Pharmaprojects, the leading source of worldwide intelligence on pharmaceutical R&D, reports that there are just 22 active TB drugs in R&D under development by pharmaceutical companies worldwide - a startlingly low figure for a disease with such a heavy global burden.

Officially declared a global emergency by the World Health Organisation in 1993, two billion people - one third of the world's population - are thought to be infected with the Mycobacterium tuberculosis pathogen, and TB is the largest cause of death from any single infectious disease.

Furthermore, after almost 40 years in decline, the number of TB deaths is increasing, a problem exacerbated by global trade and mass population mobility. According to Pharmaprojects, there has been a concurrent rise in the number of TB therapeutics under development since 1995, but the numbers are in no way keeping pace with the growing problem of TB.

TB is currently treated with various drug cocktails, based on drugs discovered over 4 decades ago. Treatment is expensive and lengthy, usually taking 6-12 months to complete. Poor management of TB programmes, particularly in developing countries bearing the brunt of the burden, is contributing to the emergence of drug-resistant strains. Some progress has been made to simplify and boost compliance with treatment regimens, but what is really needed are effective drugs that work quickly, and new drug development strategies to tackle the growing problem of resistant strains.

To this end, the sequencing of the M. tuberculosis genome is beginning to yield results. Axxima is one company developing TB therapeutics against a novel target discovered through its genomics/proteomics drug discovery platform and earlier this year, Pharmaprojects reported on a drug discovery programme being carried out by Lupin, which has so far yielded 3 preclinical compounds. Another exciting therapeutic strategy is being carried out by Phage Genomics, which is developing a bacteriophage product.

Pharmaprojects also highlights important developments in vaccine programmes. Most notable was the news in January that Corixa and GlaxoSmithKline have started Phase I safety testing of their recombinant TB vaccine. According to the US National Institute of Allergy and Infectious Diseases, over 90 vaccine candidates have been tested in animals. However, this vaccine is the first new TB vaccine to be tested in humans in the US in more than 60 years. Moreover, it is the first recombinant TB vaccine ever to be tested in humans. Hot on its heels is Oxxon Pharmaccines' vaccine candidate, which Pharmaprojects also reported to be in clinical trials earlier this year.

"There have been very exciting advances in the science over the last few years with developments in genome-based biology following on from sequencing of the M. tuberculosis genome," says Professor Douglas Young, who chairs the Stop TB Vaccines Working Group. However, "Pharma enthusiasm for TB is limited by a combination of high-risk science and market uncertainty," he notes.

Indeed, a number of factors contribute to a general reluctance for industry investment in anti-infectives, not least the limited financial returns on drugs that are used in an acute setting. Furthermore, only 5% of TB sufferers can afford treatment - a poor incentive for private investment.

While the market size is enormous in terms of patient numbers, the global TB market is estimated at only US $500 million. According to Pharmaprojects, just 50 TB development programmes have been pursued in the 20+ years that the database has been tracking pharmaceutical R&D. The lack of commercial motivation is compounded by a significant attrition rate: of the 50 TB programmes mentioned, 27 have been abandoned.

Nevertheless, the general consensus is that the long-term solution to tackling TB will come through a union of public and private expertise. The Global Alliance for TB Drug Development is a non-profit organisation pursuing such partnerships, which has built up a portfolio of 10 pipeline candidates. PA-824 is the first product of public-private collaboration, under joint-development by Chiron and the TB Alliance. PA-824 has shown promising preclinical activity and is expected to enter the clinic this year. Most importantly, it acts via a novel mechanism - a crucial feature in the fight against resistant TB.

Partnership between the public and private sectors offers a practicable way to reinvigorate TB drug development. "For 40 years, TB drug development was at a near standstill. Today, we have a robust pipeline, which is a quantum leap from where the world was 3 years ago," said Dr. Maria C Freire, Chief Executive Officer of the Global Alliance for TB Drug Development.

A number of companies are spinning out TB research to non-profit initiatives, including Novartis' pioneering Institute for Tropical Diseases, which will focus on TB drug discovery.

Development of drug candidates will then be teamed with the TB Alliance on a non-profit basis for endemic countries. GlaxoSmithKline and AstraZeneca have put similar TB initiatives in place. Pharmaprojects expects to see some rapid and innovative changes in industry involvement in TB research, and will continue to monitor future developments.

(13/4/04)