• ClinicalTrials.gov Identifier:  NCT00076557
• Phase I/II, open-label, phase 1/2 open-label study

Terminated ^*, Last Update Posted: April 4, 2007^*, closed ²⁸

• 18 years or older Males with severe FIX deficiency
• > 20 EDs of treatment with FIX protein

Presence of inflammatory muscle disease (e.g., myositis) ²⁹

AAV2, HEK293 cells ²⁹

FIX is assembled by exon 1, a portion of the human FIX intron I and exons 2-8 of the human F9 gene ²⁹

Data regarding the vector regulatory elements of the utilized expreswsion cassette were taken from here ²⁹ and summarized as follows:

• Cytomegalovirus (CMV) enhancer/promoter fragment
• Exon 1 and 1.4-kb portion of intron 1 of the human F9 gene
• Exons 2-8 of the human FIX cDNA (FIX cDNA)
• SV40 late polyadenylation sequence

Intramuscular injections ²⁹

• Co. 1: 2e11 (3) 
• Co. 2: 6e11 (3)
• Co. 3: 1.8e12 (2)

2 - 10 months

OS ²⁹

4/8 subjects with detectable FIX levels higher than the baseline in the range of 0.3%-1.2% (8 - 52 weeks) as follows: 

• Subject A had a 1% level measured 52 weeks after vector injection
• Subject B also showed measurable increases in FIX levels, from a baseline of less than 0.3%, up to 0.8%
• Subject D had a level of 0.7% at 8 weeks, with a baseline of 0.2%
• Subject G had a level of 0.8% at 4 weeks after treatment
• All other FIX levels, measured at least 14 days after factor concentrate infusion, were less than 1% in the remaining subjects

Not reported

Circulating levels of FIX were too low for a therapeutic effect ²⁹

Not reported

• IM injection was well-tolerated in all subjects, with n osystemic symptoms
• In one subject a 5-fold elevation in the creatine phosphokinase (CPK) returned to baseline 1 week after injection ²⁹

• 1 subject had a mild inflammatory reaction to the tattoo dye that was injected at a few sites, that resolved without treatment  
• 5/8 pts. developed small hematomas or pain at one or more vector injection sites, which resolved uneventfully 
• 4/8 pts. developed transient minor abnormalities (hematoma, induration, transient numbness) at the site of muscle biopsy ²⁹    

Not reported

No abnormalities in serum chemistries ²⁹

Not applicable

Not reported

Not applicable

Not applicable

Not reported

  *   ClinicalTrials.gov
28. Nathwani, A.C., Gene therapy for hemophilia. Hematology Am Soc Hematol Educ Program, 2019. 2019(1): p. 1-8.
       Gene therapy for hemophilia | Hematology, ASH Education Program | American Society of Hematology (ashpublications.org)      
29. Manno, C.S., et al., AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood, 2003. 101(8): p. 2963-72.
       AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B | Blood | American Society of Hematology (ashpublications.org) 

AAV, Adeno-associated virus; AEs, Adverse events; ABR, Annualized bleeding rate; AEs: adverse events; AIR, Annualized FVIII/FIX infusion rate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CH, Chromogenic Assay; Co., cohort; DOACs, Direct oral anticoagulants; D, days; EDs, exposure days; FIX, factor IX; FIX-Padua, gain of function FIX variant; FVIII, factor VIII; gc, genome copies; HEK cells, human embryonic kidney cells; IQR, interquartile range; IRR, Infusion-related reaction; NAbs, neutralizing antibodies; OS, One-stage clotting assay; Pop., population; pt., patient/participant; pts., patients/participants; P1, Participant 1; PI, phase I; PBGD, porphobilinogen deaminase; PBMC, peripheral blood mononuclear cells; SAEs, serious adverse events; SFU, spot-forming units; TAC, tacrolimus; ULN, upper limit of normal; VCN, vector copy number; vg, vector genomes; W, weeks; WT, wild type; Y, year