Developing better tuberculosis drugs

06 April 2022
Waipapa Taumata Rau, University of Ƶresearchers have taken three new tuberculosis drugs to clinical trial – an amazing success rate.

It’s a global pandemic that’s killed millions, sickened many more and caused considerable economic damage. Highly prevalent, it’s spread through the air, often within households or crowded indoor environments. 

We’re not talking about Covid-19. We’re talking about tuberculosis. 

Tuberculosis (TB), which is caused by the Mycobacterium tuberculosis bacterium, has been infecting people for thousands of years. Fortunately, researchers are making strides in the fight against one of the world’s oldest and most devastating pandemics.

In their long-running collaboration with the global not-for-profit , Distinguished Professor  and Senior Research Fellow  have been part of a team that has succeeded in taking three new tuberculosis drugs to clinical trial – an amazing success rate that could potentially improve and perhaps save the lives of millions.

Sir Bill Denny

The world’s deadliest infectious disease

Although Covid-19 has killed more people in the last few years, TB has been the world’s deadliest infectious disease over the longer term. In 2020, about 10 million new patients fell ill with TB, while 1.5 million died – and numbers have been similar for years. 

Although New Zealand is considered a low-prevalence country, it still sees about 300 cases a year. Most patients come from higher-incidence countries, but New Zealand-born patients, like TB patients elsewhere, are more likely to be suffering from socio-economic deprivation. About half of the New Zealand-born patients in 2011-15 were Māori, making TB an equity issue.

Some countries in the Pacific have high rates of TB, particularly Papua New Guinea, Kiribati and the Marshall Islands. Papua New Guinea, considered by the World Health Organisation to have a high TB burden, has seen its incidence rate rise notably in the last decade.

Moreover, about one in four people in the world are thought to be infected without showing symptoms. While some people with latent TB never get sick, others develop active illness years or decades later. 

Active tuberculosis, if untreated, kills over half of patients within five years. Treatment, however, isn’t easy. 

The first-line treatment involves multiple pills a day for at least six months. The side effects can be severe, and because many TB patients live in places where healthcare is difficult to access, it’s often difficult for them to consistently complete their lengthy drug regimen.

Unfortunately, incomplete or stop-and-start treatment can result in multi-drug-resistant TB, or MDR-TB. Last year, there were nearly 600,000 cases of MDR-TB worldwide. 

Treatment for MDR-TB is even more difficult, longer and more expensive than treatment for drug-sensitive “regular” TB. It can involve daily injections for at least six months, 12-24 pills a day for as long as 24 months, and two IV infusions a day for six to 24 months. In all, it can take as many as 14,000 pills to treat a single patient with drug-resistant TB. Even with all this, a cure isn’t guaranteed, with a reported global success rate of just 59 percent. About one in three deaths worldwide due to antimicrobial resistance are due to drug-resistant TB.

If treatment for MDR-TB fails, patients can develop extensively drug-resistant TB (XDR-TB), which is resistant to four rather than two commonly used TB drugs. Treatment for XDR-TB is even harder, more expensive and more prone to failure than MDR-TB. Both MDR-TB and XDR-TB can be directly transmitted to others, so they are growing threats.

A better regimen to fight drug-resistant tuberculosis

In recent decades, pharmaceutical companies have not invested much into tuberculosis drug development because it is largely a disease of lower-income countries and the potential for profit is low. TB Alliance has stepped in to fill the gap. 

For over 20 years, TB Alliance, which is funded by a range of donors including governments and private organisations such as the Bill & Melinda Gates Foundation, has worked directly with research and development partners including the University of Auckland. Headquartered in New York City, its mission is to develop better, faster acting and affordable tuberculosis drugs.

L to R: Peter Choi, Leon Lu, Bill Denny, Anna Giddens, Ivo Dimitrov and Hamish Sutherland

Denny leads the longest-running academic collaboration with TB Alliance. In 2005, he and his team were working with a U.S. pharmaceutical company when one of its senior biologists suggested Denny get in touch with TB Alliance because his lab had worked on similar chemistry to its new project.

“I noted that seemed unlikely to work, but he said any such letter would go to the TB Alliance collaborations advisor for comment, and he was that person,” recalls Denny. “So UniServices funded a trip to New York, I presented, and we got a one-year initial contract that still funds five scientists here to this day.”

TB Alliance’s greatest success to date is the breakthrough drug regime, BPaL, which stands for its three dugs – bedaquiline, pretomanid and linezolid. The regime, approved by the U.S. Food and Drug Administration (FDA) in 2019, is the first to show significant efficacy in treating MDR-TB and XDR-TB. 

The BPaL regimen is relatively short, at six months or less for most patients, compared to 24 months or longer for the traditional regimen. It’s purely oral, which means it can be administered on an outpatient basis. Clinical trials showed approximately 90 percent of patients were cured and suffered fewer side effects than with traditional treatment. The typical XDR-TB regimen has only a 43 percent success rate.

“The launch of BPaL is the first example of a drug regime being developed from start to finish and successfully brought to market by a not-for-profit organisation,” says Kerryn Kilkenny, the UniServices business development manager (health) who has been working with Denny and his team.

“It demonstrates a new pathway to market for industry-neglected diseases through public-private partnerships.”

Improving the drug production process

Dame Margaret Brimble

Other teams at the University of Ƶalso work on tuberculosis drugs.

One of these is led by Distinguished Professor , who took on a shorter-term project funded by TB Alliance to optimise the synthetic route to bedaquilline, increase the yield of product and make the manufacturing process more cost effective.

“The challenge is that bedaquilline has a very complex structure, so it’s hard to synthesise,” says Brimble.

“Drug companies will often go with a compound that’s proved to be good in clinical trials even if the synthesis isn’t very efficient, because they can always improve the synthesis later on if the drug works well. And in this case, it’s worth doing.”

Brimble and her team managed to improve several of the steps in the synthesis and came up with some promising alternative avenues to make the molecule. 

Further refining a breakthrough drug regime

While significantly safer and more effective than the traditional regime, some of the BPaL drugs still carry important risks of side effects. Even before BPaL was approved, Denny’s team started working on “next generation” replacements for bedaquiline and pretomanid with the goal of finding alternatives with better pharmacological and safety properties.

A pretomanid alternative the Ƶteam developed didn’t make it beyond Phase One clinical trial. However, Denny and his team have found two possible alternatives to bedaquiline. Their two new compounds, currently known by the none-too-catchy names of TBAJ-587 and TBAJ-876, appear in animal models to be safer and more effective than bedaquiline. 

"[Drug discovery is] a bit like Lego. You put bits of the molecule on and take bits off and change things around. Through an iterative process of testing, we figure out what’s better or worse."

Hamish Sutherland 

TBAJ-587 and TBAJ-876 are currently in Phase One human clinical trials, so they’re largely out of the team’s hands. If one or both get through clinical trials, the better one could replace bedaquiline as a safer alternative in the BPaL regime.

Sutherland, who joined the team in 2007, says it’s important for him to know he’s “doing something that’s good for the world.” He also enjoys the challenge of the chemistry. 

“It’s a bit like Lego,” says Sutherland of the drug discovery process. “You put bits of the molecule on and take bits off and change things around. Through an iterative process of testing, we figure out what’s better or worse. We must have made close to a thousand molecules on the way to coming up with TBAJ-587 and 876, so it’s a long process.”

The next targets

Denny, Sutherland and their team aren’t done yet in their quest to better treat tuberculosis. Still working with TB Alliance, they’re in the early stages of work to target and inhibit other enzymes of the bacterium. 

“Any target we can go after, we will,” says Sutherland. “Drug resistance will be a driver forever, so we need to expand the material biologists and doctors have to target TB in all its forms.” 

“We’re also always looking to reduce drug toxicity in all its forms,” says Denny. “Side effects can make people stop taking their medications, and that can lead to drug resistance, so making better drugs also combats drug resistance.”

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