On Aug. 14, the U.S. Food and Drug Administration (FDA) approved a new drug, pretomanid, to fight tuberculosis (TB). Pretomanid was developed by The Global Alliance for TB Drug Development (TB Alliance), a non-profit organization dedicated to developing and delivering new tuberculosis drugs.
This follows the 2012 approval of another TB drug called bedaquiline, the first new medicine to fight TB in more than 40 years. TB — caused by the bacterium Mycobacterium tuberculosis (MTB) — affects the lungs (mainly) as well as other organs/tissues (such as the spine) and is one of the most deadly diseases.
According to the Centers for Disease Control and Prevention (CDC) a staggering 1.9 billion people (about one fourth of the world’s population) are infected with MTB. Most people infected with TB do not show any symptoms of the disease and are considered to have a latent form of the disease.
However, about 10 percent of latent TB progress into symptomatic TB disease. Initially the symptoms of TB disease are mild, such as coughing and can be easily mistaken as an allergic reaction or a lingering cold or flu infection.
Over time the disease progresses into persistent coughing that lasts for weeks and other symptoms can include weight loss, fever and night sweats. When left untreated, TB becomes lethal and ultimately kills the patient.
The CDC reported that in 2017, out of the 10 million symptomatic TB cases (people who became sick with TB) 1.3 million ultimately succumbed to the disease resulting in one TB-infected individual dying every 18 seconds. According to the World Health Organization, this places TB as the 10th leading cause of death worldwide. The majority of TB-related deaths occur in low and lower-middle income countries, whereas the disease is relatively rare in high-income countries.
Why does TB kill so many people in the world when most infectious diseases can now be effectively managed with antibiotics? To answer this question, it is pertinent to briefly survey the development of TB medications and treatment outcomes. In the 1800s, TB killed one in seven adults in the Western world.
The development of powerful TB drugs started after the discovery in 1882 of Mycobacterium tuberculosis by Dr. Robert Koch, considered as the father of modern microbiology. Koch would later receive the Nobel Prize in Physiology and Medicine in 1905 for his work on MTB.
It would take over 60 years before the first two effective drugs against MTB, para-amino salicylic acid (PAS) and streptomycin would be identified by the Swedish chemist, Jörgen Lehmann (PAS) and the U.S. biochemists Selman Waksman, Albert Schatz, and Elizabeth Bugie (streptomycin). Waksman was also awarded the Nobel Prize in Physiology and Medicine in 1952 for his discovery of streptomycin.
These two important and historical TB drugs were supplanted by newer, better tolerated and more effective drugs, such as isoniazid (INH) and rifampicin (RMP). Unfortunately, a high percentage of TB patients carry strains of the pathogen that are resistant to rifampicin (referred to as rifampicin-resistant TB or RR TB) or resistant to both isoniazid and rifampicin (referred to as multi-drug resistant TB or MDR TB).
In 2016, it was estimated that about 600,000 people had MDR TB or RR TB, which were mainly concentrated in China, India, Russian Federation, Indonesia, South Africa and Nigeria. About 40 percent of patients with MDR TB or RR TB (240,000 out of the estimated 600,000) died of the disease, making MDR/RR TB one of the most lethal diseases. Worryingly, about six percent of MDR TB patients were also resistant to other antibiotics (this is referred to as extensively drug resistant TB (XDR)) and the prognosis of these patients is the worst.
Clearly there is a need for newer TB drugs, with mechanism(s) of action that are different from existing drugs in order to combat MDR/RR or XDR TB. It will be desirable if such new drugs, in addition to novel modes of action, are also fast acting. Currently, TB patients have to have medications for nine months in order to stand a chance of being cured. Such long schedules can lead to low compliance, especially in cases where patients experience adverse drug reactions.
The FDA approved pretomanid in combination with bedaquiline and linezolid for the treatment of TB of the lungs, specifically for highly treatment-resistant TB. Pretomanid (formerly called PA-824) has a complex mode of killing MTB and involves modes that are similar to existing drugs (such as inhibiting the cell wall of the pathogen, similar to what isoniazid does) as well as novel mechanisms that are unique to pretomanid (such as inhibiting the bacterial respiration). Because pretomanid’s mode of action is different from other existing TB drugs, it is hoped that resistance towards the new drug combination will be slow to develop. As a combination therapy, the different drug components “attack” MTB at various sites to overwhelm the pathogen.
Can we now close the chapter on TB now that two new and highly effective drugs have been approved in the last decade? Firstly, 89 percent of treatment intolerant or MDR, XDR pulmonary TB patients who took the three-drug regimen, pretomanid-bedaquiline-linezolid, recovered within six months, implying that there is still a clinical need to cater for the 11 percent non-responders. Secondly, it will be foolhardy to assume that resistant MTB strains to these newly approved TB medicines will not emerge. Bacteria have enormous capacity to evolve even under extreme hostile environment.
One of the classic ways that bacteria develop resistance to drugs is the over-expression of proteins, called efflux proteins, which pump drugs out of the bacteria. Additionally, bacteria have the capacity to modify drugs to render them not active. Some of the common adverse reactions seen with the combination regimen were damage to nerves (peripheral neuropathy) and low blood sugar.
Such adverse effects could lead to poor patient compliance and subsequent development of resistance as well as treatment failures. The issue of pricing has not been fully resolved but it must be noted that many of the people who suffer from TB are from resource-poor areas and can hardly afford drugs priced at more than $3 per treatment.
Despite the aforementioned concerns, it is time to celebrate this great advance made in TB treatment. Another reason to celebrate is that TB Alliance supported the entire arduous process of pretomanid development through FDA approval and established a new paradigm for a successful public-private partnership for delivering new therapeutics against dangerous human pathogens. It highlights the power of cooperation and collaboration to tackle long-standing global problems.
Herman O. Sintim is the drug discovery professor of chemistry, and Richard J. Kuhn is the Trent and Judith Anderson distinguished professor of science at Purdue University.