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: 2024-11-221
  • 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 follows2-37

  • 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)

Follow-up periods reported across different publications were as follows:

  • Up to 3 years, as reported in reference #2
  • 6 to 16 months of follow-up, as reported in reference #3
  • A median follow-up of 6.7 ± 1.0 years, as reported in reference #6
  • A median follow-up of 13.0 years (range: 11.1 to 13.8 years), as reported in reference #7

 

OS

Efficacy details

Data on FIX activity following gene therapy, as reported in multiple publications from a single clinical trial, are summarized below, including follow-up durations, dose cohorts, and FIX expression levels:

Summary of FIX Activity Levels After Gene Therapy Across Studies

Reference

Follow-up Period

Cohort

Mean FIX Activity (IU/dL)

Study Findings on FIX Activity


#2


6–16 months


All participants


2%–11% of normal


Early follow-up; AAV-mediated FIX expression observed

 


#3

 


Median 3.2 years

Low-dose

1.8 ± 0.7

A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating FIX to a level that was 1 to 6% of the normal value over a median period of 3.2 years

Intermediate-dose

2.5 ± 0.9

High-dose

5.1 ± 1.7



#6



Median 6.7 ± 1.0 years

Low-dose

1.9 ± 0.6


Transgenic FIX activity levels have remained stable in all 10 subjects treated in the initial dose escalation/extension arm 

Intermediate-dose

2.3 ± 0.3

High-dose

5.1 ± 1.4





#7



Median 13 years

Low-dose

1.7 ± 0.3


Over a median study period of 13 years, the FIX activity remained stable

Intermediate-dose

2.3 ± 0.5

High-dose

4.8 ± 1.7


As of Dec 31, 2023

High-dose (median)

5.2 (IQR: 3.5–5.7)


Difference vs. low/intermediate: 3.3 IU/dL

Low + Intermediate (median)

1.9 (IQR: 1.8–2.1)

 

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:

Comparison of the annual bleeding episodes before and after gene transfer in all dose cohorts 

 

Variable / Dose

Low Dose

Intermediate dose

High Dose

Annual bleeding episodes / Patient

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)

                       

Long-term data on annualized bleeding rates, as reported in reference #7, are summarized in the table below:

Reduction in Annualized Bleeding Rates Following Gene Therapy

Population / Subgroup

Time Point

Median ABR (IQR)

Median Reduction Factor (IQR)

All participants (n = 10)

Before gene therapy

14.0 (12.0–21.5)

9.7 (3.7–21.8)

~13 years post gene therapy

1.5 (0.7–2.2)

High-dose group (n = 6)

Before gene therapy

21.0 (16.2–27.2)

16.4 (9.7–31.3)

~13 years post gene therapy

1.0 (0.4–2.0)

Patients with FIX >3 IU/dL at 6 months post-treatment

1 year post gene therapy

5.3 (3.3–9.0)

3.9 (2.1–8.2)

11 years post gene therapy

1.5 (0.6–2.3)

 

Data on FIX concentrate use from the year before and the year after vector infusion were published in reference #2 and are summarized in the table below:

Median FIX use change in IU per kg (IQR) from the year before and the year after vector infusion


Group

Before Gene TransferMedian (IQR), IU/kg/year

After Gene TransferMedian (IQR), IU/kg/year

% Reduction, p-value

Co. 1– Co. 3 (n = 10)

2613 (1671–4513)

206 (79–948)

92%, P = 0.002

High-dose cohort, Co. 3 (2×10¹² vg/kg, n = 6)

2613 (1627–3487)

171 (60–432)

96%, P = 0.03


Data on FIX concentrate use 13 years after gene therapy, as reported in reference #7, are summarized in the table below:

Annual FIX Concentrate Use Before and 13 Years After Gene Therapy


Group

Pre-Gene Therapy-Median (IQR), IU/kg/year

13 Years Post-Gene Therapy Median (IQR), IU/kg/year

Median Reduction Factor (IQR)

All participants (Co. 1– Co. 3, n = 10)

2613 (1671–4513)

367 (60–1597)

12.4 (2.21–27.1)

High-dose cohort, Co. 3 (2×10¹² vg/kg, n = 6)

2613 (1627–3487)

171 (60–432)

14.7 (11.9–27.1)

 

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

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:

Reported Grade III SAE in P5 (Co. 3: 2e12 vg/kg)

AST

AST-ULN

ALT

ALT-ULN

143 IU/L

37 IU/l 

202 IU/L

41 IU/L

  • 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:

Study agent related/possible related AEs

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


Most recent update on Adverse Events, were extracted from Table S2 in reference #7, is summarized below:

Summary of Adverse Events by Vector Dose Level in following Gene Therapy


Adverse Event Category


Total No. of AEs

2×10¹¹ vg/kg(n = 2)

6×10¹¹ vg/kg(n = 2)

2×10¹² vg/kg(n = 6)

Incidence

Events

Incidence

Events

Incidence

Events

Any adverse event

354

2 (100%)

98

1 (100%)

32

6 (100%)

224

Serious adverse events

11

 

3

 

1

 

6

  • Probably related

             

    – Transaminases increased

4

   

1 (17%)

4

   

  • Possibly related

             

    – Adenocarcinoma of the prostate

1

1 (50%)

1

       

    – Non-mucinous adenocarcinoma in situ of the lung

1

   

1 (17%)

1

   

  • Unrelated

             

    – Joint infection

1

1 (50%)

1

       

    – Pneumothorax

1

   

1 (17%)

1

   

    – Sinus bradycardia

1

     

1 (50%)

   

    – Tibia fracture

1

1 (50%)

1

       

Adverse events related to scAAV2/8-LP1-hFIXco

15

 

2

 

1

 

12

    – Adenocarcinoma of the prostate

1

1 (50%)

1

       

    – Blood hematocrit decreased

3

       

2 (33%)

3

    – Blood RBC decreased

1

       

1 (17%)

1

    – Hypertension

1

1 (50%)

1

       

    – Non-mucinous adenocarcinoma in situ of the lung

1

       

1 (17%)

1

    – Splenomegaly

1

     

1 (50%)

   

    – Transaminases increased

7

       

2 (33%)

7

 

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)
  7. Reiss UM, Davidoff AM, Tuddenham EGD, Chowdary P, McIntosh J, Muczynski V, Journou M, Simini G, Ireland L, Mohamed S, Riddell A, Pie AJ, Hall A, Quaglia A, Mangles S, Mahlangu J, Haley K, Recht M, Shen YM, Halka KG, Fortner G, Morton CL, Gu Z, Hayden RT, Neufeld EJ, Okhomina VI, Kang G, Nathwani AC. Sustained Clinical Benefit of AAV Gene Therapy in Severe Hemophilia B. N Engl J Med. 2025 Jun 12;392(22):2226-2234. doi: 10.1056/NEJMoa2414783. PMID: 40499172. Sustained Clinical Benefit of AAV Gene Therapy in Severe Hemophilia B - PubMed

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