SAN RAFAEL, Calif.,
Jan. 10, 2021 /PRNewswire/
-- BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) today announced
positive topline results from its ongoing global Phase 3 GENEr8-1
study of valoctocogene roxaparvovec, an investigational gene
therapy for the treatment of adults with severe hemophilia A.
This is the largest global Phase 3 study to date for any gene
therapy in any indication, with 134 participants. All
participants in the study received a single dose of valoctocogene
roxaparvovec and completed a year or more of follow-up.
Data from the GENEr8-1 Phase 3 study with a mean follow-up of
71.6 weeks showed that in the pre-specified primary analysis for
Annualized Bleeding Rate (ABR) a single dose of valoctocogene
roxaparvovec significantly reduced ABR by 84% from a prospectively
collected 4.8 (median 2.8) at baseline to 0.8 (median 0.0) bleeding
episodes per year (p-value <0.0001), among a pre-specified group
of prior participants in a non-interventional baseline
observational study (rollover population; N=112). 80% of
participants were bleed-free starting at week five after treatment.
Valoctocogene roxaparvovec also significantly reduced the mean
annualized Factor VIII in the rollover population by 99% from 135.9
(median 128.6) to 2.0 (median 0.0) infusions per year (p-value
<0.0001).
Table 1: Mean/Median Annualized Bleeding Rate (ABR) and
FVIII Infusion Rate in Phase 3 GENEr8-1 Study Rollover Population
(N=112) from Week 5 Through Week 52 at Nov.
2020 Cut Off
|
Phase
3
Rollover
Population*
On Factor VIII
prophylaxis, before
valoctocogene roxaparvovec infusion
N=112
|
Phase
3
Rollover
Population*
After
valoctocogene roxaparvovec
infusion
N=112
|
|
Mean
(SD)
Median
(IQR)
|
Mean
(SD)
Median
(IQR)
|
Annualized
Bleeding Rate
(bleeding
episodes
per
year)
|
4.8 (6.5)
2.8 (0.0,
7.6)
|
0.8 (3.0)
0.0 (0.0,
0.0)
|
Annualized
FVIII
Infusion
Rate (infusions per
year)
|
135.9
(52.0)
128.6 (104.1,
159.9)
|
2.0 (6.4)
0.0 (0.0,
0.9)
|
|
*See study
descriptions for patient population information.
|
At the end of the first year post-infusion with valoctocogene
roxaparvovec, participants in the modified intent-to-treat (mITT)
population (N=132) had a mean endogenous Factor VIII expression
level of 42.9 (SD 45.5, median 23.9) IU/dL, as measured by the
chromogenic substrate (CS) assay, supporting the marked clinical
benefits observed with abrogation of bleeding episodes and Factor
VIII infusion rate. Factor VIII expression declined at a slower
rate compared to the Phase 1/2 study, and remained in a range to
provide hemostatic efficacy. In a subset of the mITT population
that had been dosed at least two years prior to the data cut date
(N=17), Factor VIII expression declined from a mean of
42.2 (SD 50.9, median 23.9) IU/dL at the end of year one to a
mean of 24.4 (SD 29.2, median 14.7) IU/dL at the end of year two
with continued hemostatic efficacy demonstrated by a mean ABR of
0.9 (median 0.0) bleeding episodes per year.
Table 2: Factor VIII Activity Levels in 6-Month
Intervals
Median
Factor
VIII Activity,
IU/dL
|
Phase 3
Rollover
Population
(N=112)
Mean
(SD)
Median
|
Phase 3
mITT
Subset
Population
(N=17*)
Mean
(SD)
Median
|
Phase
1/2
6e13
vg/kg
Cohort
(N=7)
Mean
(SD)
Median
|
Phase
1/2
4e13
vg/kg
Cohort
(N=6)
Mean
(SD)
Median
|
Week
26
|
55.1
(57.4)
38.6
|
43.9
(42.1)
33.8
|
71.0
(41.6)
61.2
|
18.0 (8.7)
18.0
|
Week
52
|
43.6
(45.3)
24.2
|
42.2
(50.9)
23.9
|
63.6
(36.5)
60.3
|
21.1
(12.3)
23.8
|
Week
76
|
|
27.9
(30.6)
15.8
|
53.9
(31.2)
50.2
|
20.6
(15.4)
21.3
|
Week
104
|
|
24.4
(29.2)
14.7
|
36.4
(26.3)
26.2
|
12.3 (8.2)
11.6
|
*Includes only
HIV-negative subjects dosed 2 or more years prior to Nov 2020 data
cut date. One participant was lost to follow-up at 66.1 weeks and
was henceforth imputed to have a Factor VIII activity of 0 IU/dL
through 104 weeks.
|
Please see Figure 1: Box-and-Whiskers Plot.
This is the first statistical evidence demonstrating ABR
superiority in a gene therapy trial. These data give us
confidence in this groundbreaking alternative to existing therapies
and bring us one step closer to a potential new treatment choice to
fulfill an unmet medical need for people with hemophilia A," said
Steven W. Pipe, MD, Professor of
Pediatrics and Pathology, Coagulation Director, Special Coagulation
Laboratory Laurence A. Boxer, MD Research Professor of Pediatrics
and Communicable Diseases Department of Pathology Michigan Medicine
at the University of Michigan and
investigator in the Phase 3 study. "This data set adds to the
growing body of scientific and clinical data around valoctocogene
roxaparvovec gene therapy for hemophilia A and creates the
possibility for a new treatment paradigm."
"Over the past seven years, we have conducted rigorous
scientific research and clinical programs to address the unmet
medical needs of people with severe hemophilia A," said
Hank Fuchs, M.D., President of
Worldwide Research and Development at BioMarin. "The decades-long
aspirations of the hemophilia community are at the forefront of our
ongoing commitment to advance this promising investigational gene
therapy for the treatment of severe hemophilia A. We are very
encouraged by these data and look forward to working with
regulatory authorities, treating physicians, and people with
hemophilia A to further understand the potential of this gene
therapy."
"Although factor replacement therapy has been shown to be a safe
and effective treatment modality in hemophilia, it suffers both
from incomplete prevention of joint disease and having a high
treatment burden with recurring needs for intravenous infusions,
which can limit important daily activities out of fear of
bleeds," said Guy Young, M.D.,
Director, Hemostasis and Thrombosis Program at Children's Hospital
Los Angeles and Professor of Pediatrics (Clinical Scholar), Keck
School of Medicine of University of Southern California.
"Novel therapeutic approaches such as gene therapy offer the
prospect for both complete prevention of bleeds and subsequent
joint damage and eliminating the burden associated with current
treatments resulting in an improved quality of life."
Valoctocogene Roxaparvovec Safety
Overall, in the Phase 3 study, valoctocogene roxaparvovec has
been well tolerated by the 134 participants who received
a single 6e13 vg/kg dose. No participants developed inhibitors to
Factor VIII, or thromboembolic events. One participant was
lost to follow-up. Infusion-related reactions were
effectively mitigated by managing infusion rates.
Alanine aminotransferase (ALT) elevation (115 participants,
86%), a laboratory test of liver function, remained the most
common adverse event (AE). Other common adverse events
were headache (51 participants, 38%), nausea (50 participants,
37%), aspartate aminotransferase (AST) elevation (47
participants, 35%), arthralgia (38 participants, 28%) and fatigue
(37 participants, 27%). Twenty-two (16.4%) participants
experienced a total of 43 serious adverse events (SAEs), and all
SAEs resolved.
Common, steroid-related side effects can occur with temporary
use of corticosteroid (or alternative immunosuppressants) to manage
ALT elevation. These side effects have generally been grade 1/2 in
intensity, manageable and reversible. Isolated grade 3
steroid-related sides effects (e.g., diabetes, hypertension, weight
gain, bone fractures) were observed with longer-term higher dose
corticosteroid administration. Corticosteroid-related grade 3 SAEs
emerged as a safety issue with extended use of corticosteroids
which were reversible with only one event of weight gain
ongoing.
Overall, in the Phase 1/2 study, the safety profile of
valoctocogene roxaparvovec remains consistent with previously
reported data with no delayed-onset, treatment-related
events. No participants developed inhibitors to Factor VIII,
and no participants withdrew from the study. No participants
have developed thrombotic events. The most common adverse
events associated with valoctocogene roxaparvovec occurred early
and included transient infusion-associated reactions and transient,
asymptomatic, and mild to moderate rise in the levels of certain
proteins and enzymes measured in liver function tests with no
long-lasting clinical sequelae.
GENEr8-1 Study Description
The global Phase 3 GENEr8-1 study evaluates superiority of
valoctocogene roxaparvovec at the 6e13 vg/kg dose compared to the
current standard of care, FVIII prophylactic therapy. All
study participants had severe hemophilia A at baseline, defined as
less than or equal to 1 IU/dL of Factor VIII activity. The
study included 134 total participants, all of whom had a minimum of
12 months of follow-up at the time of the datacut. The first
22 participants were directly enrolled into the Phase 3 study, 17
of whom were HIV-negative and dosed at least 2 years prior to the
datacut date (referred to as the subset). The remaining 112
participants (rollover population) completed at least six months in
a separate non-interventional study to prospectively assess
bleeding episodes, Factor VIII use, and health-related quality of
life while receiving Factor VIII prophylaxis prior to rolling over
to receive a single infusion of valoctocogene roxaparvovec in the
GENEr8-1 study.
Regulatory Status
BioMarin is working with the U.S. Food and Drug Administration
(FDA) to align on steps forward to obtain marketing approval for
valoctocogene roxaparvovec gene therapy for severe hemophilia A.
The FDA recommended that the Company complete the Phase 3 study and
submit two-year follow-up safety and efficacy data on all study
participants. Additionally, the European Medicines Agency (EMA)
requested one-year results from the full Phase 3 study to inform
their benefit-risk assessment. To facilitate this submission within
the EMA regulatory framework, BioMarin withdrew the MAA and plans
to resubmit the MAA with these data to the EMA in the second
quarter of 2021 following discussions with the Agency.
The FDA has granted valoctocogene roxaparvovec Breakthrough
Therapy Designation. BioMarin's valoctocogene roxaparvovec
has received orphan drug designation from the FDA and EMA for the
treatment of severe hemophilia A. The Orphan Drug Designation
program is intended to advance the evaluation and development of
products that demonstrate promise for the diagnosis and/or
treatment of rare diseases or conditions.
Call and Webinar to be Held Today, January 10, 2021 at 7:15
PM Eastern Time
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Phase 1/2 Dose Escalation Study Description
The Phase 1/2 dose escalation study is ongoing and continues to
monitor participants long-term. In the study, a total of 15
patients with severe hemophilia A and Factor VIII activity levels
less than or equal to 1 IU/dL received a single dose of BMN 270,
seven of whom were treated at a dose of 6e13 vg/kg and six of whom
were treated at a lower dose of 4e13 vg/kg. The other two
participants were treated at lower doses as part of dose escalation
in the study and did not achieve therapeutic
efficacy.
Robust Clinical Program
BioMarin has multiple clinical studies underway in its
comprehensive gene therapy program for the treatment of severe
hemophilia A. In addition to the global Phase 3 study
GENEr8-1 and the ongoing Phase 1/2 dose escalation study, the
Company recently began enrolling participants in a Phase
3b, single arm, open-label study to
evaluate the efficacy and safety of valoctocogene roxaparvovec at a
dose of 6e13 vg/kg with prophylactic corticosteroids in people with
hemophilia A. The Company is running a Phase 1/2 Study with
the 6e13kg/vg dose of valoctocogene roxaparvovec in approximately
10 participants with pre-existing AAV5 antibodies, as well as
another Phase 1/2 Study with the 6e13 vg/kg dose of valoctocogene
roxaparvovec in people with hemophilia A with active or prior FVIII
inhibitors.
About Hemophilia A
People living with hemophilia A lack sufficient functioning
Factor VIII protein to help their blood clot and are at risk for
painful and/or potentially life-threatening bleeds from even modest
injuries. Additionally, people with the most severe form of
hemophilia A (FVIII levels <1%) often experience painful,
spontaneous bleeds into their muscles or joints. Individuals
with the most severe form of hemophilia A make up approximately 50
percent of the hemophilia A population. People with
hemophilia A with moderate (FVIII 1-5%) or mild (FVIII 5-40%)
disease show a much-reduced propensity to bleed. The standard
of care for individuals with severe hemophilia A is a prophylactic
regimen of replacement Factor VIII infusions administered
intravenously up to two to three times per week or 100 to 150
infusions per year. Despite these regimens, many people
continue to experience breakthrough bleeds, resulting in
progressive and debilitating joint damage, which can have a major
impact on their quality of life.
Hemophilia A, also called Factor VIII deficiency or classic
hemophilia, is an X-linked genetic disorder caused by missing or
defective Factor VIII, a clotting protein. Although it is passed
down from parents to children, about 1/3 of cases are caused by a
spontaneous mutation, a new mutation that was not inherited.
Approximately 1 in 10,000 people have Hemophilia A.
About BioMarin
BioMarin is a global biotechnology company that develops and
commercializes innovative therapies for serious and
life-threatening rare and ultra-rare genetic diseases. The
Company's portfolio consists of six commercialized products and
multiple clinical and pre-clinical product candidates. For
additional information, please visit www.biomarin.com.
Information on BioMarin's website is not incorporated by reference
into this press release.
Forward Looking Statements
This press release contains forward-looking statements about the
business prospects of BioMarin Pharmaceutical Inc., including
without limitation, statements about the development of BioMarin's
valoctocogene roxaparvovec program generally, and the Phase 3
results particularly; the impact of valoctocogene roxaparvovec gene
therapy for treating patients with severe hemophilia A, the
potential for valoctocogene roxaparvovec to reduce or eliminate
bleeds, reduce the number of Factor VIII infusions, and the ongoing
clinical programs generally. These forward-looking statements
are predictions and involve risks and uncertainties such that
actual results may differ materially from these statements. These
risks and uncertainties include, among others: results and timing
of current and planned preclinical studies and clinical trials of
valoctocogene roxaparvovec, including final analysis of the above
data and additional data from the continuation of these trials; any
potential adverse events observed in the continuing monitoring of
the patients in the clinical trials; the content and timing of
decisions by the FDA, the EMA and other regulatory authorities; the
content and timing of decisions by local and central ethics
committees regarding the clinical trials; our ability to
successfully manufacture the product candidate for the preclinical
and clinical trials; and those other risks detailed from time
to time under the caption "Risk Factors" and elsewhere in
BioMarin's Securities and Exchange Commission (SEC) filings,
including BioMarin's Annual and quarterly Reports on
Forms 10-K and 10-Q, and future filings and reports by
BioMarin. BioMarin undertakes no duty or obligation to update any
forward-looking statements contained in this press release as a
result of new information, future events or changes in its
expectations.
BioMarin® is a registered trademark of BioMarin Pharmaceutical
Inc.
Contacts:
|
|
|
|
Investors
|
Media
|
Traci
McCarty
|
Debra
Charlesworth
|
BioMarin
Pharmaceutical Inc.
|
BioMarin
Pharmaceutical Inc.
|
(415)
455-7558
|
(415)
455-7451
|
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