1/2 dose-escalation clinical study ³

Non-commercial, Avigen/CHOP ²⁸ 

• Males ≥ 18 years old with pre-treatment AAV titers up to 1:17 and severe hemophilia B with Factor IX activity level < 1% of normal
• > 20 EDs of treatment with Factor IX protein

Subjects who must remain on, or desire to remain on, a regimen of prophylactic infusion of FIX protein

AAV2/ HEK293 cells

FIX-WT is composed of the human F9 cDNA interrupted by a 1.4 kb fragment of intron 1 ³

According to this reference ³ the APOE-HCR/hAAT enhancer/promoter is composed of :

• The human alpha1-antitrypsin (hAAT) promoter                  
• The hepatic locus control region and a single copy of the APOE enhancer (APOE-HCR)

The human F9 cDNA is interrupted by a 1.4 kb fragment of intron 1

Trough hepatic artery ³

• Co. 1: 8e10 (2) 
• Co. 2: 4e11 (3), 
• Co. 3: 2e12 (2) ^a

^a Lower doses in Co. 1 and Co. 2 did not result in a detectable increase in FIX activity 
       

12 - 40 months

Not reported

• All subjects in Co. 1 and Co. 2 exposed FIX activity levels < 1%  
• Both subjects in Co. 3 exposed short-term expression levels with FIX activity peaks at 3% and 11%

Peak at week 2 and maintained for approximately 4 and 10 weeks

Not applicable, FIX expression persisted in one subject for 10 weeks ³

Not reported

• None of the subjects experienced adverse reactions like fever, chills, nausea or vomiting observed after vector infusion ³
• 3/7 subjects developed small hematomas at the site of catheter insertion in the groin ³

No AEs possibly/likely related to Study Agent reported ³

Not reported

• Co. 1: 2/2 pts. within normal range,
• Co. 2: 1/3 pts. (105 IU/L / week 6) 
• Co. 3: 1/2 pts. (532 IU/L /week 4-5 )

• Co. 1: 2/2 within normal range, 
• Co. 2: 1/3, (67 IU/L, 6 weeks),
• Co. 3: 1/2, (approx. 200 IU/L, 4-5 weeks)

Yes (only reported for 1 pt. in the 4e11 gc/kg group)

Not applicable

Yes, in Subject E in Co. 3 (1/2 pts.) exposing therapeutic FIX expression levels, low pretreatment NAb titer of 1:2 and ALT elevation, FIX activity declined as follows: 

Not reported

3.    Manno, C.S., et al., Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the
       host immune response. Nat Med. , 2006. 12(3): p. 342-7.
      Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response - PubMed (nih.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)

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