Chugai Pharmaceutical : Anti-CD20 Monoclonal Antibody Rituxan Approved for the Prevention of Recurrence of Neuromyelitis Optica Spectrum Disorder

Zenyaku Kogyo Co., Ltd.

Chugai Pharmaceutical Co., Ltd.

Anti-CD20 Monoclonal Antibody Rituxan Approved for

the Prevention of Recurrence of Neuromyelitis Optica Spectrum Disorder

TOKYO, June 20, 2022 --Zenyaku Kogyo Co., Ltd.(Japanese-only website) and Chugai Pharmaceutical Co., Ltd.(TOKYO: 4519) announced today that Zenyaku obtained regulatory approval from the Ministry of Health, Labour and Welfare (MHLW), for an anti-CD20 monoclonal antibody Rituxan® intravenous injection 100 mg and 500 mg [generic name: rituximab (genetical recombination)] (hereafter, "Rituxan") for the prevention of recurrence of neuromyelitis optica spectrum disorder (including neuromyelitis optica). Rituxan obtained orphan drug designation for this indication in June 2020, and Zenyaku filed the application for regulatory approval in October 2021.

Rituxan is an anti-CD20 monoclonal antibody that specifically binds to CD20, a protein expressed on B cells, excluding stem cells and plasma cells. It attacks target B cells using the immune system equipped with the human body, and damages cells.

This approval is based on the results of an investigator-initiated phase II/III clinical study (RIN-1 study)1 which evaluated Rituxan for the reduction of relapse in Japanese patients with neuromyelitis optica (NMO) or neuromyelitis optica spectrum disorder (NMOSD). This study was conducted at eight hospitals in Japan, mainly led by Dr. Tahara, Chief of the Clinical Research Center, Dr. Oeda, Director of Clinical Research Center and Dr. Sawada, Vice President, of the National Hospital Organization Utano National Hospital, and was funded by the Japan Agency for Medical Research and Development.

NMOSD is an inflammatory disease of the central nervous system, characterized by severe optic neuritis and transverse myelitis.2,3,4 The disease can lead to continual and significant decrease in quality of life due to permanent neurological disability. It is a designated intractable disease with the prevalence of 5.3 per 100,000 people in Japan.5 About 90% of NMOSD patients are female,2,6 and the onset peaks in the late 30s to early 40s.6,7 If not treated, the frequency of recurrence is reported as an average of 1 to 1.5 times per year, with the level of disability progressively worsening due to repeated recurrences.8 A major factor in the pathogenesis of NMOSD is thought to be cell injury caused by autoantibodies against aquaporin-4, which is expressed on astrocytes in the central nervous system.9 Rituxan prevents recurrence of NMOSD by eliminating CD20-positive B cells in the blood, thereby suppressing the production of new autoantibodies.

Zenyaku and Chugai will continue working closely together so that Rituxan may contribute to the

treatment of NMOSD (including NMO).

Trademarks used or mentioned in this release are protected by law.

Sources

1. Tahara M, Oeda T, Okada K, Kiriyama T, Ochi K, Maruyama H, Fukaura H, Nomura K, Shimizu Y, Mori M, Nakashima I, Misu T, Umemura A, Yamamoto K, Sawada H. Safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (RIN-1 study): a multicentre, randomised, double-blind,placebo-controlled trial. Lancet Neurol. 2020 Apr;19(4):298-306. doi: 10.1016/S1474-4422(20)30066-1. Epub 2020 Mar 18.
2. Guidelines for the management of multiple sclerosis and neuromyelitis optica committee, Guidelines for the management of multiple sclerosis and neuromyelitis optica 2017, Ver.1. Tokyo: Igaku-Shoin; 2017 pp2-19 (Japanese only)
3. K Fujihara. Pathophysiology and treatment of neuromyelitis optica: Disease concepts and
   diagnostic criteria. J Kira ed. Latest approaches: Multiple sclerosis and neuromyelitis optica.
   Nakayama shoten. 2012: P304-313. (Japanese only)
4. Kira J. Multiple sclerosis in the Japanese population. Lancet Neurol. 2003;2(2):117-127.
5. Japan Intractable Diseases Information Center. Available from:https://www.nanbyou.or.jp/. Accessed June 2022. (Japanese only)
6. Nagaishi A, Takagi M, Umemura A, et al. Clinical features of neuromyelitis optica in a large Japanese cohort: comparison between phenotypes. J Neurol Neurosurg Psychiatry. 2011;82(12):1360-1364.
7. Miyamoto K, Fujihara K, Kira JI, et al. Nationwide epidemiological study of neuromyelitis optica in Japan. J Neurol Neurosurg Psychiatry. 2018;89(6):667-668.
8. Kitley J, Leite MI, Nakashima I, et al. Prognostic factors and disease course in aquaporin-4antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan. Brain. 2012; 135(Pt 6): 1834-1849.
9. Ratelade J, Asavapanumas N, Ritchie AM, et al. Involvement of antibody-dependent cell- mediated cytotoxicity in inflammatory demyelination in a mouse model of neuromyelitis optica. Acta Neuropathol. 2013; 126(5): 699-709.

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