Will SimpliciTB make TB treatment simpler ?

Shobha Shukla *

Taking the encouraging results of its N-005 study one step forward, TB Alliance has initiated SimpliciTB a pivotal clinical study to evaluate the efficacy, safety and tolerability of a novel and potentially shorter 4 drug regimen for patients with drug-sensitive (DS) as well as multi drug-resistant (MDR) pulmonary TB.

The new drug regimen BPaMZ comprising four different antibiotics Bedaquiline (B), Pretomanid (Pa), Moxifloxacin (M) and Pyrazinamide (Z) will be administered for 4 months to patients of DS-TB, and for 6 months to patients with MDR-TB with mono-resistance to rifampicin or isonaizid.

What is SimpliciTB?

SimpliciTB is a pivotal, multi-centric, open-label partially randomized clinical study targeting at least 26 centres in 10 countries in Africa, Asia, Europe and South America. A total of 450 participants (150 per treatment group) will be enrolled and assigned to the following treatment arms:

o Participants with DS-TB will receive BPaMZ daily for 4 months;
o Participants with DS-TB will receive HRZE/HR combination tablets daily for 6 months; and
o Participants with DR-TB (MDR-TB as well as mono-resistance to isonaizid or rifampicin) will receive BPaMZ daily for 6 months.

The study would evaluate if an all-oral BPaMZ drug regimen has the potential to shorten and simplify treatment for both DS-TB and MDR-TB. It will test and compare the efficacy of a 4 month treatment with the BPaMZ regimen, in people with DS-TB, to that of the current 6 month treatment regimen of isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE), to determine whether BPaMZ can shorten the duration of therapy. The study will also assess BPaMZ’s potential to treat DR-TB (with mono-resistance to rifampicin or isonaizid) in 6 months. Currently, treatment for MDR-TB is complicated, expensive, and lengthy- lasting for 9 to 24 months- involving a wide variety of medicines that have debilitating side-effects.

The N-005 study

As mentioned earlier, the BPaMZ regimen has been previously studied in a 2 month long Phase 2b N-005 clinical study conducted on 240 patients (180 patients with DS-TB and 60 patients with DR-TB) at 10 sites in 3 countries (Uganda, South Africa, and Tanzania). Study results showed that the best regimen was a combination of all four drugs- BPaMZ-, that resulted in the highest level of bactericidal activity among all its four parallel treatment arms.

At the end of 2 months, participants receiving BPaMZ cleared TB bacteria from their sputum 3 times faster than those on the standard (HRZE) treatment regimen, with almost all of them having culture conversion after 2 months of treatment. The study also found that a daily dose of Bedaquiline (200 mg) is at least as active and safe as the labelled dose. This could lead to a simpler daily dosing with fewer pills and an overall less complicated treatment for patients.

How is SimpliciTB different from N-005?

SimpliciTB will build on the encouraging results of N-005. While NC-005 only examined BPaMZ in multi drug-resistant TB (it also looked at other combinations of B, Pa and Z in DS-TB), SimpliciTB will test BPaMZ regimen in both, drug-sensitive and drug-resistant TB patients, over a longer period of time, with many more participants, and with a much larger geographic scope.

The study is expected to enrol 450 people with TB, (including 150 who are mono-resistant to isoniazid or rifampicin) across 26 centres in 10 countries in Africa, Asia, Europe and Latin America. It will examine the time to culture negative status over 8 weeks, as well as durable cure, through 12 and 24 month follow-ups.

The first patients have already been enrolled at the National Centre for Tuberculosis and Lung Disease in Tbilisi, Georgia. The study is slated to end in 2021, with the potential for making interim results available earlier.

According to the World Health Organization’s most recent WHO Global Tuberculosis Report, there is growing resistance to available TB drugs, which means the disease is becoming more deadly and difficult to treat. WHO estimates that in 2016 there were 600,000 new cases with resistance to rifampicin – the most effective first-line drug—of which 490,000 had MDR-TB.

“As resistance to current TB treatments continues to grow, we need to introduce all-oral drug regimens that can treat every person with TB in 6 months or less, regardless of their resistance profile. If proven successful in SimpliciTB, the BPaMZ regimen would represent a major step toward this goal by bringing down the treatment duration for the vast majority of TB patients to as less as 3-4 months, thus reshaping the treatment landscape of TB, especially for people with MDR-TB, who currently face an arduous 9-24 month treatment journey that is too often unsuccessful”, said Mel Spigelman, President and CEO of TB Alliance.

If successful, the all-oral BPaMZ drug regimen tested in SimpliciTB will shorten TB treatment to a duration that would be more easily manageable by patients and public health services, and provide a more effective, safer and affordable treatment for the growing number of patients suffering from drug- resistant TB, bringing us nearer to the goal of ending TB by 2030.