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New TB drug shows promise in phase 2 trials

The search for better TB drugs got a boost recently with the presentation of promising findings from a study conducted in South Africa on an experimental medication called quabodepistat.

While three tuberculosis medicines have been registered in South Africa over the past decade, treatment still comes with several side effects and requires taking multiple different medicines, typically for six or more months.

In Spotlight, Elri Voigt reports on the latest and other TB studies presented at a conference in Denver, Colorado.

She writes:

Arguably, the biggest TB news at the Conference on Retroviruses and Opportunistic Infections (CROI) was that the experimental new TB drug quabodepistat performed well in a phase 2b/c clinical trial. This means the drug can now proceed to a pivotal phase 3 trial (medicines are typically approved by regulators only after positive results in phase 3 trials).

The interim study results presented at CROI indicated that quabodepistat in combination with bedaquiline and delamanid, and given for four months to people with drug susceptible TB, is safe and efficacious, compared with the six-month standard of care regimen.

The standard of care regimen, currently used in South Africa’s public sector, consists of the drugs rifampicin, isoniazid, ethambutol and pyrazinamide.

Participants were split into four study arms to either receive 10mg, 30mg or 90mg of quabodepistat (along with delamanid and bedaquline) once daily for four months, or the standard of care regimen for six months.

In the quabodepistat arms, a total of 98 study participants completed treatment, compared to 19 in the standard of care arm.

Taken together, 96% of participants in the quabodepistat arms had sputum culture conversion compared with 91% in the standard of care arm. Sputum culture conversion means TB was no longer detected in sputum samples couched up by people when those samples were grown in the lab.

The study was conducted at several sites in South Africa and was funded by Japanese pharmaceutical company Otsuka.

‘Furthest along’

Lindsay McKenna, the TB project co-director at Treatment Action Group (TAG – a New York-based NGO), told Spotlight that quabodepistat is a new drug with a new mechanism of action for inhibiting TB’s cell wall synthesis. Essentially, this means the drug interferes with the TB bacteria’s cell wall structure.

While there are a few new drugs that work the same way, quabodepistat is the furthest along.

However, there is still some way to go before we will know if quabodepistat is bound for wider use than just in clinical trials. “We need to see data on clinical outcomes first,” McKenna said, adding that quabodepistat is also being assessed in another ongoing phase 2b/c clinical trial.

“Remember that we have only seen sputum culture conversion results. Follow up is ongoing, so we will learn more when we see the proportion of participants with favourable outcomes (for example relapse-free cure) 12 months’ post-randomisation,” she said.

“Meanwhile, I think Otsuka should immediately begin working to launch a pre-approval access programme so people with unmet needs can obtain quabodepistat.”

Safety signals

Dr Simbarashe Takuva, associate director of Clinical Development at Otsuka Novel Products GmbH (an affiliate of Otsuka), who presented the results on behalf of the study team, said that overall, the quabodepistat regimen was well tolerated and considered safe.

Adverse events reported were generally described as mild or moderate, but there were some concerning signals. Grade 3 adverse events stood at 15% in the quabodepistat 10mg arm, 12% in the 30mg arm, 11% in the 90mg arm, and 5% in the standard of care arm. Grade 3 adverse events are typically serious enough to prevent someone from working.

Takuva said there were no serious adverse events (which we understand to mean grade 4/life threatening adverse events) related to the study drugs. There were also no treatment discontinuations. There was a single death in the study, a 25-year-old man who had met all study eligibility criteria but got sicker during the study.

The study drugs were halted and standard of care drugs given instead but the participant later died in hospital.

The researchers also looked for signs that quabodepistat might adversely affect the liver and the heart, but no safety signals were seen in either.

“The data presented didn’t raise concerns about any treatment related cardio- or hepatotoxicity signals, however, it was a relatively small study, and the inclusion criteria were conservative,” McKenna said.

One snag is that the results presented at CROI did not provide a clear answer regarding which of the three quabodepistat dosages in the study is preferable. Based on the clinical data, Takuva said it was difficult to determine which was best to use.

However, he said additional research was focusing on pharmacokinetic and pharmacodynamic data, which would hopefully provide more information on the ideal dose.

“Follow up on this study is ongoing. We await the final results of our phase 2 trial toward the end of the year,” he said.

No study participants with HIV

One big limitation was that the study did not enrol anyone with HIV. Takuva said there was a strict exclusion criterion for CD4 counts.

Initially, the CD4 count cut-off for the study was set at above 500 cells/mm3, then was amended to 350 cells/mm3, and finally, dropped to above 250 cells/mm3, but by that time it was too late to enrol anyone with HIV.

When asked about this, Takuva told Spotlight the protocol did include the provision to recruit people with HIV, but it was not feasible to include any. However, people with HIV will be considered as important to include in any phase 3 trials in the future.

Treating DR-TB in people with HIV

Research was also presented at CROI looking specifically at the progress of people with HIV in the landmark endTB trial. Other results from endTB were previously reported and the trial is widely considered one of a handful of key trials transforming the treatment of drug-resistant forms of TB.

The researchers found that two nine-month regimens studied in endTB did particularly well in people with HIV. The two regimens were: bedaquiline/linezolid/moxifloxacin/pyrazinamide and bedaquiline/clofazimine/linezolid/levofloxacin/pyrazinamide.

Some disappointments

In a disappointing development, researchers reported that a study testing a three-month regimen for the treatment of drug-susceptible TB was stopped early after an interim review found it had poor efficacy compared with the six-month standard of care.

The regimen contained the drugs clofazimine and rifapentine, among others. It means that for now the shortest regimen for treating drug-susceptible TB validated in a clinical trial remains a four-month regimen containing the medicines rifapentine and moxifloxacin, among others.

That four-month regimen is not yet in wide use, even though findings confirming its safety and efficacy were reported in 2020.

We also received some bad news on an experimental TB vaccine called H56:IC31. The idea of H56:IC31 was to vaccinate people who were just cured of TB to prevent the disease from coming back – people whose TB is deemed to be cured have an increased risk of contracting it again.

Despite promising signs in earlier studies, the vaccine failed to reduce TB recurrence in a phase 2 clinical trial of more than 800 people.

TB treatment’s impact on mental, physical health

Another interesting study conducted in South Africa and presented at CROI looked at the changes in mental and physical health experienced by TB patients before and after treatment. It found their quality of life and physical fitness was reduced at the start of treatment but did improve by the end.

The researchers looked at 200 study participants split between South Africa, Zambia, Malawi, Mozambique and Zimbabwe. Their mental and physical health was assessed when they started TB treatment through a standardised short form quality of life survey, depression assessed through a patient health questionnaire, and their physical health tested using a six-minute walk test.

They were assessed again when treatment ended, and data were compared to see what had changed.

Overall, their physical quality of life increased by 39% by the end of TB treatment, mental quality of life increased by 19%, ability to do a six-minute walk increased by 15% and depression scores decreased by 26%.

Long-acting therapies for TB

Long-acting therapies have been making waves for some time in HIV treatment and a long-acting injection and ring are currently being offered in pilot projects in South Africa.

Two studies of long-acting therapies in mice presented at CROI show at least some movement in this area as well when it comes to TB. Such long-acting therapies have particular potential for TB preventive therapy – with, for example, what is now a three-month course of pills given as a single long-acting injection.

One study found that a long-acting injectable form of the drug rifapentine had similar efficacy to a one-month course of preventive therapy in pill form, while another had similarly promising findings for an injection using a long-acting formulation of a diarylquinoline (a class of TB drugs that include bedaquiline).

It is anticipated these early proof of concept mouse studies will be followed by studies in humans.

 

Spotlight article – New TB drug shows promise, but experimental vaccine disappoints (Creative Commons Licence)

 

See more from MedicalBrief archives:

 

Clinical trial reveals ‘breakthrough’ treatment options for MDR-TB

 

A rapid review of CROI 2021 Virtual

 

Advances in paediatric tuberculosis from 52nd Union World Conference on Lung Health

 

New TB regimen reduces treatment time by a third — clinical trial

 

 

 

 

 

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