New Data Shows Durable and Consistent Effects on
Mean Annualized Growth Velocityfor up to 12 months with Increases
of 46%-65% from Baseline
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. After 12 months of daily dosing at 15
µg/kg/day, the cohort 3 patients (n=10) experienced a 46% or 1.9
cm/year increase in mean annualized growth velocity from baseline
(p-value = 0.02). (See Table 2). These findings provide
evidence of durability of effect consistent with previously
presented 6-month data for these patients, which demonstrated an
annualized increase of 50% or 2.0 cm/year in mean annualized growth
velocity. In addition, 6-month data for 12 patients who were
initiated on a lower dose and switched to 15 µg/kg/day showed an
increase of 65% or 2.3 cm/year in mean annualized growth velocity
from baseline (p-value = 0.002).
Vosoritide at 15 µg/kg/day was well tolerated and
there were no treatment-related serious adverse events or adverse
events leading to discontinuation. Consistent with the
initial 6-month data, in the newly released data, all adverse
events assessed as related to study drug were mild to
moderate. Over 12 months of dosing at 15 µg/kg/day, injection
site reactions and hypotension (asymptomatic decreases in blood
pressure) were the most common drug related adverse events,
reported by 90% and 40% of cohort 3 patients, respectively.
All injection site reaction events were mild and the majority were
resolved in one hour. All adverse events of hypotension were
mild, transient and resolved without intervention. Safety
data from lower dose cohort subjects who increased their dose to 15
µg/kg/day for at least 6 months was generally comparable to the
12-month safety data; however, two subjects experienced symptomatic
events associated with a decrease in blood pressure, only one of
which was deemed by the investigator to be related to study
drug. Both subjects continued to receive their daily dose of
vosoritide without dose modification. The phase 2 study is
also evaluating a higher dose of 30 ug/kg/day. Preliminary
data after several months of treatment has shown that this dose is
similarly well tolerated with no new safety findings.
A consistent effect in increasing urinary cyclic
guanosine monophosphate (cGMP), a urinary pharmacodynamic
biomarker, provides further evidence of durable pharmacologic
activity of the 15 µg/kg/day dose over the 12-month observation
period in cohort 3.
“We’re encouraged by the consistency of the data
from six to 12 months in both safety and efficacy, and plan to
initiate a Phase 3 study by the end of the year,” said Hank Fuchs,
MD, Chief Medical Officer at BioMarin. “By addressing the
root cause of achondroplasia with vosoritide treatment and
normalizing annualized growth velocity in children with
achondroplasia, we ultimately hope to improve the medical
complications of disproportionate bone growth.”
“Children with achondroplasia are likely to experience a variety
of medical complications caused by the condition,” said Ravi
Savarirayan, M.D., Ph.D. Professor, Department of Paediatrics,
University of Melbourne and Lead Investigator for the vosoritide
Phase 2 study. “A treatment like vosoritide has the potential
to decrease medical complications and to increase function and
quality of life.”
While the Phase 2 efficacy endpoint centers on mean annualized
growth velocity, BioMarin hopes that that longer treatment may lead
to improvement in many of the complications that can be associated
with achondroplasia, such as disproportionality, though longer
time of treatment and/or a controlled study may be required to
demonstrate this effect.
By the end of 2016, BioMarin is planning to
initiate a single Phase 3 randomized controlled study over 12
months in children with achondroplasia ages 5-14 with a subsequent
long-term open-label extension subject to discussions with
regulatory authorities. 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: Subject Disposition and
Demographics
Category |
Cohort 3 (n=10) |
Cohorts 1 and 2 (n=12)* |
Subjects Enrolled and Treated at 15 µg/kg/day |
10 (100 %) |
12 (100% |
Subjects Who Completed 6 Months at 15 µg/kg/day |
10 (100%) |
12 (100%) |
Subjects Who Completed 12 Months at 15 µg/kg/day |
10 (100%) |
N/A |
Age (years) at Enrollment |
|
|
Mean (SD) |
8.0 (1.63) |
7.6 (1.88) |
Min, Max |
6, 11 |
5, 10 |
Gender (n, %) |
|
|
Male |
4 (40%) |
6 (50%) |
Female |
6 (60%) |
6 (50%) |
*Subjects 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)
Table 2: Vosoritide Summary of
Efficacy Results from Phase 2 Study in Children with
Achondroplasia
Efficacy Analysis: Annualized Growth
Velocity |
Time Point |
6 Months |
12 Months ** |
6 Months |
Annualized Growth Velocity |
Cohort 315
µg/kg/daily(n=10) |
Cohort 3 15
µg/kg/daily(n=10) |
Cohorts 1, 215
µg/kg/daily(n=12) |
Baseline |
|
|
|
Mean (SD), cm/Year |
4.0 (2.3) |
4.0 (2.3) |
3.6 (0.96) |
Median |
|
4.1 |
|
|
4.1 |
|
|
3.5 |
|
Post-Treatment |
|
|
|
|
|
|
|
Mean, (SD), cm/year |
6.1 (1.1) |
5.9 (0.92) |
5.9 (1.6) |
Median |
|
5.9 |
|
|
5.6 |
|
|
5.6 |
|
Change from Baseline |
|
|
|
|
|
|
|
Mean (SD), cm/year |
2.0 (2.0) |
1.9 (2.0) |
2.3 (1.9) |
Nominal
p-value* |
0.01 |
0.02 |
0.002 |
Percent increase from Baseline |
|
50 |
% |
|
46 |
% |
|
65 |
% |
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
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 three dose cohort study,
patients were treated with either 2.5 µg/kg/daily, 7.5 µg/kg/ daily
or 15 µg/kg/ daily, respectively. A total of 26 children with
achondroplasia with an average age of 7.8 years were enrolled in
the study. Based on the safety profile observed to date
across the three dose cohorts, all subjects participating in the
Phase 2 study were offered the dose of 15 µg/kg/daily during the 18
month extension study. An additional 9 patients were enrolled into
a fourth cohort of 30 µg/kg/daily at the end of last year and
initial growth velocity data from this cohort will be reported
later this year.
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.[i][ii]
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, per the World
FactBook 2014 edition which translates into approximately 96,000
potential patients. 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 final results 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.
[i] Hecht JT, Francomano CA, Horton WA, Annegers JF. Am J Hum
Genet. 1987; 41: 454-464.
[ii] Wynn J, King TM, Gabello MJ, Waller DK, Hecht JT. Am J Med
Genet A. 2007; 143A: 2502-2511.
Contact:
Investors:
Traci McCarty
BioMarin Pharmaceutical Inc.
(415) 455-7558
Media:
Debra Charlesworth
BioMarin Pharmaceutical Inc.
(415) 455-7451
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