Highest Dose (30 µg/kg/day) Shows Approximately
50% Increase in Mean Annualized Growth Velocity, Comparable
with 15 µg/kg/day dose
BioMarin Pharmaceutical Inc. (NASDAQ:BMRN) today provided an update
on its Phase 2 study of vosoritide, an analog of C-type Natriuretic
Peptide (CNP), in children with achondroplasia, the most common
form of dwarfism, at the American Society of Human Genetics 2016
Meeting. Results from 8 children in cohort 4, who completed
six months of daily dosing at 30 µg/kg/daily experienced a 46% or
2.1 cm/year increase in mean annualized growth velocity from
baseline (p-value = 0.03). These data are comparable to those
observed at the lower dose of 15 µg/kg/day in cohort 3.
Results from 10 children in cohort 3, who completed six months of
daily dosing at 15 µg/kg/day experienced a 50% or 2.0 cm/year
increase in mean annualized growth velocity from baseline (p-value
= 0.01). (See Table 2.)
Vosoritide was generally well tolerated at all
doses. The majority of adverse events (AEs) were mild and no
serious AEs were reported as study drug-related. Across all doses,
injection site reactions and hypotension were the most common
drug-related AEs. All injection site reaction events were
mild and transient. AEs of hypotension were mild, transient and
resolved without medical intervention, and the majority were
asymptomatic and reported in context of routine blood pressure
measurements. No new safety findings were observed at the 30
µg/kg/day dose.
“Studying the higher dose in Phase 2 informed the
design of our Phase 3 study in vosoritide. While vosoritide
at the higher dose of 30 µg/kg/day was generally well-tolerated,
the data support our use of the lower dose of 15 µg/kg/day in the
Phase 3 study,” said Hank Fuchs, MD, Chief Medical Officer at
BioMarin. “We believe that growth velocity is an important
measurement in developing vosoritide, which has the potential to
address the complications associated with achondroplasia. We
are grateful to the children and their families who are
participating in this study.”
“Vosoritide represents a potential, first-of-its-kind treatment
for this form of dwarfism, and these clinical studies could provide
new insights into improved management of this condition,” said
Julie Hoover-Fong Director, Greenberg Center for Skeletal
Dysplasias, Johns Hopkins University and lead author of the poster
of the Vosoritide Phase 2 data update at ASHG.
By the end of 2016, BioMarin intends to initiate a
one-year, randomized, placebo-controlled Phase 3 study in children
with achondroplasia ages 5-14 with a subsequent open-label
extension. Children in this study will have completed a
minimum six-month natural history study to determine their
respective baseline growth velocity prior to entering the Phase 3
study. The company believes based on discussions with global
health authorities that change in growth velocity from baseline as
an endpoint could lead to registration. The company plans to
augment these data with supportive evidence concerning
proportionality and functionality. As is often the case,
discussion of ancillary evidence, such as final adult height to be
collected, is ongoing. In addition, BioMarin is planning a
separate Phase 2 study evaluating the effect of vosoritide in
infants and toddlers. Vosoritide has Orphan designation in
both the United States and Europe.
Table 1: Phase 2 Trial Disposition
and Demographics
Category |
Cohorts 1 and 2 Switched to 15
µg/kg/day (n=12)* |
Cohort 3 15
µg/kg/day(n=10) |
Cohort 430 µg/kg/day(n=9)** |
Children Enrolled and Treated at 15 µg/kg/day |
12 (100%) |
10 (100 %) |
9 (100%) |
Children Who Completed 6 Months at 15 µg/kg/day |
12 (100%) |
10 (100%) |
N/A |
Children Who Completed 12 Months at 15 µg/kg/day |
N/A |
10 (100%) |
N/A |
Children Who Completed 6 Months at 30 µg/kg/day |
N/A |
N/A |
8 (89%) |
Age (years) at Enrollment |
|
|
|
Mean (SD) |
7.6 (1.88) |
8.0 (1.63) |
6.9 (1.17) |
Min, Max |
5, 10 |
6, 11 |
5, 8 |
Gender (n, %) |
|
|
|
Male |
6 (50%) |
4 (40%) |
4 (44%) |
Female |
6 (50%) |
6 (60%) |
5 (56%) |
|
|
|
|
*Children increased dose to 15 µg/kg/day after at
least 6 months at 2.5 and/or 7.5 µg/kg/day; 4 of original 16
subjects in Cohorts 1 and 2 did not initiate dosing at 15 µg/kg/day
due to subject decision to withdraw from the study (2), declining
extension study (1), and growth plate closure (1)**One child in
cohort 4 discontinued from treatment due to finding of a rare
congenital abnormality of conduction identified on routine study of
ECG monitoring, which was not associated with symptoms, and patient
was removed from treatment for precautionary reasons.
Table 2: Phase 2 Summary of Efficacy Results in
Children with Achondroplasia
Efficacy Analysis: Annualized Growth
Velocity |
Time Point |
6 Months
|
12 Months ** |
6 Months
|
6 Months |
Annualized Growth Velocity |
Cohorts 1, 215
µg/kg/daily(n=12) |
Cohort 3
15 g/kg/daily(n=10)
|
Cohort 315
g/kg/daily(n=10) |
Cohort
430 µg/kg/daily(n= 8)*** |
Baseline |
|
|
|
|
|
|
|
|
|
Mean (SD), cm/Year |
3.6 (1.0) |
4.0 (2.3) |
4.0 (2.3) |
4.5 (1.2) |
|
|
|
|
|
Median |
|
3.5 |
|
|
4.1 |
|
|
4.1 |
|
|
4.5 |
|
Post-Treatment |
|
|
|
|
|
|
|
|
|
Mean, (SD), cm/year |
5.9 (1.6) |
5.9 (0.9) |
6.1 (1.1) |
6.6 (1.2) |
|
|
|
|
|
Median |
|
5.6 |
|
|
5.6 |
|
|
5.9 |
|
|
7.0 |
|
Change from Baseline |
|
|
|
|
|
|
|
|
|
Mean (SD), cm/year |
2.3 (1.9) |
1.9 (2.0) |
2.0 (2.0) |
2.1 (2.1) |
|
|
|
|
|
Nominal p-value* |
0.002 |
0.02 |
0.01 |
0.03 |
Percent increase from Baseline |
|
65 |
% |
|
46 |
% |
|
50 |
% |
|
46 |
% |
Based on means (%) |
|
|
|
|
|
|
|
|
|
* Nominal p-value, not adjusted for multiplicity** Mean
Annualized Growth Velocity change from baseline increases to 2.0
cm/year (50% increase) if one patient who missed majority of doses
between 6 and 12 months is excluded ***8 children have non-missing
annualized growth velocity at both baseline and 6 months.
Phase 2 Study Design
Children in this study completed a minimum six
month natural history 901 study to determine their respective
baseline growth velocity prior to entering the Phase 2 study with
vosoritide. The Phase 2 trial was an open-label,
sequential cohort dose-escalation study of vosoritide in children
with achondroplasia. In this four dose cohort study, children
were treated with either 2.5 µg/kg/day, 7.5 µg/kg/ day, 15 µg/kg/
day or 30 µg/kg/ day, respectively. A total of 35 children
with achondroplasia with an average age of 7.6 years were enrolled
in the study. Based on the efficacy and safety profile
observed, all children participating in the first two cohorts of
the Phase 2 study, who remained in the study, were offered the
higher dose of 15 µg/kg/day during the 18 month extension study.
Children in the third (15 ug/kg/day) and fourth (30 ug/kg/day)
cohorts will remain on their current dose during the extension
study.
About Achondroplasia
Achondroplasia, the most common form of human dwarfism, is
characterized by failure of normal conversion of cartilage into
bone, which results in disproportionate short stature. This
condition is caused by a mutation in the fibroblast growth factor
receptor 3 gene (FGFR3), a negative regulator of bone growth.
Beyond disproportionate short stature, people with achondroplasia
can experience serious health complications, including foramen
magnum compression, sleep apnea, bowed legs, mid-face hypoplasia,
permanent sway of the lower back, spinal stenosis and recurrent ear
infections. Some of these complications can result in invasive
surgeries such as spinal cord decompression and straightening of
bowed legs. In addition, studies show increased mortality at every
age.
More than 80% of children with achondroplasia have parents of
average stature and have the condition as the result of a
spontaneous gene mutation. The worldwide incidence rate of
achondroplasia is about one in 25,000 live births. Vosoritide
is being tested in children whose growth plates are still "open,"
typically those under 18 years of age. This is approximately
25 percent of people with achondroplasia. In the United
States, Europe, Latin American and the Middle East, there is
currently no licensed medicines for achondroplasia.
About BioMarin
BioMarin is a global biotechnology company that develops and
commercializes innovative therapies for people with serious and
life-threatening rare disorders. The company's portfolio consists
of five commercialized products and multiple clinical and
pre-clinical product candidates.
For additional information, please visit www.BMRN.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 vosoritide; the continued clinical development of
vosoritide; the final results of the Phase 2 trial of vosoritide;
the timing and design of the planned Phase 3 and Phase 2 studies;
and actions by regulatory authorities. 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 vosoritide; our ability to successfully manufacture
vosoritide; the content and timing of decisions by the U.S. Food
and Drug Administration, the European Commission and other
regulatory authorities concerning vosoritide; and those factors
detailed in BioMarin's filings with the Securities and Exchange
Commission, including, without limitation, the factors contained
under the caption "Risk Factors" in BioMarin's 2015 Annual Report
on Form 10-K, and the factors contained in BioMarin's reports on
Form 10-Q. Stockholders are urged not to place undue reliance on
forward-looking statements, which speak only as of the date hereof.
BioMarin is under no obligation, and expressly disclaims any
obligation to update or alter any forward-looking statement,
whether as a result of new information, future events or
otherwise.
BioMarin® is a registered trademark of BioMarin
Pharmaceutical Inc.
Contact:
Investors:
Traci McCarty
BioMarin Pharmaceutical Inc.
(415) 455-7558
Media:
Debra Charlesworth
BioMarin Pharmaceutical Inc.
(415) 455-7451
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