HTB

TMC207 reduces time to sputum conversion in phase II trial on patients with drug-resistant TB

22 August 2009. Related: TB coinfection.

Nathan Geffen, i-Base and TAC

The results of the first of two stages of a double-blinded phase II Tibotec trial on the TB drug TMC207 have been published in the NEJM. [1]

The randomised 47 patients in South Africa, hospitalised with multi-drug-resistant TB (MDR-TB) that was resistant to isoniazid and rifampin) to receive either TMC207 (n-23) or placebo (n=24). The study was run from 5 June 2007 to 23 January 2008.

Besides standard exclusion criteria, patients resistant to aminoglycosides, other than streptomycin, and fluoroquinolones were excluded. Other exclusion criteria were previous treatment for MDR TB, neurologic or severe extrapulmonary TB, CD4 count lower than 300 cells/mm3, ART or antifungal medication or both in the previous 90 days, or significant cardiac arrhythmia.

The dosing regimen was 400 mg once daily for weeks 1 and 2, followed by 200 mg three times a week for weeks 3-8. The study drugs were provided as TMC207 100-mg tablets (or placebo) and were taken with water immediately after breakfast. The preferred background regimen for all patients was kanamycin, ofloxacin, ethionamide, pyrazinamide, and cycloserine or terizidone. The primary efficacy end point was the time to the conversion of sputum cultures from positive to negative, defined as two consecutive negative weekly cultures.

Basleine demographics included 74% male, 55% black and 87% HIV-negative. Median age was 33 (range 18-57). Three patients were excluded from the final analysis, two because they met study exclusion criteria and one because the culture test (MGIT) was negative throughout the study despite originally being smear-positive. 41 patients (20 and 21 in the TMC207 and placebo groups respectively) completed the study.

There were no significant differences in adverse events except for nausea which occured more frequently in the TMC207 arm (n=6 vs. 1; 26% vs. 4%; p=0.04). There were two grade four events, one in each arm, both considered unrelated to TMC207.

The majority of patients achieved average steady-state plasma TMC207 concentrations above the target of 600 ng per milliliter throughout the dosing period. Sputum culture conversion did not predict average steady-state plasma concentrations of TMC207.

TMC207 resulted in 11.8 times quicker conversion to sputum-negative culture (95%CI: 2.3-61.3; p=0.0003). The conversion rate to negative culture was 48% for TMC207 (10 of 21 patients) versus 9% in the placebo group (2 of 23 patients). Treatment responses were similar irrespective of trial centre and lung cavitation. Negative sputum smear (acid-fast bacilli) at week four were 57% for the placebo group and 77% for the TMC207 group. At week 8, these were 68% for the placebo group and 84% for the TMC207 group. The change from baseline in the log count of colony-forming units (CFUs) was also measured in a sub-group of 22 patients (9 TMC207 vs. 13 placebo). The median log CFU decreased to zero by week four in the TMC207 arm and week eight in the placebo arm.

Background on TMC207

In July 2003, Janssen Pharmaceutica, a subsidiary of Johnson & Johnson (J&J) filed a patent application for quinoline derivative drugs for the treatment of mycobacterial diseases including TB. The patent was published in February 2004. [2] One of these drugs, TMC207, (originally called R207910) was first described in Science in December 2004 by Andries et al [3] and was the most effective of against TB in vivo.

Andries et al. ran experiments to select TB bacteria resistant to TMC207. They then genetically sequenced these resistant strains and found that only one gene was affected on three independent strains. This gene codes a part, F0, of ATP synthase. This is a protein that uses protons to synthesise ATP from ADP. F0 is a membrane proton channel. Researchers have therefore determined that TMC207 works by inhibiting the proton pump of ATP synthase. This is a different mechanism to current anti-TB drugs and if TMC207 is effective it will not be cross-resistant with other TB drugs.

In the Andries et al. study TMC207 much higher MICs were required for laboratory efficacy against other bacteria (a subsequent study indicated activity against Buruli ulcer and leprosy in mice [5] [6]). At appropriate concentration (10 times MIC) the drug reduced bacterial load by 3 log units after 12 days. The effect was not improved with higher concentrations, suggesting, the authors say, that the effect is time-dependent rather than concentration dependent.

Another Tibotec study showed that TMC207 has in vitro activity against latent (or dormant) TB.[7] This is because dormant TB bacteria have residual ATP synthase activity.

In another phase II study 75 treatment-naive patients with smear-positive pulmonary tuberculosis were randomised to once-daily oral TMC207 (25 mg, 100 mg, or 400 mg), 600 mg rifampin (RIF), or 300 mg isoniazid (INH) for 7 days. Significant bactericidal activity of 400 mg TMC207 was observed from day 4 onward and was similar in effect to INH and RIF over the same period. The authors concluded that TMC207 demonstrated bactericidal activity with a delayed onset and was well tolerated, and no study drug-related serious adverse events occurred. [8]

Ongoing TMC207 trials

There are five TMC207 trials registered with clinicaltrials.govof which one is complete [9-12]. The four ongoing studies are:

  • TMC207-TiDP13-C208: A phase II, placebo-controlled, double-blind, randomised trial to evaluate the anti-bacterial activity of TMC207 in subjects with newly diagnosed sputum smear-positive pulmonary infection with MDR-TB. This is the second stage of the study discussed in this summary and is currently recruiting patients including in six South African hospitals. 24 week treatment period for 150 patients with 96 week follow-up. Estimated completion May 2011.
  • TMC207-TiDP13-C110: A phase I study to examine, in 16 healthy volunteers, the interactions between TMC207 and lopinavir/ritonavir. Recruitment has not begun.
  • TMC207-TiDP13-C117: A phase I study in 16 HIV-positive people to examine the interactions between TMC and nevirapine. Recruitment has not begun.
  • TMC207-TiDP13-C209: A phase II, open-Label trial with TMC207 as part of an MDR-TB treatment regimen in 225 patients with sputum smear-positive pulmonary infection with MDR-TB. The estimated study completion date is June 2012. Recruitment has not begun.

Comment

TMC207 is the most promising of several new TB drugs that are in development, especially since it has in vitro activity against dormant TB.

Even though the need for new TB drugs is at least as great as for ARVs, registration is unlikely to be before 2011, even if the Phase 3 studies show efficacy and good safety.

Compassionate access for TMC207 should be made available for patients with XDR-TB.

References:

  1. 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
  2. Guillemont J. Patent (Intl publication number: WO 2004/011436.
    http://www.wipo.int/pctdb/en/wo.jsp?IA=EP2003050322&wo =2004011436&DISPLAY=STATUS
  3. Andries K et al. A diarylquinoline drug active on the ATP synthase of mycobacterium TB. Science. 14 Jan 2005. 307, 223-227.
    http://www.sciencemag.org/cgi/content/abstract/307/5707/223
  4. Sanger Institute mycobacterium tuberculosis H37Rv project.
    http://www.ncbi.nlm.nih.gov/sites/entrez?Db=genom eprj&cmd=ShowDetailView&TermToSearch=224
  5. Ji B et al. Bactericidal activities of R207910 and other newer antimicrobial agents against mycobacterium leprae in mice. Antimicrob. Agents Chemother. 1 April 2006. 50, 1558-1560.
    http://aac.asm.org/cgi/content/abstract/50/4/1558
  6. Ji B et al. In vitro and in vivo activities of rifampin, streptomycin, amikacin, moxifloxacin, R207910, linezolid, and PA-824 against mycobacterium ulcerans. Antimicrob. Agents Chemother. 1 June 2006. 50, 1921-1926.
    http://aac.asm.org/cgi/content/abstract/50/6/1921
  7. Koul A et al. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. J. Biol. Chem. 12 September 2008. 283, 25273-25280.
    http://www.jbc.org/cgi/content/abstract/283/37/25273
  8. Rustomjee R et al. Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary tuberculosis. Antimicrob. Agents Chemother. 1 August 2008. 52, 2831-2835.
    http://aac.asm.org/cgi/content/abstract/52/8/2831
  9. NIH TMC207-TiDP13-C208: Anti-bacterial activity, safety, and tolerability of TMC207 in patients with multi-drug resistant mycobacterium tuberculosis (MDR-TB).
    http://clinicaltrials.gov/ct2/show/NCT00449644
  10. NIH TMC207-TiDP13-C110: Interaction study in healthy volunteers with lopinavir/ritonavir.
    http://clinicaltrials.gov/ct2/show/NCT00828529
  11. NIH TMC207-TiDP13-C117: Interaction study in HIV-1 infected patients with nevirapine (NVP).
    http://clinicaltrials.gov/ct2/show/NCT00910806
  12. NIH TMC207-TiDP13-C209: Trial to evaluate the safety, tolerability, and efficacy of TMC207 as part of an individualised MDR-TB treatment regimen in patients with sputum smear-positive pulmonary MDR-TB.
    http://clinicaltrials.gov/ct2/show/NCT00910871

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