Building a pipeline for the drugs of the future

28 Mar 2008

Tatum Anderson

Source: TropIKA

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The Drugs for Neglected Diseases Initiative (DNDI), a public drug development partnership, announced in March a crucial tie-up with UK pharmaceutical company GlaxoSmithKline that will see molecules already under investigation as potential treatments for malaria, tested against parasites that cause visceral leishmaniasis (kala azar), human African trypanosomiasis (sleeping sickness), and Chagas' disease. All three belong to the so-called neglected category of diseases.

DNDI has already searched for new uses for existing molecules to uncover fexinidazole, an abandoned drug owned by Sanofi-Aventis that could enter human trials for sleeping sickness at the end of the year.

Executive Director Dr Bernard Pecoul says this technique so- called therapeutic switching - is fundamental to DNDI's strategy to build a robust pipeline that will deliver drugs way after 2014, the date by which the organisation has pledged to develop at least six new treatments – including two for malaria. 'We want to confirm the hypothesis that [with therapeutic switching] we can select interesting candidates for the diseases we want to tackle and repeat the example with fexinidazole in some other field, ' he says.

DNDI says it is on target to deliver treatments by the 2014 deadline – a million doses of its first malaria fixed-dose combination drug have sold since launch a year ago, and the second is expected imminently. Drugs for leishmaniasis and sleeping sickness are well on the way and represent a huge improvement over existing treatments, says Pecoul.

That is especially true of one sleeping sickness treatment. The combination of eflornithine and nifurtimox might go some way to replace a toxic arsenic-based drug called melarsoprol, which kills one out of every 20 patients. As a doctor, Pecoul spent 20 years of his career working for Médecins Sans Frontières (MSF) and witnessed at first hand the effects of melarsoprol.

'I spent quite a lot of time in the field confronted by these difficulties. We are in the process of translating the programme that we set up at the beginning of the DNDI. This part is very exciting,' he says.

But the focus is very much beyond 2014. The fact is none of these promising drugs are ideal; cheap, oral, stable in tropical climates and available in short courses, so that hospitalisation is unnecessary.

'We know that before 2014 we won't be able to develop the best treatment that is totally adapted to the situation,' says Pecoul. 'That is why in parallel we will have to go back to the discovery stage and build a pipeline'.

DNDI is building its pipeline by acting as a kind of pharmaceutical matchmaker.

It has united research institutions to share expertise in screening molecules for activity against the diseases and brought together regulators, pharma and clinical technicians to share learning on carrying out large-scale clinical trials in remote, poor areas.

The product of five public sector institutions, DNDI holds well over a hundred contracts with industry, academics and even retired scientists.

Essentially the organization negotiates the transfer of knowledge by developing new intellectual property models; it convinced Sanofi-Aventis to turn a recipe for an anti-malarial tablet into a manufactured drug in return for a year's exclusivity in sales; now it is negotiating with others to access their drug libraries or pass on knowledge to generic companies to massively increase the medicines being manufactured.

Building the pipeline has been hugely challenging, admits Pecoul. It has taken several years to establish a pipeline for Chagas's disease. The delay has been caused in part by the disease's complexity. Research over the last three years has concentrated on trying to better understand it. But crucially, viable compounds are hard to find. 'We organised a call for projects but received very few. We have been obliged to go very proactively and try to find [Chagas] projects,' says Pecoul. The Chagas pipeline should be place by the end of the year.

It has also been forced to fill gaps in its pipeline. When it emerged that there was no sufficient skills in lead optimisation within its network- to synthetically modify biologically active compounds - it found two firms in the US and India to do the job and pledged to invest $50 million over the next five years.

Ultimately, however, DNDI is preparing for its own extinction. By building intellectual property models and clinical trial and research networks, it is creating a kind of blueprint for future drug development projects. Public research facilities in disease-endemic countries could then easily strike deals with pharmaceutical companies to develop their own drugs. Should that happen, DNDI would no longer be necessary.

'We strongly believe DNDI is a model that should be transferred and made more sustainable,' says Pecoul. 'In the long term we consider these solutions should come from the countries affected by the disease.'

In meantime, DNDI's own sustainability is uncertain because a five-year financial commitment by MSF ends this year. DNDI's most pressing mission for 2008, therefore, is to plug the gap.

Key Questions

Briefly, what are the priority concerns of your organisation?

To develop 6-8 new treatments for neglected diseases by the year 2014 and in parallel a robust portfolio for the development for further drugs after this time.
And, more precisely, what goals have you set?

The objective is to develop a model to respond to leads in research and development into neglected diseases that involves, as much as possible, the capability and resources in disease-endemic countries.
What is it about your organisation's approach to these issues that distinguishes you from others in this field?

That we have founding partners from public research institutions from Brazil to Kenya, is a political statement. They are the owners of DNDI and that is the difference. On a day-to-day basis, we are reporting to them.
What progress has been made so far?

Artesunate-amodiaquine fixed-dose combination (ASAQ) is available, Artesunate-Mefloquine will be manufactured imminently, combination therapies for sleeping sickness and VL (for Africa) are to be made available in the next few years. The Chagas pipeline will be in place by the end of the year.
What are the main challenges outstanding

Financial sustainability is key for us. We need to attract a set of partners that will commit money to DNDI on a relatively sustainable basis.
Which other organisations will you be working with most closely?

DNDI's Founding Partners are: