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
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
plus PA-824, bedaquiline plus pyrazinamide, PA-824 plus pyrazinamide, and PA-824
plus pyrazinamide plus moxifloxacin
– were naturally more potent than
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
noted within the press release from the TB Alliance, this particular regimen
could treat both drug-sensitive and drug-resistant strains of TB.
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.
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.
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