Ebola shows drug development can be accelerated, says Piot

Signs that Ebola is levelling off – but has detracted from fight against HIV/AIDS, malaria, TB and NTDs. ‘Market failure’ in drugs for developing world can be fixed, says Japan’s innovative GHIT Fund.

As the Ebola outbreak has continued to spread in West Africa and ravage vulnerable populations, there have, nonetheless, been voices complaining that the international focus on the disease has diverted resources away from sub-Saharan Africa’s biggest killers.

There are even claims that more lives have been lost in the region to malaria, HIV/AIDS, tuberculosis and neglected tropical diseases (NTDs) than to Ebola this year, but that these deaths have been overlooked in the face of the attention-grabbing virus.

A wry cartoon from The Washington Post circulating on Twitter summed up the irony. A fuzzy pink malaria parasite meets a stringy blue Ebola virus and says: “I kill 1.5 million people a year and I still can’t get your press. Who’s your agent?”

 

 

While the Ebola crisis is far from over, global health leaders now want to apply lessons learnt from the outbreak to help tackle the infectious diseases which kill far more people than Ebola in the developing world each year.

Ebola is causing tragedy in West Africa (Sierre Leone, Liberia and Guinea the worst affected), where the death toll is still rising and now exceeds 5,000. But its impact has to be put into context with the other infectious diseases affecting the region. HIV/AIDS, malaria and TB infect hundreds of millions of people in the world’s poorest countries every year: causing incapacity, impoverishing families and killing approximately 1.6 million, 627,000 and 1.5 million, respectively, last year.

Add to this a host of neglected tropical diseases (NTDs) estimated to affect a staggering 1 billion people in Sub-Saharan Africa, Asia and Latin America, and the extent of the burden is clear.

Global leaders say the kind of funds and urgency generated in the fight against Ebola must be applied to these bigger long-term health challenges.

 

The Big Picture

Professor Peter Piot, the microbiologist who first discovered the Ebola virus in Zaire in 1976 is one of the most respected figures in global health, and is currently Professor of Global Health at the London School of Hygiene and Tropical Medicine. He has been critical of the World Health Organization’s (WHO) initially slow response to the new outbreak, which first emerged in Guinea in December 2013.

But when the disease began to spread exponentially over the summer, WHO, governments and the global pharma industry acted decisively, and bypassed the standard protocols which regulate drug development. Most notably, this has included the fast-tracking of new treatments such as Mapp Bio’s Zmapp drug, which was given to gravely-ill patients with Ebola despite it never having been tested in humans before. Numerous pharma companies are also now working urgently on developing vaccines for Ebola via associations with governments and global alliances.

Speaking at a London meeting of the public-private alliance the Global Health Innovative Technology Fund (GHIT) held at the Embassy of Japan, Professor Piot said the Ebola experience showed new drugs for infectious diseases could be developed much faster.

“I think the Ebola crisis has shown that where there is an emergency we can accelerate development and there is no reason why it should take so long.”

Leaders at the GHIT Fund meeting all expressed their frustration at the rising cost and long timelines for developing new treatments.

Piot is the most high-profile member of GHIT, which, unlike other global health funds, has buy-in and investment from multiple pharma companies.

The GHIT Fund is made up of five Japanese pharmaceutical companies – Astellas, Daiichi Sankyo, Eisai, Shionogi and Takeda, two Japanese government ministries, and the Bill & Melinda Gates Foundation, which is increasingly the key player in global health.

This makes GHIT unusual among public-private partnerships: Piot says most organisations going by this name are not truly partnerships, because they are dominated by governments and have low pharma industry engagement. 

Just 18 months old, the GHIT fund looks different. The collaboration derives 50 per cent of its funding from Japan’s government, 25 per cent from the Gates Foundation, and 25 per cent from its five founding pharma companies – making it a genuine joint venture. Led by its dynamic American chief executive B.T. Slingsby, who has a pharma industry background, it aims to ‘transform global health R&D and accelerate drug discovery for infectious diseases’ through its strategic partnerships and major research investments.

Slingsby is direct in identifying ‘market failure’ – caused by high risk and low expected return on investment for pharma – as one of the main reasons why drugs for developing world diseases are so hard to develop, and GHIT aims to help solve these underlying problems.

The last decade has seen considerable progress in ensuring HIV/AIDS patients in the poorest nations receive antiretroviral combination drugs – but this is because there is a large market for them in the developed nations.

In contrast, new treatments for malaria and TB, and neglected tropical diseases has been painfully slow.

Slingsby says 48 per cent of the world’s population is at risk from an infectious disease, with 14 per cent already infected with one.

“If that were a market, it would be enormous, but less than 1 per cent of new drugs are for these diseases,” he says, and therefore new approaches to public-private partnerships are required.

Slingsby says the Ebola emergency has ‘usurped’ these diseases and believes it threatens the progress already made against them.

The GHIT Fund’s B T Slingsby

At the same time, he agrees that the Ebola outbreak has been a ‘catalyst for discussion’ about how to speed up drug development along a more ‘linear path’ to market, with new study designs and regulatory pathways worth investigating.

The GHIT Fund offers pharma companies a ‘No gain, no loss’ model. Firms are allowed to retain the intellectual property related to the drugs they develop, but they are usually unlikely to ever see a return on their investment, as these diseases simply aren’t profitable to treat.

In creating an organisation with genuine multi-stakeholder engagement, the Fund looks promising. Nevertheless, there are clear limits to what the collaboration can achieve. Its annual budget of $20.5 million is a drop in the ocean compared to the multi-billion R&D budgets of big pharma, and certainly dwarfed by the size of the task of tackling these killer diseases. 

Rising cost of drug development

Sir Roy Anderson, Professor of Infectious Diseases Epidemiology at Imperial College London commented: “The world has never had a period of such inventiveness – but the opportunities to take these to market have declined.”

Just as in mainstream drug development, Sir Roy says the cost of bringing a new drug to market for infectious disease is around $800 million, with most of the cost residing in phase III trials.

However there is some good news, such as Sanofi’s new dengue fever vaccine and GlaxoSmithKline’s (GSK) new malaria vaccine, called Mosquirix (RTS, S), which looks set to gain approval in 2015. It has been shown to halve the number of malaria cases in young children (aged 5-17 months at first vaccination) and cut by around a quarter cases in infants (those aged 6-12 weeks at first vaccination).

The drug could play a significant role in cutting infection rates, but its long development time – 20 years so far – illustrates the problems in infectious diseases.

Sir Roy adds that the vaccine: “wouldn’t be where it is today if it hadn’t been for the Gates Foundation”, which funded its development via the PATH Malaria Vaccine Initiative in collaboration with GSK.

Cases of malaria have been almost halved in 10 years, thanks to wider use of use pesticide-impregnated bed nets, and many deaths have been prevented by wider user of the drug artemisinin. However Professor Sir Brian Greenwood – another UK-based world leader in research present at the GHIT meeting – says these gains are ‘fragile’ with fears of resistance to the pesticide used in mosquito nets, and confirmed cases of artemisinin resistance spreading in Asia.

The GHIT partners are seeking to address these problems by funding a broad pipeline of new treatments which could help treat or cure diseases in hundreds of millions of people.

An example of the kind of work GHIT is funding is a project being led by Professor Steve Ward of Liverpool School of Tropical Medicine (LSTM) to develop a new treatment for onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis) in collaboration with Eisai.

The number of people affected by the diseases is truly staggering: 500,000 people are sightless due to river blindness, making it the second biggest cause of blindness worldwide. Meanwhile 120 million are affected by elephantiasis, the second leading cause of global disability. Part of the A-WOL Consortium, the research targets the wolbachia bacteria found inside the parasitic worms responsible for both diseases.

With the GHIT investment in place, the most promising drug candidates will proceed through advanced rounds of chemical modification and testing to identify lead candidate compounds that have a good safety and efficacy profiles, then moving on to pre-clinical testing.

Prof Ward will work with colleagues at LSTM and Eisai on chemical optimisation of drug candidates, aiming to arrive at a lead candidate for development and distribution as fast as possible.

A sense of urgency needed

Dr Nick Hamon is chief executive of IVCC, a public-private initiative also part of the Liverpool centre of excellence, and a GHIT Fund member organisation. IVCC focuses on new drugs and pesticides targeting the vectors (insects, animal or micro-organism) which transmit diseases.

Dr Hamon says generating a sense of urgency is vital. He said breakthroughs in his field are “only a long way off if we make them a long way off.”

He added: “My biggest challenge is to persuade everybody to get those development times down from 12 years to 7 years – that would have a huge impact on how many people die, and how many infections are prevented.”

Pharma’s commitment

There are numerous obstacles which slow down progress, and pharma is not immune to these problems.

Tim Wells is chief scientific officer at the Medicines for Malaria Venture. Like so many in the field, he has a worked in pharma, and knows the problems industry faces. He says market failure is a major issue, but says finding ‘just right amount of money’ – not too little and not too much – is also vital.

Another problem is pharma’s unwillingness to share data. Tim Wells says that even though there is no potential profit linked to molecules for these diseases, data is not freely available. This means companies cannot ‘peer review’ in the way that academia does, a process which allows scientific practice and data to be challenged and improved.

Nevertheless, he says that pharma is almost always willing to lend a hand.

“We always get a yes, unless that company is already involved up to its neck in other therapy areas.”

However one leader in the field told pharmaphorum that the ‘elephant in the room’ was the difficulty in guaranteeing long-term commitment from pharma.

“CEOs come and go and priorities change,” he says – a fact of life, but one which robs drug development programmes of vital impetus, expertise and funding.

One example of this in 2014 may be AstraZeneca, which is rumoured to be exiting research into TB, although the company has refused to confirm or deny speculation about its plans.

Another problem is the gulf between the early, theoretical world carried out by academics and the drug development expertise of pharma, which can only be bridged through ‘translational medicine’ approaches, such as through the GHIT Fund.

Building long-term healthcare infrastructure

Returning to the subject of the handling of Ebola, Peter Piot doesn’t mince his worlds, and says WHO “dropped the ball” in not halting the spread of the disease when it had the chance, but he says the organisation is now fulfilling its duties properly.

However, many others point to long-term weaknesses in WHO, including major cuts to its funding and the quality of its management – meaning it cannot be relied upon to drive the agenda forward on its own. That means that well-funded, well-run public-private partnerships are essential.

Of course it is also clear that new drugs and new vaccines cannot improve the health of the developing world alone. Bill Gates was also in London on Wednesday, visiting politicians in the House of Lords. He pointed out that Ebola has thrived because of a lack of health infrastructure and investment.

“We have a chance to go back into these countries and build effective primary healthcare systems so that future outbreaks will be detected sooner and stopped at an early stage.”

This help from developed nations may well be essential: even those African countries which are now moving into the middle-income range – such as Ghana and comparatively well off Nigeria – are not investing sufficiently in their healthcare systems, and certainly not in research.

 

 

Peter Piot – Director of the School and a Professor of Global Health, London School of Hygiene and Tropical Medicine

Risk and reward

The balance between risk and reward is always important in drug development – even when there is no profit at stake.

Peter Piot has been instrumental in bringing together pharma, WHO and governments to help accelerate development of treatments and vaccines – and then get them to the people who need them most. In the 1980s he played a key role in setting up research collaborations which unlocked the secrets of the HIV virus. Then from 1994 to 2008 he was head of the Joint United Nations Programme on HIV/AIDS (UNAIDS) and Assistant-Secretary-General of the UN, where he brokered a deal with pharma to distribute antiretrovirals to millions of patients in the developing world at low cost.

Now he is once again using his expertise to align the needs of pharma, governments and patients. One significant barrier in developing fast-tracked Ebola drugs and vaccines is the issue of indemnity – who would be legally liable, and potentially sued, if people suffered severe side effects or died because of these relatively untested treatments? Piot has just brokered a solution to set up a donor fund at the World Bank to cover any potential indemnity issues, clearing the way for R&D to continue.

He says this is typical of the kind of barriers to faster drug development.

“We can take away some obstacles as well as creating incentives, that is equally important,” he states.

“My take-home message from the Ebola crisis is that we can now use really accelerated ways of developing drugs – the possibility is there without taking any ethical or scientific shortcuts.

“But it will require a major behavioural change on many, many levels. It is not necessarily the money that is the issue.”

 

About the author:

Andrew McConaghie is pharmaphorum’s managing editor, feature media.

Contact Andrew at andrew@pharmaphorum.com and follow him on Twitter @pharma_phorum

 

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