• Re-examination leads to positive opinion. If approved it would be the first new TB drug in Europe in more than 40 years. MDR-TB is an orphan disease in Europe.
• Phase IIb results showed Deltyba plus OBR rendered 53% more study subjects non-infectious after two months than placebo plus OBR.
• According to the WHO, tuberculosis is one of the three most common infectious diseases. Every year, approximately 8.6 million people become sick, and nearly 1.3 million people die from TB or TB-related causes. It is estimated that 450,000 new cases of MDR-TB emerge each year, leading to 170,000 deaths annually.

Tokyo, Japan (November 25, 2013) - Otsuka Pharmaceutical Co., Ltd. (Otsuka) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has recommended approval of DeltybaTM (delamanid) in combination with a WHO recommended optimized background regimen (OBR)^*1 for the treatment of pulmonary multidrug-resistant tuberculosis (MDR-TB) . The CHMP opinion will help form the basis for a European Commission decision expected early next year.

The recommendation is a reversal of the negative CHMP opinion issued in July. In its re-examination request, Otsuka provided further analyses to support the effectiveness of Deltyba at six months. In addition, an on-going Phase 3 clinical study that completed enrolment in November will examine responses at six months in order to provide confirmation of the long-term effectiveness. Otsuka will also conduct an additional study to confirm that the current recommended dose is the most appropriate one.

"In the past two decades, MDR-TB has emerged as a significant public health threat, with strains of TB growing increasingly resistant to first-line anti-TB drugs," said Masuhiro Yoshitake, Executive Operating Officer of Otsuka and TB Global Project Leader. "We are pleased that MDR-TB patients in Europe may soon have access to Deltyba."

Deltyba is a bactericidal agent from the class of compounds known as nitro-dihydro-imidazooxazoles, which work by inhibiting synthesis of mycolic acid. The CHMP evaluated results from a 2-month Phase IIb trial (Trial 204) of 481 patients, a 6-month extension trial (Trial 208), and a 24-month long-term observational study (Trial 116), which demonstrated increased TB conversion rates with Deltyba plus OBR versus placebo plus OBR at two and six months.Deltyba was designated as an 'orphan medicine' (a medicine to be used in rare diseases) on February 1, 2008 for the treatment of tuberculosis in Europe.

Results from Trial 204 published in the New England Journal of Medicine (NEJM) showed 45.4% of study subjects treated with Deltyba 100 mg BID plus OBR, achieved sputum culture conversion (SCC), a measurement by which a patient is no longer infectious, after two months compared to 29.6% of those treated with placebo plus OBR, representing a statistically significant 53% increase.^*2

Results of the Phase IIb studies (Trial 204 and Trial 208) demonstrated that the profile of adverse events was comparable across treatment groups. The number of study subjects in Trial 204 with adverse events (AEs) receiving Deltyba (91.3% and 94.4% for the 100 mg BID and 200 mg BID groups, respectively) was similar to the number that received OBR without Deltyba (94.4%). The majority of side effects were mild to moderate among study subjects receiving Deltyba. A higher incidence of QT prolongation on scheduled electrocardiograms was observed in the Deltyba plus OBR group as compared to those receiving placebo plus OBR. However, this did not result in any clinical manifestations such as syncope or arrhythmias.

A Phase 3 trial is currently underway exploring treatment with Deltyba plus OBR in patients with MDR-TB, including those with co-existing HIV infection. The trial completed enrollment on November 8th in Estonia, Latvia, Lithuania, Moldova, Peru, Philippines and South Africa. Additionally, enrollment recently began for a pediatric clinical program evaluating the use of Deltyba, including the bioequivalence of a dispersible formulation for use with children and infants with MDR-TB.

Otsuka's Commitment to TB

Otsuka has had a TB drug discovery program for over 30 years and has been a recognized leader in TB research through its commitment to the discovery and development of new TB compounds as well as the building of a clinical infrastructure within developing countries affected by the disease. An application for marketing authorization was filed with the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan in March 2013 and the company also plans to submit Deltyba for approval with the U.S. Food & Drug Administration (FDA).

Otsuka recognizes that the introduction of new medicines alone will not solve the growing problem of TB drug misuse, which has accelerated the spread of MDR-TB and XDR-TB, particularly in Europe. A responsible access plan (RAP) was provided as part of the EMA dossier to ensure Deltyba is used rationally while in combination with other TB medicines.

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 2012 approximately 8.6 million people became sick, and nearly 1.3 million people died from TB or TB-related causes. 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 450,000 new cases of MDR-TB emerge each year, leading to 170,000 annual deaths.^*3 Twenty-seven countries around the world account for 86% of the MDR-TB burden.^*4

• *1 Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update. ISBN 978 92 4 150158 3; http://whqlibdoc.who.int/publications/2011/9789241501583_eng.pdf (Accessed21 November 2013)
• *2 Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med. 2012 Jun 7; 366(23): 2151-60
• *3 WHO - Global Tuberculosis Report 2013. http://apps.who.int/iris/bitstream/10665/91355/1/9789241564656_eng.pdf (Accessed 21 November 2013)
• *4 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 21 November2013)