For most people born in the United States in the past half century tuberculosis (TB) is a disease you only read about in the history books, to which it was consigned by the development of antibiotics such as streptomycin in the aftermath of the second world war. However, the reality of TB in the world today is very different; this is a disease that still kills over a million people every year, mostly in developing countries. Many of these deaths are due to the way TB infects people who are HIV positive, indeed TB is a leading cause of death among people with AIDS. Current treatments are ultimately effective in most cases, but the treatment regimes often require the patient to take the drugs for up to 2 years, which leads to problems of adherence as patients – many of them poor – struggle to cope with the expense of visiting clinics and with the side effects of the antibiotics over the months of treatment. In addition to these deficiencies in the current treatment regimes, the HIV/AIDS epidemic has also seen the emergence of strains of TB that are resistant to currently available antibiotics, as HIV infection increases vulnerability to TB and standard TB therapies often interact badly with antiretroviral therapy for HIV, a development which threatens the hard-won gains made against the disease over the past decades.
But thanks to animal research TB has a new enemy.
Last week the TB Alliance – a global alliance whose mission is to discover and develop better, faster-acting, and affordable drugs to fight tuberculosis – announced that the new multidrug combination therapy regime PaMZ had performed very well in an early clinical trial, clearing over 99% of the Mycobacterium tuberculosis bacteria that cause TB in 2 weeks. The results indicate that the new drug combination will have fewer side effects than current treatments, require only 4 months of treatment, be more compatible with anti-retroviral therapy for HIV, and cost far less than current first and second line treatments for TB.
A key ingredient in PaMZ is PA-824, a new drug that has not yet been approved by the FDA, and a novel aspect of the development of this therapy is that rather than seeking FDA approval for PA-824 on its own and then carrying out further studies in combination with other drugs, a lengthy process, the this therapy has been developed as a combination therapy with moxifloxacin, an antibiotic approved by the FDA for treating pneumonia and sinus infections and commonly used as a 2nd line treatment for multi-drug resistant TB, and pyrazinamide, a drug which has been used to treat TB since the 1950’s. This novel approach to drug development, which should shorten the development time for the multi-drug therapy be several years, was made possible by a recent change in the FDA regulations that is intended to make it easier to develop new combination therapies for infectious diseases and cancers. An added advantage is that licencing PA-824 for use only in combination with other anti-TB drugs will make it far more difficult for the bacteria will evolve resistance to it.
The development of PA-824 began when a class of molecules named bicyclic nitroimidazofurans were observed to have activity against M. tuberculosis in vitro, and subsequently in mice infected with M. tuberculosis. A series of derivatives of these compounds were synthesised, and over 100 found to have some anti-TB activity in vitro tests. PA-824 was one of the derivatives that performed well in vitro, but was not as potent as several other compounds in the series. However, when the more promising drugs were evaluated in mice infected with TB, PA-824 was found to have the best anti-TB activity when administered orally, and was therefore selected for further evaluation.
This was only the beginning of the road for PA-824, further studies in both mice and guinea pigs – whose response to TB infection more closely mimics that of humans than mice do – demonstrated that it could eliminate TB infection at doses well below those that caused side effects. In combination with the ability of PA-824 to kill a wide range of drug-resistant M. tuberculosis strains in vitro, these results indicated that PA-824 was an excellent candidate for inclusion in a multi-drug combination pill for TB (1). Finally a study published in 2008 examining the efficiency of several multi-antibiotic combinations reported that a combination of PA-824, moxifloxacin and pyrazinamide could clear M. tuberculosis infection more quickly than the standard first line therapy (2), paving the way for the trial whose result was announced last week.
Of course animal studies also played a key role in the evaluation of the anti-TB potential of the other two drugs used in this combination, particularly the effectiveness of pyrazinamide in treating TB in guinea pigs, and the high activity of moxifloxacin in combination therapy against a highly-virulent M. tuberculosis strain in mice.
It’s a very promising therapy, and if approved PA-824 will be the first new antibiotic approved for treating TB in over 40 years, but also a reminder that when it comes to fighting disease we must never allow ourselves to become complacent.
1) Lenaerts AJ et al.”Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models.” Antimicrob Agents Chemother. (2005) Vol. 49(6), pages 2294-2301. PMCID: PMC1140539
2) Nuermberger E et al. “Powerful bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and pyrazinamide in a murine model of tuberculosis.” Antimicrob Agents Chemother. 2008 Vol. 52(4), pages 1522-1524. PMCID: PMC2292539