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Millions of lives are hanging in the balance as resistance to TB drugs is rising and drugs to fight it are 50 years old
In the 1960s, President John F. Kennedy declared that the big goal for science in the U.S. was to get a man on the moon. The rest of the world watched in anticipation as the federal government pushed the science community, accelerating rocket science to the point where, in 1969, Neil Armstrong became the first person to step foot on the moon.
However, arguably perhaps an even greater and more impactful scientific advancement of that decade was the development of rifampicin and ethambutol, two antibiotics which, when combined with pyrazinamide and isoniazid (drugs that were developed in the 1950s), have saved the lives of tens of millions of tuberculosis patients. These four drugs constitute the first-line therapy still used to treat TB today— 50 years later—everywhere around the world.
Tuberculosis is a communicable disease that has plagued humanity for thousands of years. It has been found in Egyptian mummies and chronicled in ancient Greece; historians also believe the disease inspired the vampire folklore of Eastern Europe. The disease still kills 1.5 million people every year.
Over the last half century, tuberculosis has also evolved. Like any bacterial infection, exposure to insufficient antibiotic therapy, either too short or too little, can result in resistance to the antibiotics.
Treatment with the first-line combination requires patients to take the drugs for six to nine months. However, once the immediate symptoms subside, many patients stop taking their drugs on a regular basis leading to the development of resistance. Treatment of drug resistant tuberculosis takes 18 months or longer, requiring a much more complicated, toxic, expensive and less effective drug regimen, curing less than half of those treated.
Over the next decade, the World Health Organization expects that TB will drain $1-3 trillion from the world’s poorest countries. And if drug resistance is not addressed, TB could cost the global economy $16.7 trillion by 2050—the equivalent of the European Union’s current economic output.
HARSH SIDE EFFECTS
There have been two newly approved drugs for drug resistant tuberculosis—bedaquiline and delamanid. However, the addition of these drugs to the current treatment of drug resistant TB decreases the time to clear TB from of the patient’s lungs, but does not shorten or simplify treatment.
In fact, treatment with either of the new drugs is more expensive and brings added side effects. The big challenge is how to translate scientific advancements into transformative medical care that will lead to improved outcomes with simpler, better tolerated, and more affordable therapies.
Two clinical trials that launched recently will take significant steps in this direction. The STAND trial will test three drugs in combination: pretomanid—a new drug with no known existing resistance—along with moxifloxacin and pyrazinamide. The STAND trial is a phase 3 clinical trial, the last step before the combination can be approved for treating patients.
The second trial is in the second to last step, phase 2b, and is testing two new drugs with no known resistance—bedaquiline and pretomanid—along with pyrazinamide. Both of these regimens consist of only oral drugs and based on the preclinical data, treatment duration would range from 3 to 4 months.
There is one more trial that will launch soon, one that will test three drugs with no significant resistance, bedaquiline, pretomanid and linezolid. This third trial will be conducted in only patients with extensively drug resistant TB as the side effects of linezolid at this time preclude its use in drug sensitive TB.
Unfortunately, the research pipeline behind these combinations is thin. The TB Alliance just launched a Phase 1 trial of another new drug, TBA-354, and it is the first novel compound to enter the clinic for TB in six years.
Regardless of whether the late stage trials show success or not, we desperately need more drug candidates. As is true for all bacterial infections, the tuberculous bacillus will evolve and develop resistance to new drugs. With judicious use the process of generating resistance can be slowed down, but we need to continue to expand research efforts to protect future generations of TB patients.
We need more resources and more partners, but a key to progress is support of further research. President Kennedy dedicated $24 billion to land a man on the moon. In contrast, the total amount invested today in research on not just TB but all other “neglected diseases” as well is roughly $3.2 billion a year—this includes all spending around the world from all government, NGOs, and private sector entities.
Developing new antibiotics should not be so much more difficult than rocket science. The solution is a simple math exercise. Billions now or trillions later, with millions of lives hanging in the balance. Humanity can ill afford another 50 years without new antibiotics.
Mel Spigelman is the president and chief executive of the Global Alliance for TB Drug Development (TB Alliance). He is regarded as one of the world’s leading experts in tuberculosis and TB drug development.
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