Novartis announced that it has received regulatory approval in Japan from the Ministry of Health, Labour and Welfare (MHLW) for once-daily Gilenya (fingolimod) 0.5mg for the prevention of relapse and delay of progression of physical disability in adults with multiple sclerosis (MS), and for Illaris (canakinumab) subcutaneous (s.c.) injection 150mg, the first treatment for adults and children with cryopyrin-associated periodic syndrome (CAPS).

In the US, Gilenya is approved for relapsing forms of MS. In the EU, Gilenya is approved for people with highly active relapsing-remitting MS despite treatment with beta interferon, or in patients with rapidly evolving severe relapsing-remitting MS.

The Ilaris approval is also extended to include all CAPS disease phenotypes: familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID).

“Today's announcement demonstrates our continued commitment to bringing innovative new treatments to patients where there is significant unmet need,” said David Epstein, Head of the Pharmaceuticals Division of Novartis. “Strengthening our presence in Japan is a major priority for Novartis and we are pleased that the Japanese Health Authority have acknowledged the positive benefit-risk profiles of both Gilenya and Ilaris.”

The Japanese approval of Gilenya was based on the largest clinical trial programme submitted to date for a new MS drug, including phase II data in Japan, and comprised data from clinical studies showing significant efficacy in reducing relapses, the risk of disability progression, and the number of brain lesions detected by magnetic resonance imaging (MRI), a measure of disease activity.

MS, an autoimmune disease, is designated as a specified disease by the Ministry of Health, Labour and Welfare and reportedly affects approximately 14,000 patients diagnosed and registered in Japan.

“Until now, there has been only interferon beta as an approved treatment for prevention of relapse in patients with MS in Japan,” said Dr Yasuto Itoyama, director, National Centre Hospital, National Centre of Neurology and Psychiatry. “Fingolimod has a novel mechanism of action that is different from existing drugs and its high efficacy has been confirmed in clinical studies in Japan and overseas. With its convenience as a once-daily oral formulation, we expect that fingolimod will become an important treatment option for MS patients in Japan.”

Gilenya (fingolimod), licensed from Mitsubishi Tanabe Pharma Corporation, is the first in a new class of drugs that modulates sphingosine 1-phosphate (S1P) receptors. It has been approved in more than 50 countries, including the US, Australia, Canada, EU members, Switzerland, Brazil, and Japan.

Gilenya demonstrated superior efficacy in relapse rates compared to interferon-beta-1a (IM), a commonly prescribed treatment, showing a 52% relative reduction in annualized relapse rate at one year in a pivotal head-to-head trial in patients with relapsing-remitting multiple sclerosis. In a two-year, placebo controlled study, Gilenya showed a 30 per cent relative reduction in risk of sustained disability progression over two years versus placebo, as measured by the EDSS (Expanded Disability Statue Scale) and confirmed after three months.

In clinical trials, the most common Gilenya side effects were headache, liver enzyme elevations, influenza, diarrhoea, back pain, and cough. Other Gilenya-related side effects include transient, generally asymptomatic, heart rate reduction and atrioventricular block upon treatment initiation, mild blood pressure increase, macular edema, and mild bronchoconstriction.

The rates of infections overall, including serious infections, were comparable among treatment groups, although a slight increase in lower respiratory tract infections (primarily bronchitis) was seen in patients treated with Gilenya. The number of malignancies reported across the clinical trial program was small, with comparable rates between the Gilenya and control groups.

Ilaris is a fully human monoclonal antibody that binds selectively to interleukin-1 beta (IL-1 beta), one of the inflammatory cytokines, neutralizing its activity. Ilaris is administered by subcutaneous injection once every eight weeks.

CAPS is a disease that comprises three different phenotypes, FCAS, MWS and NOMID, that are caused by the overproduction of IL-1 beta which induces an inflammatory reaction. Onset of symptoms starts at birth or childhood, and various symptoms such as fever, joint pain, rash, headaches, fatigue and conjunctivitis recur throughout patients' lives. In severe cases these may induce impaired hearing and vision, bone and joint deformities and nephropathy.

“Since no treatment was established for CAPS in the past and only symptomatic therapies were available in Japan, the needs of patients and their families had not been sufficiently met,” said Professor Shunpei Yokota of the Department of Child Health and Development, Yokohama City University School of Medicine. “This is a very exciting development for the treatment of CAPS, as Ilaris produces a rapid remission of symptoms and inherently has the potential to improve patients' quality of life and their outcome.”

The clinical trial programme of Ilaris for CAPS in Japan started in October 2009 and the drug received orphan drug status in August 2010. The submission in Japan was supported by a clinical programme that included a local clinical study involving 19 patients and it comprised data from both non-Japanese and Japanese CAPS patients. In this study, Ilaris rapidly produced complete remission of symptoms in 94.7% and 100% of patients, at 24 and 48 weeks of administration respectively. Ilaris was generally well tolerated and there was no consistent pattern of adverse events apart from a slight increase in upper respiratory infections. The most common adverse events were nasopharyngitis and stomatitis.

Ilaris (canakinumab) is approved in more than 50 countries, including the EU, US and Switzerland for the treatment of adults and children as young as four with CAPS. Canakinumab is also being studied in other diseases in which IL-1 beta plays a key role in causing inflammation, such as JIA, gouty arthritis and secondary prevention of cardiovascular events. Not all potential patients with these diseases would be eligible for treatment with canakinumab, if approved.

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