August 17, 2020
Ohara Pharmaceutical Co., Ltd.

Glucarpidase (Genetical Recombination) “OP-07”
Receives Orphan Drug Designation from MHLW
On August 17, 2020, Ohara Pharmaceutical Co., Ltd. (Head office: Koga City, Shiga
Prefecture; President: Seiji Ohara) received Orphan Drug Designation from theMinistry of Health, Labour and Welfare (hereinafter “MHLW”) for Glucarpidase(genetical recombination) (hereinafter “OP-07”) as an enzyme preparation thathydrolyzes methotrexate (MTX), with “antidote for patients with delayed excretion of
methotrexate in methotrexate/leucovorin salvage therapy” as an expected indication.
High-dose MTX therapy (synonymous to methotrexate/leucovorin salvage therapy)
is one of the important chemotherapies for acute lymphoblastic leukemia,
osteosarcoma, malignant lymphoma, etc. However, an adverse drug reaction has
been reported that MTX intoxication results from the delayed excretion of MTX due
to impaired renal function caused by MTX crystals deposited on kidney tubules.
Existing therapies for MTX intoxication include supportive therapy aimed at excreting
MTX from the body (large volume infusion, urine alkalinization and administration ofdiuretic), as well as leucovorin salvage therapy. However, it is known that there arerare cases where serious MTX intoxication occurs despite these preventivetherapies.1) Therefore there exists an unmet medical need for fast-acting therapeutic
drug with a detoxifying effect.
OP-07 is able to quickly reduce MTX levels in blood by hydrolyzing MTX, thereby
detoxifying MTX intoxication. This drug was designated as an orphan drug in the U.S.
and Europe in 2003, and was approved in the U.S. in January 2012. In Japan, a phase
II clinical study is in progress. Upon approval of OP-07 for the indication above, it will
become the first drug in Japan that directly and quickly reduces MTX levels in bloodby hydrolyzing MTX in blood.
The number of patients to be included in the scope of treatment with OP-07 is
estimated at around 572 to 8,500 per annum in Japan.
We are committed to continue our efforts to deliver OP-07 to patients as quickly aspossible.

[References]
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 Cterminal glutamic acid residue in MTX as a folic acid analog, and produces 4-deoxy-4amino-N10-methylpteroic acid (DAMPA) and glutamic acid.
In the U.S., OP-07 was approved for the following indication in January 2012 and ismarketed as Voraxaze® by BTG International Inc of the U.S.: “VORAXAZE is indicated toreduce toxic plasma methotrexate concentration (greater than 1 micromole per liter) in
adult and pediatric patients with delayed methotrexate clearance (plasma methotrexate
concentrations greater than 2 standard deviations of the mean methotrexate excretion
curve specific for the dose of methotrexate administered) due to impaired renal function.”[What are orphan drugs?]
Orphan drugs refer to drugs which have been reviewed and designated by the MHLW
as drugs for diseases with less than 50,000 patients in Japan and have high unmet
medical needs.
[About Ohara Pharmaceutical Co., Ltd.]
Ohara Pharmaceutical Co., Ltd. is one of the unique Japanese pharmaceuticalcompanies that focus on the development and distribution of orphan drugs mainly in thefield of childhood cancer treatment as well as generic drugs taking the prevention of
medical accidents into consideration. In the Midterm 3-year plan that started in FY2018,
Ohara is committed to addressing medical issues under the theme, “To Challenge unmet
medical needs,“ applying the catch-phrase, ”Challenge 2020.“ Ohara is planning tofurther expand these activities into emerging countries mainly in Asia as well as otherregions.