• Tolvaptan was discovered by Otsuka in Japan and, if approved by the EMA, would become the first pharmaceutical therapy in Europe for patients with ADPKD
• ADPKD is an inherited genetic disease that causes cyst growth in the kidneys, which gradually impairs their functioning. There is no current pharmaceutical treatment option
• Otsuka's development of tolvaptan as a treatment for ADPKD illustrates the company's commitment to address significant patient needs for diseases that traditionally have not been a priority for the pharmaceutical industry

Tokyo, Japan, December 27, 2013 - Otsuka Pharmaceutical Co., Ltd. announced today that the European Medicines Agency (EMA) has accepted the submission of a marketing authorisation application (MAA) for the potential approval of tolvaptan for the treatment of autosomal dominant polycystic kidney disease (ADPKD). Phase III clinical trial results that form the basis of the regulatory filing were published in the New England Journal of Medicine.^*i

"Otsuka is delighted that the EMA will review the tolvaptan MAA for the treatment of ADPKD, based on compelling data from our pivotal three-year Phase III clinical trial," said Ole Vahlgren, CEO & President, Otsuka Europe. "If approved, tolvaptan will represent a breakthrough for patients with a disease for which there are currently no licensed treatments."

Tolvaptan is a selective V₂ vasopressin receptor antagonist that has been hypothesised to slow the progression of ADPKD by reducing the development and growth of kidney cysts.

ADPKD is a hereditary genetic disease characterised by the development of multiple, non-malignant cysts in the kidneys due to inherited or acquired genetic mutation(s).^*ii,iii,iv Cyst growth and expansion in both kidneys leads to slow deterioration of kidney function, and in approximately 50% of patients, to end-stage renal disease (ESRD) and renal failure.^*v ADPKD typically results in symptom manifestations (e.g. hypertension and kidney pain) in adulthood.^*v Half of all ADPKD patients will require dialysis or transplantation by the age of 60 and people with ADPKD account for up to 1 in 10 people on maintenance dialysis.^*vi,viiThe condition is estimated to affect approximately 200,000 people in Europe.^*ii

The Committee for Medicinal Products for Human Use (CHMP), a committee within the EMA, is responsible for evaluating the application and will provide a recommendation on whether tolvaptan should receive marketing authorisation. The CHMP may request further information from the applicant before adopting an opinion. If the committee's opinion is positive, it is forwarded to the European Commission to make the final decision.

In August 2013, the EMA's Committee for Orphan Medicinal Products (COMP) granted tolvaptan orphan drug designation for the treatment of ADPKD.^*ii To qualify for orphan designation, the prevalence of the condition in the EU must not be more than 5 in 10,000. In addition, the new medicine must be of significant additional benefit to those affected by the condition, and no satisfactory method of diagnosis, prevention or treatment of the condition must exist.

In Japan, the application for ADPKD is currently under review. In the United States, Otsuka and FDA have been working together to determine the most appropriate path forward to allow tolvaptan to be available for patients suffering from ADPKD.

• *i Torres VE, Chapman AB, et al. Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease. New England Journal of Medicine. 2012;367:2407-2418.
• *ii European Medicines Agency. EU/3/13/1175. 2013. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2013/09/human_orphan_001257.jsp&mid=WC0b01ac058001d12b [Last accessed: December 2013]
• *iii Torrres VE, Harris PC, et al.Autosomal dominant polycystic kidney disease. Lancet. 2007; 369: 1287-1301
• *iv Tan Y, Blumenfeld J and Rennert H. Autosomal dominant polycystic kidney disease: genetics, mutations and microRNA. Biochimica Biophysica Acta. 2011; 1812: 1202-1212
• *v Patel V, Chowhury R, and Igarashi P. Advances in the pathogenesis and treatment of polycystic kidney disease. Current Opinion in Nephrology and Hypertension. 2009;18:99-106.
• *vi Renal Resource Centre. Polycystic Kidney Disease. Available from:http://www.renalresource.com/booklets/pkd.php [last accessed December 2013]
• *vii Christophe JL, van Ypersele de Strihou C,et al. Complications of autosomal dominant polycystic kidney disease in 50 haemodialysed patients. A case-control study. Nephrology. Dialysis. Transplantation 1996; 11:1271-1276.