Tackling TB Resistance

Tuberculosis (TB) is a pandemic disease, which has affected human beings for centuries. Documented through the ancient civilizations of India and China, and traced across the globe through the Middle Ages, the killer infection has been given various different names including ‘consumption’ and the White Plague. Consumption is one of the most common definitions due to the dramatic weight loss that is observed through the loss of appetite and persistent coughing, which are clear signs of the disease.

Caused by the bacteria Mycobacterium tuberculosis, it’s an infection that is spread between humans by airborne transfer of the bacteria through coughing, sneezing or even just speaking to one another. Historically through the 17th to 19th Centuries it was a disease considered to be a pauper problem with a self-blame image of the working classes who lived in crowded conditions. Combined with the industrial revolution, these conditions provided a perfect environment for the bacterial killer to spread rapidly and effectively. Primarily affecting the lungs, although extra-pulmonary TB can also occur, other clinical observations are night sweats, fever, chills and fatigue.

It wasn’t until 1944 and the discovery of streptomycin that there was an antibiotic treatment for consumption following many failed efforts of treatment through containment and isolation. This was followed in the 1950s with the development of Isoniazid—a mycobactericidal compound—and the antibiotic Rifampicin in the 1970s. At the same time as pharmacological therapies were emerging, scientists had been actively working to develop vaccines. In 1906 French development scientists created the first effective vaccine aptly named the BCG (Bacille Calmette-Guérin) after the creators. Although this was used in France in the early 1920s it wasn’t taken on board further afield until the late 1940s and 1950s. Ironically, although there have been attempts to find alternative vaccinations, to this day this is still the only vaccine available for the prevention of TB.

Since the development of the BCG vaccine it has been widely used globally and it’s currently estimated to be delivered to 80% of newly born babies across the world. It had been hoped that it would be feasible to eradicate this awful killer, but although there has been a rapid decline in deaths in the developed world, the World Health Organization (WHO) declared a global health emergency in 1993 and again in Africa in 2005 following resurgence of multidrug resistant strains of the bacteria in the 1980s. In addition, with the arrival of HIV around the same time frame there is now an established link with the risk of developing TB and the virus—it is 26-31 times greater in these patients. Bearing in mind the prevalence of HIV in Africa and other parts of the developing world it’s clear to see why TB has reared its ugly head again with a vengeance.

Currently, according the WHO, TB remains one of the top 10 causes of death worldwide with 1.4 million deaths attributed to it in 2015 and 10.4 million becoming ill. In the same year almost 90% of cases occurred in 6 countries in Asia and Africa and almost half a million people are suspected of suffering from multidrug resistant TB (MDR-TB) strains.

Standard treatment regimens generally comprise of four anti-TB drugs—isoniazid, rifampicin and a fluoroquinolone—to be taken over a period of 6 months. Recurrence of the disease is treated by four, if not more effective antibiotics for a period of 18-24 months. However over recent years the bacteria has mutated even more so and newer definitions of extensively drug-resistant TB—XDR-TB is resistant to three or more TB drugs—and in the past 10 years totally drug-resistant TB have emerged. Something has to be done in order to reach the goal of the WHO to beat the world TB epidemic by the end of 2030.

The TB Alliance is a not-for-profit organization dedicated to the discovery and development of better, faster-acting, and affordable tuberculosis drugs that are available to those who need them. It is a funded agency, which relies on support of donors to fund its development work that includes the FDA and USAID. Working in partnership with universities, government agencies, public agencies and a small number of pharma companies, it aims to develop new TB drugs alongside maximizing the treatment regimens of established drug entities. Although TB is still at global pandemic levels there are fewer than 20 known compounds with activity against mycobacterium, which leaves a massive hole in a therapy area where resistance is well known to be increasing.

One of the established partnerships of the TB Alliance is between John Hopkins University (Baltimore) and the Medicines Patent Pool (MPP), which is a UN-backed organization supporting development and access to medicines for poorer countries in the specific areas of HIV, Hep-C and TB. Of late, the partnership has been working together to clinically develop Sutezolid, a drug candidate which has demonstrated interesting activity in combination with other TB drugs in treatment of the condition. Sutezolid is an oxazolidinone, the same class of drug as linezolid, which is also under investigation by the TB Alliance in early Phase II and Phase III clinical trials. In some ways it’s absurd that there are so few treatment options for TB which is a globally devastating condition, however it looks like the alliance combined with the MPP are making progress.

In March 2017 the MPP announced a sublicensing agreement for the clinical development of Sutezolid in partnership with the TB Alliance and the patent owner John Hopkins University. Using the combination of the other known licensed drugs that are acknowledged to have activity against the mycobacterium has great potential to provide another treatment against XDR-TB, which is becoming increasingly difficult to combat and unfortunately increasingly common. The license, which the MPP holds now gives them the rights to approach interested parties to investigate the possibilities of developing treatments for both sensitive and resistant TB strains and to look at combinations with other drug entities to create new multi-pronged attacks on the bacteria.

In line with further work from the TB Alliance who have Phase I, II, III & IV trials ongoing using a mix of pharmaceutical agents including Ethambutol, Pyrazinamide, Isoniazid, Pretomanid, Moxifoxacin, Linezolid and Bedaquiline, the outlook for identifying new treatments looks very positive, regardless of identification of new drug entities. Several of these drugs are listed on the WHO’s List of Essential Medicines and are generic, cost effective medicines with simple routes of administration, which is in line with the TB Alliance strategy to be successful in developing better, faster-acting, and affordable tuberculosis drugs that are available to those who need them. Alongside activities such as the MPP-TB Alliance project, they are hopefully well on track to hit their target of beating TB by 2030.