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Testing Drugs For Resistant TB Seen As Prelude To Trials In Wider Population

Executive Summary

A Phase II trial of Johnson & Johnson's investigational tuberculosis drug TMC207 is highlighted in a June 4 New England Journal of Medicine editorial by NIAID's Cliffton Barry, not only for its positive results, but for its contribution to encouraging trial designs that could facilitate TB drug development

A Phase II trial of Johnson & Johnson's investigational tuberculosis drug TMC207 is highlighted in a June 4 New England Journal of Medicine editorial by NIAID's Cliffton Barry, not only for its positive results, but for its contribution to encouraging trial designs that could facilitate TB drug development.

The editorial and accompanying study data, appearing the same week as an FDA advisory committee on TB drug development, reinforce the idea that FDA's leadership is preparing for significant collaborations with other health agencies (1 (Also see "Hamburg/Sharfstein Agenda For FDA Emphasizes Collaboration" - Pink Sheet, 1 Jun, 2009.), p. 6).

NEJM also published results from the first stage of the Phase II study of TMC207 (diarylquinoline), sponsored by J&J subsidiary Tibotec, which enrolled a total of 47 patients with multi-drug-resistant TB. But plans for the drug are not limited to that population, according to the study.

An Oncology-like Approach To Infectious Disease

"Demonstration of anti-tuberculosis activity in patients with multi-drug-resistant TB paves the way for larger-scale trials of first-line anti-tuberculosis combination therapy for patients with drug-susceptible TB," notes Andreas Diacon, University of Stellenbosch, et al.

Barry, a scientist at the National Institute of Allergy and Infectious Diseases, applauds that sentiment. Testing oncology drugs in patients with advanced disease has been "a standard prelude to efficacy in the target population," he notes.

Researchers have been moving toward that oncology-like approach in the TB arena, where information gathered from small multi-drug-resistant-TB trials could be used to better formulate the larger, more expensive Phase III efficacy trials needed for drug-susceptible TB, he points out.

"This trial of TMC207 seems to be the first completed study" conducted with that in mind.

The trial also is important because it shows that diarylquinoline, a new class of drug that attacks a new target - ATP synthase - has therapeutic value, Barry says. Efforts already are under way to develop drugs against this target, he adds.

Enrollment is ongoing for the second stage of the TMC207 study, Brian Westfall of Tibotec reported during a June 3 meeting of FDA's Anti-Infective Drugs Advisory Committee. The session was convened to discuss endpoints for accelerated approval of multi-drug-resistant TB therapies (see 2 (Also see "Tuberculosis Trial Design: FDA/Company Endpoint Talks Go Public At Cmte." - Pink Sheet, 8 Jun, 2009.)).

Positive Results For An Add-On Therapy

The positive results for TMC207 are based on findings that the addition of the compound to a standard drug regimen for multi-drug-resistant TB reduced the time in which sputum cultures were converted from positive to negative, using the mycobacteria growth indicator tube system with liquid broth medium.

Conversion rates were 48 percent in the TMC207 arm, with 10 of 21 patients converting, and 9 percent in the placebo group, with two of 23 patients converting.

In addition, sputum samples were assessed for smears for acid-fast bacilli. Rates of negative smears at week four were 77 percent for the TMC207 arm and 55 percent for the placebo group; 84 percent for the TMC207 group and 68 percent for the placebo group at week eight.

During the multi-center trial, 23 subjects were randomized in a double-blind fashion to active treatment with TMC207 for eight weeks and 24 were randomized to placebo for eight weeks. Patients in the TMC207 arm received 400 mg of the drug once daily for weeks one and two, and 200 mg three times per week for week three through eight.

All patients received standard background therapy with kanamycin, ofloxacin, ethionamide, pyrazinamide, and cycloserine or terizidone. After eight weeks, all patients continued on the background regimen and were followed for another 96 weeks.

No patients discontinued treatment early because of adverse events. "Overall side-effect profiles were similar in the two treatment groups, with nausea, unilateral deafness, arthralgia, hemoptysis, hyperuricemia, pain in the extremities, rash, and chest pain being the most common adverse events associated with treatment," the investigators said.

- Cathy Dombrowski ([email protected])

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