The current study includes clinical trial Phase I designed to perform first in a human dose of PGA40 to evaluate pharmacokinetics of  Xyntha®  and PGA40, respectively. in patients with severe hemophilia A (Part 1). And then the subjects will be proceeding to prophylaxis treatment period (Part 2) for 6 months to complete at least 50 EDs to evaluated safety and efficacy of PGA40. 
Additional PK of PGA40 will be assessed following approximately 4 months of prophylactic treatment of PGA40 to evaluate changes in PK parameters as indicators of inhibitor incidence in accordance with EMA guideline for the development of new FVIII. 
Only the adult male patients with long exposure to FVIII products (150 EDs or above) without inhibitor formation will be enrolled in the trial to check inhibitor incidence of PGA40. Testing for FVIII inhibitors will be carried out periodically in all patients until the end of a study visit by utilizing sensitive Nijmegen modification of the Bethesda assay. If inhibitors are identified, the patients will be withdrawn from the clinical trial and the inhibitor level will be monitored at further visits.

Treatment

Drug: PGA40 250 IU, 500 IU, 1000 IU
Dosage: Determined based on PGA40 PK assessment
Frequency of dosing: Determined based on PGA40 PK assessment
Period: 50 ED ~ about 6 months
Route: IV

Arm Label

Target Number of Participant

Arm Type

Arm Description

Drug: PGA40 250 IU, 500 IU, 1000 IU
Dosage: Determined based on PGA40 PK assessment
Frequency of dosing: Determined based on PGA40 PK assessment
Period: 50 ED ~ about 6 months
Route: IV

Gender

Age

Description

To be eligible for study entry, subjects must satisfy all of the following criteria:
1.	Male aged ≥ 12 to ≤ 65 years.
2.	Male subjects with the diagnosis of severe (FVIII:C < 1%)hemophilia documented in medical records.
3.	Previously treated with plasma-derived and/or recombinant FVIII products for a minimum of 150 EDs (based on the subject’s medical records). Cryoprecipitate and frozen plasma treatment are not considered as a treatment.
4.	No history of FVIII inhibitors based on the subject’s previous medical records. 
5.	No detectable FVIII inhibitors (≥0.6) Bethesda units [BU]) as assessed by a central laboratory at the time of screening.
6.	Subject who are HIV negative. If, HIV positive viral load < 400.000 copies/mL and CD4+ lymphocyte count 200/μL at screening 
7.	Subjects who are willing to undergo a prophylactic treatment for at least 50 EDs. 
8.	Non-bleeding state (i.e., no clinical signs of active bleeding) at the time of administration of Investigational product for measurement of recovery in relation to the administration of the first dose and/or at the pharmacokinetic session. 
9.	Subject and/or legal representative has provided signed ICF.

Subjects will be excluded from the study if one or more of the following criteria are applicable:
1.	Known hypersensitivity (allergic reaction or anaphylaxis) to any FVIII products or hamster protein.
2.	Previous defined medical record of arterial thrombotic events (i.e. deep vein thrombosis, stroke, pulmonary embolism, myocardial infraction and arterial embolus) 
3.	Abnormal renal function (serum creatinine >2 times the upper limit of normal at screening).
4.	Active hepatic disease with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level > 5 times the upper limit of normal at screening.
5.	Diagnosis of an inherited or acquired hemostatic defect other than hemophilia A.
6.	Platelet count < 100,000/μL based on medical records and/or based on local laboratory values at screening.
7.	A clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect subject’s safety or compliance.
8.	Patients who are receiving immunotherapy drugs other than chemotherapy, anti-RNA tumor virus chemotherapy, or who use oral or intravenous corticosteroids chronically within 3 months of screening. However, short-term (within 14 days) prednisone / methylprednisolone is allowed for the treatment of diseases such as synovitis and asthma, according to the physician's judgment.
9.	Use of an investigational medicinal product within 30 days prior to the first PGA40 administration. 
10.	Subjects who received blood transfusions within 30 days of screening.

Evaluate PK characteristics of PGA40

Visit 2, Visit 3, Visit 7

Demonstrate safety of PGA40

Visit 3 ~ Visit 9

Demonstrate the hemostatic efficacy of PGA40 severe hemophilia A subjects under prophylactic treatment. Demonstrate the hemostatic efficacy of bleeding episode (BE) treatment by PGA40 in severe hemophilia A subjects

Visit 3 ~ Visit 9

Evaluate the incidence of FVIII inhibitor development during 6 months and 50 EDs PGA40 treatment period.

Visit 3 ~ Visit 9