March 29th, 2021
Ohara Pharmaceutical Co., Ltd.

Glucarpidase (Genetical Recombination) "OP-07"
Application Filed for Marketing Authorization for Methotrexate Intoxication
Ohara Pharmaceutical Co., Ltd. (Head office: Koga City, Shiga Prefecture; President: Seiji
Ohara) has filed an application for marketing authorization to the Ministry of Health, Labour andWelfare (hereinafter, “MHLW”) for Glucarpidase (genetical recombination) (hereinafter, "OP-07"),an enzyme that hydrolyzes methotrexate (hereinafter, “MTX”), as a therapeutic agent for MTX
intoxication.
This application is filed based on the efficacy and safety results of eight clinical studies conductedin Japan and overseas, including Study CPG2-PII below.
OP-07 acquired Orphan Drug Designation by the MHLW on August 17, 2020.
[Study CPG2-PII]
This is a phase II study conducted as an investigator-initiated study in Japan. The purpose ofthis study was to evaluate the blood MTX level-reducing effect of OP-07 in patients with delayed
MTX excretion of high-dose MTX therapy.
We are committed to continue our efforts to deliver OP-07 to patients as quickly as possible.

[About methotrexate (MTX) intoxication]
High-dose MTX therapy (synonymous to MTX/leucovorin salvage therapy) is one of the importantchemotherapy regimens for acute lymphoblastic leukemia, osteosarcoma, malignant lymphoma,etc. As an adverse drug reaction of the high-dose MTX therapy, however, it has been reported that
MTX intoxication results from the delayed MTX excretion due to impaired renal function caused by
MTX crystals deposited in the kidney tubules. MTX intoxication exposes various organs to highlevels of MTX for a long time, which may cause histological damage.
Existing therapies for MTX intoxication include supportive therapy aimed at excreting MTX fromthe body (high-volume infusion, urine alkalinization and administration of diuretics), as well as
leucovorin salvage therapy. However, there have been rare cases with a fatal outcome despite
these preventive therapies,1) indicating that patients may die if early treatment is not provided.
Therefore, there is an unmet medical need for a fast-acting therapeutic drug with a detoxifying
effect.
[What are orphan drugs?]
Orphan drugs refer to drugs designated by the Minister of Health, Labour and Welfare fordiseases with less than 50,000 patients in Japan, considered to be of particularly high medical
needs through the relevant review.
[Reference]
1)

Chabner BA, Allegra CJ. Antifolates. In: Chabner BA and Longo DL. Cancer Chemotherapy,Immunotherapy and Biotherapy: principles and practice, Sixth Edition. Philadelphia: Wolters
kluwer. 2019, 92-113.

[About OP-07]
OP-07 is a glutamate carboxypeptidase that is derived from the Variovorax paradoxus(Pseudomonas sp. RS16) strain, and is a protein with the molecular weight of approx. 83 kDa,
consisting of two sub-units that have 390 amino acid residues. It hydrolyzes the C-terminal glutamic
acid residue in MTX as a folic acid analog, and produces 4-deoxy-4-amino-N10-methylpteroic acid
(DAMPA) and glutamic acid.
OP-07 was approved in January 2012 in the U.S., and it is marketed as Voraxaze® by BTG
International Inc. The current indication approved in the U.S. is as follows: "VORAXAZE is acarboxypeptidase indicated to reduce toxic plasma methotrexate concentration (greater than 1
micromole per liter) in adult and pediatric patients with delayed methotrexate clearance (plasmamethotrexate concentrations greater than 2 standard deviations of the mean methotrexate
excretion curve specific for the dose of methotrexate administered) due to impaired renal function."
The developer of OP-07, BTG International Inc., licensed Ohara Pharmaceutical, which has filed
an application for marketing authorization in Japan.

[About Ohara Pharmaceutical Co., Ltd.]
Ohara Pharmaceutical Co., Ltd. is a pharmaceutical company that discovers and develops
orphan drugs and generic drugs as its mainstay business. The company particularly focuses onthe development and marketing of orphan drugs for pediatric cancer and other areas, and on thedevelopment, manufacturing and marketing of generic drugs that feature the prevention of medicalaccidents. Ohara Pharmaceutical aims to become a company that provides total healthcare
solution by promoting innovations not only in treatment, but also for prevention, diagnosis andaftercare that affect the quality of healthcare, in the substantially changing healthcare environment
and improving treatment outcome.