A Phase 1/2 Study of SHP648, an Adeno-Associated Viral Vector for Gene Transfer in Hemophilia B Subjects

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety and dose escalation of SHP648 an adeno-associated viral vector for gene transfer in hemophilia B participants.

Detailed Description
-----------------
This study will consists of 3 dose cohorts with 2-7 participants in each of the three ascending dose cohorts. Initially 2 participants will be dosed in Cohort 1, followed by dosing of up to 5 additional participants if the cohort is expanded. Participants in cohort 2 and 3 will receive 2-fold or 3-fold dose escalation to their respective preceding cohort doses if required.

Official Title
-----------------
An Open-Label, Multinational, Phase 1/2 Study of the Safety and Dose Escalation of SHP648, an Adeno-Associated Virus Serotype 8 (AAV8) Vector Expressing FIX Padua in Hemophilia B Subjects

Conditions
-----------------
Hemophilia B

Intervention / Treatment
-----------------
* Genetic: SHP648


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male, aged 18 to 75 years at the time of screening. Established severe or moderately severe hemophilia B (plasma FIX activity lesser than or equal to [<=] 2 percent (%) measured following greater than or equal to [>=] 5 half-lives of most recent exposure to exogenous FIX) and either >= 3 hemorrhages per year requiring treatment with exogenous FIX or use of prophylactic therapy. History of greater than (>) 50 exposure days to exogenously administered FIX concentrates or cryoprecipitates. Sexually active men must agree to use barrier contraception (combination of a condom and spermicide) or limit sexual intercourse to post-menopausal, surgically sterilized, or contraception-practicing partners for a minimum of 6 months after administration of SHP648, or until SHP648 genomes are no longer detected in the semen (whichever is sooner). Signed informed consent. Exclusion Criteria: Bleeding disorder(s) other than hemophilia B. Documented laboratory evidence of having developed inhibitors (>= 0.6 Bethesda Units [BU] on any single test) to FIX proteins at any time. Documented prior allergic reaction to any FIX product. Anti-AAV8 neutralizing antibody titer >= 1:5. Known hypersensitivity to prednisolone or prednisone, or to any of the excipients. Having a disease in which treatment with prednisolone or prednisone is not tolerated (including, but not limited to osteoporosis with vertebral fractures, severe labile hypertension, and brittle diabetes). Evidence of markers of potential underlying risk for autoimmune mediated hepatic disease: Anti-smooth muscle antibody (ASMA) titer >= 1:40. Values of 1:31 to 1:39 will be flagged as possibly abnormal and the Investigator and Medical Monitor will evaluate the participant for eligibility Elevated anti-liver-kidney microsomal antibody type 1 (LKM1) titers Total Immunoglobulin G (IgG) > 1.5x upper limit of normal (ULN) Antinuclear antibody (ANA) titer > 1:320 OR ANA titer > 1:80 if demonstrated concurrently with alanine aminotransferase (ALT) that is > ULN Active Hepatitis C: as indicated by detectable hepatitis C virus ribonucleic acid (HCV RNA) by polymerase chain reaction (PCR). Hepatitis B: If surface hepatitis B virus (HBV) antigen is positive. Receiving chronic systemic antiviral and/or interferon therapy within 4 weeks prior to enrollment. Clinically significant infections (e.g., systemic fungal infections) requiring systemic treatment. Known immune disorder (including myeloma and lymphoma). Concurrent chemotherapy or biological therapy for treatment of neoplastic disease or other disorders. An absolute neutrophil count lesser than < 1000 cells per cubic millimetre (cells/mm^3). Markers of hepatic inflammation or cirrhosis as evidenced by 1 or more of the following: Platelet count < 150,000/microliter (μL) Albumin <= 3.5 gram per deciliter (g/dL) Total bilirubin > 1.5x ULN and direct bilirubin >= 0.5 milligram per deciliter (mg/dL) ALT or Aspartate aminotransferase (AST) > 1.0x ULN Alkaline phosphatase > 2.0x ULN History of liver biopsy or imaging indicating moderate or severe fibrosis (Metavir staging of F2 or greater) History of ascites, varices, variceal hemorrhage, or hepatic encephalopathy FibroSURE Score >= 0.4 Prothrombin time international normalized ratio (INR) >= 1.4 Serum creatinine > 1.5 mg/dL. Human immunodeficiency virus (HIV) if cluster of differentiation 4 (CD4)+ cell count <= 200 mm^3 and/or viral load > 20 copies per milliliter (copies/mL). Urine protein > 30 mg/dL. Body mass index > 38. Orthopedic or other major surgery planned within 6 months after enrollment. Acute or chronic disease that, in the opinion of the Investigator, would adversely affect participant safety or compliance or interpretation of study results. Received an AAV vector previously or any other gene transfer agent in the previous 12 months prior to Study Day 0. Significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, congestive heart failure, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary disease (including obstructive pulmonary disease). History of arterial or venous thrombosis / thromboembolism, or a known pro-thrombotic condition. Recent history of psychiatric illness or cognitive dysfunction (including drug or alcohol abuse) that, in the opinion of the Investigator, is likely to impair participants ability to comply with protocol mandated procedures. Participation in another study involved with an investigational agent. Participant is family member or employee of the Investigator.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Cohort 1 participants will receive a single intravenous (IV) infusion of SHP648 on the day of dosing (Day 0). | Genetic: SHP648<br>* Participants will receive a single IV infusion of SHP648 in Cohort 1, 2, 3 on Day 0.<br>* Other names: AAV8.ss-3xCRM8-TTR-FIX_R338Lopt;|
| Experimental: Cohort 2<br>Cohort 2 participants will receive a single IV infusion of SHP648 at a 2 to 3-fold escalation of Cohort 1 on the day of dosing (Day 0). | Genetic: SHP648<br>* Participants will receive a single IV infusion of SHP648 in Cohort 1, 2, 3 on Day 0.<br>* Other names: AAV8.ss-3xCRM8-TTR-FIX_R338Lopt;|
| Experimental: Cohort 3<br>Cohort 3 participants will receive a single IV infusion of SHP648 at a 2 to 3-fold escalation of Cohort 2 on the day of dosing (Day 0). | Genetic: SHP648<br>* Participants will receive a single IV infusion of SHP648 in Cohort 1, 2, 3 on Day 0.<br>* Other names: AAV8.ss-3xCRM8-TTR-FIX_R338Lopt;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With SHP648 Related Serious and Non- Serious Adverse Events (AEs) | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and that did not necessarily have a causal relationship with this investigational product (IP) or medicinal product. A Serious adverse event (SAE) was an AE resulting in any of the following outcomes: death; Life-threatening event; required or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly. | From study start date to Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Factor IX (FIX) Levels Before and After SHP648 Infusion | Plasma FIX levels before and after SHP648 infusion were planned to be reported. | From study start date to Month 12 | 
| Annualized Bleed Rate (ABR) Before and After SHP648 Infusion | ABR was to be assessed based upon each individual bleeding episode. A bleed episode was defined as subjective (example, pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FIX. ABR before and after SHP648 administration was planned to be reported. | From study start date to Month 12 | 
| Number of Participants With Positive Binding Antibody Titers to Adeno-Associated Virus (AAV8) | Number of participants with positive binding antibodies titers to AAV8 was planned to be reported. | From study start date to Month 12 | 
| Number of Participants With Positive Neutralizing Antibody Titers to AAV8 | Number of participants with positive neutralizing antibodies to AAV8 was planned to be reported. | From study start date to Month 12 | 
| Number of Participants With T-cell Response to AAV8 | Number of participants with T-cell response to AAV8 was planned to be reported. | From study start date to Month 12 | 
| Number of Participants With T-cell Response to FIX Transgene Products | Number of participants with T-cell response to FIX transgene products was planned to be reported. | From study start date to Month 12 | 
| Duration of SHP648 Genomes Present in Bodily Fluids | Duration of SHP648 genomes present in bodily fluids such as serum, blood, saliva, urine, stool, and semen was planned to be reported. | From study start date to Month 12 | 
| Percent Change in Consumption of FIX Before and After Gene Transfer | Percent change in consumption of exogenous FIX before and after gene transfer was planned to be reported. | From study start date to Month 12 |