Summary Information For: AAVrh10, FIX-WT, DTX101, NCT02618915
AAVrh10, FIX-WT, DTX101, NCT02618915
Haemophilia B
Dimension Therapeutics
General Study Information
  • ClinicalTrials.gov Identifier: NCT026189151
  • A Phase I/II Open-Label, Safety and Dose Finding Study 
  • Terminated (Sponsor decision, not due to any safety concerns related to DTX101)1
  • Last Update Posted: November 14, 20181
  • Male ≥ 18 years of age.
  • Moderate/severe or severe hemophilia B (baseline FIX activity ≤ 2% of normal or documented history of FIX activity ≤2%)
  • At least 100 days exposure history to FIX
  • Anti-AAVrh10 neutralizing antibody titer > 1:5
  • Participation (current or previous) in another gene therapy study.

AAVrh101/ not reported

Codon-optimized FIX-WT2

The expression cassette2 includes

  • Liver-specific enhancer element
  • Liver-specific promoter element

Systemic3

  • Co. 1: 1.6e12 (3)
  • Co. 2: 5.0e12 (3)
  • ≥32 weeks reported here2
  • ≥ 52 weeks reported here4

OS1

Efficacy details

Data on FIX activity following gene therapy, as published in reference #2, are summarized below:

  • Peak FIX levels in Co. 1 were achieved between W8 and W14 and ranged from 5% - 11%
  • Peak FIX levels in Co.2 ranged from 12% - 20% and were reached between W3 and W8

More detailed data on FIX activity levels following gene therapy were extracted from ClinicalTrials.gov1 and are summarized in the table below:

Mean (SD) FIX activity (IU/dL) change from baseline over time as presented here

weeks post treatment

Co. 1 (1.6e12 GC/kg, n=3)

Co. 2 (5.0e12 GC/kg, n=3)

week 2

16.33 (14.503)

10.13 (7.988)

week 4

8.67 (7.234)

14.47 (10.835)

week 6

5.00 (1.732)

9.80 (4.687)

week 8

14.67 (17.786)

11.80 (6.646)

week 12

11.33 (4.933)

5.80 (2.207)

week 16

7.67 (3.215)

5.47 (3.066)

week 24

2.33 (1.528)

2.47 (2.214)

week 32

9.33 (11.846)

10.13 (2.702)

week 40

15.33 (23.965)

12.80 (16.008)

End of Study / Early Withdrawal

1.67 (0.577)

22.47 (1.380)

 

Data on mean time to peak FIX response, as published in reference #2, are summarized below:

The mean time to peak factor response per cohort

Cohort

Co. 1 (1.6e12 GC/kg)

Co. 2 (5e12 GC/kg)

Peak FIX levels reached between

8-14 weeks

3-8 weeks

  • An asymptomatic rise in alanine aminotransferase (ALT) level was observed
    • at approximately the time of peak FIX level and was followed
    • by a gradual reduction in FIX level to near baseline in all but one subject

Data on the annualized bleeding rate, as published in reference #2, are summarized below:

ABR in a time frame of W0 – W52

Cohort

Co. 1 (1.6e12 GC/kg)

Co. 2 (5e12 GC/kg)

No. of pts.

3

3

Mean (SD) ABR

8.7 (5.53)

5.0 (1.00)

 

Data on the annualized use of FIX replacement therapy, as published in reference #1, are summarized below:

Calculated mean (SD) in a time frame of W0 – W52 of the annualized use of FIX

Cohort

Co. 1 (1.6e12 GC/kg)

Co. 2 (5e12 GC/kg)

No. of pts.

3

3

Mean (SD)

350115.2 (522106.19)

64246.5 (805.34)

  • See reference #1 for data on average weekly use of FIX replacement therapy
Safety Details

No infusion related reactions reported

 

ALT elevations were reported as AEs here2

ALT elevations

Co. 1 (5e12 gc/kg)  

Co. 2 (2e13 gc/kg)

Affected pts.

4/6 pts.

1/6 pts.

ALT peak (U/L)

(≤3.0 or ≤5.0 x ULN)

914 U/L


    Steroid protocol was initiated with normalization of ALT levels2

Treatment-Related Adverse Events (TRAEs), that are defined as any event not present before exposure to study product or any event already present that worsened in severity or increased in frequency after exposure to study product are shown here1

Cohort

Co. 1 (5e12 gc/kg)

Co. 2 (2e13 gc/kg)

time frame

52 weeks 

44 weeks

TRAE

Affected / at Risk (%)

Affected / at Risk (%)

All TRAEs

3/3 (100%)

3/3 (100%)

All Serious TRAEs

1/3 (33.33%)

0/3 (0%)

 

Musculoskeletal and connective tissue disorders that were presented as SAE is also shown here1

Cohort

Co. 1 (5e12 gc/kg)

Co. 2 (2e13 gc/kg)

time frame

52 weeks

44 weeks

SAE

Musculoskeletal and connective tissue disorders

No. / Affected pts. at risk (%)

 1/3 (33.33%)

0/3 (0%)


Other AEs not including SAEs affecting 3/3 (100%) pts. and 3/3 (100%) pts. are presented here1
    

Not reported

Data regarding peaks and timing of ALT elevations were taken from here2  and summarized as follows:

  • In 4/6 pts. peak ALT values ≤3.0 or ≤5.0 x ULN  were considered either as Grade 1 or 2 AEs
  • In 1/6 pts. peak ALT value of 914 U/L was considered as Grade 4 AE
  • Rise in ALT levels were observed at approx. the  time of peak FIX level between 8 -14 weeks

Not reported

Data regarding the immune capsid directed T cell activation were taken from here4  and summarized as follows:

  • 4/6 (described as limited/6-8 weeks)
  • 1/6 in Co. 2 with strong CD4+ T, IL-2+, IFNγ+ response to FIX that did not persist            

Normalised ALT levels but did not prevent FIX loss in most patients2

  • Yes, 5/6 (gradual reduction to baseline levels in all but 1 participant)2

Not reported

References:
  1. Safety and Dose Finding Study of DTX101 (AAVrh10FIX) in Adults With Moderate/​Severe to Severe Hemophilia B. Available at: Study Details | Safety and Dose Finding Study of DTX101 (AAVrh10FIX) in Adults With Moderate/Severe to Severe Hemophilia B | ClinicalTrials.gov
  2. Pipe, S., et al., 101HEMB01 Is a Phase 1/2 Open-Label, Single Ascending Dose-Finding Trial of DTX101 (AAVrh10FIX) in Patients with Moderate/Severe Hemophilia B That Demonstrated Meaningful but Transient Expression of Human Factor IX (hFIX). Blood, 2017. 130(Suppl. 1): p. 3331. 101HEMB01 Is a Phase 1/2 Open-Label, Single Ascending Dose-Finding Trial of DTX101 (AAVrh10FIX) in Patients with  Moderate/Severe Hemophilia B That Demonstrated Meaningful but Transient Expression of Human Factor IX (hFIX) - ScienceDirect
  3. 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)
  4. Calcedo, R., et al., Immune Responses in 101HEMB01, a Phase 1/2 Open-Label, Single Ascending Dose-Finding Trial of DTX101 (AAVrh10FIX) in Patients with Severe Hemophilia B. Blood 2017. 130(Suppl. 1): p. 3333. Immune Responses in 101HEMB01, a Phase 1/2 Open-Label, Single Ascending Dose-Finding Trial of DTX101 (AAVrh10FIX) in Patients with Severe Hemophilia B | 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