SAN RAFAEL, Calif.,
June 18, 2019 /PRNewswire/
-- BioMarin Pharmaceutical Inc. (NASDAQ:BMRN) announced that
the New England Journal of Medicine (NEJM) published online
today results from a Phase 2 dose-finding and extension study for
vosoritide, an investigational analog of C-type Natriuretic Peptide
(CNP), in children with achondroplasia. The data demonstrated that
vosoritide was generally well tolerated with a mild side effect
profile and resulted in a sustained increase in annualized growth
velocity for up to 42 months in children aged 5 to14 years with
achondroplasia, the most common form of disproportionate short
stature in humans. The results will also appear in the
July 4th printed issue.
In addition, the company announced that it had met its
enrollment goal of the first cohort (n=30) of a separate Phase 2
study of vosoritide in infants and young children ages two to five
years.
"Our research continues to investigate the potential of
vosoritide to assist in skeletal growth in children with
achondroplasia," said Ravi
Savarirayan, M.B., B.S., M.D., lead author of the NEJM study
and investigator from the Murdoch Children's Research Institute,
Royal Children's Hospital, University of
Melbourne, Parkville, Victoria,
Australia. "I am hopeful that this ongoing clinical
development program will be able to demonstrate a meaningful
difference for children with achondroplasia."
The NEJM publication described results of an ongoing open-label,
Phase 2 study in children with achondroplasia, where vosoritide
demonstrated a sustained increase in height and associated height Z
scores for up to 42 months of treatment in children in cohort 3
receiving a continuous dose of 15 µg/kg/day. Annualized growth
velocity increased from baseline in all cohorts during each
12-month interval by 1.10 to 2.34 cm/year through 42 months. In
cohort 3 (n=10) receiving 15 μg/kg continuous dosing from baseline,
the mean annualized growth velocity derived between 30 and 42
months was 5.51 cm/year representing a 1.46 cm/year (95% CI −0.15,
3.07) change from baseline. In cohort 4 (n=9) receiving 30 μg/kg
continuous dosing from baseline, the mean annualized growth
velocity between 18 and 30 months was 5.60 cm/year representing a
1.10 cm/year (95% CI −0.27, 2.48) change from baseline.
"The results published today by NEJM demonstrate the importance
of researching a therapeutic option that explicitly addresses the
underlying cause of achondroplasia," said Hank Fuchs, M.D., President, Worldwide Research
and Development at BioMarin. "The rapid completion of enrollment in
the two to five year old cohort of our ongoing infant and toddler
Phase 2 study is an important milestone for our clinical
program. We are grateful to the children and their families
for their participation in our ongoing clinical trials as we
continue to investigate important and sustained outcomes for those
with achondroplasia, as well as contribute to the body of
scientific literature on achondroplasia."
Once-daily subcutaneous administration of vosoritide was
associated with a side-effect profile that was generally mild.
Injection-site reactions were mild and transient. Blood pressure
and pulse rate were monitored frequently after the initial dose was
administered. All reductions in blood pressure from test to test
were reported as non-serious and transient and resolved without
medical intervention; none resulted in interruption or
discontinuation of the study-drug regimen. Serious adverse events
occurred in four children and included grade 3 obstructive sleep
apnea, grade 1 tonsillar hypertrophy, grade 3 thyroglossal cyst,
and grade 3 syrinx. No deaths occurred. No adverse events related
to disproportionate skeletal growth or clinically significant
adverse cardiovascular effects were observed. In addition,
there were no reports of grade 3 or higher or serious
hypersensitivity reactions.
Height Z-scores also continued to improve over 42 months and
there was proportional growth between the upper and lower body
segments. Standing height was converted to an age and sex
appropriate Z-score by comparison with Centers for Disease Control
and Prevention reference standards for average-height children.
Dose-dependent increases in height Z-scores were observed in the
children who received a dose of up to 15.0 µg/kg/day for 6 months;
those who received a dose of 30.0 µg/kg/day had a similar increase.
Vosoritide resulted in a sustained increase in height Z-score for
up to 42 months; the mean increase from baseline to 42 months was
1.03±0.57 (95% CI 0.62, 1.43) in cohort 3; the mean increase from
baseline to 30 months was 1.06±0.30 (95% CI 0.81, 1.31) in cohort
4. These improvements in Z-scores represent closure of
approximately 15-20% of the "growth gap" of 5-6 SD between
average-height and children with achondroplasia in 42 months.
Confidence intervals evaluating changes from baseline in
annualized growth velocity, Z-scores, and upper-to-lower body
segment ratio were considered descriptive and no adjustment for
multiplicity was made.
Vosoritide has been granted orphan drug designation in both
the United States and Europe.
Phase 2 Dose Finding Study
The primary objectives of the open-label, sequential cohort,
dose-finding study were to evaluate the safety and tolerability of
daily subcutaneous vosoritide and to determine the dose to carry
forward to Phase 3. Secondary objectives were to evaluate the
effects of vosoritide on change from pre-treatment baseline in
annualized growth velocity (cm/year), height Z-scores, and body
segment proportionality, the vosoritide pharmacokinetic (PK)
profile, and biomarkers of vosoritide activity, and endochondral
ossification.
Phase 2 Study in Infants and Young Children Ages 0 to 5
Years
The Phase 2 vosoritide study is a randomized, placebo-controlled
study of vosoritide in approximately 70 infants and young children
with achondroplasia, aged zero to less than 60 months, for a period
of 52 weeks. The study will be followed by a subsequent
open-label extension trial when all subjects receive active
treatment. Children in this study will have completed a minimum
three-month baseline study to determine their respective baseline
growth prior to entering the Phase 2 study. The primary objectives
of the study are to evaluate safety, tolerability, and the effect
of vosoritide on height Z-scores, which is the number of standard
deviations in relation to the mean height of age-matched, average
stature children. The company also plans to augment the height
Z-score data with assessments including proportionality,
functionality, quality of life, sleep apnea, and foramen magnum
dimension, as well as the advent of major illnesses and
surgeries.
Phase 3 Study
BioMarin expects top line results from the fully enrolled Phase
3 study of vosoritide in children by year end 2019. The
global Phase 3 study is a randomized, placebo-controlled study of
vosoritide in approximately 110 children with achondroplasia ages
five to 14 for 52 weeks. The study will be followed by a subsequent
open-label extension where all subjects receive active
treatment. Children in this study will have completed a
minimum six-month baseline study to determine their respective
baseline growth velocity prior to entering the Phase 3
study. Vosoritide is being tested in children whose growth
plates are still open. This is approximately 25% of people with
achondroplasia. The primary endpoint of the study is the
change in growth velocity from baseline over one year in children
treated compared to placebo. The company also plans to augment
the growth velocity data with assessments of proportionality and
functionality.
Lifetime Impact Studies
BioMarin is conducting lifetime impact of achondroplasia
studies in Europe (LIAISE) and
Latin America (LISA) to contribute
to the understanding of the impact of achondroplasia.
About Achondroplasia
Achondroplasia, the most common form of disproportionate short
stature in humans, 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% of people with achondroplasia. In the U.S., Europe, Latin
America and the Middle
East, there are currently no licensed medicines for
achondroplasia.
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 seven commercialized products and
multiple clinical and pre-clinical product candidates. For
additional information, please visit www.biomarin.com. Information
on such 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. (BioMarin),
including, without limitation, statements about: the development of
BioMarin's vosoritide program generally; the potential benefits of
vosoritide for infants and young children; the continued clinical
development of vosoritide; the timing, design and conduct of the
planned Phase 2 study in infants and young children and of other
ongoing and possible future studies of vosoritide; the expected
results of such studies, the ability to use the primary objectives
of the Phase 2 study to support the use of vosoritide in infants
and young children; BioMarin's expectation of top line results from
the fully enrolled Phase 3 study of vosoritide in children by year
end 2019 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 enroll
participants into such clinical trials, 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 other
risks and uncertainties detailed from time to time under the
caption "Risk Factors" and elsewhere in the BioMarin's Securities
and Exchange Commission (SEC) filings, including, without
limitation, BioMarin's Quarterly Report on Form 10-Q for the
quarter ended March 31, 2019, and
future SEC 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.
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BioMarin
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