Accelerating the search for new TB drugs - he who shares wins

In 2010, TB killed nearly 1. 4 million people worldwide. But despite the disease's prevalence and the ineffective nature of the current treatment regime for TB, only one new drug candidate has been submitted for approval in the US in the last 40 years. Elly Earls meets Dr Carl Nathan, part of the TB Drug Accelerator project, to find out how seven pharmaceutical companies and four research institutions have joined forces to make sure the next 40 years are significantly more productive – and not just for TB.

At any given moment, more than 12 million people are suffering from active TB, which is the second leading infectious cause of death worldwide. Indeed, in 2010 alone, the worldwide pandemic, which is second only to HIV as an infectious killer of adults worldwide, infected 8.8 million people and killed 1.4 million.

But why does TB, which, unlike HIV, is a curable, preventable disease, still have such a huge impact on global health? In two words: antibiotic resistance.

"In 2010 alone, the worldwide pandemic, which is second only to HIV as an infectious killer of adults worldwide, infected 8.8 million people and killed 1.4 million."

The current treatment regimen for TB, known as Directly Observed Therapy - Short Course (DOTS), is a six month process, which involves patients taking a cocktail of powerful antibiotics, and 20 to 30% of patients drop out of therapy before completion. Not only does this low compliance rate lead to increased mortality, it also results in high levels of TB drug resistance, as well as allowing patients to continue to infect others.

In fact, a large international study published in the Lancet medical journal in August 2012 revealed that rates of both multidrug-resistance TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) are even higher than experts previously thought, and are threatening global efforts to curb the spread of the disease. Even more worryingly, things are only set to get worse.

Indeed, Tracy Dalton from the United States Centers for Disease Control and Prevention, who led the Lancet study, said that so far XDR-TB has been reported in 77 countries and as more individuals are diagnosed with and treated for drug-resistant TB, more resistance to second-line drugs is expected to emerge. Moreover, the World Health Organization (WHO) predicts that more than two million people will contract MDR-TB by 2015.

Because of this, there is clearly a pressing need for new therapies, which is not being met by the pharmaceutical industry: although Johnson & Johnson has recently submitted one near-term candidate for MDR-TB for approval in the US, this is the first new agent to be submitted for approval in 40 years.

Evidently, something more radical needs to be done. Enter the TB Drug Accelerator (TBDA).

What is the TBDA?

A consortium of seven pharmaceutical companies and four research institutions, the TBDA project, which is backed by $20m in funding from the Bill & Melinda Gates Foundation, aims to develop a regimen for TB that can cure patients in only one month, compared to the current six. Near-term objectives are to develop five new pre-clinical drug candidates with treatment-shortening potential within five years and proof-of-concept for a one-month, three-drug regimen within ten years.

"The World Health Organization (WHO) predicts that more than two million people will contract MDR-TB by 2015."

"Shortening the therapy time is key to avoiding losing new drugs, the way we've lost the old ones to drug resistance," said Dr Carl Nathan, a professor at Weill Cornell Medical College, one of the four research institutions involved in the TBDA project. "In any event, we need to have a completely new set of drugs because resistance is already so common to all the drugs we have. But on top of that, if the treatment is shorter, the problem of people stopping their treatment prematurely should be minimised."

To speed the discovery of drugs able to treat TB in a significantly shorter timeframe than those currently available, the seven Big Pharma giants that have signed up for the TBDA (namely Abbott Laboratories, AstraZeneca, Bayer, Eli Lilly, GlaxoSmithKline, Merck and Sanofi) are collaborating on early-stage research and have all provided access to certain parts of their in-house compound libraries.

They are also being helped by scientists at the US Infectious Disease Research Institute, the National Institute of Allergy and Infectious Disease, Texas A&M University and Weill Cornell Medical College.

Beyond TB treatment

But for Nathan, the impact of this project could go significantly beyond finding new drugs to treat TB; in fact, it could be the beginning of a new paradigm for the pharmaceutical industry.

Not only are some of the biggest companies in the pharmaceutical industry collaborating with academia; they're also working with each other. "It's three axes at once, all of which are relatively uncommon," he emphasised.

"Near-term objectives are to develop five new pre-clinical drug candidates with treatment-shortening potential within five years."

"And the model is potentially one that could be translated, with some modifications, to other diseases such as cancer, cardiovascular disease, neurodegenerative disease and metabolic disease," Nathan added. "I think the pharmaceutical industry is looking at this as one of several experiments of ways to access innovations earlier, cut redundancies, share things in the pre-competitive space and experiment with different formats."

Indeed, even within the TBDA, there are many different kinds of collaboration taking place. "For example, GSK has opened its campus to incoming scientists from academia," Nathan said. "I've had a post doc working for a year inside GSK and there's full integration into the life of GSK. The post docs are screening the whole corporate compound collection and the hits are shared with us here in New York. It's very, very unusual."

It may be unusual, but there's no doubt that it makes sense: while academia understands the basic science, Big Pharma can translate this into medicines that work.

"We bring a sense of the biology, we bring facilities that are quite unusual in industry for Biosafety Level 3 work with TB, and we bring experience with the genetics, the biochemistry and the animal biology," Nathan elaborated. "In industry, they bring higher quality compound collections, a portfolio of information about the compounds, and a whole suite of resources that are potentially available to academia but are just exceedingly expensive (such as tests on very large numbers of clinical isolates or large collections of drug-resistant strains.)"

However, there is one danger. If every company, research institution and TB initiative (many of which share personnel with the TBDA) share their information at this early stage, how does the industry ensure the diversity necessary to create effective new treatments for diseases such as TB?

"You have to avoid a single command centre," Nathan stressed. "Sharing this information early is very valuable and some degree of integration is really important, but it's essential to avoid monopolising. Diversity is essential to solve a problem like this."

Yet, for some of the biggest names in the industry, the TBDA does seem to have got the balance right. "Innovative partnerships are critical to helping us solve the most pressing challenges of global health," said Trevor Mundel, president of the Global Health Program at the Bill & Melinda Gates Foundation. "It's our hope that the TBDA will set a precedent for drug discovery and serve as a resource for others."

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