Global burden of TB

As per WHO report, one-third of the world's population is currently infected with the TB of which 80% are from the 22 high-burden countries alone. Global incidence of TB is increasing by 0.6% per annum. At least one person in the world is newly infected with the TB bacilli every second. Left untreated, each person with active TB will infect (on average) 10-15 people every year.450, 000 new Multiple Drug Resistant (MDR) -TB cases are estimated to occur every year. An estimated 5% of TB patients are co-infected with HIV

Inadequacy of existing therapy

The current TB treatment relies on the “Directly Observed Therapy” (DOT) which is combinatorial therapy involving 4 medicines (known as first-line drugs). This "short" course treatment for TB combines isoniazid, rifampicin, pyrazinamide, and ethambutol for two months, then isoniazid and rifampicin alone for a further four months. The patient is considered cured at six months (although there is still a relapse rate of 2 to 3%). For latent tuberculosis, the standard treatment is six to nine months of isoniazid alone. Though proven effective this treatment regimen is too long and risk prone as discontinuation of courses leads to the development of new deadly drug resistant strains.

Emergence of drug resistance

The inadequacy and flawed administration of existing treatment has resulted in the emergence of MDR (multiple drug resistant) and XDR (extremely drug resistant) TB. MDR-TB is defined by resistance to the two most commonly used drugs in the current four-drug (or first-line) regimen, isoniazid and rifampicin. And XDR-TB is defined as TB that is resistant to any fluoroquinolone, and at least one of three injectable second-line drugs (capreomycin, kanamycin, and amikacin), in addition to isoniazid and rifampicin. In such cases treatment with existing first line drugs along with second line drugs and antibiotics can take up to two years or more, and is highly complex, expensive, and toxic. It is estimated that a third of all MDR-TB patients die owing to the heavy dose regimen and complications associated with treatment. 70% of XDR-TB patients die within a month of diagnosis. According to      recent reports 12 Indian patients have been detected with the new form of TB namely the Totally Drug Resistant TB (TDR-TB). This, combined with the rising tolls of MDR-TB and XDR-TB calls for immediate innovative scientific interventions

The emergence of MDR-TB and XDR-TB along with the neglected status of the disease calls for innovative scientific interventions. There is an urgent need of faster and simpler treatment regimen for TB that requires novel and potent drugs

Current status of TB drug discovery:

It has been estimated that, of the 1,556 new chemical entities marketed worldwide, between 1975 and 2004, only three were for tuberculosis. Development of a TB drug pipeline is essential after decades of apathy. There are still far too few compounds that represent new chemical classes with novel mechanisms of action and a low probability of encountering drug resistance.

The market size has been a major driving force for new drug discovery programs in major pharmaceutical companies. It has been roughly estimated that the discovery and development  of a new drug costs approximately between US$ 250-800 million and takes about 12 years. Although the big pharmaceutical companies have made commendable contribution to the discovery of drugs for several diseases yet the initiatives for the discovery and development of drugs for infectious diseases such as tuberculosis are lacking.

The prohibitive cost of Intellectual Property protection and maintenance, and the confidentiality of drug development do not allow collective efforts of the best brains of the world at national laboratories and academic institutions to work together with industry.

Solving the bottlenecks at early stages of drug discovery like target identification, target validation, etc is key to finding novel drugs for TB. Only availability of rigorously validated targets and lead compounds that inhibit them could mitigate the risks of pharmaceutical companies in bringing such drugs to the market. OSDD aims to provide a platform for knowledge sharing and collaborative research leading to identification of novel drug targets. This global collaborative effort is expected to reduce the time expended in conventional drug discovery process.

A decentralized, web based, community wide effort where students, scientists from different laboratories, universities, institutes and corporations could work together for a common cause could bring down the cost of drug discovery by knowledge sharing and collaborations. The OSDD process of discovery of new chemical entities will be in the public domain. The new chemical entities will be made available for public good as soon as they are discovered

Nature describes TB as an orphan giant that claims millions of lives every year. No new TB drugs have been developed in the past almost 50 years. It is often described as the disease of the poor and the pharma industries tend to bypass drug discovery for TB owing to the lack profitable markets.                                               

• TB diagnostics, like sputum microscopy and chest x-rays, currently in use is more than 100 years old and can only detect half of all active cases of TB. It also does not distinguish drug-sensitive from drug-resistant disease. As a consequence, many patients are given drugs that are destined not to work
• Today’s first-line TB drugs are more than 47 years old and must be taken for 6-9 months, while treating MDR-TB usually takes 18-24 months. Inconsistent treatment breeds drug-resistant strains that increasingly defy current medicines. Faster acting drugs are needed to shorten treatment duration, and new drugs that attack novel targets are needed to fight resistant strains of M.tb.
• Today’s TB vaccine, which is more than 85 years old, provides some protection against severe forms of TB in children but is unreliable against pulmonary TB, which accounts for most of the worldwide disease burden. (Source : Global TB Alliance)

Not just health

Not only that TB is major global health burden robbing people of their lives, TB is also a major hindrance in economic development of the poor, infecting adults in their most productive years (15-44) with impact on gross productivity of nations. TB can be extremely isolating for those infected with the disease. Studies show that individuals succumbing to TB rate their quality of life as significantly lower than those of healthy peers. TB effects women, in particular, isolating them from their families and devastating their abilities to parent their children due to fears of infecting them. The lack of productivity leads to lack of financial contribution to family and ultimately has a devastating impact on gross productivity of nations. The World Bank estimates that loss of productivity attributable to TB is 4 to 7% of some countries' GDP. Entire economies are affected by the world's TB epidemic, stifling human development on a large scale. TB will rob the world's poorest countries of an estimated $1 to $3 trillion over the next 10 years.(Source : Global TB Alliance)

TB research is an insular field and TB drug pipeline has been subjected to decades of apathy. Despite the advances in research and technology there are still far too few compounds that represent new chemical classes with novel mechanisms of action and a low probability of encountering drug resistance. The market size has been a major driving force for new drug discovery programs in major pharmaceutical companies. Although the big pharmaceutical companies have made commendable contribution to the discovery of drugs for several diseases yet the initiatives for the discovery and development of drugs for infectious diseases such as tuberculosis have been bypassed due to lack of market incentives. The prohibitive cost of Intellectual Property protection and maintenance, and the confidentiality of drug development prevent collective efforts of the best brains of the world at national laboratories and academic institutions to work together with industry.