Otsuka Pharmaceutical Co., Ltd. (Otsuka) is pleased to announce our entry into an exclusive worldwide licensing agreement with Ionis Pharmaceuticals, Inc. (Ionis) for rights to manufacture and market Ionis' ulefnersen (generic name; development code is ION363), a drug candidate under development for the treatment of patients with amyotrophic lateral sclerosis (ALS) caused by mutation of the fused in sarcoma (FUS) gene.

This agreement marks Otsuka's second introduction of an antisense oligonucleotide (ASO) medicine from Ionis, following our acquisition of development and sales rights in Europe and Asia, including Japan, for the hereditary angioedema attack suppressant drug donidalorsen (generic name).

ALS is a serious neurodegenerative disease that causes rapid muscle weakness in the limbs and respiratory muscle paralysis. Once the disease has manifested, it generally continues to progress, and in a few years it can become difficult to breathe spontaneously. The number of ALS patients worldwide is on the rise, and it is estimated that by 2040 there will be over 300,000 people with the disease.^*1.

FUS-ALS is caused by mutations in the FUS gene. It is the second most common causative gene for ALS in Japan and the third or fourth most common in Europe and the United States. Unlike typical ALS, FUS-ALS is more common in younger people, with the average age of onset being around 40, and is characterized by extremely rapid progression of the disease.^*1,2

This drug candidate, discovered and developed by Ionis, aims to treat FUS-ALS, a neurodegenerative condition caused by the accumulation of abnormal FUS protein in neurons due to a genetic mutation, by inhibiting production of the mutated FUS protein. Delivery is by intrathecal administration every 12 weeks. Ionis is conducting the ongoing phase 3 trial for ulefnersen in multiple countries, including Japan, subject to cost reimbursement by Otsuka starting in 2025. If development and then regulatory reviews proceed successfully, ulefnersen could become the first treatment for FUS-ALS.

Under the terms of the agreement, Otsuka will pay Ionis an upfront payment of U.S. $10 million, plus milestone payments based on achievement of regulatory approvals and sales targets. Ionis is also eligible to earn royalties on product sales. Otsuka will apply for regulatory approvals and exclusively carry out manufacturing and sales of the product worldwide.

Makoto Inoue, president and representative director of Otsuka Pharmaceutical Co., Ltd. commented, "Otsuka Pharmaceutical is committed to the global development of treatments for rare diseases such as autosomal dominant polycystic kidney disease (ADPKD), IgA nephropathy, lupus nephritis, hereditary angioedema (HAE) and phenylketonuria (PKU) in order to respond to underaddressed medical needs. Through our expanded collaboration with Ionis Pharmaceuticals, we will strive to contribute to the treatment of patients worldwide with ALS accompanied by FUS mutations."

*1 Nature Communications （https://www.nature.com/articles/ncomms12408）

*2 Journal of Human Genetics (https://www.nature.com/articles/s10038-022-01055-8)