is much better in terms of efficacy and safety, it’s far from convenient. We’ve been striving to come up with some simple oral therapies which could be distributed in a primary healthcare setting or even in a village setting with minimum requirement for infrastructure.

Now we are in the process of completing a Phase II/III trial for a sleeping sickness drug and we’re preparing submission for registration. It’s a short-course, 10-day therapy of an oral medicine. We have another candidate, which started its first Phase II/III studies, and we’re hoping this is going to be a single dose cure for stage 1 and stage 2 sleeping sickness, so in terms of a straightforward medicine that could be used in resource-poor settings, this would be fantastic.

Rich Soll: DNDi has made significant strides in developing new technologies as well. Can you give us an example?

Charles Mowbray: One example is that we got involved in pediatric HIV in 2011, recognizing that young children and babies weren’t well served with existing HIV medicine. Unfortunately, once every two minutes a baby is born HIV positive. It’s not an area where traditional pharma would be particularly interested in working. It’s an extremely difficult patient population to develop medicines for with lots of problems and risks for traditional pharma. These babies are growing up HIV positive, and so the treatments available to them are not adapted to kids, and a key drug in the preferred regimen tastes really awful. Previously it was only available as a syrup or a tablet. A tablet is no good for young kids. They also often live in countries where climates are extreme, so having limited shelf life stability is not convenient. So we’re working hard at coming up with properly adapted treatments. Our goal here is audacious – it’s a 4-in-1 combination therapy, a boosted protease inhibitor plus two nucleoside analogues, and a taste-masked formulation – something that mothers can sprinkle on the kids’ food and they get all four treatments and it doesn’t taste bad. We have also found that some of these kids are unfortunate to also be infected with TB and they’re on drugs for that, so they need a specific treatment to ensure there is no negative interaction between the HIV and the TB treatment, so we have developed a super boosted protease inhibitor treatment for them as well. These important things really make a difference. It’s been challenging, and I’m incredibly impressed by the progress that my colleagues have made in just a few years.

Rich Soll: Some of these neglected diseases have different stages. How do you deal with that?

Charles Mowbray: Leishmaniasis has different forms: visceral leishmaniasis, for example, is an acute and rapidly fatal disease if untreated. There’s also a cutaneous form of the disease where the parasites reside in the skin and produce very unpleasant, slow-to-heal lesions across people’s bodies. Sometimes those can become even more complicated, destroying the nose and face and around the joints. Unfortunately, now there are more and more patients infected with leishmaniasis who also have HIV, both diseases of the immune system, and they both make each other more difficult to treat. So understanding the needs of these patients and trying to work out how to optimize the current therapies means that we recognize that even within a particular disease there are even more extreme needs that we need to address.

Rich Soll: What is the status of some of DNDi’s treatments for leishmaniasis?

Charles Mowbray: We’ve already successfully produced some combination therapies, which are now in use; they are on the WHO’s Essential Medicines List (EML) and they are used in Africa and India. We’re also about to get a change in the recommendation in Latin America. Those are already making a difference for patients. The new compounds that are coming through are obviously in development; as you know it takes some years to complete the development and to get the compounds registered and then advocate for changes in national and regional policies for them to be recognized as first line or second line treatments.

We work with ministries of health, governments, and regional health organizations so we can anticipate and prepare the way to facilitate rapid registration and rapid adoption in multiple countries in order to get the treatments to patients as quickly as we can.

Rich Soll: Leishmaniasis and Chagas disease are part of DNDi’s Neglected Tropical Diseases (NTD) Drug Discovery Booster consortium. Can you tell us more about this collaborative effort?

Charles Mowbray: When DNDi was created, we could only screen a few compounds a month because they were really difficult assays to work on. By working with some of our partners some things have improved and now we have high content screening; we can actually screen against these intracellular parasites and test bigger libraries of compounds. Basically, we can mine our partners’ compound library for a range of neglected tropical diseases. Traditionally, early stage drug discovery is an expensive and time-consuming process. Our booster program uses a multilateral, simultaneous search process across participating companies, which allows us to access compounds generated over many decades of research. We’re about a year and a half into the program now and it’s been more effective than we ever dreamed it would be. We have five major pharmas working with us on this project, and people are really excited about it. It’s a different way of approaching drug discovery.

Rich Soll: It takes a unique breed of person to be doing this kind of work. How did DNDi assemble such a diverse group of people?

Charles Mowbray: We wanted a wide range of disciplines – pre-clinical scientists like myself, clinicians, real disease experts, especially for neglected diseases, advocates, fundraisers, communicators, operations people, and a finance team – all the different disciplines and skill sets that we need to make an organization like this work. We’re a very global organization as well – although we’re headquartered in Geneva, Switzerland we also have regional offices around the world. They can be involved in conducting clinical trials, fundraising, advocacy, research, and a whole range of activities – Latin America, Africa, India, Malaysia, Japan, and the U.S. Some come from a humanitarian background, many have worked with MSF or other organizations in the field, and they really understand the challenges of helping patients in some of the most difficult conditions and most remote areas. We also have people who have a long history of working with the pharmaceutical industry, and traditional for profit projects, and they bring in those skills and connections to help us. I would say they are all very passionate and very motivated.

Rich Soll: What is your proudest achievement at DNDi?

Charles Mowbray: The NTD booster program was my idea and I was fortunate enough to be given the opportunity and space to try to make that fly. To witness what we’ve been able to do in a relatively short amount of time is exciting. Another highlight for me was that earlier this year, we nominated a candidate for leishmaniasis; it’s a project I’ve been working on for some years. There’s a molecule that’s developing through the pre-clinical stage at the moment. In less than a couple of years that could be in human volunteers and then on to patients. We are focused on the best science for the most neglected diseases. I can’t think of a more motivating place to work.

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