The novel antibiotic candidate sorfequiline has the potential to shorten and improve tuberculosis (TB) treatment when combined with pretomanid and linezolid (SPaL), according to new clinical trial results presented today at the Union World Conference on Lung Health in Copenhagen, Denmark.

The phase 2 clinical trial, conducted by the TB Alliance across 22 sites in Georgia, the Philippines, South Africa, Uganda, and the United Republic of Tanzania, found that the SPaL regimen was effective and safe when administered for the treatment of TB for 8 weeks, as opposed to the standard treatment time of 6 months. 

The randomized controlled study involved 309 participants with newly diagnosed, smear-positive, drug-sensitive TB who were randomly assigned to five different treatment arms: 

• Three doses of sorfequiline (25 mg, 50 mg, or 100 mg) in combination with pretomanid and linezolid for 8 weeks, followed by a continuation phase of isoniazid and rifampicin (HR) for either 7 or additional 18 weeks
• The BPaL regimen (bedaquiline, pretomanid, and linezolid) for 26 weeks
• The standard-of-care treatment for TB, consisting of an 8-week intensive phase with isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE), followed by 18 weeks of HR

The endpoint was the time to stable sputum conversion by week 8. Participants assigned to sorfequiline could stop treatment at week 15 if their sputum was negative at week 8 and their TB symptoms had resolved. 

Eight-Week Advantage Emerges

The study found that by week 8, the proportion of participants with stable sputum conversion was: 

• 31%, 46%, and 59%, respectively, for the 25-mg, 50-mg, and 100-mg SPaL regimen
• 45% for the BPaL regimen
• 45% for the HRZE arm

The proportions of participants who met the stopping criteria at week 15 were 28%, 46%, and 64%, respectively, in the 25-mg, 50-mg and 100-mg SPaL arms. 

Overall, the study found that the SPaL regimen had greater activity against TB than the standard-of-care HRZE regimen, suggesting that TB treatment time could be greatly reduced. In addition, sorfequiline had greater activity than bedaquiline and a comparable safety profile to the standard-of-care for people with drug-sensitive TB. 

“If these findings are confirmed in a phase 3 clinical trial, SPaL could represent a significant advance in TB treatment towards TB Alliance’s goal of developing an ultra-short, one month treatment for all forms of active TB,” Maria Beumont, MD, chief medical officer at the TB Alliance, told Medscape News Europe.

Experts Upbeat, Questions Remain 

Alberto Matteelli, MD, full professor of infectious diseases at the University of Brescia, Italy, and director of the WHO Collaborating Centre for TB/HIV and TB elimination at Brescia University, told Medscape News Europe that the results were “encouraging.” 

“SPaL represents one of the hopes for shortening TB treatment down to 8 weeks, a true game changer for TB elimination,” said Matteelli, who was not involved in the study.

“A further future option for TBAJ-876 [the original name of sorfequiline] is the intramuscular administration that could strengthen treatment adherence and further reduce the treatment duration to 1 month.”

He noted, however, that several important questions remained. He emphasized the need for a phase 3 study on a much larger number of patients, raised concerns about the possibility of sorfequiline having a similar weakness to bedaquiline in terms of rising resistance, and mentioned the need to find a place for SPaL as a first-line treatment for multidrug-resistant or all TB cases. 

Sorfequiline and bedaquiline both belong to the diarylquinoline class of antibiotics that work by inhibiting a key enzyme that is essential for the bacteria to generate bacteria. 

In 2012, the FDA approved bedaquiline for drug-resistant TB treatment, the first new antibiotic to be approved for TB treatment in decades. It received conditional marketing authorization in the EU in 2014. However, numerous countries — including some in Europe — are showing a concerning rise in TB cases that are resistant to bedaquiline. 

Next: Phase 3

Beumont said the phase 3 clinical trial of SPaL will enroll participants with drug-resistant TB. 

“If the phase 3 results are successful, SPaL will represent a shorter treatment option to treat all those strains of drug-resistant TB, as well as some that are resistant to bedaquiline. More research is needed to fully confirm this hypothesis,” she added. 

“Given the continual evolution of the TB bacterium and its capacity to develop resistance to existing therapeutics, maintaining a robust global pipeline of novel TB drugs is essential. Only through the discovery and development of novel compounds and treatment regimens can we effectively sustain progress toward the global eradication of TB.”

SPaL is an all-oral TB treatment. The TB Alliance plans on exploring the delivery of a sorfequiline-based regimen as a long-acting injectable, a formulation that could help reduce treatment duration to 1 month. The phase 3 clinical trial will commence in some high-burden countries in 2026. 

Beumont is chief medical officer of the TB Alliance, which conducted the study. Matteelli reported no relevant financial relationships.