SAN RAFAEL, Calif.,
Dec. 21, 2020 /PRNewswire/ --
BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) today announced that
children in the open-label long-term extension of the Phase 3 study
of vosoritide, an investigational, once daily injection analog of
C-type Natriuretic Peptide (CNP), maintained an increase in
Annual Growth Velocity (AGV) through the second year of continuous
treatment. These analyses are the result of the combination
of data of the same patients enrolled in three consecutive
trials. In the first trial, a "run in" period consisted of
longitudinal measurement of height in all patients prior to
receiving treatment. After at least six months observation in
the run-in trial, 121 patients were randomized 1:1 to receive
either placebo or vosoritide at a dose of 15 ug/kg/day. One
year later, patients previously receiving placebo were crossed over
to receive vosoritide in an open-label treatment extension study,
while those patients previously on vosoritide remained on
treatment.
A first analysis, comparing all children randomized and
treated with vosoritide for two years (n=52) to all children from
the run-in study who were randomized to receive placebo with an
untreated observation period of two years (n=38),
showed improvement in one-year height change in the treated
group relative to the untreated group that was similar in the
second year of treatment, 1.79 cm, as in the first year of
treatment, 1.73 cm. The cumulative height gain over the 2-year
treatment period was 3.52 cm compared to untreated children, which
is the sum of the first year (1.73) and the second year
(1.79).
Yearly change in
standing height (cm)
|
Year
1
|
Year
2
|
Untreated (N=38*),
mean (SD)
|
3.96
(0.92)
|
3.82
(0.99)
|
Vosoritide
(N=52**), mean (SD)
|
5.69
(0.97)
|
5.61
(1.09)
|
Treatment effect
(95% CI)
|
1.73 (1.33 -
2.14)
|
1.79 (1.35 -
2.24)
|
P-value***
|
<0.0001
|
<0.0001
|
|
*38 participants were
enrolled in the run-in study more than 12 months and were at least
5 years of age at that point of time in advance of randomization
and therefore contribute at least two years of evaluation of height
in the absence of treatment.
**Data from 6
patients were unavailable due to patient withdrawals during Year 2
(n=2) and due to restrictions in study conduct because of Covid-19
(n=4). The patients whose data are not available due to
Covid-19 are still on treatment.
*** p-value for
unadjusted treatment effect.
|
A second supportive analysis evaluated the treatment effect of
vosoritide administered continuously for over two years, including
all children regardless of the duration of prior observation
(N=119; 58 treated and 61 untreated children). This analysis showed
a mean improvement in AGV in the vosoritide treated group of
1.69 cm/year, compared with untreated subjects, calculated over the
entire observation period. A similar method was used in the
analysis of the effect of one year's treatment with vosoritide
previously published in The Lancet on Sept.
5, 2020, demonstrating a placebo-adjusted improvement in AGV
of 1.57 cm/year. (Table 2 in Lancet publication, DOI:
https://doi.org/10.1016/S0140-6736(20)31541-5 ).
In the vosoritide treated group, AGV declined by -0.14 cm/year
during the second year of vosoritide treatment compared to the
baseline AGV established in the 6 months prior to the first year of
treatment. This decline is similar to the annual AGV decline with
age that has been observed in natural history studies, as well as
during one year of treatment with placebo (-0.12 cm/year), further
supporting the maintenance of treatment effect.
Retention of subjects on treatment was high with 93% of patients
originally randomized to receive vosoritide remaining on treatment
two years later.
Vosoritide was generally well tolerated with no new safety
concerns. Serious adverse events observed in the trial
were representative of common childhood illnesses and were deemed
unrelated to vosoritide. No new safety findings have emerged,
and clinically inconsequential blood pressure changes were mild,
transient and self-limiting.
"BioMarin is committed to the long-term follow up of children
participating in vosoritide studies and the overall health of
people with achondroplasia. We look forward to sharing more
data on wider health measures that either require a longer
treatment period or starting treatment at a younger age. We
are also specifically studying the impact of vosoritide in infants
at risk of serious and potentially fatal medical complications
related to achondroplasia," said Hank
Fuchs, M.D., President Worldwide Research and Development at
BioMarin. "We are grateful for the support of the children
and their families who are in these studies, the clinical trial
investigators and their staffs, BioMarin employees, and the
community. We look forward to sharing more detailed
information at an upcoming medical meeting and further contributing
to the scientific body of knowledge about vosoritide and its
potential impact over time."
"Follow up data from extension studies are critical to expanding
our understanding of the wider impact of achondroplasia," said
Melita Irving, Clinical Geneticist
at Guy's and St Thomas' NHS Foundation Trust, London, UK and investigator for the vosoritide
clinical program at the Evelina London Children's Hospital.
"BioMarin has developed a comprehensive clinical program designed
to address the effects on health and day to day living by
evaluating proportionality, functionality, quality of life, sleep
apnea, and foramen magnum dimension."
Vosoritide Safety
The 2-year data demonstrated that vosoritide, administered at
15ug/kg/day was generally well tolerated with no new safety
findings. The majority of adverse events (AEs) were mild and
no serious adverse events were reported as study drug-related.
Injection site reactions were the most common drug-related
AEs, and all were transient. No clinically significant blood
pressure decreases or new safety findings were observed.
Regulatory Status
BioMarin's marketing applications for vosoritide are currently
under review by both the Food and Drug Administration (FDA) and the
European Medicines Agency (EMA), and if approved would be the first
therapy for achondroplasia in the U.S. and Europe. The FDA's
Prescription Drug User Fee Act target action date is August 20, 2021. The Committee for
Medicinal Products for Human Use (CHMP) opinion is expected in
Europe in the second half of
2021.
Vosoritide has also received orphan drug designation from the
FDA and EMA for the treatment of children with achondroplasia. 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.
Robust Clinical Program
Description of Phase 3 Extension Study
This is an ongoing open-label long-term extension study to a
completed pivotal, double-blind, placebo-controlled study of
vosoritide in children with achondroplasia. A total of 119 children
were enrolled in the extension study after completion of the
pivotal phase 3 study and are receiving open-label treatment with
vosoritide 15 mcg/kg daily. Vosoritide is being tested in children
whose growth plates are still "open." This is approximately
25% of people with achondroplasia. The extension study is
evaluating safety, AGV, and cumulative annual height gain until
participants reach final adult height. A wide range of
secondary and exploratory endpoints include anthropometric measures
such as height Z-score, body and limb proportionality and joint
geometry; biochemical, biomarker and radiological assessments of
bone growth and health; and evaluations of health-related quality
of life (HRQoL), developmental status, and functional
independence. These additional endpoints address the overall
impact vosoritide has on achondroplasia.
Description of Phase 2 Study for Children at Risk of
Life-Threatening Foramen Magnum Compression
This is a Phase 2 randomized, controlled, open-label clinical
trial with an open-label extension to investigate the safety of
vosoritide in infants with achondroplasia at risk of requiring
cervicomedullary decompression surgery to alleviate compression at
the foramen magnum, the opening in the base of the skull through
which the spinal cord passes. In addition, the study will also
measure a secondary endpoint to evaluate the effect of vosoritide
on growth of the foramen magnum volume through MRI scans.
Within a month of study initiation in November, two of the planned
20 (10%) participants enrolled.
Foramen magnum compression is the foremost life-threatening
complication of achondroplasia in infants. This study investigates
the safety of vosoritide in infants aged 0 -1 years of age with
achondroplasia who have evidence of foramen magnum compression
at-risk for requiring cervicomedullary decompression surgery. Those
infants are under close observation for the appearance of
neurological signs of progressive foramen magnum compression, and
the current standard of care is palliative with many eventually
requiring surgery. The study aims to enroll approximately 20
infants, who will be randomized to either current standard of care
plus vosoritide treatment or current standard of care alone for a
two-year period. After the two-year randomized period,
children in the study would be eligible to receive vosoritide in an
open-label, 3-year additional extension period. The study will
examine the incidence of adverse events between the two
groups, volume MRI measurements of the foramen magnum, skull
and spine, and progression to requiring decompression surgery.
Description of Phase 2 Study in Infants and Young Children
Ages 0 to 5 Years
This is a Phase 2 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
three-to-six 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- and
gender-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. Currently, cohorts 1 and 2 are fully enrolled
and cohort 3 is 85% (17/20) enrolled. The remaining
study participants to enroll are in the observational period and
are expected to be dosed in 1Q 2021.
About Achondroplasia
Achondroplasia, the most common form of skeletal dysplasia
leading to disproportionate short stature in humans, is
characterized by slowing of endochondral ossification, which
results in disproportionate short stature and disordered
architecture in the long bones, spine, face and base of the
skull. This condition is caused by a change 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 the need for 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, the Middle East, and
most of Asia Pacific, 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 six 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 development program generally and
specifically about the results of the extension of the Phase 3
trial, the maintenance of AGV after two years, the similarity of
AGV and height gain in the first and second years of the Phase 3
study, the similarity of AGV and height gain to earlier studies,
the continued clinical development of vosoritide and the timing and
conduct of such clinical program; the enrollment expectations for
ongoing clinical trials; the possible results of such studies, the
timing of decisions by health authorities about marketing
applications, and the Company's plans to discuss provision of the
two-year data with health 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: final analysis
of the extension of the Phase 3 data, 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 record data during a global pandemic, 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 September 30, 2020,
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.
Contacts:
|
|
Investors
|
Media
|
Traci
McCarty
|
Debra
Charlesworth
|
BioMarin
Pharmaceutical
Inc.
|
BioMarin
Pharmaceutical Inc.
|
(415)
455-7558
|
(415)
455-7451
|
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SOURCE BioMarin Pharmaceutical Inc.