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Tackling the TB threat

After 30 years of limited investment in TB drugs, the disease area is seeing a resurgence

The tuberculosis (TB) market is historically one of perceived low value, limited growth and reduced opportunities for the pharma industry, the consequence of which has been poor investment in R&D, limited treatment options and a stagnant market.

However, the continued health, social and economic problems that the disease poses, alongside the emergence of multidrug-resistant forms and rising infection rates in the developed world, have renewed interest in the development of effective prophylactic and therapeutic options.

An increasing patient population is driving the growth of a previously flat market, and several initiatives within both public and private sectors are creating an environment with multiple opportunities for the industry.

Coupled with the considerable unmet needs of patients with TB, this could be an opportune time for companies considering investing in this market.

Better therapies required
TB, caused by the pathogen Mycobacterium tuberculosis, currently infects one-third of the world's population. According to the World Health Organisation (WHO), 2004 saw an estimated 1.7 million deaths from TB and almost 9 million new cases. By 2010, the number of new cases globally is expected to rise to 11.6 million. A complication is the emergence of multidrug-resistant TB (MDR-TB), plus the fact that HIV and TB form a lethal combination; TB is currently the leading cause of death in HIV-positive people. Aside from the humanitarian crisis the disease poses, the social and economic costs of TB are enormous. The Global Alliance for TB Drug Development (TB Alliance), a not-for-profit public-private partnership, estimated that the annual total public sector costs of TB treatment in the US in 2001 ranged from Ä141.9m to Ä348.4m ($182m to $447m).

TB is treated currently with a combination of four first-line antibiotics; the standard preferred regimen comprises daily doses of isoniazid and rifampin for six months, with pyrazinamide and ethambutol taken for the first two months. No new TB drug class has been introduced for more than 30 years, so the many shortcomings with today's lengthy treatment regimens are simply tolerated. Current control programmes are expensive and difficult to manage, and the WHO-promoted treatment and control strategy, DOTS (Directly Observed Treatment Short-course) reaches only a fraction of TB patients. A shorter regimen would allow patients to be treated more cost-effectively, reduce side effects and improve poor compliance.

Furthermore, the regimen for the treatment of latent TB (infection with no active disease) can last for up to 12 months, aggravating these problems.

On top of this, the emergence of MDR-TB, which must be treated with second-line, often toxic products, calls for newer efficacious drugs with improved side-effect profiles that combat resistant or persistent organisms.

There is, therefore, urgent need for new compounds that reduce the duration of treatment required, prevent progression from infection to disease and improve the treatment of MDR strains. Improved prophylactic measures are also required; the current BCG vaccine, developed in the 1920s, is unreliable, failing to prevent infection in as many as 80 per cent of those who receive it and providing adults with little immunity.

Lifesaving vaccines
While no new TB drugs have been brought to market since the launch of rifampin in the 1960s, several firms are now taking steps to bring their own novel treatments to the clinic. Alongside efforts to improve the immunogenicity of the BCG vaccine, a number of companies are developing new TB vaccines, making use of advances in technology. While traditionally difficult for vaccine manufacturers to secure funding, healthcare provision (in particular the supply of lifesaving vaccines) is important in the economic development of poor countries, and would provide an effective long-term investment for these companies.

Table 1 (opposite) provides an overview of some of the vaccines and medicines currently in development. Among these is a recombinant adenoviral vector TB vaccine, currently in phase I trials, being developed by Crucell and Aeras Global TB Vaccine Foundation, an international non-profit academia-industry partnership. The vaccine uses an Ad35 vector and is designed to manage the problem of pre-existing immunity in humans without compromising its immunogenic properties.

Further along the pipeline, in phase II trials, is Mtb72F, a collaborative venture between GlaxoSmithKline (GSK), the Aeras Foundation and TB-VAC (the EU-supported consortium that aims to develop improved vaccines) for the prevention of M tuberculosis infection in children, and as an adjunct to TB treatment in adolescents and adults. This vaccine, which is a fusion protein of two M tuberculosis antigens formulated in a proprietary GSK adjuvant, has been shown to be safe and immunogenic in phase I/IIa trials, with trials in HIV-infected patients and other target populations planned.

TB-VAC is also collaborating with the UK's Oxford University on MVA-Ag85A, a vaccine currently in phase I and II trials. Early clinical data show the vaccine to be safe and highly immunogenic. Future trials are planned for children and infants, and high-risk groups such as HIV-infected patients, with phase III trials expected between 2008 and 2013.

Small molecule development
PA-824, a cyclodextrin-formulated nitroimidazole analog from the TB Alliance, is the first TB pharmaceutical developed by a non-profit organisation to enter clinical trials. Its mechanism of action appears to interfere with both protein and cell wall biosynthesis. The drug has no CYP450 interactions and is therefore not expected to interfere with HIV antiretroviral drug treatment. However, it has shown limitations in efficacy, poor solubility and synthesis is expensive.

Also now in phase I trials is Otsuka's nitro-dihydroimidazo-oxazole derivative, OPC-67683, which has shown activity against both drug-sensitive and MDR-TB strains, demonstrating superior bactericidal activity to rifaximin and isoniazid against a panel of clinical isolates. In pharmaco- kinetic studies, this compound, which inhibits the synthesis of mycolic acid, demonstrated good absorption and tissue distribution.

The novel anti-TB compound, TMC-207, transferred for clinical development from Johnson & Johnson to Tibotec, has been hailed as `the darling of the TB community'. Early data show the compound to be well tolerated in humans, while in preclinical studies its use in combination therapy was shown to halve the treatment time required compared with standard drug combinations.

TMC-207 acts on a new TB target, interfering with the proton pump for mycobacterial ATP synthase, a unique mechanism of action that helps to explain the observed lack of cross-resistance to current TB drugs.

Among the antibiotics in development, Sequella's orally active diamine antibiotic, SQ-109, could have the potential to replace one or more drugs in the current TB regimen. Having recently entered phase I trials, SQ-109 enhanced the activity of rifampin and isoniazid in a mouse model of TB, reducing the effective treatment time. The drug inhibits cell wall synthesis, a mechanism of action that is distinct from standard TB therapies.

The TB Alliance and Bayer have launched a global study into the potential of antibiotic moxifloxacin in shortening standard treatment. Moxifloxacin targets DNA gyrase, a mechanism of action not shared by current TB drugs. Preliminary studies showed that it may reduce treatment time by up to four months. Nearly 2,500 patients are being enrolled in the phase II global study, the goal of which is to register moxifloxacin so that it can become a key component of shorter first-line TB treatment. Phase II trials are expected to be completed by 2007.

A promising peptide
SciClone/Verta's synthetic dipeptide for drug-resistant TB, SCV-07, has also shown promise. Through its effects on T-helper type 1 cells, it stimulates the immune system to fight infection. Data from phase II trials of an injectable formulation showed no systemic or local adverse effects, while a US phase I study of an oral formulation showed its comparability with the injectable form. Preclinical studies in combination with BCG resulted in a significantly superior protective effect, compared with BCG alone.

Discovery programmes
Some early-stage research programmes are also underway under the auspices of the TB Alliance. A partnership with GSK consists of four projects intended to yield new compounds that attack M tuberculosis on multiple levels. Under investigation are pleuromutilins, a novel class of antibiotics that inhibits bacterial protein synthesis, and two mycobacterial target-based projects: isocitrate lyase (Icl) and InhA, an enzyme involved in the synthesis of fatty acids.

Icl is required to provide nutrients essential for M tuberculosis to survive under conditions of slow growth; candidates emerging from the programme are expected to be effective at killing persistent or slow-growing bacteria. InhA inhibitors have the capacity for bactericidal activity without causing resistance. The fourth project will screen GSK's antimicrobial libraries for novel compounds that have the ability to kill M tuberculosis; these will be tested for compatibility with antiretrovirals.

The TB Alliance is also identifying better quinolone and macrolide antibiotics.

Outlook for this sector
In 2001, a report by the TB Alliance forecast the potential market for a new TB drug to be between Ä478m and Ä523.2m ($612m and $670m) by 2010, with the internal rate of return for a new TB drug to range from 15 to 32 per cent. Through the support of public-private partnerships, however, development costs can be shared and the risks reduced.

It appears, given the number of prophylactic and therapeutic programmes that are currently ongoing, only a few of which are highlighted here, that the pharma industry is indeed responding to the call to develop treatments for TB that are more efficacious and patient-friendly. Alongside the WHO's DOTS programmes, the activities of the TB Alliance have provided a framework to encourage drug development by industry and academia, while reducing the risk involved. With many potential new therapies only just moving into clinical trials, and cases of TB on the rise, the market looks set to be highly lucrative for the first novel TB drug to be launched in over 30 years.

The author
Justine Hookes is a content manager, drug information and literature, at Thomson Scientific. This article is based on data taken from the Thomson Pharma database (

2nd September 2008


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