Dear All,
September 27, 2021
Ohara Pharmaceutical Co., Ltd.

Glucarpidase (Genetical Recombination) “MegludaseⓇ”
Marketing Authorization Approval
Ohara Pharmaceutical Co., Ltd. (Head Office: Koka City, Shiga Prefecture; President andCEO: Seiji Ohara; hereinafter, referred to as “our company”) has obtained marketing
authorization from the Ministry of Health, Labour and Welfare, which granted regulatory
approval for ”MegludaseⓇ injection for intravenous use 1000” (generic name: glucarpidase(genetical recombination); development code: OP-07; hereinafter, referred to as “Megludase”)
as a therapeutic agent for “detoxication in case of delayed methotrexate elimination withmethotrexate-leucovorin rescue therapy,” on September 27, 2021.
This authorization has been granted based on the efficacy and safety results of the clinicalstudies conducted in Japan and overseas, including the investigator-initiated study (hereinafter, referred to as “CPG2-PII study”).
“Megludase” is used as a therapeutic agent in the US. In addition, “Megludase” acquired anOrphan Drug Designation from the Ministry of Health, Labour and Welfare on August 17, 2021.
[About CPG2-PII study]
This phase II study in Japan was conducted as an investigator-initiated study funded by theJapan Medical Association. The purpose of this study was to evaluate the blood MTX levelreducing effect of glucarpidase in the event of delayed MTX excretion, in patients with delayed
MTX excretion after methotrexate-leucovorin (hereinafter “MTX-LV”) rescue therapy, with therate of achievement of CIR (Clinically important reduction (of the MTX concentration)) as theprimary endpoint. As a result, the CIR achievement rate was 76.9% (10 out of 13 patientsevaluated for efficacy). Many of the adverse events recognized in this study appeared to becaused by MTX, and those for which a causal relationship with this agent could not be denied
were Grade 3 or lower in 2 patients.
Contact details for inquires regarding this issue:
Ohara Pharmaceutical Co., Ltd.
Representatives: Omori, Ro
TEL: +81-3-6740-7701 FAX: +81-3-6740-7702

[About delayed MTX excretion]
MTX-LV rescue therapy is one of the important chemotherapy regimens for acutelymphoblastic leukemia, osteosarcoma, malignant lymphoma, etc. However, as an adverse
drug reaction of MTX-LV therapy, it has been reported that delayed MTX excretion develops
due to impaired renal function caused by the deposition of MTX crystals in the kidney tubules.
As a result of this delayed MTX excretion, various organs are exposed to high levels of MTX
for long periods, which may cause histological damage.
Existing therapies for delayed MTX excretion include a supportive therapy aimed atenhancing excretion of MTX from the body (high-volume infusion, urine alkalinization, andadministration of diuretics), an LV administration aimed at reducing MTX toxicity, and a blood
purification therapy aimed at directly reducing the blood MTX level. However, in spite of theseprocedures and treatments, there have been rare cases with a fatal outcome,1) indicating thatpatients may die if early therapeutic intervention is not provided.
[About Megludase]
Megludase (generic name: glucarpidase (genetical recombination)) is a glutamate
carboxypeptidase that is derived from the Variovorax paradoxus (Pseudomonas sp. RS16)
strain and is a protein with a molecular weight of approx. 83 kDa, consisting of two sub-units
with 390 amino acid residues. It hydrolyzes the C-terminal glutamic acid residue in MTX as afolic acid analog, producing 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamicacid.
Megludase was approved in January 2012 in the U.S., and is marketed as Voraxaze® by
BTG International Inc. The current indication approved in the U.S. is as follows: “VORAXAZE
is a carboxypeptidase indicated to reduce toxic plasma methotrexate concentration (greaterthan 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 toimpaired renal function.”
In Japan, our company markets this drug under license from Protherics Medicines
Development Ltd. (a BTG Company), which developed the drug.
[What are orphan drugs?]
Orphan drugs refer to drugs designated by the Minister of Health, Labour and Welfare fordiseases with fewer than 50,000 patients in Japan, considered to have particularly highmedical needs based on the relevant review.

[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 focuseson the development, manufacturing and marketing of orphan drugs for pediatric cancer andother areas, and on the development, manufacturing and marketing of generic drugs thatfeature in the prevention of medical accidents. Ohara Pharmaceutical aims to become acompany that provides a total healthcare solution by promoting innovations not only intreatment, but also for the prevention, diagnosis and aftercare that affect the quality ofhealthcare in the substantially changing healthcare environment and improving the treatment
outcome.
[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.