Summary Information For: AAV8, FIX-WT, scAAV2/8-LP1-hFIXco, NCT00979238
AAV8, FIX-WT, scAAV2/8-LP1-hFIXco, NCT00979238
Haemophilia B
Non-commercial
General Study Information
  • 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/ HEK293T3 [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 follows2-36:

  • 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

Efficacy details

1-62-3, 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

 

Annual bleeding episodes are taken over from  Table 22 

 

Low dose

Intermediate Dose

High Dose

Annual bleeding episodes

P1

P2

P3

P4

P5

P6

P7

P8

P9

P10

Before gene transfer - no.

3

13

12

12

15

3

22

20

36

29

After gene transfer - no. (% reduction)

1 (63)

7 (46)

19 (158)

2 (87)

10 (34)

0 (100)

1 (95)

1 (95)

1 (98)

2 (93)

 

 

Median AIR change in IU per kg (IQR) from the year before and the year after vector infusion as presented here2 

Median (IQR) annual use of FIX concentrates

Co. 1Co. 3 (10 pts. totally)

Co. 3 (2e12 vg/kg, n = 6)

Before gene transfer - IU/kg

2613 (1671 - 4513)

2613 (1627 - 3487)

After gene transfer — IU/kg

206 (79 - 948) 

2613 (1627 - 3487)

% of reduction, p-value

92%, P=0.002 

96%, P=0.03

 

Safety Details

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

P5 (Co. 3: 2e12 vg/kg) experienced a grade III SAE related to study agent considering ALT and AST elevation peaks at D58 as follows6:

AST

AST-ULN

ALT

ALT-ULN

143 IU/L

37 IU/l 

202 IU/L

41 IU/L

by W10 post gene transfer P5 received a short course of corticosteroids and liver enzymes had returned to the normal range6

Additionally, study agent related/possible related among other AEs are presented here2 as follows:      

Event

No. of Events

Grade

Relation to Study Agent 

Lethargy

1

1

Possible

Anemia

11

1

Possible

Increase in ALT levels

1

3

Related

Increase in ALT levels 

1

2

Related

Increase in ALT levels 

4

1

Related

 

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. 32-3: (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

References:
  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