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National Institute of
General Medical Sciences
A gene therapy known as DTX101 has shown early promise for the treatment of adults with hemophilia B, according to the company developing the therapy.
DTX101 is designed to deliver stable expression of factor IX (FIX) in patients with hemophilia B.
Preliminary results from a phase 1/2 trial showed that DTX101 can increase FIX expression in these patients, allowing some to forgo prophylactic and on-demand treatment.
However, 5 of the 6 patients enrolled in this trial experienced elevations in alanine aminotransferase (ALT), with 1 patient experiencing a grade 4 adverse event as a result.
These results were released by Dimension Therapeutics, Inc., the company developing DTX101.
DTX101 is a non-replicating, recombinant adeno-associated viral vector, AAVrh10, with a codon-optimized FIX gene expressing wild-type FIX protein.
The phase 1/2 study of DTX101 has enrolled 6 patients, ages 28 to 70, with moderate/severe to severe hemophilia B. They had baseline FIX expression of ≤ 2%, which requires either prophylactic or on-demand recombinant FIX therapy.
These 6 patients were divided into 2 dose cohorts. Cohort 1 (n=3) received DXT101 at 1.6 x 1012 GC/kg. And cohort 2 (n=3) received 5 x 1012 GC/kg.
All patients have been in post-treatment follow-up ranging from 6 weeks to 52 weeks.
Efficacy
Researchers observed evidence of efficient liver transduction of DTX101 across the 2 cohorts.
Patients in the low-dose cohort achieved peak FIX expression levels of 10% to 11%, which stabilized to between 3% and 4% at last follow-up (weeks 24, 48, and 52).
Patients in the second dose cohort achieved peak FIX expression of 13%, 20%, and 12% at weeks 4, 8, and 8, respectively. FIX activity was 5% and 8% in 2 patients at 12 weeks of follow-up. It was 7% for the third patient at 7 weeks.
None of the patients in cohort 2 have required prophylactic or on-demand recombinant FIX therapy for spontaneous bleeds post-dosing.
Safety
None of the patients experienced a drug-related serious adverse event as of the January 28, 2017, data cutoff.
Five of the 6 patients had elevations in ALT. All elevated liver enzymes were clinically asymptomatic with no elevations of gamma-glutamyl transferase, alkaline phosphatase, or bilirubin.
Patient 3 in cohort 2 experienced a grade 4 adverse event due to an elevated laboratory ALT (defined as > 800 IU/L).
Preliminary findings from 2 patients in each cohort prompted the administration of a standard tapering course of corticosteroids to treat mild, asymptomatic elevations in ALT (52-98 IU/L).
The third patient in cohort 2 also received corticosteroids, experiencing a peak ALT of 914 IU/L, and was at 431 IU/L at 6 weeks post-dosing.
As of the January 28, 2017, data cutoff, 2 of 3 patients in cohort 2 had ALT levels in the normal range. Cohort 1 patients were all clinically stable and off steroids, with ALT levels in the normal range.
Dimension Therapeutics said it expects cohort 2 will continue to receive a standard tapering course of corticosteroid therapy.
As required by the trial protocol, the company reported the ALT levels for patient 3 in cohort 2 to the Data Safety Monitoring Committee, the US Food and Drug Administration, and the appropriate regulatory authorities.
The company said it will await their feedback prior to initiating dosing of cohort 3.
“We are encouraged by the apparent efficiency of gene transduction and the early trend we are seeing in sustained FIX activity across both cohorts with our wild-type FIX AAVrh10 vector in patients,” said Annalisa Jenkins, MBBS, chief executive officer of Dimension Therapeutics.
“We continue to explore the therapeutic window for DTX101 as our data mature and in light of the ALT rises that appear to be associated with a decline in FIX activity.”
