Alliance starts human TB drug testing
promising tuberculosis drug in humans. This development represents
the first novel compound of a new class to be introduced for the
treatment of TB in more than 40 years.
PA-824 was first identified in 1995 by researchers at PathoGenesis, later acquired by Chiron Corporation. A member of the novel nitroimidazole class, its potential as an anti-tuberculosis agent was demonstrated in preclinical studies that indicated that it has sterilising potency and a novel mode of action that could shorten treatment times.
Its mode of action targets the both actively and slowly-growing Mycobacterium tuberculosis (M.tb). In vivo studies showed that the drug kills M.tb effectively in both the initial, intensive phase as well as in the later continuation phase of TB therapy.
This demonstrates that the drug has both bactericidal and sterilising activity, combining in a single compound the most effective attributes of isoniazid and rifampin, which is the current choice of TB drug therapy.
Current projections of TB incidence and mortality reflect the need for new, shorter TB therapy. Between 2000 and 2020 it is estimated that nearly 1 billion people will be newly infected from TB, 200 million will become sick and 35 million will die.
"To reach our goal of shortening TB therapy, we must create novel regimens that incorporate new drugs with different and complementary modes of action," said Dr Mel Spigelman, director of research and development at the TB Alliance.
"PA-824's profile means its introduction into a new regimen could help shorten treatment time dramatically and overcome some of the challenges with TB treatment, such as multi-drug resistance and the treatment of TB-HIV co-infected patients," he added.
The four current treatments require patients to take a drug cocktail of up to 22 pills in a day for about six months. The major advantage to PA-824 over existing treatments is that it promises to replace one or two of the four drugs and shorten the treatment period to no more than two months.
TB is a leading cause of death among people living with HIV/AIDS. However, treating the two diseases at the same time is difficult because of negative interactions between some ARVs used to treat HIV/AIDS and TB drugs. Early studies of PA-824 indicate that it could be safely used with HIV/AIDS therapies.
The Phase I clinical study, to be conducted by the Nebraska-based MDS Pharma Services, will evaluate the safety, tolerability, and pharmacokinetics of single doses of PA-824 in healthy, male volunteers.
In the last decade, TB cases have grown 20 per cent worldwide with the highest burden in the most impoverished communities. If these trends continue, TB incidence will increase by 41 per cent in the next twenty years.
The four main TB drugs, Isoniazid (1952), Rifampin (1963), Ethambutol (1962) and Pyrazinamide (1954) have been the core TB treatments for close to 40-50 years and while they have been phenomenally successful, the emergence of drug resistant TB strains have exposed their age and weaknesses.
