CLINICAL NEWS
Attendees browse the poster hall at the 2017 ASH Annual Meeting.
First Successful Gene Therapy Performed
for Hemophilia A
In an ongoing phase I/II study of patients with
hemophilia A, those who received a single infu-
sion of BMN 270 (an adeno-associated virus
serotype 5 [AAV5] vector containing the B-
domain-deleted F8 gene) had improved levels of
factor VIII (FVIII), with 11 of 13 treated patients
achieving normal or near-normal FVIII levels.
“Because hemophilia A is an X-linked single
gene disorder of FVIII, it is an ideal candidate for
gene therapy,” said lead author K. John Pasi, MD,
from Barts and The London School of Medicine
and Dentistry in the United Kingdom, during
his presentation of the results at the 2017 ASH
Annual Meeting. “The clinical data to date for this
investigational gene therapy exceeded our expec-
tations, in increasing FVIII levels and reducing
the annualized bleed rate.”
The phase I/II, first-in-human, dose-escalation
BMN 270-201 trial enrolled men with severe
hemophilia A (FVIII <1 IU/dL) who had at least
150 days of previous exposure to FVIII concen-
trate or cryoprecipitate. Patients were infused
with a single intravenous dose of BMN 270 at four
doses: 6×10 12 vg/kg, 2×10 13 vg/kg, 6×10 13 vg/kg, or
4×10 13 vg/kg. “Prophylactic corticosteroids were
initiated in the first three cohorts out of an abun-
dance of caution, after one patient had alanine
aminotransferase (ALT) elevation.”
Dr. Pasi reported results from patients in the
two highest dose cohorts: 6×10 13 vg/kg (n=7) and
4×10 13 vg/kg (n=6).
As of July 28, 2017 (data cutoff), patients
had been followed for up to 19 months, and all
patients began producing FVIII.
In the cohort receiving 6×10 13 vg/kg, FVIII
activity plateaued by 20 weeks following infu-
sion with BMN 270. FVIII levels remained in the
normal range (86-122 IU/dL) through follow-up,
with a median FVIII level of 90 IU/dL (range =
65-107 IU/dL) at 78 weeks.
Patients receiving the lower dose (4×10 13 vg/kg)
experienced steady increases in FVIII levels at up
to one year of follow-up, “with levels approaching
or within the lower end of the normal range of
FVIII activity,” Dr. Pasi said. Median FVIII level
ASHClinicalNews.org
was 34 IU/dL (range = 28-40 IU/dL) at 20 weeks,
and in the three patients who were followed for at
least 48 weeks, median FVIII level was 49 IU/dL
(range not provided).
This gene therapy appears to have long-lasting
effects following a single infusion, compared with
FVIII infusions, a standard of care for patients
with severe hemophilia A. Before enrollment in
this study, participants required a median of 155.5
infusions per year (range = 112-183 infusions) in
the high-dose cohort and 138.5 infusions per year
(range = 122-157 infusions) in the low-dose co-
hort. After infusion, patients in both dose cohorts
discontinued prophylactic FVIII infusions. From
four weeks after infusion through the final follow-
up visit, 10 of the 13 patients had no episodes of
bleeding that required FVIII treatment.
“This clinical result has the potential to improve
the lives of patients who now must infuse them-
selves with factor VIII as often as every other day,
Dr. Pasi said. “With this experimental treatment,
we are researching whether it may be possible for
hemophilia A patients to reduce or eliminate FVIII
treatment over an extended timeline.”
No patients showed evidence of an adverse im-
mune system response. Patients experienced only
mild, grade 1, asymptomatic ALT increases, reported
in all seven people in the 6×10 13 vg/kg cohort and
four of six in the 4×10 13 vg/kg cohort. All but one
patient in the low-dose cohort have a normal ALT
level as of last follow-up, and all but one person in
this groups is off of corticosteroid therapy.
As a limitation of the study, the authors noted
that they did not assess the possibility of vector inte-
gration, and they were not able to explain the vari-
ability of FVIII activity levels among participants.
The authors report financial relationships with
BioMarin Pharmaceutical, the manufacturers of
BMN 270.
REFERENCE
Pasi JK, Rangarajan S, Kim B, et al. Achievement of normal circulating factor VIII
activity following BMN 270 AAV5-FVIII gene transfer: Interim, long-term efficacy and
safety results from a phase 1/2 study in patients with severe hemophilia A. Abstract
#603. Presented at the 2017 American Society of Hematology Annual Meeting,
December 11, 2017; Atlanta, GA.
ZUMA-1 at One Year:
Durable Responses to
Axicabtagene Ciloleucel
in Patients With
Aggressive NHL
In October 2017, axicabtagene ciloleucel became the
second chimeric antigen receptor (CAR) T-cell therapy
approved by the U.S. Food and Drug Administration,
and the first gene therapy approved to treat patients with
non-Hodgkin lymphoma (NHL), based on results of the
phase II ZUMA-1 trial. At the 2017 ASH Annual Meeting,
researchers shared an update from the trial, which showed
that patients are maintaining the impressive response rates
at one year. Results were published simultaneously in the
New England Journal of Medicine.
“Lon