SAN RAFAEL, Calif.,
Dec. 9, 2017 /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 (formerly BMN 270), an investigational
gene therapy treatment for severe hemophilia A. The updated results
will be presented during an oral presentation at the 59th American
Society of Hematology (ASH) Annual Meeting and Exposition by
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. On Monday, Dec. 11, 2017, Professor Pasi will
present the data, which will include sustained normal or
near-normal Factor VIII levels in severe hemophilia A for most
patients with a maximum follow up of 19 months. Previously,
the company provided updated data on the 4e13 vg/kg dose on
Oct. 18, 2017 and on the 6e13 vg/kg
dose on July 11, 2017 at a medical
meeting.
The data presented at ASH is the most current data (Nov. 16, 2017 cut off) and includes 78 weeks of
data for the 6e13 vg/kg dose and 48 weeks of data for the 4e13
vg/kg dose.
"With 1.5 years of data on valoctocogene roxaparvovec, our
understanding of this novel gene therapy is considerable, and we
are looking forward to drawing on that knowledge in the Phase 3
GENEr8 studies, which we expect will begin enrolling patients this
month," said Hank Fuchs, M.D.,
President, Worldwide Research and Development at
BioMarin. "We're pleased that this work is being presented in
one of the most highly regarded peer reviewed publications and at a
pace that is faster than other in vitro gene therapies. This most
current data presented at ASH combined with the one-year data
published in NEJM will contribute to an increase in understanding
within the scientific community about gene therapy in general and
specifically about the exciting new developments in a potential
one-time treatment for severe hemophilia A."
Efficacy Data of 4e13 vg/kg Dose as Presented at ASH
As of Nov. 16, 2017, a total of
six patients with severe hemophilia A, who had all been treated
with prophylactic Factor VIII pre-study, received a single dose of
valoctocogene roxaparvovec at 4e13 vg/kg. Since the last data
update provided on Oct. 18, 2017, the
three patients with the longest follow-up (at week 48) have Factor
VIII activity levels that are in or near to the normal range with
both median and mean values of 49%. Median annualized bleed and
factor VIII use rates for the 4e13 vg/kg cohort were zero after
Week 4 when their Factor VIII activity rose above 5%.
According to the World Federation of Hemophilia rankings of
severity of hemophilia A, the mild hemophilia A range of Factor
VIII activity levels is between 5% and 40%, and the normal range of
Factor VIII activity levels for people without disease is between
50% and 150%, in each case expressed as a percentage of normal
factor activity in blood.
Factor VIII Levels (%) of 4e13 vg/kg Dose Patients* by Visit
(N=6) at Nov. 16, 2017 data
cut
Week**
|
4
|
8
|
12
|
16
|
20
|
24
|
28
|
32
|
36
|
40
|
44
|
48
|
4e13 vg/kg
Dose
|
|
|
|
|
|
|
|
|
|
|
|
|
n
|
6
|
6
|
6
|
6
|
6
|
6
|
6
|
6
|
6
|
3
|
3
|
3
|
Median
Factor VIII Level***
(%)
|
4
|
15
|
21
|
29
|
34
|
28
|
34
|
42
|
38
|
48
|
56
|
49
|
Mean
Factor VIII Level***
(%)
|
5
|
13
|
19
|
26
|
31
|
29
|
31
|
37
|
35
|
50
|
61
|
49
|
Range
( low,
high)
|
(2,10)
|
(3,21)
|
(6,32)
|
(5,38)
|
(7,45)
|
(7,43)
|
(4,44)
|
(4,54)
|
(4,55)
|
(37,64)
|
(45,83)
|
(38,60)
|
*All patients had severe hemophilia A at baseline, defined as
less than or equal to 1% of Factor VIII activity levels, expressed
as a percentage of normal factor activity in
blood.
**Weeks were windowed by +/- 2 weeks
***
Bolded numbers are in the mild to normal range of Factor VIII
activity as defined by the World Federation of Hemophilia,
http://www.wfh.org/en/page.aspx?pid=643 (link current as
of Dec. 6, 2017). Factor VIII levels
are determined by one-stage assay.
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 Nov. 16, 2017 data
cut
|
Before
valoctocogene
roxaparvovec Infusion
|
After
valoctocogene roxaparvovec
Infusion
|
|
Median (mean,
SD)
|
Median (mean,
SD)
|
Annualized
Bleeding Rate* (bleeding episodes per year per
subject)
|
8.0 (12.2,
15.4)
|
0.0 (0.6,
1.4)
|
Annualized FVIII
Use Rate*
(infusions per
year per subject)
|
155.5 (146.5,
41.6)
|
0.0 (2.0,
4.8)
|
*Post-infusion data were based on data after Week 4.
Efficacy Data on 6e13 vg/kg Dose as Presented at ASH
As of the Nov. 16, 2017 data
cutoff, all seven patients at the 6e13 vg/kg dose had been followed
for at least 78 weeks post infusion. Median and mean Factor
VIII levels from week 20 through 78 for the 6e13 vg/kg dose cohort
have been consistently within the normal range, expressed as a
percentage of normal factor activity in blood. At 78 weeks
post infusion, the median and mean Factor VIII levels of the 6e13
vg/kg cohort are 90 and 89% respectively. Median annualized
bleed and factor VIII use rates for the 6e13 vg/kg were zero after
Week 4. After 52 weeks of follow-up, the phase 1/2 study
protocol specified that planned patient visits were reduced in
frequency from once every one to two weeks to once every three
months. Consequently, as of May 31,
2017 when all patients in the 6e13 vg/kg dose had reached 52
weeks of follow up, all patients in the 6e13 vg/kg dose converted
to a quarterly follow-up visit schedule.
Factor VIII Levels (%) of 6e13 vg/kg Dose Patients* by Visit
(N=7) at Nov. 16, 2017 data
cut
Week**
|
20
|
24
|
28
|
32
|
36
|
40
|
44
|
48
|
52
|
65
|
78
|
6e13 vg/kg
Dose
|
|
|
|
|
|
|
|
|
|
|
|
N***
|
7
|
7
|
7
|
6
|
7
|
7
|
7
|
7
|
7
|
7
|
7
|
Median
Factor VIII Level****
(%)
|
97
|
101
|
122
|
99
|
99
|
111
|
105
|
105
|
89
|
98
|
90
|
Mean
Factor VIII Level****
(%)
|
118
|
129
|
123
|
122
|
116
|
124
|
122
|
106
|
104
|
93
|
89
|
Range
(low,
high)
|
(12, 254)
|
(12, 227)
|
(15, 257)
|
(26, 316)
|
(31, 273)
|
(17, 264)
|
(20,242)
|
(23,195)
|
(20, 218)
|
(16,145)
|
(11,179)
|
*All patients had severe hemophilia A at baseline, defined as
less than or equal to 1% of Factor VIII activity levels, expressed
as a percentage of normal factor activity in
blood.
**Weeks were windowed by +/- 2 weeks and after 52
weeks, measurements were taken every 3
months
*** For week 32, one patient did not
have a Factor VIII activity level available.
****Bolded
numbers are in the normal range of Factor VIII as defined by the
World Federation of Hemophilia,
http://www.wfh.org/en/page.aspx?pid=643 (link current as
of Dec. 6, 2017). Factor VIII levels
are determined by one-stage assay.
Valoctocogene Roxaparvovec Reduces Bleeds and Factor VIII
Use: Summary of Annualized Bleeding Rate (ABR) and FVIII
Infusions of 6e13 vg/kg Dose Patients Previously on Prophylaxis
(N=6)* at Nov. 16, 2017 data
cut
|
Before
valoctocogene roxaparvovec Infusion***
|
After
valoctocogene roxaparvovec Infusion****
|
|
Median (mean,
SD)
|
Median (mean,
SD)
|
Annualized
Bleeding** Rate(bleeding episodes per year per
subject)
|
16.5 (16.3,
15.7)
|
0.0 (0.5,
1.2)
|
Annualized FVIII
Infusions**
(infusions per
year per subject)
|
138.5 (136.7,
22.4)
|
0.0 (6.1,
14.9)
|
*A 7th patient received Factor VIII on demand and
was not included in analysis.
**Post infusion data were
based on data after Week 4
***Obtained from medical
records.
****5 of 6 patients had 0 bleeds requiring
Factor VIII infusions and 0 Factor VIII infusions after Week
4.
Quality of Life (QoL)
Patients who received the 6e13 vg/kg dose demonstrated improved
total scores when assessed with the Haemo-QoL-A questionnaire, a
validated health-related quality of life (hrQoL) measurement tool
for patients with hemophilia, as early as 16 weeks, with
maintenance of hrQoL scores above the minimal clinically important
difference (MCID) range (i.e., total score increase of 5.2 to 7.9,
based on prior studies) through 78 weeks after receiving a single
dose of valoctocogene roxaparvovec. By week 16, patients
achieved a clinically meaningful improvement from baseline,
with a mean hrQoL score increase of 13.4 and a standard deviation
(SD) of 11.2. At week 78, the mean hrQoL score increase was
16.6 with an SD of 11.9. The improvements above the MCID
range of the Haemo-QoL-A total scores were supported by
improvements achieved across all six domains tested, i.e.
Consequences of Bleeding, Physical Functioning, Role Functioning,
Emotional Impact, Treatment Concern, and Worry.
Change from Baseline in Total Health-Related Quality of Life
(hrQoL) Score of 6e13 vg/kg Dose Cohort at Nov. 16, 2017 data cut
|
6E13 vg/kg
Dose Cohort (N=7)
|
Total hrQoL
Score
|
Change from
Baseline
|
Baseline
|
Mean (SD)
|
71.9
(16.6)
|
(na)
|
|
Median
|
76.2
|
(na)
|
Week
16
|
Mean (SD)
|
85.3
(13.0)
|
13.4
(11.2)
|
|
Median
|
84.7
|
6.0
|
Week
28
|
Mean (SD)
|
84.8
(12.5)
|
12.9
(13.7)
|
|
Median
|
87.5
|
8.0
|
Week
52
|
Mean (SD)
|
81.6
(15.1)
|
9.6 (12.7)
|
|
Median
|
86.7
|
7.0
|
Week 78
(n=5)
|
Mean (SD)
|
80.6
(14.4)
|
16.6
(11.9)
|
|
Median
|
87.6
|
13.7
|
SD = standard deviation; na = not applicable.
New England Journal of Medicine Publishes 1
Year Data on 6e13 vg/kg Dose Data
The company also announced that the New England Journal of
Medicine (NEJM) published an independent peer-reviewed article
on the ongoing Phase 1/2 study to evaluate safety and
efficacy of investigational gene therapy, valoctocogene
roxaparvovec, at the 6e13 dose in men with severe hemophilia A at
52 weeks.
The NEJM article, "AAV Gene Transfer in Patients with Severe
Hemophilia A," concluded that valoctocogene roxaparvovec is
associated with the "sustained normalization" of Factor VIII
activity over a period of one year in six of seven study
participants who received the 6e13 vg/kg dose with stabilization of
hemostasis and a "profound" reduction in Factor VIII use in all
seven participants. The article also concluded that safety
findings were limited to elevations in liver function tests and
notes the relatively small sample size. For additional safety data,
see Safety section in press release.
Valoctocogene Roxaparvovec Safety
Overall, valoctogogene roxaparvovec has been well-tolerated by
patients across all doses, including the two patients who received
the lowest doses of 6e12 and 2e13 vg/kg, respectively. No
patients developed inhibitors to Factor VIII, and no patients
withdrew from the study. The most common adverse events (AEs)
across all dose cohorts were alanine aminotransferase (ALT)
elevation (11 patients, 73%); arthralgia (9 patients, 60%);
aspartate aminotransferase elevation (8 patients, 53%); headache (7
patients, 47%); back pain, fatigue and upper respiratory tract
infection (5 patients, 33%). Two patients reported serious
adverse events (SAEs) during the study. One patient was
hospitalized for observation after developing Grade 2 pyrexia with
myalgia and headache within 24 hours of receiving valoctocogene
roxaparvovec. The event resolved within 48 hours following
treatment with paracetamol, an over-the-counter treatment for pain
and fever. The event was assessed as related to valoctocogene
roxaparvovec. The other SAE was assessed as not related to
valoctocogene roxaparvovec, attributed to a planned knee surgery to
treat hemophilic arthropathy, and Grade 1 in severity. No
complications were reported.
Upcoming GENEr8 Studies
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). Both Phase
3 GENEr8 studies will be open-label single-arm studies to evaluate
the efficacy and safety of valoctocogene roxaparvovec.
GENEr8-1 will enroll its first patient this month, and GENEr8-2
will enroll the first patient at the start of 2018. The
primary endpoint will be a change from baseline FVIII activity
level, and the secondary endpoints will measure annualized FVIII
replacement therapy use rate and annualized bleed rate.
BioMarin will also begin a Phase 1/2 Study with the 6E13kg/vg
dose and with approximately 10 patients who are AAV5
positive. The first patient is expected to enroll in the
first half of 2018.
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 largest gene therapy
manufacturing facilities in the world, which is located in
Novato, California. Good
Manufacturing Practices (GMP) production of valoctocogene
roxaparvovec has commenced and will support clinical development
activities and anticipated commercial demand. This facility is
capable of supporting approximately 2,000 patients 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.
About Hemophilia A
Hemophilia A, also called Factor VIII (FVIII) deficiency or
classic hemophilia, is a 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. As an
X-linked disorder, hemophilia A mostly affects males, occurring in
approximately 1 in 5,000 male births. People living with the
disease are not able to form blood clots efficiently and are at
risk for excessive bleeding from modest injuries, potentially
endangering their life. People with severe hemophilia often bleed
spontaneously into their muscles or joints. The standard of care
for the 43% of hemophilia A patients who are severely affected, is
a prophylactic regimen of Factor VIII infusions three times per
week. Even with prophylactic regimens, many patients still
experience microbleeds and spontaneous bleeding events that result
in progressive joint damage.
About BioMarin
BioMarin is a global biotechnology company that develops and
commercializes innovative therapies for patients with 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 Statement
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, the impact of
valoctocogene roxaparvovec gene therapy for treating patients with
severe hemophilia A, the potential for valoctocogene roxaparvovec
to bring Factor VIII levels to normal and to reduce or eliminate
bleeds, the planned Phase 3 studies, the planed Phase 1/2 study, or
other possible future clinical studies of valoctocogene
roxaparvovec. 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; any potential adverse events observed in the
continuing monitoring of the patients in the Phase 1/2 trial; 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; 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 Quarterly Report on Form 10-Q for the
quarter ended September 30, 2017, 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 trademarks 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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