HIV Treatment Bulletin

Faster conversion rates with TMC-207 versus placebo plus OBT for the treatment of MDR-TB

Polly Clayden, HIV i-Base

TMC207 is the first in a new class (diarylquinoline) of anti-tuberculosis (TB) drugs to inhibit mycobacterial ATP synthase. It has the potential to improve treatment of both drug-sensitive (DS) and multidrug- resistant (MDR) TB.

In an oral presentation, David McNeely first provided some background information on this drug. [1] TMC-207 previously increased culture conversion by approximately 40% in MDR TB patients in an 8-week trial (see below). These findings were published in the NEJM and we reported them in the August 2009 issue of HTB. [2, 3]

He also showed several key pharmarmacokinetic findings from the phase 1 trials. These were: a positive food effect with TMC-207 giving a two-fold increase in drug exposure when taken with a meal; coadministation of rifampicin lowers TMC207 levels by 50% and coadministartion of lopinavir/ritonavir (LPV/r) modestly increases TMC-207 exposure by 22%. Unpublished information on nevirapine shows a similar interaction. These data suggest the potential to administer the drug with antiretrovirals. Dr McNeely noted that this did not occur in the early trials in patients, as this information was not available. The drug also has a long terminal half-life and does not reach steady state by day 14.

He reported that, to October 2010, 595 participants had received TMC-207 in all trials: 217 healthy volunteers; 147 DS and MDR-TB patients (79 for 24 weeks). There is also an open label trial (Breathe) in which 231 MDR TB patients have been enrolled that is ongoing.

In the second part of this presentation, Andreas Diacon showed findings from TMC-207 C208 stage 2. This randomised, double-blind, placebo-controlled trial is in two stages. It is conducted in patients with newly diagnosed smear positive pulmonary MDR-TB. Following a one-week washout period, patients were randomised to receive optimised background therapy (OBT) plus TMC-207 or placebo.

TMC-207 was dosed at 400mg once daily for 14 days and then 200mg TIW (three times a week).

In Stage 1, conducted in South Africa, 47 patients received 8 weeks of TMC207 (n=23) or placebo (n=23). They then continued their MDR-TB treatment with background regimen alone. All stage 1 patients have completed the trial. Stage 1 found a significant increase in the proportion of culture negative subjects among those who received TMC207 compared to placebo (48% vs. 9% at week 8). There was a 58% reduction in mean time to culture conversion in those who received TMC-207 compared to placebo.

In Stage-2, 161 patients were randomised to receive 24 weeks of either TMC207 or placebo added to the same 5-drug background regimen. All stage 2 patients have completed 24 weeks of TMC207/placebo plus OBT. They are now completing 18–24 months treatment with 2nd line TB drugs (without TMC207/placebo).

Stage 2 was a multi country trial conducted in Brazil, India, Latvia, Peru, Phillipines, Russia, South Africa and Thailand.

The objective was to demonstrate superiority of TMC-207 compared to placebo at 24 weeks. The primary endpoint was time to sputum culture conversion (MGIT). Participants who discontinued during 24 weeks were considered failures irrespective of their culture status at time of discontinuation.

The secondary endpoint was culture conversion rates at 24 weeks.

At baseline about 65% of patients were men, with a median age of 33 years, 85% were HIV-negative and they weighed about 53kg. Patients had confirmed resistance to isoniazid and rifampicin and had not received second line TB treatment previously. HIV-positive patients had a CD4 count greater than 300 cells/mm3 and were not receiving antiretroviral treatment. No patient had significant extrapulmonary TB or other illness.

Of the total randomised patients (80 TMC-207, 81 placebo), 160 were included in the ITT analysis (one patient randomised to the TMC-207 arm, did not receive study drug). The researchers also conducted a modified ITT analysis of 132 patients. Exclusions included, non-MDR patients (4 TMC-207 and 8 placebo), XDR patients (3 TMC-207 and 4 placebo) and patients, for whom, culture results were not evaluable.

OBT was a 5-drug standardised background regimen: ethionamide, pyrazinamide, ofloxacin, kanamycin and terizodone/cycloserine.

Dr Diacon noted that there were high rates of baseline resistance to kanamycin at baseline among patients from European sites. He also noted worryingly high rates of resistance to pyrazinamide across all sites. In vitro evidence suggests there may be good synergy between TMC-207 and pyrazinamide.

Adverse events were similar across both groups. None were serious and discontinuations were unrelated to the study drug.

He reported that the addition of TMC-207 to a 5-drug OBT regimen resulted in faster culture conversion within 24 weeks, p=0.003. It also gave a shorter median time to 50% culture conversion of 12 vs 18 weeks. And there was a higher sputum conversion rate at 24 weeks of 79 vs 58%, p=0.008.

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These results are very promising and phase 3 trials will begin this year. Discussions between Tibotec and regulatory authorities in the US and Europe are ongoing and data should be submitted to the FDA and EMA for accelerated or conditional approval this year.

Demand for early access to this drug is already considerable. Activist organisations published an open letter to Tibotec calling for expanded access. This letter was handed over at the beginning of the World Lung conference at which the presentations discussed here were made. The company has committed, both in a teleconference on 7 January and in the OpenForum meeting in Addis Ababa in August 2010, to accelerate access. In countries that have a regulatory framework for pre-registration access, such as South Africa, this will be the preferred method. Although expanded or accelerated access has been the norm for HIV drugs, TMC 207 could set precedence for these strategies with TB drugs. Tibotec needs to maintain a balance between making it available fast to those in greatest need and ensuring it is used judiciously.

Tibotec intends to carry out a trial that will collect safety data in countries that do not provide for pre-registration access and this will allow drug-resistant patients with limited options to access TMC207. Quite reasonably, Tibotec is concerned that it only partners with health-delivery institutions that are capable of ensuring high adherence. There are also plans to include TMC207 in studies with the investigational drug in development from Otsuka Pharmaceuticals, OPC-67683. This is a nitroimidazole and is in phase 2b. It is especially important that OPC-67683 or other drugs under investigation for DR-TB, such as PA-824, become available soon after TMC207, so as to reduce the risk of continuously adding TMC207 to potentially failing second-line regimens and consequently risking a high rate of TMC207 resistance.

References:

  1. McNeeley D et al. TMC-207 versus placebo plus OBT for the treatment of MDR-TB: a prospective clinical trial. The International Journal of Tuberculosis and Lung Health. S3 41st Union World Conference on Lung Health. 11-15 November 2010.
    http://uwclh.conference2web.com/content/187
  2. Diacon AH et al. The diarylquinoline TMC207 for multidrug-resistant Tuberculosis. NEJM. 2009 June 4. 360, 2397-2405. (4 June 09).
    http://content.nejm.org/cgi/content/abstract/360/23/2397
  3. Geffen N. TMC207 reduces time to sputum conversion in phase II trial on patients with drug-resistant TB. HIV Treatment Bulletin. August 2009.
    http://i-base.info/htb/4403