Explain to us Hilleman Labs’ focus and strategy and how this differentiates your organisation from other R&D labs working in the same space.
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Dr Davinder Gill
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The overarching strategy for Hilleman Labs as an organisation is to focus on working on developing transformational technologies for vaccine development with the public health needs of the low income countries in mind. Focussing on coming up with a portfolio that we could deliver.
And so we asked the question: in a low income country why is it that so many children do not get to celebrate their first birthday? And the answer is that in most cases, the reason is that the child had a serious pulmonary or diarrhoeal infection. So, we decided to build a portfolio around endemic viral diseases and develop vaccines which could impact infant mortality and reduce infant morbidity.
And so we have a programme in thermo-stable rotavirus vaccine, where we’ve made some good technical results and progress. The next goal will be to advance this programme into clinical development.
Very recently, we have added a programme to develop a high impact oral cholera vaccine with cross protection against Enterotoxigenic Escherichia coli (ETEC) diarrhoea, in collaboration with Gotovax AB, a biopharmaceutical company, spin off from the University of Gothenburg. This will be at a significantly lower price than the ones currently available in the market.
As a strategy, in order for us to demonstrate impact, Hilleman Labs decided that we would focus on fixing vaccines that exist but which have not been designed for the developing world. So much of the work we are doing, whether it is the rotavirus or the cholera vaccine, is about optimising existing vaccines. This will allow us in a time span of five years to achieve proof of concept.
This is different from a strategy where we take a significant unmet need, in say, malaria, HIV, tuberculosis, or dengue and try to come up with something novel. This is a long-term strategy. Our primary goal is to demonstrate clinical proof of concept in the next three to five years.
And since both are essentially optimisation projects, where in the case of the rotavirus vaccine, it is about reformulating the current vaccine for thermo-stability and in the case of the cholera vaccine, it is about making it more affordable. It is about combining the manufacturing aspect with the thermostbility aspect.
So what we are hoping is to achieve accelerated clinical development studies and so to move much faster through clinical development rather than the usual phase I, II and III stages. This is our road map and strategy for the next few years.
What business model are you putting in place to achieve these goals?
Hilleman Labs operates on the for-income, not-for-profit principle. At the moment, we have support from our founders, which is Merck and Wellcome Trust, but our goal is that once we have established products, we will pursue options like whether its client income, or project related collaborations, in-licensing income, etc.
And of course, down the line, once we have the products approved, some royalty income as the products move into the market.
So that is the operating model as our goal is to ultimately become financially sustainable.
But we donot think that is possible without establishing a good foundation and demonstrating that we can actually take these concepts from pre clinical to proof of concept stage.
Once we do that, there is a commercial potential to each product which is why we spent so much time picking the products/projects based on their impact on public health. These two aspects are the bedrock of our operating model.
In early July, Prime Minister Narendra Modi added four new vaccines to India’s Universal Immunization Programme (UIP). The rationale is that the vaccines against rotavirus, rubella and polio (injectable) will expedite India’s progress on meeting the Millennium Development Goal 4 targets to reduce child mortality by two-thirds by the year 2015 and meet global polio eradication targets. The fourth vaccines, an adult vaccine against Japanese encephalitis will be introduced in districts with high levels of the disease to reduce the disease burden. There has been some criticism that this is going to add to the cost of the programme. What are your views on this issue?
I think it is a step in the right direction because when you consider the high mortality and morbidity associated with each of these vaccines. India has large birth cohort, with around 27 million babies annually. The costs of getting these infants vaccinated, at 95 per cent coverage is already an expensive proposition. Nonetheless, I think you have to look at the overall impact these vaccine will have in further improving child mortality and reducing child morbidity.
I think that the rotavirus and injectable polio vaccines make a lot of sense due to the heavy mortality and morbidity associate with rotavirus. India is now polio free which means that we now have to think of the post eradication end game so the transition from the oral to the injectable polio vaccines makes a lot of sense. With respect to the rubella and the Japanese encephalitis vaccines, I think these too make a lot of sense.
Of course, it does not end there. Maybe there is an argument to be made that measles second dose coverage needs to be increased and improved. So also what about pneumococcal vaccines, given that the burden of pneumococcal diseases is also pretty high so should we consider adding these too to the national vaccination programme? So I think it is a good start and going forward, I feel that there may be further additions to the UIP. For instance in enteric diseases like cholera where we have a programme ourselves which also tends to have a huge disease burden in India.
How are the vaccines being developed by Hilleman Labs superior to those already in the market?
One other area we are also working on, outside of thermostabilty, is some very unique, cheap, simple but effective delivery devices. These are the single container closure devices which allow very easy reconstitution and easy delivery of dry formulated vaccines for oral delivery. So it is a combination of these kinds of technologies that we think will ultimately improve the access.
The other part of course is the affordability. And this is where we will look at the production cost, etc. We have quite a bit of effort in conjugate vaccines which as a class are very complex so it adds to the cost of production. I mentioned rotavirus, cholera. So we are also looking at what can we do to address the cost issues. Also, there is only one WHO pre qualified supplier as of now of the cholera vaccine (Shanta Biotech) but with the size of the disease burden, will one supplier be enough? So our strategy is to develop vaccines with better protection at lower cost. Cholera is caused from enteric infection with the bacterium Vibrio cholerae primarily (~99 per cent) of the O1 serotype. By transferring a functional wbeT methyl transferase gene into the genome of an O1 Inaba strain, our partners, Gotovax AB, a University of Gothenburg spin-off biopharmaceutical company, have created a resulting ‘Hikojima’ strain that stably expresses both the Ogawa and Inaba serotype antigens on its surface; thus improving the stability and efficacy of the vaccine candidate as well as significantly reducing the cost of production. So our vaccine will provide better protection than Shanchol and yet at a price significantly lower than the Shanchol price because of our whole manufacturing strategy is to vastly improve and optimise.
So when you combine these strengths of better effectiveness, lower manufacturing cost as well as thermostability and better drug delivery, our product is superior to the existing product especially from a global stock piling perspective in cholera epidemic areas.
The products coming out of Hilleman Labs’ research pipeline are not being developed only for India and will be used in other countries with the same geographical and climatic conditions. So can you give us any time line to the launch of these products?
Both the rotavirus and cholera vaccines are in the pre-clinical stage, finishing up some toxicology studies which will be followed by animal studies. The toxicology studies should finish by the end of this year for both programmes and we would begin clinical trials next year. As both are basically optimisation studies, we are looking at accelerated clinical development, which means that in the case of the rotavirus vaccine we would look at immunological bridging studies based on sero-conversion.
In the case of the cholera vaccine, we would look at non-inferiority against existing vaccines primarily Shanchol. We think we can achieve these clinical endpoints in the 2017-18 time frame, which will then bring us to registration in our first geography, which could be India or outside of India. Then we will expand from there, looking at WHO pre qualification, etc.
Hilleman Labs was established in 2009, the R&D facilities were started in 2011, so its going to be almost a decade before the first product hits market. Any learnings from this process and could it have been shortened?
This is a learning process for any kind start up/joint venture of this nature because unlike traditional biotech start ups which have a germ of an idea to convert into a product, in the case of Hilleman Labs, the vision was established, the concept put in place, the entity launched but then we had to ask what problem are we going to solve, are we the right people to solve this problem, and if we solve the problem is anyone going to care? Answering those questions unfortunately took longer than we estimated. Crafting that strategy and deciding what is going to be practical for us took time but now that’s in place and we are at the implementing stage.
I think any research activity takes a long time to decide the approach, etc. There is no short cut or formula for that. Especially when you have to pay attention to not just clinical proof of concept but also to the process. Ultimately we need to have a very robust factory ready process because we need to meet very stringent regulations. In fact I would argue that given these factors, eight to nine years is a relatively short period of time. What’s really crucial for us is execution of our strategy. We need to move fast, execute flawlessly but we also need to keep in mind that we are going to need a lot of help. We are talking to companies to help us in clinical development and some of the manufacturing issues, given that Hilleman Labs ourselves are not going to be doing the commercial manufacturing ourselves. All those conversations are happening in parallel.
What are the kind of companies you are talking to at this stage?
We are talking to vaccine manufacturers in India, and of course we have the unique advantage of have a good cohort of such organisations within India. And Hilleman Labs being a global company, we are also looking at such players in the South East Asia area. We began these conversations a year or so ago and now we are narrowing them down. We are hoping that as the rotavirus and cholera vaccine programmes progress, we will take these talks to the next level. We will have to decide who will be our clinical development partner, and then our manufacturing partner. In what geography will we do the manufacturing? And how does that align with some of the early registrations that we will seek in those geographies? We hope to make these decisions soon.