Sirturo Earns Full FDA Approval for Multidrug-Resistant TB

More than a decade after bedaquiline (Sirturo) received an accelerated approval status for the treatment of multidrug-resistant pulmonary tuberculosis, the US Food and Drug Administration (FDA) has granted the drug traditional approval. Bedaquiline is indicated as part of a combination regimen for adults and children aged 5 years and older who weigh at least 15 kg and who have pulmonary tuberculosis caused by Mycobacterium tuberculosis resistant to at least rifampin and isoniazid.

“Bedaquiline is absolutely, unquestionably saving lives out there, and it’s not just saving lives: The old treatments for drug-resistant TB could easily go to 18 months and often went to 24 months and had terrible failure rates along with awful side effects. Bedaquiline has allowed much shorter regimens that are working with much more efficacy,” said David Sherman, PhD, professor and chair of microbiology in the Center for Infectious Disease Research at the University of Washington in Seattle.

A member of the diarylquinoline class of drugs, bedaquiline has a unique mechanism of action. It targets subunit c of mycobacterial adenosine triphosphate (ATP) synthase, resulting, essentially, in a depletion of the energy supply for Mycobacterium tuberculosis.

Clinical Trials

Bedaquiline earned its wings based on results of an FDA-mandated post-marketing phase 3 trial. The STREAM stage 2 study, which confirmed the drug’s clinical benefit, compared two bedaquiline-containing regimens with an injectable combination.

The STREAM stage 2 trial was a randomized, phase 3, noninferiority trial conducted at 13 hospital clinics in seven countries that had prespecified tests for superiority if noninferiority was shown. The study enrolled individuals aged 15 years or older who had rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance.

The first phase of the study, STREAM stage 1, showed that a 9-month injectable regimen was noninferior to the World Health Organization (WHO) 2011 recommendation of a 20-month injectable regimen. The 9-month regimen was recommended by the WHO in 2016 but was set aside in 2020 when concerns of hearing loss associated with aminoglycosides prompted the WHO to endorse a 9-month bedaquiline-containing, injectable-free alternative.

STREAM stage 2 used a 9-month injectable regimen as its control, comparing it against both a fully oral 9-month bedaquiline-based treatment and a 6-month oral bedaquiline regimen that included 8 weeks of a second-line injectable.

The primary outcome was a favorable status at 76 weeks, defined as cultures that were negative for Mycobacterium tuberculosis without a preceding unfavorable outcome (death, bacteriologic failure or recurrence, or major treatment change).

In all, 83% of patients assigned to the oral regimen had a favorable outcome compared with 71% of those assigned to the control regimen.

“It is preferable to use bedaquiline as part of an all-oral regimen. The injectable medications (such as amikacin and kanamycin) have substantial toxicity, including permanent hearing loss,” said Serena P. Koenig, MD, MPH, associate professor of medicine at Harvard Medical School and an infectious disease specialist at Brigham and Women’s Hospital in Boston.

Safety

Rates of grade 3 or 4 adverse events were similar across all three study groups, but patients who took the all-oral regimen had significantly lesser ototoxicity than controls (2% vs 9%). The rate of ototoxicity was 4% for patients assigned to the 6-month oral plus injectable regimen compared with 8% for controls.

The drug label contains a black-box warning cautioning prescribers about the increased risk for death, as seen in one placebo-controlled trial of adults, and about the risk for QT prolongation.

Sherman noted that cardiotoxicity was initially a concern during bedaquiline’s development because the drug targets ATP synthase, an essential source of energy stores in virtually every cell of the body. In addition, there was an increased incidence of QT prolongation in preclinical studies. The deaths seen in the placebo-controlled trial, however, while unexplained, did not appear to be caused by QT prolongation.

The efficacy of the drug and its important role in shorter-duration regimens significantly outweigh its potential toxicities, he said.

“I consider bedaquiline to be safer than the injectable medications, particularly when EKG monitoring can be conducted and when use of other QT prolonging medications is avoided,” said Koenig.

Sirturo is marketed by Johnson & Johnson Innovative Medicine (formerly Janssen Pharmaceutical).

Sherman and Koenig had no conflicts of interest to disclose.