• ClinicalTrials.gov Identifier: NCT00979238
• PI open-label, dose-escalation study  ⁷

• Active, not recruiting ^*
• Last Update Posted: June 18, 2021 ^*

• Males ≥ 18 years of age with established severe HB (FIX:C<1u/dl)
• Treated/exposed to FIX products for at least10 years or 50 EDs

• Detectable antibodies reactive with AAV8 
• Received an AAV vector or any other gene transfer agent in the previous 6 months

AAV8/ HEK293T ^{6 supplementary appendix}

Codon-optimized FIX encoded in a self-complementary AAV vector ⁶

LP1 that is based on the earlier described liver-specific APOE-HCR/hAAT enhancer/ promoter construct that is encoded by:

• A compact sequence length of 448 bp instead of 754 bp ⁴²

Further expression cassette elements include:

• A modified simian virus 40 (SV40) small t antigen intron
• A SV40 late polyA signal (SV40 LpA) ⁴²

Systemic ²⁸

Co. 1 - Co. 3 were treated with an initial vector preparation (full: empty capsidratio at 1:10) as follows ^6, 7-8:

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

Co. 4 and Co. 5 were treated with a new vector preparation (full: empty capsid ratio at 1:3) as follows ⁸: 

• Co. 4: 2e12 (2)
• Co. 5: 5e12 (2)

166 (median) ^6-7, 8 years ⁸

OS

1-6 ^6-7, 2-5 ⁸ (stable expression over a mean of 6.7 years)

FIX levels in P4 increased to a peak of 4%, 4 weeks after gene transfer ⁶

Median AIR change in IU per kg (IQR) from the year before and the year after vector infusion is presented here ⁷ as follows:

The systemic infusion of scAAV2/8-LP1-hFIXco was not associated with clinically significant changes ⁷ like:

• Pulse
• Respiration rate
• Blood pressure 
• Temperature either during or after vector infusion

P5 (Co. 3: 2e12 vg/kg) experienced a grade III SAE related to study agent considering ALT and AST elevation peaks at D58 as follows ⁸:

by W10 post gene transfer P5 received a short course of corticosteroids and liver enzymes had returned to the normal range ⁸

Additionally, study agent related/possible related among other AEs are presented here ⁷ as follows:      

Not reported

• 4/6 pts. in Co. 3 (40-202 IU/L/7-10 weeks) ^6-7
• 3/4 pts. in Co. 4+5 ⁸ (peak level/timing not reported)

• AST levels: (143 IU/L, week 7) ^6-7 in P5 (Co. 3) 
• The same pt. had an ALT level of 202 IU/L /6 
• AST levels for Co. 4-5 were not reported ⁸

• Yes, in Co. 2 and Co. 3 ^6-7: (200-400 SFU/ million PBMC/within 12 weeks to > 1 year) 
• Co. 4-5: not reported ⁸

Yes (8-12 weeks) ⁷ 

• Yes, 50-70% reduction in 3/4 pts in Co. 3 with ALT elevations + T-cell response ⁷
• Yes, in two-thirds of the pts. in the 2e12 vg/kg dose cohort decline in FIX levels, occurring within 3 months of gene transfer was associated with an asymptomatic rise in liver enzymes ⁸

Not reported

 *  ClinicalTrials.gov
6. Nathwani, A.C., et al., Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med, 2014. 371(21): p. 1994-2004.
    Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B | NEJM
7. Nathwani, A.C., et al., Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med, 2011. 365(25): p. 2357-65.
    Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B | NEJM
8. Nathwani, A.C., et al., Adeno-Associated Mediated Gene Transfer for Hemophilia B: 8 Year Follow up and Impact of Removing "Empty Viral Particles"
    on Safety and Efficacy of Gene Transfer. Blood, 2018. 132(Suppl. 1): p. 491.
    Adeno-Associated Mediated Gene Transfer for Hemophilia B:8 Year Follow up and Impact of Removing "Empty Viral Particles" on Safety and Efficacy of
    Gene Transfer | Blood | American Society of Hematology (ashpublications.org)
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)
42. Nathwani, A.C., et al., Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette
      enable highly efficient transduction of murine and nonhuman primate liver. Blood, 2006. 107(7): p. 2653-61.
      Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient
      transduction of murine and nonhuman primate liver | 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