• 6 August 2007
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Focus on treating TB steps up

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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.

TB Alliance Portfolio
  • Discovery (Organization)

  • Nitroimidazole Analogs (University of Auckland and University of Illinois at Chicago)

  • Quinolones (KRICT/Yonsei University)

  • Multi-Functional Molecules (Cumbre)

  • Bacterial Topoisomerase Inhibitors (GlaxoSmithKline)

  • InhA Inhibitors (GlaxoSmithKline)

  • Pleuromutilins (GlaxoSmithKline}

  • Focused Screening - 2 projects (GlaxoSmithKline)

  • Riminophenazines (Institute of Materia Medica/BTTTRI)

  • Screening and Target Identification (AstraZeneca)

  • Malate Synthase Inhibitors (GlaxoSmithKline/Rockefeller Texas University, A&M)

  • New Targets (University of Pennsylvania)

  • Protease Inhibitors (Queen Mary, University of London)

  • Proteasome Inhibitors (Cornell University)

  • Protein Synthesis Inhibitor (Pharma)

  • Clinical Development (Organization)

  • Moxifloxacin (ethambutol sub.) (Bayer)

  • Moxifloxacin (isoniazid sub.) (Bayer)

  • Nitroimidazole PA-824 (Chiron/Novartis)

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.

TB drugs

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.

"India accounts for 30% of the total global TB burden"

-Dr PR Narayanan, Director, TRC, Chennai
Tuberculosis Research Centre (TRC), Chennai, is one of the International Centers for Excellence in research, funded by National Institute of Allergy and Infectious Diseases (NIAID) and National Institutes of Health (NIH), USA and completed 50 years in 2006.

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?
The estimated number of bacillary cases was 3.8 million, the number of abacillary cases was estimated to be 3.9 million and that for extra-pulmonary cases was 0.8 million giving a total burden of 8.5 million. India, at present, accounts for 30 percent of the total global TB burden.

What is the percentage of XDR and MDR-TB cases prevalent in India and which are the drugs successful against these?
The MDR prevalence in Indian settings, based on our studies, is as follows. It is 1-3 percent in new cases, among treated cases 12-14 percent and among CATII failures 33-40 percent. The exact prevalence of XDR-TB is not known but it is assumed to be 2-4 percent of MDR-TB cases.
The drugs that are used in the treatment of MDR-TB are quinolones, aminoglycosides, thiomides, cycloserine, PAS, thiacetazone, pyrazinamide and ethambutol.
XDR management is not yet defined. Drugs like PAS, thiacetazone, pyrazinamide and ethambutol may be of use.

To what extent are the presently available drugs combating TB?
Currently available anti-TB drugs are considered to be 100 percent regimens (establishing cure among all patients harboring sensitive organisms) under trial conditions and currently the program is able to cure about 85 percent of new patients and 50-70 percent of already treated patients.
The program also helps the patients by providing Directly Observed Therapy within two kilometers of their residence.
These drugs are freely available and the drug logistics of the program are good in all parts of our country.

What are some of the recent projects going on at TRC and which are the newer drugs in the pipeline?
The ongoing project of TRC is efficacy and safety of immunomodulator (Mycobacterium W) as an adjunct therapy in category II pulmonary tuberculosis.
Newer quinolones ( Moxifloxacin ) and compounds from Lupin and Tibotec are some of the new products.

How successful has India been with the anti-TB approach?
The Revised National Tuberculosis Control Program (RNTCP), based on the Directly Observed Therapy Strategy (DOTS), began as a pilot in 1993 and was launched as a national program in 1997. Rapid RNTCP expansion began in late 1998 and the entire country was covered under DOTS by March 24, 2006. This can be considered as the first major achievement. As of 25 July 2007, a total of 7,321,357 patients were treated and 1,317,844 lives were saved.

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.

Jahanara Parveen



"Lilly 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?
The data on the number of patients is more anecdotal and less reliable. However, the WHO report of global TB control indicates that there are approximately 44,600 MDR-TB patients in India every year. Some other figures say it is slightly higher than this. Globally India and China are responsible for about 50 percent of the MDR-TB cases. China leads in the number of MDR-TB cases with India following closely and Russia and South Africa being other high burden countries. India accounts for 20 to 22 percent of the global pie.
The MDR-TB initiative is in its fifth year now since its inception in 2003. Please elaborate on this commitment.
In 2003, we started with work on transfer of technology which was to ensure drug supply at concessionary prices, and then various efforts were made to establish Centers of Excellence (CoEs) in research and training and developing the training tools required for healthcare professionals for treatment, surveillance and infection control. Towards this, we have partners such as International Council of Nurses (ICN), International Federation of Red Cross and Red Crescent Societies (IFRC), International Hospital Federation (IHF), Harvard Medical School and Partners in Health (PIH), Purdue University (USA), TB Alert & TB Survival Project, Center for Disease Control (CDC), World Economic Forum (WEF), World Health Organization (WHO) and World Medical Association (WMA).

What is Lilly's contribution to drug development for TB treatments?
Lilly has announced a public-private partnership that would conduct early phase discovery research for new medicines including emerging resistant strains. The partnership will be a not for profit, drug research organization based in Seattle, USA and would draw on the resources of Lilly as well as leading researchers and organizations. Lilly would open its library of more than 5,00,000 medicinal compounds to researchers, who will test and screen them for possible TB treatments. Other partners contributing to the effort include Afya World Medicines, Infectious Disease Research Institute, Jubilant Biosys, Merck & Company, the Seattle Biomedical Research Institute, and the University of Washington, Department of Global Health.

What are the challenges in combating MDR-TB in a country like India?
Treating MDR-TB is a challenge in itself, as the treatment duration is long. The drugs have severe adverse reactions and adherence and compliance can become an issue. Treatment for normal TB takes 6-12 months, whereas for MDR-TB it is more than 24 months. As soon as the person feels slightly better, he/she stops taking the drugs. So this non-adherence or non-compliance may lead to development of further resistance.

What is Lilly's approach to tackle MDR-TB?
In India, we have a very robust national tuberculosis program known as RNTCP II . The RNTCP Phase II program looks at MDR-TB as a standard of care issue, that is to say that they emphasize that the best prevention of a growing problem of MDR-TB would be to have a strong and well performing Directly Observed Therapy Strategy (DOTS)–with high detection and cure rates. We are trying to support the GoI's initiative in various ways, which is again based on what we are doing globally. This includes transfer of technology, increasing the availability and supply of drugs, training healthcare workers and surveillance of programs for community support. Globally we have four focus countries -- China, South Africa, Russia and India. In each of these we have technology transfer partners to produce cycloserine and capreomycin, Lilly's two legacy drugs. The partners are Aspen Pharmacare in South Africa, Hisun Pharmaceutical in China, Shasun Chemicals and Drugs in India, and SIA International in Russia. Lilly wants to empower communities battling with the disease and it believes in the Chinese proverb, "If you give a man a fish, you feed him for a day, but if you teach a man to fish, you feed him for a lifetime."

Who are your partners in the battle against MDR-TB?
We are working with the government, institutions and some media partnerships are on the way. We are going to partner with IMA (Indian Medical Association) in taking forward the guidelines to private practitioners. Private practitioners are very crucial stakeholders in TB treatment because in India 50 percent of the population goes to private practitioners who don't follow the approved regimen. If wrong prescriptions are given and non-adherence resistance develops, a patient might develop MDR-TB.
We would also be working with the government at the Central and state level. We would be working with media for greater communication to reduce the stigma attached to the issue. Also we would be working with country-based organizations and an international organization, TB Alert to take this forward in community-based settings.

Shalini Gupta

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