- Category: Tuberculosis (TB)
- Published on Tuesday, 12 June 2012 00:00
- Written by Liz Highleyman
An experimental antibiotic drug, delamanid (OPC-67683), demonstrated good activity against highly-resistant tuberculosis (TB), clearing infection in more than 40% of participants in a Phase 2b trial, researchers reported in the June 7, 2012, New England Journal of Medicine. The drug is currently being studied in HIV positive people taking antiretroviral therapy (ART).
Tuberculosis is prevalent throughout the world -- especially in resource-limited settings -- and it is the leading cause of death for people with HIV worldwide. In recent years concern has arisen about multidrug-resistant Mycobacterium tuberculosis (MDR-TB), which does not respond to the standard first-line medications isoniazid and rifampin, and extensively drug-resistant TB (XDR-TB), which is resistant to most or all available therapies, making development of new drugs an urgent priority.
Delamanid, developed by Japan's Otsuka Pharmaceutical Co., is a nitro-dihydro-imidazooxazole derivative that inhibits synthesis of mycolic acid, an important component of TB bacteria cell walls. If approved, it would introduce the first new class of TB drugs in nearly 50 years.
Maria Tarcela Gler from Makati Medical Center in Manila and colleagues conducted a randomized multinational clinical trial that included 481 patients with pulmonary MDR-TB in 9 countries (China, Estonia, Egypt, Japan, Korea, Latvia, Peru, Philippines, and the U.S.). The median age was 35 years (range 18-64 years) and 68% were men; almost all were HIV negative.
Participants were randomly assigned to receive delamanid, at a dose of 100 mg or 200 mg twice-daily, or else placebo for 8 weeks, all in combination with a background regimen meeting World Health Organization (WHO) guidelines, which typically consisted of 4-5 other drugs.
The researchers tested sputum cultures weekly using both liquid and solid methods. Sputum-culture conversion was defined 5 or more consecutive cultures showing no M. tuberculosis growth.
- After 2 months of treatment, 45.4% of participants in the delamanid 100 mg group and 41.9% in the 200 mg group had liquid sputum cultures negative for MDR-TB, compared with 29.6% in the placebo group (P = 0.008 and 0.039, respectively).
- 24%, 23%, and 13% of patients, respectively, achieved sputum-culture conversion by week 5 of treatment.
- Delaminid was generally well tolerated overall.
- 3% of participants stopped treatment due to adverse events.
- The most common side effects were gastrointestinal symptoms such as nausea or vomiting, mostly mild to moderate.
- 10% of patients receiving 100 mg and 13% receiving 200 mg delamanid developed prolonged QT interval (a type of abnormal heartbeat), versus 3.8% of placebo recipients.
- QT prolongation was not associated with clinical events such as syncope (fainting) or arrhythmias in this short study.
"Delamanid was associated with an increase in sputum-culture conversion at 2 months among patients with multidrug-resistant tuberculosis," the study authors concluded. "This finding suggests that delamanid could enhance treatment options for multidrug-resistant tuberculosis."
"Existing TB treatment regimens are long and cumbersome, which can lead to incomplete treatment, resulting in an increased risk of relapse and developing drug resistance," lead investigator Manfred Danilovits from Tartu University Hospital in Estonia said in an Otsuka press release. "This study shows that delamanid, when added to a background regimen consistent with WHO guidelines, may help achieve earlier sputum conversion thereby reducing infectiousness and enhancing overall treatment options for MDR-TB."
In an accompanying editorial, Richard Chaisson and Eric Nuermberger from the Center for Tuberculosis Research at Johns Hopkins described the results as "significant but modest," and noted that the trial did not help establish optimal combination regimens to use with delamanid.
"It is important to accelerate research to identify the best regimens of new and existing drugs and guide clinicians in the most effective application of these drugs," they wrote.
A study looking at 6 months of delamanid combination therapy with 30 months of follow-up is now underway. Otsuka is also testing delamanid in HIV positive people on antiretroviral treatment -- crucial research due to the potential for drug-drug interactions.
MT Gler, V Skripconoka, E Sanchez-Garavito, et al. Delamanid for Multidrug-Resistant Pulmonary Tuberculosis. New England Journal of Medicine 366(23):2151-2160. June 7, 2012.
RE Chaisson and EL Nuermberger. Confronting Multidrug-Resistant Tuberculosis. New England Journal of Medicine 366(23):2151-2160. June 7, 2012.
Otsuka Pharmaceutical Co. The New England Journal of Medicine Publishes Efficacy Results of Otsuka's Delamanid for Multidrug-Resistant Tuberculosis. Press release. June 6, 2012.