• 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

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:

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

• 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:

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

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

No infusion related reactions reported

ALT elevations reported as AEs in reference #2 are summarized in the tables below:

• Steroid protocol was initiated with normalization of ALT levels
   

Treatment-emergent adverse events (TEAEs), as reported on ClinicalTrials.gov (reference #1) and summarized below,
were defined as events not present before exposure to the study product, or pre-existing events that worsened in severity
or increased in frequency following exposure:

Musculoskeletal and connective tissue disorders reported as SAEs on ClinicalTrials.gov (reference #1) are summarized in the table below:

Other AEs not including SAEs affecting 3/3 (100%) pts. and 3/3 (100%) pts. are also reported on ClinicalTrials.gov¹

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

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