Can AMT-060 Gene Therapy FIX Hemophilia B?

After a single infusion of AMT-060 (an adeno-associated virus-5 vector [AAV5] carrying a corrected human factor IX [FIX] gene), patients with hemophilia B experienced increases in FIX activity and reductions in spontaneous bleeds, according to results of a phase I/II study published in Blood. Patients achieved these responses without developing detectable inhibitors or a T-cell response against the therapy, noted Wolfgang Miesbach, MD, PhD, of the University Hospital Frankfurt in Germany, and co-authors.

“Improvement of disease severity was observed in all participants and allowed the majority to discontinue FIX prophylaxis,” the authors wrote of the findings. These results further support the role of gene therapy in “correcting” hemophilia; at the 2017 ASH Annual Meeting, investigators reported the first successful gene therapy in hemophilia A.

This multinational, open-label, first-in-human, dose-escalation study included 10 adult male patients with either a severe FIX deficiency (defined as FIX <1%) or moderately severe FIX deficiency (defined as FIX 1-2%) and a severe bleeding phenotype. Nine participants had severe hemophilia B (FIX activity of <1.0 IU/dL), and one had moderate hemophilia B (FIX activity of 1.5 IU/dL). At the time of enrollment, nine patients previously received FIX prophylaxis, and one with severe hemophilia was using on-demand therapy as needed.

Dosing cohorts included:

  • 5×1012 gc/kg (low dose; cohort 1; n=5; median age = 69 years; range = 35-72 years)
  • 2×1013 gc/kg (high dose; cohort 2; n=5; median age = 35 years; range = 33-46 years)

Participants remained on their pre-study regimen of FIX prophylaxis after AMT-060 until six to 12 weeks post-treatment. If patients achieved FIX activity ≥2.0 IU/dL for at least two consecutive measurements, they were allowed to taper FIX replacement over a two-week period. If this FIX level was maintained, they were encouraged to withhold prophylaxis.

Patients in cohort 1 were generally older, had more severe arthropathy, and – despite prophylactic FIX (average = 4,000 IU weekly) – experienced more bleeds in the year prior to study entry, compared with cohort 2.

Patients prospectively reported bleeding and FIX consumption using an electronic diary. Diaries were reviewed at study visits (once-weekly in cohort 1 and twice-weekly in cohort 2 for up to 12 weeks, then every two weeks from weeks 12 to 26, and quarterly between six months and one year). Quarterly visits will continue until three years post-therapy, followed by twice-annual visits from years three to five. The study is ongoing, with a planned follow-up of five years.

of disease
severity was
observed in
all participants
and allowed
the majority
to discontinue
FIX prophylaxis.”

—Wolfgang Miesbach, MD, PhD

As of November 8, 2016 (the planned interim analysis), three patients in each dosing cohort experienced 14 treatment-related adverse events (AEs). Four patients reported increased liver enzymes, three of whom were in cohort 2. Three serious AEs were reported: mild, asymptomatic elevations in liver enzymes; short, self-limiting fever in the first 24 hours post-treatment; and alanine transaminase elevation.

The mean endogenous FIX activity increased to 4.4 IU/dL (95% CI 1.5-7.3) in cohort 1 and to 6.9 IU/dL (95% CI 2.6-11.3) in cohort 2. “Following a single administration [of AMT-060], FIX activity increased to levels classified as mild in six [patients] and moderate in four participants,” the authors wrote, “and remained stable for the duration of follow-up.”

Treatment with AMT-060 reduced the need for FIX use by 81 percent in cohort 1 and by 73 percent in cohort 2, for an overall reduction of 79 percent.

Patients also experienced a lower mean annualized bleeding rate (ABR). In cohort 1, ABR decreased by 53 percent (from 9.8 to 4.6); in cohort 2, ABR decreased by 70 percent (from 3.0 to 0.9). The ABR was “still relatively high post-treatment” in cohort 1, the authors noted, which they said may be related to preexisting joint damage. “It will be of interest in this population whether continuing improvements in arthropathy and decrease of ABR will be observed with longer-term follow up,” they wrote. Mean annualized rate of traumatic bleeds remained stable in both cohorts.

The improvements in FIX activity and bleed rates allowed most patients who were receiving FIX prophylaxis (n=8/9) to discontinue, leading to “large reductions in annualized factor consumption from approximately 2.64 million to 563,507 IU,” the investigators concluded.

The researchers reported that treatment was well tolerated and effective, including in “those with low-titer antibodies, suggesting no likely impact of low-titer immunoglobulin (Ig) G or IgM on transduction, clinical effectiveness, or cellular immune response following treatment.”

The results are limited by the study’s small patient population, restricted range of doses studied, and lack of a comparator arm. In addition, pretreatment data were collected retrospectively and bleeding was patient-reported, which could have introduced bias. Variation in patient characteristics between the two cohorts (including older age, poorer bleed control, and more extensive joint damage in cohort 1) “makes direct comparison of clinical outcomes between the two [dosing] cohorts challenging,” the researchers added.

uniQure supported the study.

The corresponding authors report financial support from uniQure, Novo Nordisk, Bayer, Shire, Biotest, Pfizer, Octapharma, LFB, CSL Behring, Sobi, Biogen, BPL, Baxter, Sanquin, Boehringer Ingelheim, Bristol-Myers Squibb, and Aspen. uniQure provided editorial support for the original manuscript.


Miesbach W, Meijer K, Coppens M, et al. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood. 2017 December 15. [Epub ahead of print]