− JR-141 is a potentially transformative therapy designed to deliver proteins to the brain and peripheral tissues to treat neuronopathic features along with somatic symptoms of Hunter syndrome via intravenous administration

− Takeda to exclusively commercialize JR-141 outside the U.S. (except Japan and certain other Asia-Pacific countries) upon regulatory approval

− Takeda receives a separate option to obtain an exclusive license to commercialize in the U.S. after completion of the global Phase 3 program

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) and JCR Pharmaceuticals Co., Ltd. (TSE:4552) (“JCR”) announced today a geographically-focused exclusive collaboration and license agreement to commercialize JR-141 (INN: pabinafusp alfa), an investigational, next-generation recombinant fusion protein of an antibody against the human transferrin receptor and iduronate-2-sulfatase (IDS) enzyme for the treatment of Hunter syndrome (also known as Mucopolysaccharidosis type II or MPS II). Hunter syndrome is caused by a deficiency of IDS and manifests in different forms. JR-141, applied with J-Brain Cargo®, JCR’s proprietary blood-brain barrier (BBB) technology, is engineered to transport the therapeutic enzyme across the BBB to directly reach the brain and address both the somatic and neuronopathic manifestations of the disease, which can lead to progressive cognitive decline.

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Under the terms of the exclusive collaboration and license agreement, Takeda will exclusively commercialize JR-141 outside of the United States, including Canada, Europe, and other regions (excluding Japan and certain other Asia-Pacific countries). JCR will receive an upfront payment for such ex-U.S. license, and is eligible to receive additional development and commercial milestones as well as tiered royalties on potential sales. The two companies will collaborate to bring this therapy to patients as quickly as possible upon completion of the global Phase 3 program, which will be conducted by JCR.

Takeda receives an option under a separate option agreement, which allows Takeda to acquire an exclusive license to commercialize JR-141 in the U.S. upon completion of the Phase 3 program.

“Takeda is committed to continuously improving the way Hunter syndrome is treated. JR-141 introduces a new way to deliver proteins across the blood-brain barrier, overcoming our current challenges to treat the underlying neuronopathic manifestations of Hunter syndrome and help maintain or improve cognitive function in these patients,” said Dan Curran, M.D., Head, Rare Genetics & Hematology Therapeutic Area Unit at Takeda. “We will work closely with JCR to apply our expertise in enzyme replacement therapies with the hope of bringing this potentially transformative therapy to patients as quickly as possible.”

“JCR is pleased to have reached an agreement with Takeda who is well placed to achieve our common goal of maximizing the impact of JR-141,” said Shin Ashida, President, Chairman of JCR. “Our mission is to provide transformative treatment options as soon as possible to patients with lysosomal storage disorders (LSDs) with central nervous system symptoms, such as Hunter syndrome. JR-141 is the first-ever approved biopharmaceutical in Japan that penetrates the blood-brain barrier. I expect that we will be able to achieve this mission through our partnership with Takeda to deliver a new treatment option to Hunter patients around the world as swiftly as possible.”

JR-141 met its primary endpoint in an open-label Phase 2/3 clinical trial in Japan demonstrating significant reductions in heparan sulfate (HS) in the cerebrospinal fluid, a biomarker for assessing the drug’s effectiveness in reducing disease-causing substrate in the central nervous system, in all subjects for whom measurements were available after 52 weeks of treatment. Somatic disease control was maintained in patients who switched from standard enzyme replacement therapy (ERT). The study also demonstrated an improvement in somatic symptoms in participants who had not previously received standard ERT prior to the start of the trial. Additionally, a neurocognitive development assessment demonstrated maintenance or improvement of age-equivalent function in 21 of the 25 patients at one year. There were no reports of serious treatment-related adverse events in the trial.¹

About JR-141

JR-141 is a recombinant fusion protein of an antibody against the human transferrin receptor and iduronate-2-sulfatase, the enzyme that is missing or malfunctioning in subjects with Hunter syndrome. It is expected to be effective against the neuronopathic manifestations of the disease by crossing the BBB through transferrin receptor mediated transcytosis using J-Brain Cargo®, JCR’s proprietary BBB technology. Uptake into cells is mediated through the transferrin receptor and mannose-6-phosphate receptor. JCR has advanced development activities by establishing the necessary evidence from the molecular design stage to the nonclinical and clinical trial phases. In non-clinical trials, JCR has confirmed both high affinity binding of JR-141 to transferrin receptors, and passage across the BBB into neuronal cells as evidenced by electron microscopy.

In addition, JCR has confirmed that using J-Brain Cargo® technology, enzymes are taken up into various brain tissues. A decrease in substrate accumulation has also been confirmed in an animal model of Hunter syndrome.^2,3,4 In several clinical trials with JR-141, JCR obtained evidence of reduction of heparan sulfate concentrations in the CSF, a biomarker for assessing the drug’s effectiveness in reducing disease-causing substrate in the central nervous system, consistent with the results obtained from non-clinical studies. JCR also obtained clinical results that demonstrate positive effects of JR-141 on neurocognition.^5,6,7,8

JR-141 was approved by the Ministry of Health, Labour and Welfare and marketed since May 2021 under the brand name “IZCARGO® I.V. Infusion 10mg.”

About Hunter Syndrome

Hunter syndrome is a severely debilitating, rare lysosomal disease caused by a deficiency of iduronate-2-sulfatase, an enzyme that is needed to break down substances in the body called glycosaminoglycans (GAGs).⁹ Without this enzyme, GAGs can build up, causing a range of disease-related signs and symptoms.^9,10 Roughly two of every three patients with Hunter syndrome are also affected with progressive cognitive decline.¹¹ Hunter syndrome affects 1 in 162,000 total live births, and almost exclusively males.¹²

About Takeda Pharmaceutical Company Limited

Takeda Pharmaceutical Company Limited (TSE: 4502/NYSE: TAK) is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to discover and deliver life-transforming treatments, guided by our commitment to patients, our people and the planet. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Rare Genetics and Hematology, Neuroscience, and Gastroenterology (GI). We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people’s lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries and regions. For more information, visit https://www.takeda.com.

About JCR Pharmaceuticals Co., Ltd.

JCR Pharmaceuticals Co., Ltd. (TSE 4552) is a global specialty pharmaceuticals company that is redefining expectations and expanding possibilities for people with rare and genetic diseases worldwide. We continue to build upon our 46-year legacy in Japan while expanding our global footprint into the US, Europe, and Latin America. We improve patients’ lives by applying our scientific expertise and unique technologies to research, develop, and deliver next-generation therapies. Our approved products in Japan include therapies for the treatment of growth disorder, Fabry disease, acute graft-versus host disease, and renal anemia. Our investigational products in development worldwide are aimed at treating rare diseases including MPS I (Hurler, Hurler-Scheie and Scheie syndrome), MPS II (Hunter syndrome), Pompe disease, and more. JCR strives to expand the possibilities for patients while accelerating medical advancement at a global level. Our core values – reliability, confidence, and persistence – benefit all our stakeholders, including employees, partners, and patients. Together we soar. For more information, please visit https://www.jcrpharm.co.jp/en/site/en/.

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1. Okuyama T, Eto Y, Sakai N, et al. A phase 2/3 trial of pabinafusp alfa, IDS fused with anti-human transferrin receptor antibody, targeting neurodegeneration in MPS-II. Molecular Therapy. 2021;29(2):671-679.

2. Sonoda, et al. A Blood-Brain-Barrier-Penetrating Anti-human Transferrin Receptor Antibody Fusion Protein for Neuronopathic Mucopolysaccharidosis II. Mol Ther. 2018; 26(5): 1366-74.

3. Morimoto, et al. Clearance of heparin sulfate in the brain prevents neurodegeneration and neurocognitive impairment in MPS II mice. Mol. Ther. 2021; https://doi.org/10.1016/j.ymthe.2021.01.027.

4. Yamamoto et al. Nonclinical Safety evaluation of pabinafusp alfa, an anti-human transferrin receptor antibody and iduronate-2-sulfatase fusion protein, for the treatment of neuronopathic mucopolysaccharidosis type II. Mol Genet Metab Rep. 2021; https://doi.org/10.1016/j.ymgmr.2021.100758.

5. Okuyama, et al. Iduronate-2-sulfatase with Anti-human Transferrin Receptor Antibody for Neuropathic Mucopolysaccharidosis II: A Phase 1/2 Trial. Mol Ther. 2020; 27(2): 456-464.

6. Okuyama, et al. A Phase 2/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II. Mol Ther. 2020; 29(2): 671-679.

7. Giugliani, et al. Iduronate-2-sulfatase fused with anti-human transferrin receptor antibody, pabinafusp alfa, for treatment of neuronopathic and non-neuronopathic mucopolysaccharidosis II: Report of a phase 2 trial in Brazil. Mol Ther. 2021; https://doi.org/10.1016/j.ymthe.2021.03.019.

8. Giugliani, et al. Enzyme Replacement Therapy with Pabinafusp Alfa for Neuronopathic Mucopolysaccharidosis II; an Integrated Analysis of Preclinical and Clinical Data. Preprints 2021; 2021090192.

9. Wraith JE, et al. Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr. 2008; 167(3):267-77.

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