Novel TB combination regimen shows potent activity in randomised short-term clinical trial

A new TB drug, PA-824, showed very potent early bactericidal activity in a randomised 14-day study in people with TB, when used in combination with the established antibiotic moxifloxacin, and pyrazinamide, an existing TB drug, according to a presentation by Dr Stephen Murray of the Global Alliance for TB Drug Development (the TB Alliance) on Monday at the 19^th International AIDS Conference (AIDS 2012) in Washington DC.  

The study results (published on the same day in The Lancet), suggested that the early bactericidal activity in the combination arm was much greater than what was observed in the five other arms, one of which involved standard TB treatment – though the size of the study was not large enough to prove a significant difference between the arms.

Nevertheless, the findings in human patients seemed to match the activity predicted by a mouse model that Dr Murray said could be used to identify the most potent new TB combination regimens to take forward quickly into clinical development.

In addition to being the first clinical confirmation of a new TB drug’s activity, the particular regimen is interesting for two other important reasons.

First, in addition to being potent against drug-sensitive TB, it is expected to be active against most drug-resistant strains of TB – potentially shaving more than a year off of the time it takes to treat a person with MDR-TB and possibly even extensively drug-resistant TB.

Second, the regimen should not have any major drug-drug interactions if given at the same time as antiretroviral therapy (ART) to HIV-positive people with TB.

So many potential combinations, so little time

After decades without any new drugs specifically developed for TB, the TB drug pipeline, if not exactly overflowing, is at least looking somewhat more respectable. However, TB treatment is where the very idea of combination therapy originated – and thus it comes with the territory that new TB drugs must ‘get along well’ in combination with other TB drugs.

But the interactions between TB drugs against the mycobacterium TB are complex. If there is a drug-drug interaction, giving two drugs together doesn’t always make for a more effective combination, or there could be interactions that lead to toxicity. On the other hand, in some cases, drug combinations are more than the sum of their parts – they could be synergistic.

In addition, since TB medication often has to be given to people who need to take ART, working well in a combination without drug-drug interactions with antiretroviral drugs could be to a new drug’s advantage.

So, when there are already several established drugs with anti-TB activity, and several drugs in the development pipeline, there are hundreds of potential combinations that could be studied – and hundreds of thousands of people dying for lack of better TB treatment. Researchers can’t take decades to test all the possible TB drug combinations with the new drug before it gets to market.

This is the very sort of problem preoccupying the TB Alliance, a not-for-profit TB drug development organisation supported by the Bill & Melinda Gates Foundation, Irish Aid, UKAid, USAID, and the US Food and Drug Administration. While there are a couple of companies with TB drugs a little further along in clinical development, the TB Alliance has made it their business to find as many potential new TB drugs as possible, and do what it can to speed the development of faster-acting, affordable TB drug regimens.

Their solution to the question of ‘what combinations to test first’ was to test them all in a mouse model of TB to see what worked best.

And, indeed, now they have evidence that what they see in the mouse model seems to happen in humans.

“The regimen of PA-824 plus moxifloxacin plus pyrazinamide has shown really very dramatic improvement over a number of other combinations, which is a reflection of its effect in reducing levels of tuberculosis in the lungs of mice in this particular model,” Stephen Murray told the conference.

The NC-001 study

The data came out of the NC-001 study, which, Dr Murray noted, “is really the first novel combination early bactericidal study”.

Early bactericidal studies have been used in the past to evaluate individual drugs, like TMC207 (bedaquiline). These studies take patients who are newly diagnosed with tuberculosis and treat them for a short time (after which they are given standard treatment immediately). As in the mouse model, the researchers count the amount of bacteria in the lungs, measured by taking serial sputum samples every 16 hours.  

NC-001 randomised 85 people with TB at two sites in South Africa (only six were HIV positive). Fifteen patients each were randomised to one of six arms: Rifafour (the standard four-drug TB treatment) and five arms that contain single novel drugs or a combination of novel drugs.

After randomisation, the patients were treated for 14 days, with serial sputums collected to determine M.TB colony forming unit counts. In addition, they also inoculated the sputum to see the time to positivity (TTP) to evaluate the amount of bacterial load in the sputum using a liquid culture.

This was the first bactericidal combination study to include PA-824, which is a nitroimidazole, in the same class of drug as Otsuka Pharmaceutical’s delamanid (which has moved into phase III studies and which ought to be available on expanded access). This means there is a decent chance such synergy will be seen with either drug, and also that a competitive drug in the same class marketed by a non-profit could keep prices of these new regimens low.

In this study, one of the arms provided TMC207 (bedaquiline) by itself, since it is known to have a bactericidal effect on its own. All the combinations however – of Rifafour, bedaquiline plus PA-824, bedaquiline plus pyrazinamide, PA-824 plus pyrazinamide, and PA-824 plus pyrazinamide plus moxifloxacin – were naturally more potent than monotherapy.

Of particular note, however, PA-824 plus pyrazinamide showed a dramatic synergistic effect, both in the mouse and the human CFU measurement model.

However, Dr Murray said that at best, PA-824 and bedaquiline had an additive effect. “When you look at PA-824 with TMC207, we don’t see much of an enhancement, though it looks like it’s a little bit better than TMC207 alone, but it really is no different than PA-824.”

“But… as we saw in mice, the combination PA-824 plus PZA plus moxifloxacin has the largest effect. This effect really distinguishes itself from the other combinations with TMC207,” he said. Though one wonders why there wasn’t a three-drug combination with bedaquiline including moxifloxacin. Oddly, for a non-profit alliance, this seemed to be a rather proprietary treatment of their own not-for-profit product.

Nonetheless, the novel three-drug combination was profoundly potent; within two weeks, it killed more than 99% of patients’ TB bacteria.

As noted within the press release from the TB Alliance, this particular regimen could treat both drug-sensitive and drug-resistant strains of TB.

“Treating drug-sensitive and drug-resistant TB with the same regimen can simplify the delivery of TB treatment worldwide,” said Andreas Diacon, MD, the trial’s principal investigator and lead author of the Lancet study.

A second trial called New Combination 2 (NC-002) was launched earlier this year to test the PaMZ combination over two months in patients, further advancing it through clinical development. NC-002 is currently enrolling patients and will be conducted at eight sites in South Africa, Tanzania and Brazil.

Dr Mario Raviglione, MD, Director of the Stop TB Department at the World Health Organization added that testing multiple new TB drug candidates simultaneously has already proven to be a major advance. “Because of testing drugs in combination, we have already saved several years in the research process to find new, effective regimens to treat TB,” Dr Raviglione said in the press release.