SAN RAFAEL, Calif.,
May 28, 2019 /PRNewswire/
-- BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) announced
today an update to its previously reported results of an
open-label Phase 1/2 study of valoctocogene roxaparvovec, an
investigational gene therapy treatment for adults with severe
hemophilia A. The three-year update demonstrated that bleed
rate control with valoctocogene roxaparvovec 6e13 vg/kg dose was
maintained for a third year with a median Annualized Bleed Rate
(ABR) of 0 and mean ABR of 0.7 in that year. In addition,
Factor VIII levels in the 6e13 vg/kg dose appeared to be
approaching a plateau in year three. Factor VIII levels
measured with the chromogenic substrate (CS) assay at the end of
year three were mean and median of 32.7 IU/dL and 19.9 IU/dl,
respectively, compared with mean and median of 36.4 IU/dL and 26.2
IU/dL, respectively, at the end of year two. The full updated
results will be submitted for presentation at the International
Society on Thrombosis and Haemostasis 2019.
"These data confirm that valoctocogene roxaparvovec has the
potential to profoundly impact the lives of people with severe
hemophilia A through a sustained reduction in bleeds and factor
VIII usage," said Hank Fuchs, M.D.,
President, Global Research and Development at BioMarin.
"Importantly, we've now observed that maintenance of factor
expression is a function of expression level and time. Therefore,
by three years post a one-time infusion of valoctocogene
roxaparvovec, we anticipate we are nearing the plateau of
expression. More conservative statistical modeling anticipates that
bleeding control will be maintained for at least eight years after
gene transfer. This is fantastic news for the hemophilia
community."
"With three years of data, it's clear that valoctocogene
roxaparvovec has the potential to change the way we treat this
debilitating disease, which can improve the quality of life for
people with severe hemophilia A," said John
Pasi, M.B., Ch.B., Ph.D., from Barts and the London School
of Medicine and Dentistry and primary investigator for this Phase
1/2 study. "For people who have had to inject themselves with
factor VIII every other day to prevent bleeding, this treatment has
the potential to be transformational."
Annualized Bleed Rate and Factor VIII Use in 6e13 vg/kg
Cohort
In the 6e13 vg/kg cohort, the data showed substantial and
sustained reductions in bleeding that required Factor VIII
infusions. In the year prior to study entry, the mean ABR was 16.5
and the median was 16.3. After three years, the ABR was a
mean of 0.7 and a median of zero. This represents a 96%
reduction in mean (ABR) over three years, with continued absence of
target joints and target joint bleeds during the three years
observed. In the first, second and third years, 71%, 86% and 86%,
respectively, of study participants had zero bleeds requiring
Factor VIII infusions compared to 14% who had zero bleeds requiring
Factor VIII infusions in the year prior to study entry. There was a
96% reduction in mean FVIII usage over three years. In the
first, second and third years, there was a 98%, 94%, and 96%
reduction in mean FVIII usage, respectively.
Valoctocogene Roxaparvovec Reduces Bleeds and Factor VIII
Use: Summary of Annualized Bleeding Rate (ABR) and FVIII
Usage of 6e13 vg/kg Dose Patients Previously on Prophylaxis (N=6)*
at April 1, 2019 data cut
6e13 vg/kg
Dose
|
Before
valoctocogene
roxaparvovec
Infusion***
|
After
valoctocogene
roxaparvovec
Infusion**** during
Year 1
|
After
valoctocogene
roxaparvovec
Infusion**** during
Year 2
|
After
valoctocogene
roxaparvovec
Infusion**** during
Year 3
|
|
Median (mean, SD)
|
Median (mean, SD)
|
Median (mean, SD)
|
Median (mean, SD)
|
Annualized
Bleeding** Rate
(bleeding episodes per year per subject)
|
16.5
(16.3,
15.7)
|
0.0
(0.9, 2.2)
|
0.0
(0.2, 0.4)
|
0.0
(0.7, 1.6)
|
Annualized FVIII
Infusions**
(infusions per year per
subject)
|
138.5
(136.7,
22.4)
|
0.0
(2.1, 5.3)
|
0.0
(8.8,
21.0)
|
0.0
(5.5, 9.4)
|
*A 7th patient received Factor VIII on demand
prior to treatment with BMN 270 and was not included in
analysis.
**Post infusion data were based on data after
Week 4
***Obtained from medical records.
****5
of 6 participants had 0 bleeds requiring Factor VIII infusions and
4 of 6 participants had 0 Factor VIII infusions after Week
4.
Annualized Bleed Rate and Factor VIII Use in 4e13 vg/kg
Cohort
In the 4e13 vg/kg cohort, the data showed substantial and
sustained reductions in bleeding requiring Factor VIII infusions.
In the year prior to study entry, the mean Annualized Bleed Rate
(ABR) was 12.2 and the median was 8. After two years, the ABR
was a mean of 1.2 and a median of zero. This represents a 92%
reduction in mean Annualized Bleed Rate (ABR). In the first
and second years, 83% and 67%, respectively, of study participants
had zero bleeds requiring Factor VIII infusions compared to 17%
requiring Factor VIII infusions in the year prior to study
entry. There was a 97% reduction in mean FVIII usage over two
years. In the first, and second years, there was a
71% and 86% reduction in mean FVIII usage,
respectively.
Valoctocogene Roxaparvovec Reduces Bleeds and Factor VIII
Use: Summary of Annualized Bleeding Rate (ABR) and FVIII Use
Rate of 4e13 vg/kg Dose for Patients Previously on Prophylaxis
(N=6) at April 1, 2019 data
cut
4e13 vg/kg
Dose
|
Before
valoctocogene
roxaparvovec
Infusion
|
After
valoctocogene
roxaparvovec Infusion
during Year 1
|
After
valoctocogene
roxaparvovec Infusion
during Year 2
|
|
Median
(mean,
SD)
|
Median
(mean,
SD)
|
Median
(mean,
SD)
|
Annualized
Bleeding Rate*
(bleeding episodes
per year per subject)
|
8.0
(12.2,
15.4)
|
0.0
(0.9, 2.2)
|
0.0
(1.2, 2.4)
|
Annualized FVIII
Use Rate*
(infusions per
year per subject)
|
155.5
(146.5,
41.6)
|
0.0
(2.0, 4.3)
|
0.5
(6.8,
15.6)
|
*Post-infusion data were based on data after Week 4.
Factor VIII Activity Levels for 6e13 vg/kg Cohort
For the 6e13 vg/kg cohort, mean Factor VIII activity levels over
three years support reductions in bleed rates and show a flattening
rate of decline in the chromogenic substrate (CS) and one-stage
(OS) assays expressed as an international unit per deciliter
(IU/dL). At the end of the first, second and third years,
post-infusion, mean Factor VIII activity level of the 6e13 vg/kg
cohort was 64.3, 36.4 and 32.7 IU/dL respectively as measured by
the CS assay. The mean results of the OS assay at the end of
the first, second and third year were 103.8, 59.0, and 52.3 IU/dL,
respectively. The median Factor VIII activity levels at the
end of the first, second and third years were 60.3, 26.2 and 19.9
ID/dL respectively as measured by the CS assay. The median
results of the OS assay at the end of the first, second and third
year were 88.6, 45.7, and 29.8 IU/dL, respectively. During
the second and third year from receiving the infusion, factor VIII
levels in the 6e13 vg/kg dose declined at the rate of 5.72 IU/dL
per year based on the slope of the linear regression of all the
factor VIII data from weeks 53 to week 156.
Mean and Median Factor VIII Activity Levels (IU/dL) of 6e13
vg/kg Dose Patient Visit at Year End (N=7) at April 1, 2019 Data Cut*
|
Year
1**
|
Year
2**
|
Year
3**
|
Mean
(Median) Factor VIII Activity Levels (IU/dL)
as Measured using
Chromogenic Substrate Assay
|
64.3
(60.3)
|
36.4
(26.2)
|
32.7
(19.9)
|
|
|
|
|
Mean
(Median) Factor VIII Activity Levels (IU/dL)
as Measured using
One-Stage Assay
|
103.8
(88.6)
|
59.0
(45.7)
|
52.3
(29.8)
|
*All patients had severe hemophilia A at baseline, defined as
less than or equal to 1 IU/dL of Factor VIII activity
levels.
**Weeks were windowed by +/- 2 weeks before 104
weeks, after 104 weeks, weeks were windowed by +/- 4 weeks, and
for week 32, one patient did not have a Factor VIII activity
level available.
Factor VIII Activity Levels for 4e13 vg/kg Cohort
For the 4e13 vg/kg cohort, mean Factor VIII activity levels over
two years support reductions in bleed rates and also show a
flattening rate of decline in the one-stage (OS) and chromogenic
substrate (CS) assays expressed as an international unit per
deciliter (IU/dL). At the end of the first and second years,
post-infusion, mean Factor VIII activity level of the 4e13 vg/kg
cohort was 21.0 and 14.7 IU/dL respectively as measured by the CS
assay. The mean results of the OS assay at the end of the
first and second year was 31.4 and 23.2 IU/dL respectively.
The median Factor VIII activity levels at the end of the first and
second years were 22.9 and 13.1 IU/dL, respectively as measured by
the CS assay. The median results of the OS assay at the end
of the first and second year was 31.7 and 23.5 IU/dL
respectively. During the second year from receiving the
infusion, factor VIII levels in the 4e13 vg/kg dose declined at the
rate of 1.56 IU/dL per year based on the slope of the linear
regression of all the factor VIII data from weeks 53 to 104.
Mean and Median Factor VIII Activity Levels (IU/dL) of 4e13
vg/kg Dose Patient Visit at Year End (N=7) at April 1, 2019 Data Cut*
|
Year
1**
|
Year
2**
|
Mean
(Median) Factor VIII Activity Levels (IU/dL)
as Measured using
Chromogenic Substrate Assay
|
21.0
(22.9)
|
14.7
(13.1)
|
|
|
|
Mean
(Median) Factor VIII Activity Levels (IU/dL)
as Measured using
One-Stage Assay
|
31.4
(31.7)
|
23.2
(23.5)
|
*All patients had severe hemophilia A at baseline, defined as
less than or equal to 1 IU/dL of Factor VIII activity
levels.
**For analysis, weeks were windowed by +/- 2
weeks before 104 weeks and for week 32, one patient did not
have a Factor VIII activity level available.
Factor VIII Activity Level Changes Continued to be Expression
Level Dependent, Slowed in Year Three, and Appears to be
Approaching Plateau
The three years of data available suggest that a loss of factor
VIII expression is dependent on the level of expression and appears
to decline slower as time and expression level decline. At
the current rates of decline, based on a statistical model of
expression as a function of level and time to extrapolate
hemostatic efficacy, it appears that the Factor VIII activity
levels are approaching a plateau and project sustained Factor VIII
expression for an extended period of time.
The estimates of durability of bleed control are based on a
statistical model developed by the company to estimate the average
time until factor levels approach 5 IU/dl. Extrapolation
beyond week 156 assumes a continued decline at a rate equal to the
estimated slope for the FVIII activity of the 6E13 vg/kg dose from
>52 weeks to ≤ 156 weeks based on a linear regression (slope:
-5.72 IU/year) until mean FVIII activity reaches that observed in
the 4e13 vg/kg levels at Year 2. At that point, the model
assumes the rate of decline based on the estimated slope for 4E13
vg/kg dose from > 52 weeks to ≤ 104 weeks based on a linear
regression (slope -1.56 IU/year).
Conference Call and Webcast to be Held May 28, 2019 at 8:00 AM
Eastern Time
Interested parties may access a live video webcast that will
include audio and slides of the presentations via the investor
section of the BioMarin website. A replay of the meeting will
be archived on the site for one week.
For those who choose not to listen and view the event via
webcast, dial-in information for the audio portion of the webcast
can be accessed using:
U.S. / Canada Dial-in Number: (866) 502-9859
International Dial-in Number: (574) 990-1362
Conference ID: 2295086
Replay Dial-in Number: (855) 859-2056
Replay International Dial-in Number: (404) 537-3406
Conference ID: 2295086
Valoctocogene Roxaparvovec Safety
Overall, valoctocogene roxaparvovec continues to have a
favorable safety profile and has been well-tolerated by
participants across all doses, including the two participants who
received the lowest doses of 6e12 and 2e13 vg/kg,
respectively. No participants developed inhibitors to Factor
VIII, and no participants withdrew from the study. The most
common adverse events (AEs) across all dose cohorts were alanine
aminotransferase (ALT) elevation (11 participants, 73%);
arthralgia, (10 participants, 67%); aspartate aminotransferase
elevation (8 participants, 53%); headache (7 participants, 47%);
back pain, fatigue, and upper respiratory tract infection (6
participants, 40%), insomnia (5 participants, 33%), and pain in
extremity (4 participants, 27%). Beyond the two previously
reported serious adverse events (SAEs), one new SAE was reported in
the past year that involved a participant with advanced arthritis
who was hospitalized for surgery.
Registrational Studies Underway
The global Phase 3 program includes two studies with
valoctocogene roxaparvovec, one with the 6e13 vg/kg dose (GENEr8-1)
and one with the 4e13 vg/kg dose (GENEr8-2). With the
goal of evaluating superiority of valoctocogene roxaparvovec to the
current standard of care, prophylactic therapy, the sample size of
the GENEr8-1 study is approximately 130 total participants.
Enrollment completion in the newly amended GENEr8-1 study is
expected in the third quarter of 2019.
GENEr8-2, the ongoing Phase 3 study with the 4e13 vg/kg dose is
expected to complete enrollment one to two quarters after GENEr8-1
in 2020.
BioMarin now has six clinical studies underway in its
comprehensive gene therapy program for the treatment of severe
hemophilia A. In addition to the two global Phase 3 studies
GENEr8-1 and GENEr8-2, 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. Two additional and separate studies, one to study
AAV seroprevalence in people with severe hemophilia A and one
non-interventional study to determine baseline characteristics in
people with hemophilia A, are ongoing around the world.
Participants in the Phase 1/2 dose escalation study will continue
to be monitored as part of the global program
underway.
Valoctocogene roxaparvovec investigational product from
BioMarin's commercial scale manufacturing facility is being used in
all BioMarin interventional studies.
Regulatory Status
The U.S. Food and Drug Administration (FDA) granted
valoctocogene roxaparvovec Breakthrough Therapy
Designation. The FDA's Breakthrough Therapy Designation
program is intended to facilitate and expedite development and
review of new drugs to address unmet medical need in the treatment
of a serious condition. To qualify for Breakthrough Therapy
Designation, preliminary clinical evidence must show that that the
drug may demonstrate substantial improvement over existing
therapies.
The European Medicines Agency (EMA) has granted access to
its Priority Medicines (PRIME) regulatory initiative for
valoctocogene roxaparvovec. To be accepted for PRIME, an
investigational therapy has to show its potential to benefit
patients with unmet medical needs based on early clinical data.
PRIME focuses on medicines that may offer a major therapeutic
advantage over existing treatments, or benefit patients with no
treatment options. These medicines are considered priority
medicines within the European Union (EU).
BioMarin's valoctocogene roxaparvovec has also 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.
Gene Therapy Manufacturing
BioMarin has constructed one of the first gene therapy
manufacturing facilities of its kind in the world, which is located
in Novato, California. Good Manufacturing Practices (GMP)
production of valoctocogene roxaparvovec has commenced, and this
manufacturing facility will support pivotal clinical development
activities and anticipated commercial demand, if valoctocogene
roxaparvovec is approved. This facility is capable of supporting
approximately 4,000 doses per year, and the production process was
developed in accordance with International Conference on
Harmonisation guidance for Pharmaceuticals for Human Use
facilitating worldwide registration with health authorities.
In 2018, the International Society for Pharmaceutical Engineering
(ISPE) selected the Company's gene therapy manufacturing facility
as the Facility of the Year Category Winner for Project
Execution.
About Hemophilia A
People living with hemophilia A lack enough FVIII protein to
help their blood clot and are at risk for painful, potentially
life-threatening bleeds from even modest injuries.
Additionally, people with severe hemophilia A often experience
painful, spontaneous bleeds into their muscles or joints. The
standard of care for the 43 percent of individuals with hemophilia
A who are severely affected is a prophylactic regimen of Factor
VIII infusions administered intravenously two to three times per
week. Despite these regimens, many people continue to
experience 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 (FVIII) 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 is born with 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 seven 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.(BioMarin),
including without limitation, statements about the development of
BioMarin's valoctocogene roxaparvovec program generally; the Phase
1/2 study with valoctocogene roxaparvovec; the impact of
valoctocogene roxaparvovec gene therapy for treating people with
severe hemophilia A; and the projected durability of valoctocogene
roxaparvovec to maintain Factor VIII levels at hemostatic levels.
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 interim data;
additional data from the continuation of this Phase 1/2 trial, any
potential adverse events observed in the continuing monitoring of
the participants in the clinical trials; the content and timing of
decisions by the U.S. Food and Drug Administration, the European
Commission and other regulatory authorities; the content and timing
of decisions by local and central ethics committees regarding the
clinical trials; errors and deficiencies in our durability
modeling; our ability to successfully manufacture valoctocogene
roxaparvovec for the clinical trials and commercially, if
approved; 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 Quarterly Report on Form 10-Q for the quarter ended
March 31, 2019, 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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