Experimental Drug TMC207 Cuts Response Time for Multidrug-resistant Tuberculosis

		SUMMARY: Tibotec's investigational drug TMC207, added to a 5-drug combination regimen for 8 weeks, increased the cure rate for multidrug-resistant tuberculosis (MDR-TB) and reduced response time by more than half, according to study findings presented at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010) last month in Boston. A related report described good outcomes using meropenem/clavulanate in a small group of patients with extensively drug-resistant TB (XDR-TB).

By Liz Highleyman

Tuberculosis is the leading cause of death for people with HIV worldwide, and HIV positive individuals tend to experience more aggressive disease and do not respond as well to treatment.

Public health officials are especially concerned about the now-widespread MDR-TB, which is resistant to at least the 2 main first-line TB drugs, isoniazid and rifampin, as well as the more recent emergence of XDR-TB, which is also resistant to 3 or more second-line drugs, leaving patients "virtually untreatable using currently available anti-TB drugs," according to the World Health Organization.

Andreas Diacon from Stellenbosch University in South Africa and colleagues
reported results from the first stage of a Phase 2 trial that included 47 patients with newly diagnosed pulmonary MDR-TB. About 75% were men and the median age was 33 years. Participants were either HIV negative (88%) or, if HIV positive, had a CD4 count > 300 cells/mm3 and were not on antiretroviral therapy.

Participants were randomly assigned to receive either TMC207 (400 mg once-daily for 2 weeks, followed by 200 mg three times weekly) or placebo for 8 weeks, added to a 5-drug MDR-TB background regimen taken for 18-24 months. TMC207 works by inhibiting Mycobacterium tuberculosis synthesis of adenosine triphosphate.

Patients were considered cured of TB if they had 2 consecutive negative sputum cultures at least 28 days apart and no recurrence.

Results

	The addition of TMC207 to the background regimen for 8 weeks resulted in a 58% reduction in the median time to culture negativity.
	People in the TMC207 arm showed culture conversion after a median 11 weeks, compared with 18 weeks for the placebo group.
	81% of patients assigned to the TMC207 arm were culture negative at the end of the trial or last observation, compared with 57% in the control arm.
	54% of patients in the TMC207 arm and 43% in the placebo arm discontinued the trial prematurely, primarily due to loss to follow-up or voluntary withdrawal.
	26% and 21%, respectively, experienced moderate-to-severe (grade 3 and 4) adverse events.
	No serious adverse events attributable to the study drug were observed.

Based on these findings, the investigators concluded, "TMC207 administered for 8 weeks with a standardized 5-drug MDR-TB regimen was generally well tolerated and significantly increased the proportion of culture negative subjects at weeks 8 and 24 compared to placebo."

In addition, they said, "The TMC207 group converted sputum more than twice as fast as the placebo group."

Findings from stage 2 of this trial, in which 161 patients are receiving TMC207 for 24 weeks, are expected soon.

Meropenem/clavulanate

In a second study, Marie-Christine Payen?from University Hospital Saint-Pierre in Brussels and colleagues treated 4 patients with severe bilateral pulmonary XDR-TB using meropenem/clavulanate combined with only 1 or 2 second-line anti-TB drugs that remained active according to drug susceptibility testing.

They found that 3 patients -- including 1 who was HIV positive -- experienced short-term favorable outcomes. Sputum culture negativity occurred after 8, 11, and 20 weeks. Clinical status improved and lung lesions visible by X-rays decreased. All 3 were still on treatment at the time of the report.

Dr. Payen described one of these patients in more detail in a press release issued by ICAAC. A 14-year old girl from Chechnya with extensive bilateral pulmonary lesions and severe malnutrition had received first and second-line anti-TB drugs in Chechnya without improvement. The Brussels team treated her with a standard second-line regimen without success until they received her drug susceptibility results, which showed that her TB strain was only susceptible to capreomycin and linezolid. After adding meropenem/clavulanate to these 2 drugs, her clinical status rapidly improved and sputum culture conversion occurred after 11 weeks.

The remaining patient, who had a 7-year history of unsuccessful tuberculosis treatment, extensive lung lesions, and only 1 remaining active drug (capreomycin), failed to respond to meropenem/clavulanate. Therapy was interrupted after 8 months and the patient died 3 months later.

"Given the poor prognostic factors of our patients," the researchers concluded, adding meropenem/clavulanate "may have had a beneficial impact on the favorable outcome of 3 of them."

"Further studies are needed to explore the real clinical benefit of the combination of meropenem/clavulanate in the treatment of severe XDR-tuberculosis," they continued. "Potential limitations for its use include high cost, intravenous administration and lack of drug susceptibility testing."

Investigator affiliations:
Abstract L1-521a: Stellenbosch Univ., Tygerberg, South Africa; Medical Research Council, Durban, South Africa; Witwatersrand Univ., Johannesburg, South Africa; Aurum Health Inst., Johannesburg, South Africa; Tibotec, Inc., Titusville, NJ; Tibotec, Beerse, Belgium.
Abstract L1-517: CHU Saint-Pierre, Brussels, Belgium.

10/5/10

References
AH Diacon, A Pym, MP Grobusch, DF McNeeley, and others. Final Results from Stage 1 of a Double-Blind, Placebo-Controlled Trial with TMC207 in Patients with Multi-Drug Resistant (MDR) Tuberculosis (TB). 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010). Boston, September 12-15, 2010. Abstract L1-521a.

M Payen, C Martin, T Antoine-Moussiaux, and others. Four Cases of XDR-Tuberculosis Treated with Meropenem-Clavulanate. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010). Boston, September 12-15, 2010. Abstract L1-517.

Other Sources

ICAAC. Experimental use of the combination of Meropenem-Clavulanate in severe Extensively Drug-Resistant (XDR) pulmonary tuberculosis with few therapeutic options. Media advisory. September 12, 2010.

World Health Organization. Emergence of XDR-TB. Press release. September 5, 2006.