Otsuka Receives Opinion from CHMP on Delamanid

Otsuka Pharmaceutical Co., Ltd. (Otsuka) today announced the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a negative opinion for delamanid for the treatment of pulmonary multidrug-resistant tuberculosis (MDR-TB) in combination with an optimised background regimen (OBR) according to WHO guidelines in patients. The CHMP considered that the duration of treatment (two months) in the Phase IIb randomised controlled trial (Trial 204) was too short to establish the effectiveness of delamanid in treating tuberculosis when added to other anti-tuberculosis medicines.

"We are disappointed by the opinion issued by the CHMP, but remain confident in the overall strength of our filing,” said Masuhiro Yoshitake, Executive Operating Officer of Otsuka and TB Global Project Leader. "Otsuka remains committed to the development of its global TB programme and will continue working closely with the CHMP and other regulatory bodies to bring delamanid to market.”

The EMA filing was based on the combined, published results of a Phase II trial (Trial 204) in 481 MDR-TB patients at 17 centres in nine countries, and two long-term extension trials (Trials 208 and 116). Results from Trial 204 showed 45.4% of study subjects treated with delamanid 100 mg BID plus OBR, developed according to WHO guidelines for treating MDR-TB, achieved sputum culture conversion (SCC) after two months compared to 29.6% of those treated with placebo plus OBR, representing a statistically significant 53% increase.^{1 2} SCC is an indication of when a patient is no longer infectious. Additionally, a mortality benefit was observed for both MDR and XDR-TB patients who received delamanid in the trial.³

The profile of adverse events among study subjects in the Phase II trial was comparable and evenly distributed across treatment groups. Study subjects receiving delamanid experienced a higher incidence of QT prolongation on electrocardiogram than those in the placebo group. However, no clinical manifestations such as syncope or arrhythmias were observed in this study.

A randomised controlled six-month Phase III trial is underway exploring treatment with delamanid plus OBR in patients with MDR-TB, including those with co-existing HIV infection. The trial is currently enrolling in Estonia, Latvia, Lithuania, Moldova, Peru, Philippines and South Africa. Enrolment recently began for a clinical program exploring the use of delamanid in paediatric MDR-TB and will evaluate the bioequivalence of a dispersible formulation for use with younger children and infants. In addition, Otsuka filed an application for marketing authorization with the Pharmaceuticals and Medical Devices Agency of Japan in March and plans to submit delamanid for approval with the U.S. Food & Drug Administration.

Otsuka has had a tuberculosis drug discovery program for more than 30 years and has been a recognized leader in tuberculosis research through its commitment to the discovery and development of new tuberculosis compounds as well as the building of a clinical infrastructure within the developing countries affected by the disease.

About TB/MDR-TB

Tuberculosis 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 2011 approximately 8.7 million people became sick, and nearly 1.4 million people died from TB or TB-related causes.⁴ 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.⁵

About Otsuka Pharmaceutical Co., Ltd.

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 nutraceutical products for the maintenance of everyday health.

In pharmaceuticals, Otsuka is a leading firm in the challenging area of mental health and also is developing treatments for currently-untreated medical conditions. For several decades the company has been active in research on tuberculosis, a significant global public health issue. These commitments illustrate more powerfully than words how Otsuka is a "big venture” company at heart, applying a youthful spirit of creativity in everything it does.

Otsuka is a wholly owned subsidiary of Otsuka Holdings Co., Ltd., the holding company for the Otsuka Group. The chairman Akihiko Otsuka is the third generation of Otsuka family members to lead the business, whose origins date from 1921. The Otsuka Group has business operations in 25 countries and regions around the world, with consolidated sales of approximately US $13 billion for fiscal year 2012 (4/1/2012-3/31/2013.) Otsuka welcomes you to visit its global website at https://www.otsuka.co.jp/en

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¹ Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, et al. Delamanid for multidrug-resistant pulmonary tuberculosis. New England Journal of Medicine. 2012 Jun 7; 366(23): 2151-60
² SCC for both groups dosed with delamanid were statistically higher compared to placebo (p=.008 and p=.049). Results from the secondary analysis of SCC based on solid media were consistent with those of the primary analysis. 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.
³ Skripconoka, V., Danilovits, M., et al. Delamanid Improves Outcomes and Reduces Mortality for Multidrug-Resistant Tuberculosis. European Respiratory Journal. 2012 September.
⁴ WHO – Global Tuberculosis Report 2012. http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf (Accessed 13 June 2012)
⁵ 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)