Breakthroughs Blog: Tuberculosis

Heather Ignatius is the senior policy manager for the TB Alliance, a not-for-profit, product development partnership dedicated to discovering, developing, and ensuring access to better, faster-acting, and affordable drugs to fight tuberculosis (TB) and drug-resistant TB. She is also a member of the GHTC’s Steering Committee. The most recent WHO TB Control report noted that rates of TB declined this past year for the first time in decades. However, even with such progress, TB remains one of the most devastating global health crises today, with ripple effects that extend beyond health to cripple prosperity and development of regions overwhelmed by the disease. New and improved tools to prevent, diagnose, and treat TB in its many forms—including MDR-TB and XDR-TB—are vital to eradicate the disease, but a reinvention of such an arsenal can’t be achieved by any single organization. To this end, last week marked another notable achievement for TB: the launch of a collaboration between four pharmaceutical companies, along with the TB Alliance and the World Health Organization (WHO), which enables information-sharing on TB drug candidates within their respective pipelines. The partnership aims to bring these groups together to quickly and collaboratively identify and develop the most promising new TB drug regimens, regardless of sponsor. Representatives from (left to right) TB Alliance, Tibotec, Sanofi, Bayer, Sequella, and AstraZeneca gather at the CPTR Workshop to discuss new approaches to TB drug R&D. The collaboration was brokered under the Critical Path to TB Drug Regimens (CPTR), a cross-sector initiative designed to speed the introduction of shorter, safer, and more effective new TB drug regimens. The partners include AstraZeneca, Bayer, Sanofi, Tibotec, the TB Alliance, and the WHO. Combinations of drugs are required to treat TB to avoid the development of resistance. Since the launch of CPTR in March 2010, regimen development—testing and seeking the approval of combinations of new TB drugs as opposed to developing individual drugs, one at a time—is emerging as the gold standard within the field. Regimen development can telescope the time it takes to develop novel drug combinations, which show promise to shorten, simplify, and create safer and more affordable treatment. In the context of appropriate drug-sensitivity testing, novel regimens can treat both TB and MDR-TB, and truly transform the tools to fight the epidemic. CPTR and this agreement establish mechanisms for cross-sponsor information-sharing and begin to chart the course for cross-company collaborations on new TB drug regimens. Those who signed onto the agreement represent the majority of global sponsors with TB drugs in clinical development. Earlier this year, the combination of PA-824 (a novel chemical entity), moxifloxacin (an existing antibiotic not yet approved for treating TB), and pyrazinamide (an existing TB drug) completed a Phase II clinical trial. Meeting this milestones further confirmed both its potential as a regimen and the co-development approach to TB drug development. With this “proof of concept” trial completed, the door is now open to bring forward additional multi-drug combinations. Progress to develop novel drug regimens also requires advances in regulatory science to enable regulators to support and evaluate clinical trials that use this paradigm. This theme was echoed at the CPTR Workshop where this announcement was made, which featured a keynote address from the Director of the Center for Drug Evaluation and Research at the US Food and Drug Administration (FDA), Dr. Janet Woodcock. “I congratulate all of you coming together to solve what was previously perceived as an intractable problem,” said Dr. Woodcock. “Working together, we can take the steps needed to control this disease worldwide. We at the FDA, we will do everything we can do ensure that the regulatory process is not a barrier to getting this problem solved.” It is uplifting to see such a collaborative approach being to TB drug development adopted by its stakeholders, including the pharmaceutical industry. While harnessing the resources necessary to conduct future regimen trials remains a challenge, there is justifiable optimism surrounding the scope and pace of TB drug development, and in turn, the impact that the introduction of new and improved TB therapies can have on the health and prosperity of millions.

Eleonora Jiménez–Levi is a senior researcher for the Treatment Action Group (TAG), a GHTC member, and wrote this blog post in conjunction with the release of a new report from TAG about funding for tuberculosis (TB) research and development (R&D). TAG has released a new report in collaboration with the Stop TB Partnership, which finds that in 2010 the world invested just $617 million in TB R&D—less than one-third of the estimated $2 billion annual investment needed to eliminate TB as a public health threat by the year 2050. The report, Tuberculosis Research and Development: 2011 Report on Tuberculosis Research Funding Trends, 2005-2010, tracks annual research spending across six TB R&D areas against funding targets set by the Global Plan to Stop TB 2011-2015. The report offers year-to-year data on the leading TB research funders and underscores the urgency of adequate and sustained funding. Dr. Lucica Ditiu, Executive Secretary of the Stop TB Partnership, emphasized this critical need for sufficient funding by saying “with current levels of funding it will be impossible to meet the research targets of the Global Plan to Stop TB 2011-2015. This is a completely unacceptable situation, because those targets are, I would dare to say, even modest. Where is the funding to push ahead research for a point-of-care diagnostic test accessible to all, new drugs for a shorter treatment time and a fully effective vaccine?” For the sixth consecutive year, R&D for TB treatment was the most well-funded research area—growing by 19% from $192 million to $227 million. However, this was just 31% of the $740 million annual Global Plan target for TB treatment research. The report also documents significant funding declines in basic science and vaccines research, which dropped 27% and 29%, to $126.6 million and $78 million, respectively. TB diagnostics accounted for 7% of global total spending with $44.6 million—a 15% increase from 2009. The infrastructure/unspecified category grew 46% to $83 million and operational research rose 17% to $58.1 million in 2010. Measuring these totals against the Global Plan targets, the only category to come close to its annual target was operational research and the farthest one was TB diagnostics. According to the World Health Organization, there were 8.8 million people newly diagnosed with TB and 1.45 million deaths in 2010, including 1.1 million new cases and .35 million deaths among people with HIV. Resources to develop new tools to prevent, detect, and treat TB have never been more urgent. “Recent progress in TB research is clearly threatened by stagnating funding,” said TAG’s executive director, Mark Harrington. “After several years of increasing investment, TB research is finally making headway with two new promising drugs for the treatment of multi-drug resistant TB and a new drug combination active against both drug sensitive and drug resistant TB. Cutting investments now will cost lives in the future.”

John Donnelly, a writer working with the GHTC, is blogging following our trip to visit global health research projects in Kenya. This is his third post from the field. KISUMU, Kenya – The shortcomings in the tools to fight tuberculosis (TB) are stunning. There is no effective TB vaccine beyond childhood. The most common TB diagnostic tool was developed in the 1880s and fails to detect the bacterium in half of the cases. And the drugs needed to treat TB are also ancient – the most recent ones were developed more than 40 years ago. As a result, resistance to TB drugs has run wild in parts of the world. There are an estimated 440,000 cases of multi-drug resistant TB globally, and at least 58 countries have reported cases of extensively drug resistant TB, which can be incurable. “TB is an example of what happens if you fail to invest in research,” said Kevin Cain, TB Branch Chief at the KEMRI/CDC Research and Public Health Collaboration in Kisumu. The Kenya Medical Research Institute (KEMRI) and the US Centers for Disease Control and Prevention (CDC) have been partnering together in the country for more than 30 years. “It means you end up with a diagnostic tool that is over a century old, you are using drugs from the 1960s and older. And you end up with the situation we are in: many cases of extensively drug-resistant TB, which can be untreatable.” But in western Kenya, and in several other research sites around the world, clinical trials are ongoing for a new vaccine, drugs, and diagnostics. On GHTC’s trip to Kenya, we were able to see participants of a Phase II trial of a TB candidate sponsored by Aeras, a GHTC member and non-profit product development partnership (PDP) dedicated to the development of an effective and affordable TB vaccine for all age groups. Currently, the Bacille Calmette-Guérin (BCG) vaccine, which is over 80 years old, is only partially effective; it provides some protection against severe forms of pediatric TB, but is unreliable against adult pulmonary TB. The trial in western Kenya involves giving two doses to children: one on the initial visit and a second 28 days later. Dr. Samuel Ouma, a physician working on the TB trial, said that 144 children have enrolled at his clinic in Boro. The trial offers free health care to the babies enrolled in the study. We met with one of the mothers of the children in the study. Sharon Akinyi Olunga, 27, said she asked many questions before enrolling her baby, Winfrey Atieno Juma, now 13 months old. She said she was very happy she had enrolled her daughter. “It’s good for our babies,” she said. “I loved that my child should go into this research project first because if anything happened to her, whether she was sick with a cold or pneumonia, she would immediately receive free medical care. Here, funding for medical care is really difficult to get. So it put me at ease.” Olunga said there was another reason she wanted her daughter to be part of the trial: it served a greater good for children around the world. “I think of so many babies, so many children in Africa and around the world, have been helped by vaccines,” she said. “If this vaccine works, that means all those children will be helped by my baby’s participation. That makes me feel very good.” Watching Olunga was her grandmother, Hilda Auma Juma, who was in her 70s. Juma also said she was glad to see medical research in her village and in neighboring villages. “I am happy because it helps the health of all babies,” said Juma, who had nine children. She said health care has dramatically improved for mothers and children compared to the situation a half-century ago. “In my time, when I gave birth, mothers only had the faith of God to take care of the babies,” Juma said. “Now mothers have all these vaccines. Babies and children are living. We hope we may soon have more vaccines. It’s wonderful.”