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Tuberculosis: treatment and prevention

One of the most significant global diseases, effective new TB therapies are sorely needed
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Tuberculosis (TB) is a highly infectious disease caused by the bacillus Mycobacterium tuberculosis (MTB). It typically affects the lungs (pulmonary tuberculosis) but may involve other organ systems in addition (extrapulmonary tuberculosis). MTB is a small non-motile, slow-dividing bacillus that stains very weakly “Gram-positive” and can survive in a dry state for weeks. The disease is transmitted by aerosolised droplets expelled primarily by coughing, sneezing and spitting; and the infectious dose of bacteria is very small (fewer than 10 bacteria can cause infection). Most infections are asymptomatic (latent TB) but approximately 1 in 10 latent infections eventually progresses to active disease, which if left untreated, kills over 50 per cent of those so infected.

Due to the nature of transmission, those with frequent, prolonged or close contact with infected people are at the highest risk of becoming infected, with an estimated 22 per cent infection rate dependent on various factors. These factors make TB one of the most significant global diseases, especially in developing countries, and among HIV-infected individuals. The latest data from the US Centers for Disease Control (CDC) estimates that up to one third of the world's population is infected with TB, with up to 80 per cent of populations in Asia and Sub-Saharan Africa infected. This compares to an infection rate of 5-10 per cent in the USA (9,945 cases reported in the US in 2012, a 5.4 per cent decrease from 2011). Tuberculosis is the second most common cause of death from infectious disease (after those due to HIV/AIDS), with up to 1.45 million deaths occurring in 2010.

Drug-resistant TB has become a serious health issue in many countries, as the treatment required becomes longer and more expensive

TB prevention relies primarily on the vaccination of infants with the bacillus Calmette-Guérin (BCG) vaccine which is the only current widely available preventative measure. This vaccine, first used in humans in 1921, is effective against disseminated disease, but the protection offered against contracting pulmonary TB is variable. Immunity also decreases over the decade following administration and 'repeat dose' immunisation is required for those deemed at high risk. However, a number of newer vaccines are currently in development.

New vaccines
Vakzine Projekt Management is developing VPM 1002, a recombinant urease C-deficient listeriolysin expressing BCG vaccine, for the prevention of TB in subjects living in endemic regions and in people at risk of the disease in non-endemic areas. The vaccine is in phase 2 clinical development in South Africa as an intradermal injection in neonates. The concept behind the design of the vaccine is based on the assumption that the enhanced expression of lysteriolysin under optimal conditions forces the rBCG cells (normally hidden in the phagosome of the macrophage) out of the phagosome thus triggering the CD4 and CD8 cell-mediated immune response. A phase 2 clinical trial evaluating the tolerability and immunogenicity of intradermally injected VPM 1002 in newborn infants was completed in November 2012 in South Africa.

Aeras and GlaxoSmithKline (GSK) Biologicals have entered into a public-private partnership to develop GSK's tuberculosis vaccine candidate, GSK 692342. The vaccine consists of a recombinant fusion protein (Mtb72f) formulated in GSK's adjuvant system. GSK 692342 is being developed for two indications: prevention of primary tuberculosis infection in young children in highly endemic areas, and as an adjunct to treatment for tuberculosis in adolescents and adults. Phase 2 clinical studies of the vaccine candidate have been completed in Switzerland, Belgium, Gambia, South Africa and the Philippines, and are ongoing in Taiwan, India and Estonia. GSK 692342 induced a M72-specific CD4 T cell response in adult patients, with well controlled chronic HIV infection, who were receiving highly active antiretroviral therapy. All recipients were seropositive to anti-M72 antibodies one month after the second dose.

The Statens Serum Institut (SSI), Valneva and Sanofi Pasteur are collaborating in the development of a recombinantly-engineered prophylactic vaccine for TB, designated H4IC. The H4IC vaccine candidate consists of Valneva's synthetic adjuvant IC 31 and two fused immunodominant antigens, Ag85B and TB10.4, which are secreted by MTB. In February 2014, Aeras and Sanofi initiated enrolment in a phase 2 study to assess tolerability, immunogenicity and prevention of TB following administration of H4IC vaccine or BCG re-vaccination in healthy adolescents, in South Africa. Preliminary results are expected at the end of 2015. 

Early-phase development
Various other vaccine candidates are in early-phase development globally. Adis R&D Insight lists six vaccines currently in phase 1 development and 23 in development at the preclinical or research stage. These include DNA and dendritic cell vaccines among others. The Finlay Institute of Cuba is developing vaccines for the prevention of various bacterial, viral and parasitic diseases. The company's tuberculosis vaccine research is focused on multi-epitope T and B BCG-resistant strains of MTB using bacterial outer membrane protein modulators.

GenomIdea (a subsidiary of AnGes MG) is developing therapeutic DNA vaccines against TB. Vaccines are being designed to express TB heatshock protein (HSP) 64 or 65 and IL-2; preclinical development is underway in Japan. Preclinical results of the vaccine showed that intratracheal administration increased IL-2 and IFN-y production, as well as proliferation of peripheral blood lymphocytes, in cynomolgus monkeys as a model of human TB.

Treatment and management of TB infection involves long-term administration of antibiotics, primarily rifampicin and isoniazid. Effective treatment is difficult due to the unusual structure and chemistry of the bacillus cell wall which hinders entry of many drugs. Latent TB is often treated with a single antibiotic whereas active TB is best treated with antibiotic combinations. This is to reduce the chance of the bacteria developing antibiotic resistance. Drug-resistant TB has become a serious health issue in many countries, as the treatment required becomes longer and more expensive. Multi drug-resistant TB (MDR-TB) is defined as resistance to the gold standard treatment of isoniazid and rifampicin. This can progress to extensively drug-resistant TB (resistant to three or more of the six classes of second-line therapies) or in the worst case, totally-drug resistant TB, which is resistant to all currently used drugs.

Bedaquiline is a diarylquinolone compound that inhibits ATP synthase (ATPase) in MTB. This product was discovered by Johnson & Johnson and is being developed by its subsidiary Janssen Infectious Diseases BVBA. Bedaquiline has been approved for use as part of combination therapy, in adult patients with MDR-TB and has been shown to be active against drug-sensitive MTB and MDR-TB strains. The proportion of patients who became culture negative was significantly greater with bedaquiline treatment than with placebo (47.6 per cent vs. 8.7 per cent), according to data presented from the first part of a phase 2b study. However, other existing data suggests that patients taking bedaquiline in addition to standard TB therapy are five times more likely to die than those without the new drug, which has resulted in medical journal articles raising health policy questions about why the FDA approved the drug.

Otsuka Pharmaceutical is developing delamanid, a nitro-dihydroimidazo-oxazole derivative, for use as an oral anti-TB agent. Regulatory submissions have been made in the EU and Japan for the treatment of multidrug-resistant tuberculosis. Delamanid is also in phase 3 development in the US, Estonia, India, Latvia, Lithuania, Moldova, Peru, South Africa and the Philippines for this same indication. Phase 2 development in paediatric patients is underway in South Africa, the Philippines and the EU. Otsuka expects a decision from the European Commission in early 2014. 

Various other compounds are in early-stage clinical development for the treatment and management of TB including various cell wall inhibitors, ribosomal subunit inhibitors and DNA-polymerase and DNA-topoisomerase inhibitors. Preclinical and research programmes are investigating even more exotic treatment modalities such as endopeptidase Clp stimulants, DNA gyrase inhibitors, leucyl-tRNA synthetase inhibitors and electron transport complex 3 inhibitors.

Encouraging development
To encourage further discovery and development in TB treatment and management, various governments, foundations and organisations are promoting new economic models of vaccine development including large prizes and tax incentives. The Bill and Melinda Gates Foundation recently gifted $280m to the Aeras Global TB Vaccine Foundation to develop and licence an improved TB vaccine. A similar collaboration recently resulted in the development of a new fast-acting diagnostic test for TB which has almost halved the direct cost of accurate diagnosis. Despite these recent incentives and advances, TB remains one of the most deadly diseases on the planet. The rising incidence of multi- and total-drug resistant TB means that new prophylactics and therapies are sorely needed as soon as possible. However, radical changes in education and awareness programmes, increases in living standards and improved disease management as a whole are also required to properly bring this rampant disease under control.

Article by
William Stow

Adis International (Springer Healthcare), using data derived from Adis R&D Insight and Clinical Trials Insight. For further information on Adis services, please contact Daniela Ranzani on +39 02 423 4562 or email her

17th April 2014

From: Research

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