Big pharma balks at investment in TB; Genetics offers route to cure TB

March 24, 2014 12:01 am

Big pharma balks at investment in TB

By Andrew Ward

For an industry so often on the back foot over ethical issues, the approval last year of the first tuberculosis drug in 40 years was a chance to trumpet Big Pharma’s positive role in tackling global health problems.

However, while Johnson & Johnson’s launch of its bedaquiline treatment has been widely celebrated as a breakthrough, it remains an exception to the generally gloomy outlook for private sector investment in TB research and development.

More typical was the decision by AstraZeneca in January to shut a laboratory in India where it was conducting early-stage research into TB as well as malaria and neglected tropical diseases.

The UK-based company said it would continue working on an experimental TB drug undergoing Phase II trials in South Africa and pledged to share information. But its decision underscored the difficulty of persuading drugmakers to invest in the field.

Mene Pangalos, head of innovative medicines and early development at AstraZeneca, says the company thinks it can make a bigger impact in other areas.

“We have limited R&D budgets,” he says. “You can spread yourself so thin you end up not doing anything well.”

Critics point out that AstraZeneca’s priorities – cancer and cardiovascular, respiratory and autoimmune diseases – are all most common in the developed world, and cite the closure of its Indian R&D centre as proof that a new model is needed for developing drugs where there is no commercial market.

“Drug companies want to make drugs for chronic diseases that people in western countries are going to take for the rest of their lives,” says Neil Schluger, chief scientific officer of the World Lung Foundation.

“Companies will need incentivising by governments and non-governmental organisations if they are going to invest,” he adds.

TB is particularly unattractive as a commercial proposition because, unlike HIV, which affects significant numbers in rich countries, it is heavily concentrated among the indigent in poorer countries.

So why did J&J press ahead when others have retreated? In part, it stemmed from the commitment of Paul Janssen, founder of Janssen Pharmaceutica, now part of J&J, whose sister died of TB. But it required the backing of the US parent group to keep going. There were some economic incentives, including a scheme offered by US regulators under which J&J can put another, potentially more lucrative new drug through an accelerated review process as a reward for developing a TB treatment.

Wim Parys, head of R&D for global public health at J&J, says the group is not expecting to make money from bedaquiline.

“We have been extremely fortunate that we have people right to the top level of the company who have supported this product, not for any commercial reason but because it was the right thing to do,” he says.

“We just had to convince them that it was a significant drug that would change health outcomes.”

Bedaquiline, known by its brand name Sirturo, was approved by the US Food and Drug Administration last year as a treatment for multi-drug resistant tuberculosis (MDR-TB) after trials showed it cured 57.6 per cent of patients after 120 weeks, compared with a 31.8 per cent success rate for existing treatments.

Mr Parys says the discovery stemmed from Janssen scientists including TB in tests to screen new compounds for potential impact on a range of conditions.

“The only way to discover new drugs for TB is if it is part of that initial screening process,” he says.

In addition to J&J, Japan-based Otsuka also won provisional European approval in November for its delamanid treatment for MDR-TB, ending a drought in innovation. Yet, few are following these companies’ example.

 

March 24, 2014 12:01 am

Genetics offers route to cure TB

By Clive Cookson

Around the world, laboratories are working to make up for time lost during the late 20th century, when tuberculosis was ignored or seen as a health problem that had gone away.

Although some of the fruits of this research are already in trials – with 10 drugs in late clinical development and a dozen vaccines in the pipeline – much is still at the earlier stages of scientific investigation.

This month, for example, École Polytechnique Fédérale de Lausanne in Switzerland has set up a charitable foundation to develop what its scientists say is an extremely powerful antibiotic discovered through a European research programme. PBTZ169, as it is known, attacks the TB bacterium Mycobacterium tuberculosis through its strong point, the cell wall that shields it from antibiotics and the patient’s immune system.

“Our molecule makes the bacterium burst open,” says Stewart Cole, director of the Swiss study.

Animal tests show PBTZ169 is very effective when combined with two existing TB drugs, pyrazinamide and bedaquiline. “This could be the winning strategy,” says Dr Cole. “These molecules attack different targets in the bacterium. By combining them, we drastically reduce the risk it will mutate into more resistant forms.”

Early versions of PBTZ169 were not absorbed fast enough into the body, so the team enlisted new technologies such as structural biology to redesign the molecule. “Tuberculosis is often wrongly considered a disease of the past, but to fight it, we need 21st-century technologies,” Dr Cole adds.

The rising power and collapsing cost of genome sequencing are likely to provide important leads to improved TB diagnostics and drugs.

In September, the journal Nature Genetics published papers by four independent research teams on the full DNA sequences of 600 strains of M. tuberculosis from around the world. By comparing the genomes, scientists gain insights into the emergence of drug resistance and possible targets for drug development.

For example, China’s BGI (formerly Beijing Genomics Institute) discovered 121 genes and mutations strongly associated with drug resistance, which indicated a more complex genetic basis for resistance than previously suspected. “We expect our breakthrough can shed new insights for exploring the mechanisms of drug resistance and lay a solid foundation for protection against TB,” says Dongfang Li, BGI project manager.

Another recent study, published in Lancet Respiratory Medicine, demonstrated the diagnostic potential of DNA sequencing in cases where TB recurs after treatment. Until now, it has been hard for doctors to establish whether a patient has suffered a relapse of the original infection or picked up a new infection with a different strain. Genome sequencing gives the answer, which is important for managing the disease.

“What surprised us in this study is the frequency with which patients were infected with two separate strains of M. tuberculosis,” says co-author Stephen Gillespie, professor of medicine at St Andrews University. “As well as being important for TB clinical trials, this has implications for the evolution of multiple drug- resistant tuberculosis.”

Genomics has also shed light on the evolution of TB. Researchers at the Swiss Tropical and Public Health Institute in Basel sequenced the full DNA complement of 259 M. tuberculosis strains from around the world and found the bacteria must have moved out of Africa with the first modern humans more than 70,000 years ago and spread round the globe with them.

“The evolutionary paths of humans and TB bacteria show striking similarities,” says Sebastien Gagneux, the study leader. A study of skeletons from a 7,000-year-old site in Hungary by scientists at the University of Szeged found traces of TB proteins and genes in the bones. In parallel with all the genomic analysis, an international project is mapping the molecular circuitry of M. tuberculosis – the regulatory networks that adapt to changing conditions in the human body.

“We have generated the first large-scale experimental map of thousands of molecular interactions in the bacterium that enable it to cause disease,” says James Galagan of Boston University, lead author of the project’s report. The study showed, for instance, how TB bacteria cope with a low oxygen environment inside host cells and how they consume human cholesterol.

“Based on this map, we have developed the first computer models that will enable us to study more easily this challenging infectious organism and develop drugs, therapeutics and diagnostics,” Dr Galagan adds.

Molecular and genomic research of this sort will take decades to translate into widely available TB treatments, but it should ensure the pipeline of drugs does not run dry again.