Long-term Safety and Efficacy Study and Dose-Escalation Substudy of PF 06838435 in Individuals With Hemophilia B

Study Overview
=================
Brief Summary
-----------------
Long-term safety and efficacy follow-up for participants with Hemophilia B who were previously treated in the C0371005 (formerly SPK-9001-101) study, and a dose-escalation sub-study evaluating safety, tolerability, and kinetics of a higher dose with long-term safety and efficacy follow-up. Participants in the substudy do not need to have participated in C0371005.

Detailed Description
-----------------
Evaluation of the long-term level of persistence and potential late or delayed adverse events associated with PF-06838435 (formerly SPK-9001), assessment of the durability of the transgene expression, and determination of the effects of PF-06838435 on clinical outcomes in individuals who have previously received a single administration of PF-06838435 in the C0371005 study. Amendment 2 of this study incorporates a dose-escalation substudy to evaluate the safety, tolerability, and kinetics of a single IV infusion of PF-06838435 at a higher dose than that used in the C0371005 study. The dose-escalation participants will also be followed for long-term safety and efficacy.

Official Title
-----------------
A FACTOR IX (FIX) GENE TRANSFER, MULTI CENTER EVALUATION OF THE LONG TERM SAFETY AND EFFICACY STUDY OF PF 06838435 AND A DOSE ESCALATION SUBSTUDY IN INDIVIDUALS WITH HEMOPHILIA B

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

Intervention / Treatment
-----------------
* Biological: PF-06838435 (formerly SPK-9001)


Participation Criteria
=================
Eligibility Criteria
-----------------
This study is currently only enrolling into the dose-escalation substudy with subsequent long-term follow-up. The Eligibility Criteria for entry into the dose-escalation substudy is presented below: Inclusion Criteria: Able to provide informed consent and comply with requirements of the study Males age 18 to 65 years with confirmed diagnosis of hemophilia B (≤2 IU/dL or ≤2% endogenous factor IX) Received ≥50 exposure days to factor IX products No measurable factor IX inhibitor as assessed by the central laboratory and have no prior history of inhibitors to factor IX protein Agree to refrain from donating sperm and either abstain from intercourse or use reliable barrier contraception until 3 consecutive semen samples are negative for vector sequences Exclusion Criteria: Evidence of active hepatitis B or C Currently on antiviral therapy for hepatitis B or C Have significant underlying liver disease Serological evidence* of HIV-1 or HIV-2 with CD4 counts ≤200/mm3 (* participants who are HIV+ and stable with CD4 count >200/mm3 and undetectable viral load are eligible to enroll) Neutralizing antibody titers to the capsid portion of PF-06838435 above the established threshold Sensitivity to heparin or heparin induced thrombocytopenia; sensitivity to any of the study interventions, or components thereof, or drug or other allergy Previously dosed in a gene therapy research trial at any time or in an interventional clinical study within 3 months of screening visit Any concurrent clinically significant major disease or condition Unable or unwilling to comply with the study procedures

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

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

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

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

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: This study was originally designed as a long-term follow up study for individuals dosed in Study C0371005 to evaluate the overall long-term safety, durability of transgene expression, and effect on clinical outcomes of PF-06838435 mediated gene transfer. For these individuals this study will last for 5 years providing a minimum of 6 years of follow up post vector administration. Amendment 2 of this study introduces a dose-escalation substudy to evaluate the safety, tolerability, and kinetics of a single IV infusion of PF-06838435 at a higher dose(s) than that used in the C0371005 study. For these participants this study will last for a total of 6 years post vector administration.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-06838435 Dose-Escalation<br>Single intravaneous infusion of PF-06838435. After 2 participants receive initial dose, data will be evaluated and a decision will be made to escalate or reduce the dose being evaluated, increase the number of participants receiving the dose, or stop dosing. Multiple iterations may be undertaken. | Biological: PF-06838435 (formerly SPK-9001)<br>* Gene Therapy: A novel, bioengineered adeno-associated viral vector carrying human factor IX variant<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of PF-06838435 related adverse events |  | Baseline up to Year 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of clinically significant changes from baseline | Clinically significant changes in physical examination, vital signs, laboratory values. (to be reported as AEs, regardless of causality) | Baseline up to 52 weeks | 
| Incidence of protocol-defined medically important events | Clinical thrombotic events, FIX inhibitor development as assessed by Nijmegen Bethesda assay, Hypersensitivity reaction (eg, bronchospasm and anaphylaxis), Hepatic malignancy, Study intervention-related elevated hepatic transaminases that fail to improve or resolve, Malignancy assessed as having reasonable possibility of being related to study intervention (to be reported as SAEs). | Baseline up to 52 weeks | 
| Immune response against AAV capsid protein and hFIX transgene | Positive immune response based on peripheral blood mononuclear cell (PBMC) results by interferon gamma enzyme-linked immunospot assay (ELISPOT). | Baseline up to 52 weeks | 
| Coagulation Clotting Assay for FIX activity levels | Coagulation Clotting assays to assess FIX activity levels (percent of normal) | Baseline up to Year 6 | 
| Mean and standard deviation of vector-derived FIX Activity levels | Mean and standard deviation of peak and steady-state FIX Activity | Baseline up to 52 weeks | 
| Mean and standard deviation of FIX Antigen levels | Mean and standard deviation of FIX Antigen levels | Baseline up to 52 weeks | 
| Annualized bleeding rate (ABR) | ABR (not including those for surgery) | Baseline up to Year 6 | 
| Annualized (factor FIX) infusion rate | AIR (not including those for surgery) | Baseline up to Year 6 | 
| Total factor consumption (IU) | total quantity of factor infused annually (not including those for surgery) as recorded on the infusion log | Baseline up to Year 6 | 
| Total number of bleeding events | spontaneous and traumatic | Baseline up to Year 6 | 
| Haem-A-QoL | Quality-of-life (QoL) assessment | Baseline up to Year 6 | 
| EQ-5D-5L | Quality-of-life (QoL) assessment | Baseline up to Year 6 | 
| Brief Pain Inventory | Quality-of-life (QoL) assessment | Year 2 up to Year 6 | 
| McGill Pain Questionnaire | Quality-of-life (QoL) assessment | Baseline up to 52 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
gene therapy, BeneGene LTE, hemophilia, SPK-9001, Factor IX, FIX