• ClinicalTrials.gov Identifier: NCT00979238¹
• PI open-label, dose-escalation study²

• Active, not recruiting¹
• Last Update Posted: June 18, 2021¹

• 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^{3 [supplementary appendix]}

Codon-optimized FIX encoded in a self-complementary AAV vector³

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 bp⁴

Further expression cassette elements include:

• A modified simian virus 40 (SV40) small t antigen intron
• A SV40 late polyA signal (SV40 LpA)⁴

Systemic⁵

Co. 1 - Co. 3 were treated with an initial vector preparation (full: empty capsidratio at 1:10) as follows^2-3, 6:

• 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 follows⁶: 

• Co. 4: 2e12 (2)
• Co. 5: 5e12 (2)

166 (median)^2-3, 8 years⁶

OS

1-6^2-3, 2-5⁶ (stable expression over a mean of 6.7 years)

FIX levels in P4 increased to a peak of 4%, 4 weeks after gene transfer³

Data on annualized bleeding rates across the three dose cohorts were presented in Table 2 of reference #2 and are summarized as follows

Data on FIX use were published in reference #2 and are summarized in the table below:

The systemic infusion of scAAV2/8-LP1-hFIXco was not associated with clinically significant changes² like:

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

• As reported in reference #6, 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:

• By week 10 post–gene transfer, P5 received a short course of corticosteroids, and liver enzyme levels had returned to the normal range⁶

Additionally, study agent–related or possibly related adverse events, among other AEs, were extracted from reference #2 and are summarized as follows:

Not reported

• 4/6 pts. in Co. 3 (40-202 IU/L/7-10 weeks)^2-3
• 3/4 pts. in Co. 4+5⁶ (peak level/timing not reported)

• AST levels: (143 IU/L, week 7)^2-3 in P5 (Co. 3) 
• The same pt. had an ALT level of 202 IU/L /6 
• AST levels for Co. 4-5 were not reported⁶

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

Yes (8-12 weeks)² 

• Yes, 50-70% reduction in 3/4 pts in Co. 3 with ALT elevations + T-cell response²
• 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 enzymes⁶

Not reported

1. Dose-Escalation Study Of A Self Complementary Adeno-Associated Viral Vector For Gene Transfer in Hemophilia B. Available at: Dose-Escalation Study Of A Self Complementary Adeno-Associated Viral Vector For Gene Transfer in Hemophilia B - Full Text View - ClinicalTrials.gov
2. 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
3. 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
4. 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)
5. 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)
6. 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)

AAV, Adeno-associated virus; 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