Johnson & Johnson has filed an NDA seeking accelerated approval from FDA for bedaquiline (TMC-207) as an oral treatment to be used in combination therapy in pulmonary, multi-drug resistant tuberculosis (MDR-TB), the firm announced July 2.

If okayed by FDA, the compound, a diarylquinolone, would be the first approved therapy with a new mechanism of action for TB in over 40 years, but also the first drug indicated for MDR-TB. Discovered at J&J subsidiary Janssen Research & Development, LLC, bedaquiline works by targeting adenosine triphosphate (ATP) synthase, which Mycobacterium tuberculosis requires to generate energy.

The NDA is supported by 24-week data from a two-trial Phase II program; a double-blind Phase III trial testing bedaquiline against placebo, on top of background therapy, over nine months of treatment will begin enrolling patients during the fourth quarter.

The first Phase II trial in MDR-TB patients was a two-stage, placebo-controlled trial that measured time to culture conversion following a regimen of bedaquiline 400 mg once daily for two weeks, then 200 mg three times a week for the next 22 weeks. The study enrolled 161 patients who received 24 weeks of treatment, and then those patients moved into the second stage, which measured follow-up treatment ranging from 12 to 18 months. The NDA includes 72-week data from the follow-up study.

A second, open-label Phase II trial investigated the compound in 233 treatment-experienced patients. To date, the compound has demonstrated antibacterial activity against drug-susceptible and multi-drug resistant strains of TB.

Paul Stoffels, J&J’s worldwide chairman for pharmaceuticals, noted that TB kills an estimated 1.4 million patients annually and that there are inadequate therapies at present for resistant strains of the disease. MDR-TB, which incorporates strains resistant to two of the current drugs in the TB armamentarium, was estimated by the World Health Organization as presenting 650,000 cases worldwide in 2010 and causing 150,000 deaths in 2008. In the U.S. TB is an orphan disease, with an estimated 100 to 130 MDR-TB cases annually.

At study published in the June 7 issue of the New England Journal of Medicine found that China is in danger of experiencing a serious epidemic of MDR forms of tuberculosis, with double the global average of new cases. Using WHO figures as a basis for comparison, the authors wrote that "China has the highest annual number of cases of MDR-TB in the world -- a quarter of the cases worldwide." MDR-TB has been a growing problem in India for years. Last December, Zarir Udwadia, a leading Indian authority on MDR-TB, reported that a mutant strain had emerged and was proving untreatable.

Bedaquiline was included among several experimental agents tested in a Phase II combination trial backed by the Global Alliance for TB Drug Development Also see "TB Study Lights Pathway Toward Combination Drug Trial Guidance" - Pink Sheet, 20 December, 2010.. In the New Combination 1 trial, bedaquiline was tested in tandem with Novartis AG’s PA-824, an experimental nitroimidazole. The same study also tested PA-824 in combination with Bayer AG’s moxifloxacin. Combination therapy is expected to be key in combating MDR-TB.

Johnson & Johnson Files NDA Seeking Accelerated Approval Of Bedaquiline In Tuberculosis

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