New Research Shows 53% Increase in Sputum Culture Conversion (SCC) After Two Months
Phase IIb trial showed delamanid plus a background regimen rendered more study subjects non-infectious after two months than placebo plus background regimen alone.
International Phase III trial initiated in study subjects with MDR-TB, including those taking anti-retroviral drugs for co-existing HIV infection.
TB remains a critical global health issue with no new drugs in nearly half a century.
(BUSINESS WIRE)-- Otsuka Pharmaceutical Co., Ltd. (Otsuka) today announced clinical trial results on the safety and efficacy of delamanid, the company's investigational compound for the treatment of multidrug-resistant tuberculosis (MDR-TB), published in the New England Journal of Medicine (available online at http://www.nejm.org/doi/full/10.1056/NEJMoa1112433). Results from the trial showed a 53% increase in sputum culture conversion (SCC) after two months between study subjects receiving delamanid 100 mg twice-daily (BID) plus a background regimen (BR) consistent with WHO treatment guidelines compared with subjects receiving placebo plus BR alone.
In the past two decades, MDR-TB has emerged as a significant public health threat, with strains of TB growing increasingly resistant to treatment with first-line anti-TB drugs. The WHO Global Plan to Stop TB 2011-2015 has called for urgent development of new drugs with novel mechanisms of action to treat all forms of TB, including MDR-TB, which is more difficult to cure and has higher mortality rates compared to regular TB. Delamanid is from a class of compounds, known as nitro-dihydro-imidazooxazoles, which work by inhibiting synthesis of mycolic acid. The latest class of anti-TB drugs was discovered in 1963.
"TB treatment has been a priority for Otsuka for more than 30 years, and over time we have become the largest private funder of TB research and development. We are committed to addressing the urgent need for short, simple, well tolerated regimens that are effective in patients who are resistant to current regimens," said Mr. Masuhiro Yoshitake, Executive Operating Officer of Otsuka Japan and TB Global Project Leader. "The findings published today are a major step forward for the TB community and offer compelling support for bringing delamanid to market as one of the first new drugs to treat TB in more than 40 years."
Study Design
The delamanid trial was a double-blind, randomised, placebo-controlled study conducted in 17 centres in nine countries. The trial was designed to evaluate the safety, tolerability, efficacy, and pharmacokinetics of two doses of delamanid, 100 mg BID and 200 mg BID, each administered with BR, compared with placebo administered with BR. The BR was consistent with World Health Organization (WHO) recommendations for the treatment of MDR-TB. Study subjects were treated for eight weeks, during which they were hospitalised for intensive safety monitoring and sputum culture assessment. SCC at two months was selected as an established measure of successful treatment. Sputum samples were cultured using the Mycobacterial Growth Indicator Tube (MGIT)® system (known to be more sensitive than standard culture) as well as on solid mycobacteriologic culture media and had to be negative on five successive weekly cultures to be counted as achieving SCC.
A total of 481 study subjects ages 18 to 64 with suspected MDR-TB were enrolled in the study and took at least one dose of investigational medicine; of those, 402 met the criteria of positive sputum culture at baseline and were included in the efficacy analysis. The primary efficacy endpoint was the proportion of study subjects who achieved SCC by two months using the MGIT system. Several secondary endpoints were also assessed, including time to SCC conversion.
Study Findings
Results from this Phase IIb study showed that 45.4% of study subjects in the delamanid 100 mg BID group and 41.9% of study subjects in the delamanid 200 mg BID group achieved SCC in the MGIT system after two months of treatment, compared with 29.6% of study subjects in the placebo group. SCC for both groups dosed with delamanid were statistically higher compared to placebo (p=0.008 and p=0.039, respectively). Results from a secondary analysis of SCC based on solid media were consistent with those of the primary analysis. In these analyses, SCC was stringently defined as a study subject achieving at least five consecutive weekly cultures that were negative for growth of TB bacteria.
In terms of time to conversion, the study found that by the end of week five, 24% and 23% of subjects in the delamanid 100 mg BID and 200 mg BID groups, respectively, achieved SCC compared with 13% of study subjects in the placebo group. As the duration of treatment progressed over two months, SCC was significantly accelerated for the delamanid-treated groups compared with the placebo group.
"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," said Dr. Manfred Danilovits, lead investigator and tuberculosis specialist at Tartu University Hospital in Estonia. "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."
The profile of adverse events was comparable and evenly distributed across all three treatment groups with 91.3%, 94.4%, and 94.4% of study subjects from the 100 mg BID plus BR, 200 mg BID plus BR and placebo plus BR groups respectively experiencing one or more adverse events. The majority of adverse events were mild to moderate. Study subjects receiving delamanid plus BR experienced a higher incidence of QT prolongation on electrocardiogram than those receiving placebo plus BR; 10%, 13%, and 4% in the 100 mg BID plus BR, 200 mg BID plus BR and placebo plus BR groups respectively (P = 0.048 for 100-mg group and P = 0.005 for the 200-mg group. None of the QT interval prolongations were associated with any clinical manifestations such as syncope or arrhythmias.
Otsuka's Commitment to TB Treatment
Otsuka has initiated an international, randomised, controlled Phase III trial of delamanid in study subjects with MDR-TB, including those with co-existing HIV infection and taking antiretroviral therapy. In addition, a long-term, open-label surveillance study is underway to extend the efficacy and safety findings from the Phase IIb study and further assess whether sputum conversion is sustained throughout treatment and correlates to favourable outcomes at the end of treatment.
Otsuka is also committed to working with a variety of public and private partners, governments, advocates and other stakeholders on developing case management programmes and models of care that improve patient treatment options and minimize drug resistance.
About TB/MDR-TB
Tuberculosis, or TB, is a highly contagious airborne infection. Approximately one-third of the world's population is estimated to be infected with TB. According to the latest WHO Global Tuberculosis Control report, in 2010 approximately 8.8 million people became sick, and nearly 1.4 million people died from TB or TB-related causes.1 Despite substantial efforts to control TB, the disease remains a significant public health burden; in the past two decades, this burden has increased with the rise of multidrug-resistant TB, or MDR-TB, a hard-to-treat form of the disease that is resistant to first-line therapies. This resistance emerges from the misuse of TB therapies, including poor drug supply, poor drug quality, or patients' inability to complete their treatment regimens. It is estimated that 440,000 new cases of MDR-TB emerge each year, leading to 150,000 annual deaths. Twenty-seven countries around the world account for 86% of the MDR-TB burden.2
About Otsuka Pharmaceutical Co., Ltd.
Founded in 1964, Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: 'Otsuka-people creating new products for better health worldwide.' Otsuka researches, develops, manufactures and markets innovative and original products, with a focus on pharmaceutical products for the treatment of diseases and consumer products for the maintenance of everyday health. Otsuka is committed to being a corporation that creates global value, adhering to the high ethical standards required of a company involved in human health and life, maintaining a dynamic corporate culture, and working in harmony with local communities and the natural environment.
Otsuka Pharmaceutical Co., Ltd. is a wholly owned subsidiary of Otsuka Holdings Co., Ltd., the holding company for the Otsuka Group. The Otsuka Group has business operations in 24 countries and regions around the world, with consolidated sales of ¥1,154.6 billion for fiscal year 2011. For more information, visit www.otsuka.co.jp/en.
1WHO – Global Tuberculosis Report 2011. http://www.who.int/tb/publications/global_report/2011/gtbr11_full.pdf(Accessed 31 October 2011) 2 WHO– Multidrug and extensively drug-resistant TB (M/XDR-TB) - 2010 Global Report On Surveillance And Response. Available at: http://whqlibdoc.who.int/publications/2010/9789241599191_eng.pdf(Accessed 31 October 2011)
Contacts
GLOBAL:
Otsuka SA
Marc Destito, +41-78-881-03-22
Communications Director
JAPAN:
Otsuka Pharmaceutical Co., Ltd.
Masamitsu Kitada, +81-3-6361-7379
Public Relations Department
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