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01/04/2009
Japan lab strikes at tuberculosis scourge, may beat J&J, Glaxo

Hiroshi Ishikawa spent half of his career searching for a tuberculosis cure. Now, after a quarter century, he may have the drug industry’s most effective weapon to fight resistant strains of the deadly lung disease.


In 1982, when tuberculosis was under control in developed nations, Ishikawa, a researcher at Otsuka Pharmaceutical Co. in southwest Japan, began looking for new ways to attack the bacterium plaguing poor nations in Asia. The result is OPC- 67683, the first new drug against TB in more than 40 years and one of the three most advanced in development worldwide.



Ishikawa’s success comes at a time when drug-evading bacteria are transforming an infectious disease that could be treated with $20 worth of medication into an unstoppable scourge. As tuberculosis once again becomes a global threat, Ishikawa, a 62-year-old chemist, has been joined in the fight by drugmakers Johnson & Johnson, GlaxoSmithKline Plc and AstraZeneca Plc, which also are developing new TB medicines.



“We’re really desperate for some better drugs,” said Tido Von Schoen Angerer, who heads aid group Medecins Sans Frontieres’s Campaign for Access to Essential Medicines in Geneva. “We are paying the price for decades of neglect. People are dying.”



A more effective pill may bring $400 million in annual sales, according to Sequella Inc., which is developing medicines and tests for TB in Rockville, Maryland. Since the World Health Organization in Geneva declared the disease “a global emergency” in 1993, more than 40 drugs have entered development.



Partial View



Otsuka’s medicine is in the second of three stages of tests required for regulatory review. Two other compounds are as well: TMC207 from the Tibotec unit of New Brunswick, New Jersey-based Johnson & Johnson; and PA-824, which a company now owned by Swiss drugmaker Novartis AG licensed to the TB Alliance, a New York-based non-profit group supported by the Gates and Rockefeller Foundations. Glaxo and AstraZeneca have medicines in earlier stages of research.



“I think we are the front runner,” Ishikawa said. Pamela Van Houten, a Tibotec spokeswoman, said J&J’s drug candidate is also in the second of three stages of human testing and declined to compare the product to Otsuka’s.



“It is a stark contrast to what we had at the end of the 1990s,” said Paul Nunn, coordinator of the TB and HIV drug- resistance unit with WHO’s Stop TB Department.



“In the rich world, where all the pharmaceutical companies are, TB was not seen as much of a problem after the 1970s because it was felt that we had very effective treatment, which was perfectly true,” he said. “There was a complete failure to understand the true extent of the burden in developing countries.”



‘So Long’



Tuberculosis epidemics were continuing in China, Indonesia and Thailand, where Tokyo-based Otsuka built factories in the 1970s and 80s. Ishikawa said it was these patients he was trying to serve.



He and colleagues at Otsuka, the family owned discoverer of Abilify, the world’s third-bestselling schizophrenia treatment, tested about 14,000 compounds to find one capable of overcoming strains that spread like the common cold yet aren’t killed by the most powerful drugs.



“It was something the rest of the world wasn’t doing,” said Ishikawa. “There were times when management questioned the point. We’ve been at this for so long and put so much of ourselves into it, we didn’t want to give up.”



Health leaders and ministers start a three-day meeting in Beijing today organized by the World Health Organization, China’s health ministry and the Bill & Melinda Gates Foundation to galvanize action against the new TB strains.



HIV’s Role



About 40,000 people develop extensively drug-resistant, or XDR, tuberculosis annually, according to WHO. By late 2008, 55 countries and territories had at least one XDR case, threatening to derail a decade of progress in tuberculosis control, the Geneva-based agency said in a report last week.



Tuberculosis became possible to cure in the mid 1940s with the discovery of the antibiotic streptomycin. Almost all the drugs used to fight it were found in the next two decades. Their effectiveness has been hampered by HIV. TB can flourish in HIV sufferers because the AIDS-causing virus attacks T-cells, the body’s immune defenders crucial in keeping tuberculosis at bay.



Toxic and Expensive



WHO estimates 9.27 million new tuberculosis cases occurred in 2007, up from 8 million a decade earlier. The disease kills almost 2 million people a year.



Every year, about 290,000 patients pick up a form of TB known as multidrug-resistant, or MDR, that doesn’t respond to the standard six-month treatment. Almost as many develop MDR-TB from incorrect, interrupted or frequently repeated therapy. Those patients must undergo a two-year regimen with medications that are more toxic and 100 times more expensive.



Hospitalization, surgery and treatment with stronger medicines, such as Eli Lilly & Co.’s Capastat, can cost as much as $500,000 per person in the U.S. Each infectious person can pass it on to as many as 15 others annually, according to Paris- based Medecins Sans Frontieres, also known as Doctors Without Borders.



Otsuka began assessing the efficacy, safety and dosage of its antibiotic a year ago in a trial involving 430 patients with MDR tuberculosis in 10 countries. Even when treatment follows guidelines, as many as one in eight patients develop extensively drug-resistant TB, fatal in about half of cases, said Von Schoen Angerer.



‘Happy Day’



Researchers will finish recruiting test subjects this year. Patients receive either standard treatment plus the Otsuka medicine or standard treatment and a dummy pill for 56 days.



They will be monitored for two years for relapse, with results ready as early as 2012 -- a full decade after Ishikawa first tested the compound on animals.



“It was a happy day when we started pre-clinical studies, but we knew there were many more hurdles to clear,” he said.



Not least was safely mass-producing the compound, whose active ingredient is derived from an explosive and could have detonated in the factory, Ishikawa said.



The compound blocks the production of mycolic acid, a key component of the dense, waxy shell that encases the tuberculosis bug and helps it resist penicillin and most antibiotics.



“It’s been a series of twists and turns to get this far,” said Ishikawa, who has postponed retirement since 2007 to complete the research. “But I am glad that we stuck with it.”


By Kanoko Matsuyama and Jason Gale




Source: Bloomberg.com