CDI Scientists Integral Part of Decade-Long TB ‘Drug Accelerator’ Effort

Tuberculosis may not grab headlines in the developed world, but in the developing world it continues to kill an estimated 1.4 million people each and every year.

The scourge has proven exceptionally stubborn to treatments which have successfully pushed back what used to be a rampant killer in Europe and North America.

But a core group of experts including scientists and pharmaceutical leaders have come together to try to “move the needle” when it comes to this dreaded disease over the last decade. Known as the TB Drug Accelerator, it was started in 2012, and is supported by the philanthropy of the Bill and Melinda Gates Foundation.

The Hackensack Meridian Center for Discovery and Innovation (CDI) is part of this ongoing effort. In particular, the work of Véronique Dartois, Ph.D., a member of the CDI, plays a key role in the TBDA’s strategy: discovering how prospective drugs reach the location of infection in the body, and help wipe out the disease.

Dartois is one of the authors of a new paper in Nature Medicine entitled “The Tuberculosis Drug Accelerator at Year 10: what have we learned?” The paper is a retrospective about drug combinations, therapeutic strategies, and the interagency cooperation between the worldwide partners.

“This is how to get it done – how to solve this global problem,” said Dartois.

The TBDA brings together academic groups such as the Weill Medical College at Cornell University, and the University of Colorado, among others – and pairs them with the National Institutes of Health, the TB Alliance and about a half-dozen pharmaceutical companies to accelerate the progress of the work. The TBDA was developed to limit the barriers which could otherwise slow progress through competition or other inhibiting factors. The companies and the scientists all agreed to work cooperatively on tackling TB, from the outset of the group’s founding.

Dartois and colleagues report in the paper that there has been progress – but there is still work left to be done to truly turn the tide on this disease.

The goal is to develop a universal one-month regimen of drugs to cure TB patients by the year 2024. Currently there is a six-month regimen in place, which has been the standard since the 1980s.

The TBDA’s precursor is found in the Gates Foundation’s Grand Challenges in Global Health. Dartois, who was previously at the Novartis Institute of Tropical Diseases in Singapore, and fellow CDI colleague Thomas Dick, Ph.D., had experience in working on those Gates initiatives, which included scientific inquiry in TB and other treatable diseases that disproportionately strike the developing world.

Dartois and CDI experts are charged with the pharmacology aspects of the work – specifically the pharmacokinetic and pharmacodynamics (PK/PD) aspects of the TBDA’s work.

“We’re in charge of understanding if the drugs are getting where they need to go, and having the effect they need to have,” said Dartois.

“Vero’s work is critically important to reaching a solution to a global catastrophe,” said David Perlin, Ph.D., chief scientific officer and senior vice president of the CDI. “Helping patients overcome TB requires both new drugs and a keen understanding of drug delivery to the right body location and at a therapeutic level- Vero and her group are among the very best in the world  in assessing these critical parameters.”

This could be the crucial crux of the TB problem. Many of the effective drugs can’t effectively reached the locations where the bacteria propagate and proliferate – particularly in large cavities and lesions within the lungs of those infected.

Dartois and her team use animal models and mass spectrometry to best understand how the TBDA drug candidates are working, or not working, based on the biology of both the carrier, and the germ itself. Dartois and team have made key insights which have pointed the other drug discovery parts of the TBDA in the right direction, as reported in the Nature Medicine paper.

But two major hurdles still remain in the battle against TB – especially the multi-drug resistant kind. The drugs that exist now are not optimally combined for maximum effectiveness. Additionally, there are latent TB cases worldwide which continue to be sources of the disease’s spread, particularly in the developing world.

Beyond developing the universal regiment to bring the treatment time down to one month, Dartois envisions even further advances which could mean helping millions of people in years to come. She has partnered with a colleague at the University of California San Francisco to develop an algorithm which would help predict the best drug combinations based on universal case criteria. But that same methodology could eventually be used to predict what regimen would work particularly well, based on the particulars of the person’s lesions, and other infection characteristics, as well as the patient’s genetics determining whether a drug is not metabolized – or could be an outright cure.

“One day we will tailor this to the patient’s disease, down to individual lesions in the lungs,” said Dartois. “That’s what we need to truly defeat this killer.”