Update March 2013
For more information on bedaquiline's safety and efficacy, and on access issues and research gaps, see An Activist's Guide to Bedaquiline from Treatment Action Group (TAG).
Update February 2013
In December 2012, The U.S. Food and Drug Administration (FDA) granted bedaquiline accelerated approval for the treatment of adults with multidrug-resistant tuberculosis (TB). Bedaquiline (also known by its trade name, Sirturo) is the first truly novel drug to be approved to fight TB in four decades. Janssen, the drug’s sponsor, is starting to file for approval in other countries, and the World Health Organization plans to release guidelines in the first half of 2013 for the drug's use.
While access to bedaquiline is critical given the paucity of effective and tolerable treatment options for people with drug-resistant TB, further research is still necessary. Janssen must carry out a phase III study to demonstrate bedaquiline’s safety. Additional studies are also essential to determine bedaquiline’s suitability for use in children, in people who use alcohol and drugs, and along with antiretrovirals and other new TB drugs.
Read more in Treatment Action Group's press release about the approval.
Update October 2012
In June 2012, Janssen filed its new drug application with the U.S. Food and Drug Administration (FDA) for accelerated approval of bedaquiline for the treatment of MDR-TB. The FDA will hold a public hearing on bedaquiline on November 28, 2012, and is scheduled to respond to the bedaquiline application by December 29, 2012. Janssen also filed with the European Medicines Agency (EMA) in August 2012.
Original Report July 2012
ACTIVE TB DISEASE
Bedaquiline (also known as TMC207) is the first compound from a new class of drugs called diarylquinolines. Bedaquiline is being developed for DR-TB by Janssen Infectious Diseases BVBA (a subsidiary of Johnson & Johnson formerly known as Tibotec), and for DS-TB by Janssen and the TB Alliance. As noted above, in early July 2012, Janssen filed its NDA with the U.S. FDA for accelerated approval of bedaquline for treatment of DR-TB.
In late 2011, Janssen presented 24-week data from an open-label trial of bedaquiline in adults with smear-positive, confirmed MDR-TB or XDR-TB, including patients with HIV. The data indicated that adding bedaquiline to an individualized MDR-TB regimen was safe and well tolerated and resulted in an overall 81% culture conversion rate at week 24, with median times to culture conversion of 8 weeks for patients with MDR-TB, 12 weeks for patients with pre-XDR-TB, and 24 weeks for patients with XDR-TB. Responder rates were higher for patients with no cavitations (holes in the lungs caused by extensive cell death), patients with a lower extent of resistance, and patients on three or more potentially active drugs in their background regimen. Patients in the trial are being followed while they complete their background regimen.
A recent publication of the two-year follow-up results for a randomized study of 47 patients with pulmonary MDR-TB treated with either bedaquiline or placebo added to the first eight weeks of a background regimen showed that bedaquiline significantly reduced the time to culture conversion over 24 weeks, and was comparable to placebo in terms of adverse events (with the exception of nausea, which bedaquiline caused in more patients). Additionally, though the numbers were small, only one patient receiving bedaquiline acquired resistance to companion drugs (excluding ethambutol and ethionamide) versus five patients receiving placebo. Though the number of study participants involved was small, and the difference in acquired resistance not significant, there is now evidence that the addition of bedaquiline to current MDR-TB regimens may have the potential to reduce resistance.
Janssen now plans to start a phase III trial of 600 subjects with sputum smear–positive pulmonary MDR- or pre-XDR-TB (confirmed by rapid diagnostic test). Participants in the first arm will receive 9 months of bedaquiline and a background regimen. Those in the control arm will receive placebo and the background regimen. Participants in a third rollover arm, which will capture the failures from the first two arms, will receive an individualized salvage regimen. The primary endpoint will be relapse-free cure at 15 months for those in the first two arms. The final analysis will look at relapse-free cure at 21 months.
Janssen is also taking into consideration TB/HIV-coinfection and pediatric DR-TB in its development plans. The pediatric investigational plan that will guide future clinical studies of bedaquiline in children to establish safe and effective dosing based on age and development has been approved by the EMA and has been shared with the FDA.
The IMPAACT network is currently finalizing the protocol for Study 1108, a pharmacokinetic and safety study of bedaquiline in children with MDR-TB. This study of different age cohorts will begin by placing the oldest children (12–18 years) on an adult formulation of bedaquiline. All younger cohorts (6–12 years, 2–6 years, 6 months–2 years, 0–6 months) will be placed on a pediatric formulation currently in development by Janssen, sequentially from oldest to youngest, once adequate data from the preceding cohort are available. Enrollment is anticipated to start in the first quarter of 2013. The study plans to first enroll HIV-uninfected children in each age cohort, then enroll similar numbers of HIV-infected children, all with proven or presumed MDR-TB. This study is an excellent example of an appropriate pediatric study design that also takes into account TB/HIV coinfection, and of a public-private partnership.
Janssen is conducting DDI studies with ARVs known to inhibit cytochrome P450, a group of enzymes that metabolize bedaquiline. Coadministration with the boosted protease inhibitor lopinavir/ritonavir increased exposure to bedaquiline by approximately 20%, and a trial with nevirapine (NVP) indicated that steady-state NVP did not influence exposure to bedaquiline or its metabolite, and single-dose bedaquiline did not influence pre-dose NVP concentrations. An ACTG-led DDI study of bedaquiline and efavirenz (EVF) similarly showed that single-dose bedaquiline was well tolerated alone and with steady-state EFV, and that changes in bedaquiline concentrations when given with EFV are unlikely to be clinically significant. The DDI results with repeated dosing of bedaquiline have not yet been studied. Further data will be presented by the ACTG at the International Workshop on Clinical Pharmacology of Tuberculosis Drugs in September 2012.
The NIAID Division of Microbiology and Infectious Diseases (DMID) has just completed enrollment of a phase I study examining drug-drug interactions between bedaquiline and rifampin and rifabutin. Final results of this study will be available in late 2012.
LATENT TB INFECTION
The ACTG, TBTC, and IMPAACT are also planning ACTG Study A5300 (also known as TBTC Study 35) to examine regimens for preventing TB disease in those 13 years and older who have household contact with persons with confirmed DR-TB. Originally, this study planned to evaluate the efficacy and tolerability of the new compound bedaquiline compared with isoniazid, but bedaquiline’s sponsor, Janssen Infectious Diseases, is waiting for additional experience with the drug in patients before making it available for use in LTBI studies. The study design team is now looking to animal-model studies at the Johns Hopkins University to determine the best available drugs to use for DR-TB prophylaxis in place of bedaquiline. A clinical trial for DR-TB prophylaxis would constitutea critical step toward reducing DR-TB incidence.
NOVEL COMBINATIONS TO TREAT ACTIVE TB DISEASE
The TB Alliance recently completed NC001, the first TB clinical trial to evaluate multiple unapproved new TB drug candidates in combination. This two-week, phase II EBA study tested the three-drug regimen PA-824, moxifloxacin, and pyrazinamide (PaMZ). The PaMZ regimen performed significantly better than the standard of care (HRZE).
The study also tested additional two-drug combinations of PA-824, moxifloxacin, and pyrazinamide and bedaquiline to evaluate their potential as “building blocks” of future regimens. Validating what had been seen in mouse models, pyrazinamide and bedaquiline were synergistic, pyrazinamide and PA-824 had an additive effect, and PA-824 and bedaquiline did not have an additive effect.
The study was also important for helping open up a promising new regulatory pathway for new combination trials. In addition, it demonstrated that EBA studies can distinguish between treatments, not just between doses of the same treatment. NC001 also showed that measuring colony-forming units (which involves comparing the number of remaining viable bacterial cells that can grow into colonies after the experimental and control treatment) and time to positivity (TTP, which measures how long a cultured sputum sample takes to read as positive after therapy, with more effective treatment leaving fewer live bacterial cells and therefore having a longer TTP) gave similar results, helping to validate TTP as a biomarker for treatment response.
The TB Alliance is also planning study NC003, which will evaluate the EBA, safety, tolerability, and pharmacokinetics of two weeks of once-daily oral dosing of clofazimine alone, pyrazinamide alone, and various combinations of these drugs with PA-824 and bedaquiline, in comparison with standard first-line TB treatment. NC003 will enroll 105 newly diagnosed adults with smear-positive, drug-sensitive pulmonary tuberculosis. The study is expected to begin enrolling patients in late 2012, with results expected in the summer of 2013.
- Janssen(Press Release). Janssen Research & Development submits new drug application to FDA for investigational multi-drug resistant tuberculosis treatment bedaquiline (TMC207). Available from: http://www.jnj.com/connect/news/all/janssen-research-and-development-submits-new-drug-application-to-fda-for-investigational-multi-drug-resistant-tuberculosis-treatment-bedaquiline-tmc207. (Accessed on 2012 July 2)
- Haxaire-Theeuwes M, the TMC207 Team, Diacon AH, et al. Phase 2 open-label trial of TMC207 in an MDR-TB treatment regimen. Presented at: 42nd Union World Conference on Lung Health; 2011 October 26–30; Lille, France. Available from: http://www.worldlunghealth.org/confLille/images/stories/AbstractBook2011_Web.pdf; and http://uwclh.conference2web.com/content/1108. (Accessed 2012 June 26)
- Diacon AH, Donald PR, Pym A, et al. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrob Agents Chemother. 2012 Jun;56(6):3271–6. Available from:http://aac.asm.org/content/56/6/3271.abstract. (Accessed 2012 June 26)
- Haxiare-Theeuwes M. TMC207 Phase III planned confirmatory trial. Presented at: RESIST-TB Meeting; 2011 October 29; Lille, France. Available from: http://www.resisttb.org/uploads/TMC-207_Phase_III_MDR-TB_Trial_Oct_29_2011.pdf. (Accessed 2012 June 26)
- Haxaire-Theeuwes, Myriam (Janssen Infectious Diseases BVBA, Geneva, Switzerland). E-mail with: Erica Lessem (Treatment Action Group, New York, NY). 2012 April 18.
- Nachman, Sharon (HSC SUNY Stony Brook, Stony Brook, NY). Conversation with: Erica Lessem (Treatment Action Group, New York, NY). 2012 April 18.
- van Heeswijk R, Vandevoorde A, Meyvisch, et al. The effect of nevirapine on the pharmacokinetics of TMC207, an investigational antimycobacterial agent. Presented at: IAS 2011; 2011 July 17–20; Rome, Italy.
- Murray, Stephen (TB Alliance, New York, NY). E-mail with: Erica Lessem (Treatment Action Group, New York, NY). 2012 May 8.
- Hafner, Richard. (National Institute of Allergy and Infectious Diseases, Bethesda, MD). Conversation with: Erica Lessem (Treatment Action Group, New York, NY). 2012 April 17.
- Global Alliance for TB Drug Development. NC001: first TB regimen trial completed. TB Alliance; 2011 September 1. Available from: http://www.tballiance.org/newscenter/view-brief.php?id=1007. (Accessed 2012 June 26)
- Mendel C. TB Alliance Briefing: Stakeholders Association. Presented at: 2011 Stakeholders Association Meeting; 2011 November; Lille, France. http://www.tballiance.org/events/downloads/sha2011/presentations/Carl.pdf.