Wanted: Better, safer, cheaper TB drugs

The 42nd Union World Conference on Lung Health, focusing on tuberculosis (TB), HIV, tobacco control and non-communicable diseases, is currently being held at Lille from 26-30 October. Lille is the place where Professors Albert Calmette and Camille Guerin developed the current TB Vaccine BCG 90 years ago at the Institut Pasteur de Lille. Researchers and other experts from more than 100 countries are attending this 5-day conference, which has the theme of "Partnerships for Scaling-Up and Care". The conference is organised each year by the 91 years old organization International Union Against Tuberculosis and Lung Disease (The Union), which is headquartered in Paris with 13 additional offices worldwide and members from 150 countries.

Today there is more TB in the world than ever before, with 9 million new cases and 2 million deaths every year. This is having disastrous economic and social impacts, particularly in high burden countries like India. Fuelling this epidemic is the current TB treatment regimen which is almost 50 years old and is now increasing becoming inadequate. Patients have to take a complex regimen of drugs for 6 months to nearly 2 years. Many patients default on their treatment, contributing to a growing epidemic and increasing resistance to existing drugs. The cost, duration and side effects result in less than 10% of multidrug resistant TB (MDR-TB) patients receiving proper treatment. Even amongst them, nearly 50% will die. To compound the problem, the current first line TB treatment is not compatible with the commonly used antiretroviral (ARV) treatment for people living with HIV, leaving many of them without treatment options. One third of the 42 million people living with HIV globally are also infected with TB, which holds the dubious distinction of being the number one infectious killer of people living with HIV worldwide.

The world needs new better, shorter and cheaper TB treatment regimens to stem this tide of TB. The big question is how to develop a novel regimen efficiently on all susceptible populations, as opposed to the current status which requires separate development programs for drug sensitive and MDR-TB. We need unified drug-sensitive and MDR-TB development paths. Patients should be treated based on what they are sensitive to and not on what they are resistant to. However, developing new drugs is extremely challenging. One reason could be that, as TB primarily impacts the very poor, there is very little profit incentive to develop new therapies. Keeping this in mind, the Critical Path to TB Drug Regimen (CPTR) was launched in March 2010 by the Bill and Melinda Gates Foundation, the Critical Path Institute and the TB Alliance to tackle challenges facing TB drug development and reduce the time needed to develop better TB drugs. It is a cross sector initiative that aims to speed up the introduction of shorter, safer, and more effective new TB drug regimens, and not merely drugs.

The Global Alliance for TB Drug Development (TB Alliance) currently manages more than 20 projects in its pipeline, including three drug candidates, and a novel multi-drug regimen in late-stage clinical trials. A faster-acting, better TB drug regimen will improve patient compliance, increase cure rates, lower toxic side effects, and could save millions of lives. As new treatments are developed, the TB Alliance hopes to reduce the time to cure TB from the current treatment duration of two years to six months, to their ultimate goal of a TB treatment that can be administered in less than two weeks-- similar to those for many other bacterial infections. Laudable dreams indeed! And touch wood!

As of now TB Alliance has the largest pipeline of TB drugs in the world. The last 10 years were devoted to laying the foundation of finding these new drugs; and the next ten years are likely to be more exciting when research is likely to be transformed into the reality of developing more cost effective and user friendly TB drugs.

Dr Zhenkun Ma, Chief Scientific Officer at TB Alliance, emphasized the dire need for new TB treatment regimens. According to him, "The current TB treatment is a long and cumbersome 6 months therapy of 4 drug combinations, with a 4 to 6 months follow up with 2 drug combinations. It is a complicated treatment and so patient compliance is low. Another major problem is MDR-TB for which the current treatment duration is 18 months. Moreover the existing MDR-TB drugs, including injectibles, are not very effective, highly toxic and very expensive. In case of HIV/TB co infection the problem gets compounded due to severe drug-drug reactions. So treatment is again compromised. Recently we have made an exciting advancement and identified a new generation compound which is likely to address all the existing problems in TB treatment. This preclinical novel drug combination study, initiated 4 years ago, has identified multiple novel drug regimens that could reduce treatment time to 2 months or less. It is in the preclinical stage and may take around 7 years before it hits the market, provided all goes well along the line. It is a potent drug and would require less dosage as well as less cost. Preclinical trials are likely to end within one year, and then it would move to the clinical trial stage. I would request the global community to support the efforts which go into the making of new drug regimens."

Most recently TB Alliance has conceived NC001 (New Combination 1) which is a totally different way to do clinical trials. This is a phase 2 study that, for the first time, tested multiple new drugs together in combination, early in the development cycle. Before this novel experiment, one could test only one drug in that regimen at a time. This took too long. NC001 uses a new paradigm that tests combinations of three drugs simultaneously, thus reducing the time to develop a new drug regimen by up to 75%. It is a currently a phase2 early bacterial activity trial that evaluates the combination of novel TB drug regimen comprising PA-824 (a totally new drug), antibiotic moxifloxacin (which is not yet approved for TB treatment), and pyrazinamide (one of the drugs currently used in standard first line TB treatment). This three drug regimen PaMZ, shows the potential for a single regimen to treat both DS and MDR TB in 4 months from the existing 2 years. The ability to treat these two forms of TB with one regimen will simplify TB treatment worldwide. In particular, the regimen has the potential to advance treatment for MDR TB as the combination offers a shorter, simpler, safer and cheaper treatment option. Also, PaMZ has the potential to be used by TB-HIV co-infected people, with no anticipated drug interactions with anti retrovirals.

In addition to NC001, TB Alliance is going ahead with its Phase-3 clinical trial named REMox TB to test the ability of two moxifloxacin containing regimens to reduce the time of DS TB from 6 to 4 months. In 2011, additional sites were opened in India, China and Africa, and results from the trials are expected by 2014, after allowing for a one year follow up post treatment to ensure that patients do not relapse. So we may hope to get the first fruits of all the tireless efforts of researchers in another three years time.

The challenge of new drug discoveries for tuberculosis should be taken up seriously. Let us all - governments, affected communities, donors, civil society, public and private sectors - work together in partnership to scale up the efforts to find simpler and lasting cures for the dreadful disease called tuberculosis. (CNS)

Shobha Shukla is the Managing Editor of Citizen News Service (CNS). She is a J2J Fellow of National Press Foundation (NPF) USA. She is currently writing from the 42nd Union World Conference on Lung Health, Lille, France. She has worked earlier with State Planning Institute, UP and taught physics at India's prestigious Loreto Convent.

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