Letters from the lab: TB

My name is Bala and I am the director of bioscience at AstraZeneca’s dedicated TB research facility in Bangalore.

For more than 25 years I have researched TB, particularly cause of the disease, target biology, the biochemical and physiological effects of drugs on the body, as well as the body’s effects on a potential drug. I have always loved science, but I am equally driven by the fact that TB claims more than 4,000 lives every day, with over a third of them in India, where I live.

When I started my career as a PhD candidate, TB was believed to be a problem of the past, with very little research interest. The limited attention that it received in a few academic laboratories focused on debates on the cause of the disease and less on the methods by which TB can be eradicated in society. Today, we are in the midst of a global TB epidemic as declared by the World Health Organisation in the mid-90s. In recent times, not only has public interest re-awakened to this old disease, but also the research interest. The science of discovering new drugs, vaccines and diagnostics has made enormous strides in the last decade, which makes it tremendously exciting to work in this area, while simultaneously giving the satisfaction of working towards such a socially relevant cause.

AstraZeneca is focused on finding new therapies that will act on drug-resistant strains, shorten the duration of treatment, and eradicate the disease to reduce the chances of relapse or drug resistance and be compatible with HIV/AIDS therapies, because TB is the leading killer of people with HIV infection. Due to the resilient nature of the bacterium, TB treatment requires multi-drug regimens. Traditional regimen development meant that each new drug had to be tested and approved separately and then substituted or added—one at a time—into existing drug combinations. Each drug trial can last six years or longer, which means that a novel TB regimen could take decades to develop.

For the millions of people who are impacted by TB, this simply isn’t acceptable.

That’s why AstraZeneca is part of—among other collaborative efforts-- The Critical Path to TB Drug Regimens, alongside Bayer, Sanofi, Tibotec, TB Alliance, and the World Health Organization. We share information on TB compounds within our respective drug pipelines, to speed the development of shorter, safer, and more effective multi-drug treatments that are urgently needed to control the global TB pandemic. With the help of The Critical Path to TB Drug Regimens, we are working to expedite testing of promising drug regimens and identify the new regulatory pathways and other tools needed to speed the delivery of dramatically improved treatment to TB patients worldwide.

Our understanding of TB and what it will take to eradicate it has grown exponentially over the past decade and I am confident that the future is bright.

My name is Sunita and I work closely with a team of scientists in Bangalore and Boston who are researching potential new medicines to treat TB. Most of my day, however, is spent interacting with scientists who work at non-profit, academic and private institutions across the globe as part of the many collaborations that AstraZeneca has in the fight against TB. Many of them have joined hands with us in our fight against TB, e.g. The Global TB Alliance, New Medicines for Tuberculosis consortium and the Wellcome Trust.

It is my belief that new treatments for TB are unlikely to come out of just one company’s lab. First, TB will probably always need to be treated with more than one drug. Also, making antibiotics is a difficult business and we need multiple efforts to be successful. Second, the necessary treatment path is complex. Existing TB treatment regimens are long (6 to 30 months) and often require six or seven different drugs. Unfortunately, these drugs are essentially worthless in many patients with extensively resistant TB. The last truly novel TB drugs were developed in the 1970s, so it is imperative that companies like mine work with other organizations to find a solution—urgently.

AstraZeneca has thousands of potential compounds in our infection laboratories. Imagine that this is a bit like books in a library. Like a librarian, I work with my colleagues to identify which compounds might be a good match for the external scientists and organizations with whom we partner. Besides doing research in house, we will work to make these compounds available to external partners who have niche area expertise and are on the front lines in the fight against TB—for example the Bill and Melinda Gates Foundations’ TB Drug accelerator program.

It is not lost on me that TB exists in virtually every country in the world. While the poorest countries are most affected, the emerging economies of China and India have the highest prevalence rates in the world. In my circle of friends I know of at least eight people who have had TB at some stage of their lives. It is rewarding to be working on a disease that will bring benefit to friends and to patients in my country.

Having spent 20 years working in infection research, I am excited about the progress we are making. I see a lot more research into new drugs for TB both from academic laboratories and from the pharmaceutical industry. It is also heartening that people are coming together to collectively solve the problem. There are compounds in clinical trials that will pave the way for the development of future drugs. The future for TB treatment is exciting and I am glad to be a part of it.
 

My name is Meena and I conduct TB research in a bio-safety level 3 (BSL3) lab at AstraZeneca’s R&D site in Bangalore, India.

There are four bio-safety levels, 1 being the least stringent and 4 the most stringent, and these levels refer to the way infectious pathogens that are dangerous to humans are handled.

At our site in Bangalore, we have both BSL2 and BSL3 facilities. At level 3, a high level of containment is needed to work on very dangerous pathogens such as Mycobacterium tuberculosis (the cause of TB). The labs and protective equipments are quite complex, because they are supposed to protect you and your coworkers against airborne pathogens.

It is a lot of responsibility on the individual but when one thinks of the importance and commitment to the task at hand (which is, finding a new drug for TB), it feels really great. My colleagues and I have to learn and train to be comfortable in our gear when we work in these labs. The work day begins by entering an anteroom of an access-controlled laboratory and getting into the gear which looks like a spacesuit facemask, special shoes, head gear to cover the hair and two pairs of gloves.

We are testing our chemicals on live TB bacteria in test-tubes to see which ones kill these bacteria faster and better. The BSL3 lab is under lower air pressure compared to the rest of the laboratory area (negative air pressure), because nothing should come out of these labs to the outside area. There are a series of different experiments we do to check out the capability of our compounds or the chemicals (which we are hoping to convert to drugs) to kill the TB-causing bacteria and it is quite exciting for me to set up these experiments in a precise fashion. The time when we get good results from these experiments is the thrilling moment. Well, there are a lot more steps to go after this to make a ‘real drug’, but this is a great start for finding a new drug to treat TB.

I have the privilege and training to do this job at AZ with special access to these labs to work with the TB bacterium. It is important because this is where the early experiments happen—the ones that will hopefully lead us towards discovering a new drug for a major disease. Yes, it is indeed tricky- one has to conduct themselves in a careful fashion while working inside BSL3- but there’s plenty of training, state-of-the-art protective equipment and a safe facility which is re-validated every year.

My name is Scott, and I am the Project Leader for AZD5847, a tuberculosis compound that has successfully cleared phase 1 clinical trials.

From AstraZeneca’s infection labs in Boston, I lead a multidisciplinary team of scientists and clinicians to progress AZD5847 through clinical trials using a development plan that synergizes with the TB community as a whole. The goal of that community is to deliver novel combinations of new drugs at unprecedented speed – a goal that requires all parties to work cooperatively at some level. A large component of leading this project is working closely with external partners such as the National Institute of Allergy and Infectious Disease (NIAID) who will run the phase 2a study on this compound in South Africa. This study is designed to demonstrate efficacy against TB in patients with active disease.

AZD5847 is in a class of molecules called oxazolidinones. This class is very promising in that they appear to be able to kill mycobacteria in multiple forms, including actively dividing and those in a dormant state. The prototype of this series, Linezolid, has been shown in clinical trials to be highly effective in patients with Extensively Drug Resistant (XDR) TB, a form of the disease for which few or no other therapeutic options exist. Our hope is that newer generation oxazolidinones, like AZD5847, will be every bit as effective against XDR TB, but will be better tolerated by patients.

A few minutes on the TB Alliance website tells it all. TB Kills: 1.4 Million People Every Year, Over 3,800 Every Day, One Person Every 25 Seconds. Another 12 million suffer from active infection at any given time. Having an opportunity like this - to make a real contribution toward beating a pandemic disease – is what drew me to work in drug discovery in the first place. I’m sure I speak for the entire project team in saying that’s what we all dream of doing, even if just once in our career. The medical need in this disease area couldn’t be any clearer and I am proud to be a part on AstraZeneca’s effort to improve the outlook for TB worldwide.