Global Alliance at full steam for new TB drugs
"We have a goal: getting a new drug for TB registered by 2010. It's very ambitious, to achieve that and to make the product affordable," Maria Freire, Chief Executive Officer of the Global Alliance for TB Drug Development, told the Bulletin.
Launched in Bangkok in October 2000, the Global Alliance was described by WHO's Director-General Gro Harlem Brundtland as "a shining example of public and private sector partnerships to bridge the gap between market opportunities and people's needs".
The Alliance aims to get improved TB drugs to those who need them - drugs which:
shorten or simplify treatment of TB; or
provide a more effective treatment of multidrug-resistant TB; or
improve the treatment of latent TB infection; or some combination of these.
To get there "we have to work with compounds [molecules] as far along the development chain as possible" said Freire. "And that's why we're going out scouting companies, universities, and anyone who may have potential compounds to bring in and license... Each deal will be individual and tailored for that particular compound."
The compounds the Alliance is chasing fall into two categories. First come analogues, modifications or derivatives of existing compounds. "If we have a compound that treats patients in nine months [a typical treatment time in developing countries], and if we can modify that chemical to make it just as effective in only two months we'd have achieved one of our key goals" said Freire.
"That wouldn't be a novel compound family, but like a US Treasury Bond - a solid, safe investment" said Freire. "But we also want 'stock' - much riskier investments [as in new companies], but potentially with a much higher payoff. This means compounds that are novel and new, that the TB organism [Mycobacterium tuberculosis] has never seen before."
Now that scientists know the whole genome of M. tuberculosis, it is possible to sequence proteins in the organism and identify potential new targets. In a review last year in the American Journal of Respiratory and Critical Care Medicine, 2001, 163: 1055-1058, Richard J O'Brien of the Division of TB Elimination, US Centers for Disease Control and Prevention, Atlanta, and Paul P Nunn of STOP TB and WHO argued that the genome plus combinatorial chemistry and robotic screening "promises the introduction of an era of rational tuberculosis drug discovery".
According to Freire "If we had a completely novel set of compounds, since the organism will have never seen them, we would be automatically able to tackle the multidrug resistance problem. Resistance of course will arise eventually, but it will give us a very good window to attack. And hopefully we'd get a series of compounds, a family or families of compounds."
"But it's riskier because the field will not be as well known, and the toxicology will be unknown. But those kinds of compound have a possibility of high pay-off."
"We are under negotiation with compounds that fit both categories" said Freire "but the majority are analogues and derivatives".
Endemic developing countries will be central in moving these compounds forward, the Global Alliance has decided. "Our goal is to develop the drugs in such a way that they'll be affordable in endemic countries" said Freire. "So we are choosing partners in the South, such as chemists in India to help with scaling-up. And we want to team up with service providers and institutions in the South for clinical trials."
New TB drugs - why do we need them?
The existing recommended TB treatment is based on two months of four drugs - isoniazid, rifampicin, pyrazinamide, and ethambutol - followed by four months of two drugs: isoniazid and rifampicin. It's a six-month treatment, costing under US$ 10, thanks to a WHO global drug facility that handles partnerships and receives donations from different donors, and then distributes drugs free of charge to countries that need them.
But why all this effort to create new drugs? Mario Raviglione of STOP TB and WHO told the Bulletin "the present treatment is 98 - 99% effective, if the TB is not multidrug resistant".
"With multidrug-resistant TB (MDR-TB), which is resistant to at least the two most powerful of the four drugs - isoniazid and rifampicin - the efficacy drops to 50%" says Raviglione. But in the majority of cases - i.e. non-resistant TB - there are no serious side-effects, except a possible liver toxicity for isoniazid and rifampicin, a tingling numbness in the feet or hands for isoniazid, and temporary visual problems with ethambutol, "but generally they're rare and tolerable".
So if the existing drugs are good, why is it so important to develop new ones? First because the existing regimen is too long, says Raviglione. The recommended DOTS strategy, which is based on short-course chemotherapy, is called "short-course" only because it is shorter than the 12 - 24 months used 20 - 30 years ago.
The great discovery in clinical trials in the 1970s and 1980s was the synergy amongst the various different TB drugs, shortening the course to six months. However, six months is still not short enough, and causes difficulties for both patients and care programmes. "If we could get to three months, two, or even one, that would be a dream, that would be a major, major achievement that would allow us to treat TB much more easily than today" said Raviglione.
The second reason new drugs are needed is because the existing ones have to be taken so often. Currently in the first two months all four drugs must be taken every day or every other day, and in the last four months the final two drugs must be taken three times a week. "If we could have a drug that could be administered once a month for six months, by injection for example, that would make treatment much easier" said Raviglione.
The third reason is multidrug resistance. Existing "second-line" drugs to attack MDR-TB are expensive, have toxic side-effects, and have to be taken for two years because their effect is fairly weak compared to first-line drugs. "If we had better, safer and cheaper second-line drugs the treatment of MDR-TB would be a lot easier" said Raviglione.
The International AIDS Vaccine Institute (IAVI) has a similar public/ private model to the Global Alliance, says Freire. "We both want to use the best both the public and the private sector can offer. There's another group for malaria, and Médicins sans Frontières is considering setting up a group for essential medicines for the most neglected diseases."
In negotiations with the private sector the Alliance argues that the TB "market" will be worth about US$ 450 - 700 million by 2010. This is not negligible: companies estimate $ 200 million to be the threshold above which it is worth making a research and development effort on new products. Western diseases such as ovarian cancer, breast cancer, and diabetes offer markets of US$ 800 million to $1 billion, but at US$ 450 - 700 million "the pharmaceutical industry already has a real incentive to move on TB", Freire argues.
Charlene Crabb, Paris