Gene Therapy Clinical Trials Database

Summary Information For: AAVrh10, FIX-WT, DTX101, NCT02618915

Biological

AAVrh10, FIX-WT, DTX101, NCT02618915

Disorder

Haemophilia B

Sponsor

Dimension Therapeutics

General Study Information

Clinical Trial

ClinicalTrials.gov Identifier: NCT02618915¹
A Phase I/II Open-Label, Safety and Dose Finding Study

Status

Terminated (Sponsor decision, not due to any safety concerns related to DTX101)¹
Last Update Posted: November 14, 2018¹

Key Inclusion Criteria

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

Key Exclusion Criteria

Anti-AAVrh10 neutralizing antibody titer > 1:5
Participation (current or previous) in another gene therapy study.

Serotype/Vector Manufacturing Platform

AAVrh10¹/ not reported

Transgene

Codon-optimized FIX-WT²

Expression Cassette Components

The expression cassette² includes

Liver-specific enhancer element
Liver-specific promoter element

Method Of Vector Delivery

Systemic³

Cohort (Co.): vg/kg (No. of participants)

Co. 1: 1.6e12(3)
Co. 2: 5.0e12(3)

Follow - Up Weeks / Months / Years

≥32 weeks reported here²
≥ 52 weeks reported here⁴

Clotting Assay, One-Stage (OS) or Chromogenic (CH) Assay

OS¹

Efficacy details

Mean Transgene Activity, % or IU/dL

Peak FIX levels in Co. 1 were achieved between W8 and W14 and ranged from 5% - 11%²
Peak FIX levels in Co.2 ranged from 12% - 20% and were reached between W3 and W8²

Mean (SD) FIX activity (IU/dL) change from baseline over time as presented here¹
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)

Mean Time To Peak Factor Response

The mean time to peak factor response was reported here²
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 ALT levels approx. in the time of peak FIX level was followed by a gradual reduction
to baseline levels in 5/6 patients²

Annualized Bleeding Rate (ABR), (% of reduction)

ABR in a time frame of W0 – W52 as presented here²
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)

Annualized FVIII/FIX Infusion Rate (AIR)

Calculated mean (SD) in a time frame of W0 – W52 of the annualized use of FIX replacement therapy as shown here¹
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)

Average weekly use of FIX Replacement Therapy is also presented here¹

Safety Details

Infusion Related Reactions (IRR)

No infusion related reactions reported

Adverse Events (AEs) Possibly/Likely Related To Study Agent

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

Adverse Events (AEs) (Possibly/Likely) Related To Glucocorticoid

Not reported

ALT Elevations (peak level, timing)

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

AST Elevations (peak level, timing)

Not reported

Capsid Directed T Cell Activation (peak value SFU/1e6 PBMC, timing)

Data regarding the immune capsid directed T cell activation were taken from here⁴and 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

Immune Response Steroid Responsive (duration of steroid treatment)

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

Reduction/Loss Of Transgene Expression Associated With ALT Elevations (degree of reduction)

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

Reported Cancers After Vector Administration

Not reported

References:

References

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
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
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)
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)

Legend

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

Haemophilia Gene Therapy Trials Database

Summary Information For: AAVrh10, FIX-WT, DTX101, NCT02618915

General Study Information

Efficacy details

Safety Details

References: