Drug efficacious in MDR-TB

In final results of a randomized phase IIb trial, bedaquiline (Sirturo) also led to faster culture conversion when given with a preferred background regimen, according to Brian Dannemann, MD, of Janssen Research and Development in Titusville, N.J., and colleagues. Janssen Pharmaceuticals, the drug's maker, sponsored the study.

The drug also nearly doubled the cure rate after 120 weeks, according to the World Health Organization definition of cure, Dannemann and colleagues reported in the Aug. 21 issue of the New England Journal of Medicine.

In 2012, the global incidence of MDR-TB was 450,000 cases, according to the WHO, and the therapy is long and arduous with drugs that have unfavorable side effects, Dannemann and colleagues noted.

Drug-susceptible TB is treated with four so-called first-line drugs -- isoniazid (Nydrazid), rifampin (Rifadin), pyrazinamide, and ethambutol (Myambutol) -- in a 6-month standard regimen. But MDR-TB is characterized by resistance to isoniazid and rifampin and is treated for between 18 and 24 months with up to six other drugs.

Bedaquiline -- a diarylquinoline that inhibits mycobacterial ATP synthase -- is the first TB drug with a new mechanism of action to be approved for use in MDR-TB in 40 years, they added.

The FDA approved it in 2013, under the accelerated approval program, to treat people with MDR-TB for whom an effective treatment regimen is not available.

But the agency's Anti-Infective Drugs Advisory Committee had flagged some safety issues, noting that there was an imbalance in mortality between bedaquiline and placebo arms of studies presented as support for the application.

While that might seem "paradoxical," it's not unusual, according to Edward Cox, MD, and Katherine Laessig, MD, both of the FDA in Silver Spring, Md.

"Marketing applications that are reviewed by the FDA often rely on complex risk-benefit evaluations," Cox and Laessig argued in an accompanying Perspective article.

In this case, the indication is limited to a patient population with a heightened risk of death from TB and a "considerable unmet need" for treatment, they noted.

In those patients, the balance of risks and benefits is positive, they argued.

The approval was based on two trials, one in which the drug was used for 8 weeks and the current study, in which it was given for 24 weeks.

The FDA panel considered 72-week data from the study, which showed nine deaths in the bedaquiline arm and two in the placebo arm, as well as increased risk of a prolonged QTcF interval.

In the 120-week data, Dannemann and colleagues reported, the mortality imbalance remains -- 10 deaths among those treated with bedaquiline and two among those in the placebo arm.

However, the researchers reported, there is "no causal pattern evident."

One of the 10 deaths occurred during the 24-week treatment period, but all of the others were at least 12 weeks after the end of therapy, with a median time of 49 weeks, they reported.

The 2013 FDA assessment noted that both deaths in placebo patients appeared to be related to TB progression, as did five of the nine among bedaquiline patients.

There was no obvious common cause of the other four, Cox and Laessig noted.

The 10th fatality resulted from a motor vehicle accident after 130 weeks of the study, Dannemann and colleagues reported.

A confirmatory phase III trial that was required as part of the approval should help clear up the mortality risks, Cox and Laessig argued.

In the meantime, they concluded, physicians planning to use the drug should be aware of the mortality issue -- flagged in a black box warning on the label -- and ensure that patients have no other treatment options.

Dannemann and colleagues wrote that the reason for the mortality difference is "unclear."

All of the patients whose deaths were blamed on disease progression, they reported, either did not have culture conversion or reverted after conversion. As well, they all had one or more risk factors for a poor outcome.

But, they added, the 2% mortality in the placebo group was "surprisingly low," compared with rates ranging from 7% to 15% seen in other studies.

The development of bedaquiline for use in situations where efficacious and safe alternatives exist "should be approached with caution until more data have been collected to clarify the implication of the excess deaths," Dannemann and colleagues wrote.

While the safety of the drug remains an open question, the efficacy appeared to be durable, Dannemann and colleagues reported.

The researchers randomly assigned 160 patients with newly diagnosed, smear-positive MDR-TB to get placebo or 400 milligrams of bedaquiline once daily for 2 weeks, followed by 200 milligrams three times a week for 22 weeks.

Both bedaquiline and placebo were given with a preferred background regimen, which was continued for 96 weeks after the end of the active or placebo treatment.

The primary efficacy end point was the time to sputum-culture conversion in liquid broth.

In a modified intention-to-treat population, Dannemann and colleagues found:

• Bedaquiline reduced the median time to culture conversion from 125 days with placebo to 83 days, yielding a hazard ratio of 2.44, with a 95% confidence interval from 1.57 to 3.80, which was significant at P<0.001.
• At 24 weeks, culture conversion occurred in 79% of bedaquiline patients and 58% of those on placebo, a difference that was significant at P=0.008.
• At 120 weeks, the difference -- 62% versus 44% -- remained significant at P=0.04.

The WHO defines a cure in an MDR-TB patient as completing treatment with at least five consecutive negative cultures from samples collected at least 30 days apart in the final 12 months of treatment.

The agency also says that a single positive culture during that time need not rule out a cure -- if there is no clinical evidence of deterioration, a patient can be considered cured if the positive culture is followed by at least three consecutive negative cultures at least 30 days apart.

On that basis, Dannemann and colleagues reported, cure rates at 120 weeks were 58% in the bedaquiline group and 32% in the placebo group, a difference that was significant at P=0.003.

Aside from the mortality, they reported, there were no differences in rates of adverse events, treatment-related adverse events, and adverse events leading to study discontinuation.

The most frequent events were nausea, arthralgia, and vomiting, and most were grades 1 or 2, they found.

Patients taking bedaquiline saw their QTcF interval increase from baseline by 15.4 milliseconds on average, compared with an increase of 3.3 milliseconds in the placebo group.

The difference was significant at P<0.001, but after the end of the 24-week treatment period it gradually decreased, to the point where average values were similar to the placebo group by study week 60.

Despite the elevations -- including one patient who had a one-time QTcF prolongation of more than 500 milliseconds -- there were no reports of clinically significant dysrhythmias.

The researchers cautioned that the study was relatively small -- only 79 patients got bedaquiline -- and the inclusion criteria limited the number of patients with HIV co-infection.

They also noted that the study used a surrogate endpoint -- time to culture conversion -- rather than clinical cure. But the significant difference in WHO-defined cure rates at 120 weeks "provides evidence of the potential usefulness of this surrogate endpoint," Dannemann and colleagues argued.

The study was sponsored by Janssen Pharmaceuticals. Dannemann is an employee of the company.

Cox and Laessig are employees of the FDA. They made no relevant disclosures.

Primary source: New England Journal of Medicine
Source reference: Diacon AH, et al "Multidrug-resistant tuberculosis and culture conversion with bedaquiline" N Engl J Med 2014; 371: 723-732.

Additional source: New England Journal of Medicine
Source reference:Cox E, Laessig K "FDA approval of bedaquiline -- The benefit–risk balance for drug-resistant tuberculosis" N Engl J Med 2014; 371: 689-691.

Source: MedPage Today