ZeNix trial shows effectiveness of BPaL regimen for TB can be maintained with reduced dosing of Linezolid

The results of ZeNix, a phase-III clinical trial that took place in 11 sites across Georgia, Moldova, Russia and South Africa, revealed that the BPaL treatment remains effective against highly drug-resistant strains of tuberculosis (TB) with reduced dosage and/or duration of the Linezolid component of the regimen. Along with the maintenance of efficacy, there was a decrease in Linezolid-associated side effects that accompanied the reduced dosage or duration of Linezolid. The results from the trial, which was led by TB Alliance, were published in the New England Journal of Medicine, a statement from TB Alliance has said.

The BPaL regimen—which combines the antibiotics Bedaquiline (B), Pretomanid (Pa) and Linezolid (L)—received its first regulatory approval by the US Food and Drug Administration (FDA) in August 2019 as a six-month, three-drug, all-oral regimen for the treatment of people with multidrug-resistant TB, who are treatment intolerant or non-responsive as well as extensively drug-resistant TB (as defined by WHO prior to 2021). Historically, treatment of such forms of TB would take 18 months or longer, with reported global success rate of 52 per cent. BPaL has now been procured by more than 30 countries around the world, added the statement.

“These results add to the substantial evidence base for the efficacy and safety of the BPaL regimen and will enable care providers to further optimise use of the regimen,” said Mel Spigelman, MD, President and CEO, TB Alliance, in the statement, which developed Pretomanid and pioneered the use of the regimen.

He added, “We will continue to innovate and fight for access until the days of lengthy and highly toxic therapies are over for every person with TB.”

The statement also noted that a government-led study of the regimen in India called mBPaL commenced in October 2021, and is now enrolling patients at three sites out of a planned. It is scheduled to reach its primary completion in 2023 after enrolling 400 patients.

In addition, it mentioned that ZeNix was a four-arm, randomised study that enrolled 181 participants. Of these participants, 36 (20 per cent) were HIV-positive. Participants were treated for six months with Bedaquiline, Pretomanid and varying doses and durations of Linezolid, with follow up until the primary endpoint six months after completion of treatment. The study, which was double-blinded as to dosage and duration of Linezolid, sought to evaluate whether the efficacy of the BPaL regimen could be maintained while reducing a patient’s exposure to Linezolid and its associated side effects.

Participants were diagnosed with either extensively drug-resistant (XDR-) TB, pre-XDR-TB, or failed or treatment-intolerant multidrug-resistant TB. Per the modified intent to treat analysis, the success rate for participants receiving the highest dosage of Linezolid (1200 mg for six months) was 93 per cent. The efficacy level was similarly high in the remaining arms, reported as 89 per cent among participants receiving 1200 mg of Linezolid for two months, 91 per cent for those receiving 600 mg of Linezolid for six months, and 84 per cent among those receiving 600 mg of Linezolid for two months. Dosing of Bedaquiline and Pretomanid was consistent across the four arms. These findings are consistent with the 90 per cent success rate of the BPaL regimen in the Nix-TB trial, which used the 1200 mg for six months Linezolid dosage. The results of the Nix-TB trial were published in the New England Journal of Medicine in March 2020, the statement further noted.

It also said that adverse reactions reported in at least 10 per cent of trial ZeNix participants included peripheral neuropathy (38 per cent of those receiving 1200 mg of Linezolid for six months; 24 per cent of those receiving 1200 mg of Linezolid for two months; 24 per cent of those receiving 600 mg of Linezolid for six months; 13 per cent of those receiving 600 mg of Linezolid for two months). An evaluation of myelosuppression, as manifest as anaemia, found that patients had decreased haemoglobin levels related to Linezolid exposure (22 per cent of those receiving 1200 mg of Linezolid for six months; 17 per cent of those receiving 1200 mg of Linezolid for two months; two per cent of those receiving 600 mg of Linezolid for six months; seven per cent of those receiving 600 mg of Linezolid for two months).

Data from ZeNix contributed to a May 2022 rapid communication from WHO indicating new guidelines that will enable countries to treat virtually all patients with DR-TB with BPaL-based regimens. Further, a letter from the US CDC and Southeastern National TB Center was also published in the same issue, describing the treatment experience of the first 20 patients reported on BPaL in the US. The letter indicated that, by 12 months after initiation, 19 (95 per cent) patients had completed therapy with no treatment failures, recurrences or death.