Focus on treating TB steps up
Over the past few years, several factors have emerged, which are contributing to increased R&D activity in Tuberculosis (TB) therapy.
No new drug class has been introduced for over 30 years and the current market is dominated by generic products. There are only a few companies that market TB therapies. Eli Lilly, AstraZeneca, Sanofi-Aventis, Pfizer and Sandoz (Novartis's generics division) are some the global companies that have a focus on TB therapies. But in the past 10–15 years, R&D activity in TB therapy has increased for several reasons.
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The economic impact of TB is huge. More than 75 percent of TB deaths affect the population aged between 15–54 years, the most economically active segment. TB is estimated to cause lost productivity of 4–7 percent of GDP and to deplete the economies of developing countries by a total of $12 billion per year. The burden of TB in India is indeed staggering by any measure according to TB India 2007 Report. More than 80 percent of the burden of TB is due to premature death, as measured in terms of disability adjusted life years (DALYs) lost. About 17 crore workdays are lost due to the disease. And the annual economic cost of TB to the Indian economy is at least $3 billion (more than Rs 13,000 crore).
Multi-drug resistance is another major problem. Cases of extremely drug resistant TB (XDR-TB) that cannot be effectively treated with first- or second-line therapies have been reported worldwide, including in the US. WHO-led global control programs aim to halt the rise in TB incidence by 2015 and to halve the 1990 prevalence and morbidity rates globally. The costs of reaching these targets will be around $56 billion over 10 years and WHO anticipates that funding of only around 45 percent of this total will be available.
The current gold-standard treatment for active TB is a six-month regimen with rifampicin and isoniazid, supplemented in the initial two months with pyrazinamide and either ethambutol or streptomycin. This combination has the three properties required for effective TB management: antibacterial activity, capacity to inhibit the development of resistance and efficacy against persisting organisms.
According to some estimates, the sales of generic rifampicin in the US is $15-16 million. The WHO established a Global Drug Facility (GDF) in 2001 to procure and supply TB drugs to low-income countries. Svizera Europe, Lupin Pharmaceuticals, Cadila, and Strides-Sandoz are the designated preferred suppliers. The WHO GDF alone supplied $28 million worth of TB drugs to 55 countries in the last one to two years.
Lupin Pharmaceuticals manufactures and markets several branded generic TB treatments in high-burden markets and is also involved in the development of new therapies. Its lead molecule, LL-3858 is in Phase I trials.
A report by the TB Alliance estimated that in 2000 the market was worth between $412-470 million per year. This figure includes an estimated $275–318 million worldwide private TB market (based on IMS Health sales data for anti-TB drugs), an estimated $125–140 million tender market and an estimated $12.5 million for drugs to treat MDR-TB. It is estimated that the global TB market would grow to between $612–630 million by 2010.
The increased R&D activity now simmers hope that a number of new drugs for TB treatment would be found by 2015. There are some hopeful signs. AstraZeneca has a TB research facility in Bangalore focused on finding new therapies for TB. Novartis has a facility in Singapore for research in TB.
Lilly MDR-TB Partnership is a comprehensive public-private initiative led by Lilly to address the expanding crisis of multidrug-resistant tuberculosis (MDR-TB). It aims to transfer Lilly technology for the production of two key MDR-TB drugs (cycloserine and capreomycin) to four partner companies in high-burden MDR-TB countries. Lilly's total contribution to the MDR-TB partnership so far is around $135 million.
In July this year, the TB Alliance announced an innovative approach to accelerating the identification and development of new, optimized, combination drug regimens for TB. In active TB, all therapies must involve multiple drugs to prevent the development of resistance. The new, aggressive strategy will survey potential TB drug combinations in preclinical models, well before clinical evaluation, an approach that has never been employed previously in TB drug development. This new plan has the potential to significantly decrease the time it will take to develop novel optimized, combination therapies for TB.
The conventional approach to TB drug development evaluates potential compounds sequentially, substituting them individually into the existing regimen. Each alteration is studied in clinical trials, which take at least six years to complete Phase IIB and III. All told, a regimen consisting of completely new drugs would require more than 24 years of clinical development - too long to wait.
To jump start this new, aggressive approach, the TB Alliance is preparing to move PA-824--its first novel TB drug candidate--into TB patients for the first time later this year, while also working with its partners to advance moxifloxacin, another new TB treatment option with the potential to shorten treatment time--into large scale, Phase III clinical trials.
PA-824 is a nitroimidazole, a novel class of anti-bacterial agents for the treatment of TB. As a potential TB drug, it has many attractive characteristics - most notably its novel mechanism of action, its activity in vitro against all tested drug-resistant clinical isolates, and its activity as both a potent bactericidal and sterilizing agent in mice. With the completion of several Phase I trials in healthy volunteers, PA-824 will enter a Phase II Early Bactericidal Activity study in TB patients in South Africa.
Moxifloxacin is a fluoroquinolone, a subset of the quinolone class of antibiotics. Developed by Bayer HealthCare AG, moxifloxacin has demonstrated efficacy for the treatment of acute respiratory and some skin infections. It also has an excellent safety record, having been used more than 60 million times, in 104 countries. Moxifloxacin's mechanism of action differs from those of the first-line drugs currently used to treat tuberculosis, and it has demonstrated activity against TB in both in vitro and in vivo studies.
The REMoxTB Phase III clinical trial will be led by investigators at the University College London and the British Medical Research Council as part of a global clinical trial program coordinated by the TB Alliance and Bayer Healthcare AG.
To advance this new paradigm of drug combination development, the TB Alliance has initiated discussions with regulatory agencies including, but not limited to, the US Food and Drug Administration, the European Medicines Agency and the South African Medicines Control Council. The TB Alliance's "Open Forums on Key Regulatory Issues in TB Drug Development" will also continue in support of these discussions, and other issues related to accelerating TB drug development and approval.
accounts for 30% of the total global TB burden"
-Dr PR Narayanan, Director, TRC, Chennai
Dr PR Narayanan, director, TRC, Chennai, shares his thoughts with BioSpectrum on the TB cases in India.
What is the status of
tuberculosis (TB) in India?
What is the percentage of XDR and
MDR-TB cases prevalent in India and which are the drugs successful against
To what extent are the presently
available drugs combating TB?
What are some of the recent
projects going on at TRC and which are the newer drugs in the pipeline?
How successful has India been
with the anti-TB approach?
Every day in India, under the RNTCP, more than 15,000 suspects are being examined for TB, free of charge. The diagnosis of these patients and the follow-up of patients on treatment are achieved through the examination of more than 50,000 laboratory specimens. As a result of these examinations, each day, about 3,500 patients are started on treatment, stopping the spread of TB in the community. In order to achieve this, more than 600,000 health care workers have been trained and more than 11,500 designated laboratory Microscopy Centers have been upgraded and supplied with binocular microscopes since the inception of the RNTCP.
As a result of rapid expansion in diagnostic facilities, the proportion of sputum- positive cases confirmed in the laboratory is double that of the previous program and is on par with international standards. Despite the rapid expansion, overall performance remains good and in many areas is excellent. Treatment success rates have tripled from 25 percent in the earlier program to 86 percent in RNTCP
The operational feasibility of DOTS in the Indian context has been demonstrated, with 8 out of 10 patients treated in the program being cured, as compared with approximately 3 out of 10 in the previous program.
wants to empower communities battling with MDR-TB"
Lilly's philanthropic contribution to the global cause of multidrug-resistant tuberculosis (MDR-TB) management touched a whopping $135 million in 2007. In an interview, Sunita Prasad, consultant (MDR-TB & CSR), Eli Lilly, talks about Lilly's continued efforts in this direction. Excerpts:
How many people are affected by
MDR-TB in India every year?
What is Lilly's contribution to
drug development for TB treatments?
What are the challenges in
combating MDR-TB in a country like India?
What is Lilly's approach to
Who are your partners in the
battle against MDR-TB?