SAN RAFAEL, Calif.,
May 6, 2019 /PRNewswire/ -- BioMarin
Pharmaceutical Inc. (Nasdaq:BMRN) today announced that the European
Commission (EC) has granted marketing authorization for Palynziq®
(pegvaliase injection) at doses of up to 60 mg once daily, to
reduce blood phenylalanine (Phe) concentrations in patients with
phenylketonuria (PKU) aged 16 and older, who have inadequate
blood Phe control (blood Phe levels greater than 600 micromol/L)
despite prior management with available treatment options.
Palynziq, a PEGylated recombinant phenylalanine ammonia lyase
enzyme, is the first enzyme substitution therapy approved in
Europe to target the underlying
cause of PKU by helping the body to break down Phe. In
addition, the EC acknowledged that the Phase 3 trial and extension
study is suggestive of an improvement in inattention and mood
symptoms.
On March 1, 2019 BioMarin
announced that the Committee for Medicinal Products for Human Use
(CHMP), the scientific committee of the European Medicines Agency
(EMA), adopted a positive opinion for the company's Marketing
Authorization Application (MAA) for Palynziq. This is BioMarin's
second approved treatment for this rare genetic disease.
PKU is a rare genetic disease that manifests at birth and
results in a variety of cumulative toxic effects on the brain and
is marked by an inability to break down Phe, an amino acid that is
found in most forms of protein. PKU affects approximately
50,000 diagnosed patients in the developed world, and in
Europe, approximately 1 in every
10,000 newborn babies are affected by this disease.I
Approximately 18,000 patients aged 16 and older are affected by PKU
in Europe and the Middle
East. Left untreated, high levels of Phe become toxic to the
brain and may lead to serious neurological and
neuropsychiatric-related issues, affecting the way a person thinks,
feels, and acts. Due to the seriousness of these symptoms, in many
countries, infants are screened at birth to ensure early diagnosis
and treatment to avoid intellectual disability and other
complications. According to EU treatment guidelines, PKU patients
should maintain lifelong control of their Phe levels.
"The approval of Palynziq is the latest milestone after more
than 15 years of an ongoing commitment to the PKU community.
BioMarin has brought the only two approved therapies for PKU to
patients around the world, and we will continue to draw on our
expertise in PKU to advance the standard of care in this serious
rare disease," said Jean-Jacques Bienaimé, chairman and chief
executive officer of BioMarin. "Today would not be possible without
the efforts of our employees, partners in Europe, patients, families and
clinicians. We thank the European Commission for recognizing
the vast potential benefits of Palynziq for patients affected by
PKU."
"Palynziq is a new and promising treatment for the PKU
community," said Dr. Amaya Bélanger-Quintana, Head of the Metabolic
Department of the University Hospital Ramon y Cajal, Madrid, Spain. "Many adult PKU patients
struggle daily with their special diet, leading many of them to
relax or stop their treatment despite knowing the
negative consequences this will have on to their well-being.
Palynziq provides a new opportunity for adult PKU patients to
attain the metabolic control their doctors and they want for
themselves."
On May 24, 2018, the U.S. Food and
Drug Administration (FDA) approved Palynziq®
(pegvaliase-pqpz) Injection to reduce blood Phe concentrations in
adult patients with PKU, who have uncontrolled blood Phe
concentrations greater than 600 µmol/L on existing
management.
The Palynziq EC approval was based on the totality of data from
the Palynziq clinical development program including a Phase 3
pivotal study, PRISM-2, which showed that a group of patients
taking either 20 mg or 40 mg of Palynziq maintained mean blood Phe
levels at 553.0 µmol/L and 566.3 µmol/L respectively after eight
weeks, compared to their baseline in the randomized discontinuation
trial (RDT) of 596.8 µmol/L and 410.9 µmol/L. The corresponding 20
mg and 40 mg placebo treated groups mean blood Phe levels returned
to pre-treatment baseline levels of 1509.0 µmol/L and 1164 µmol/L
compared to their RDT baselines of 563.9 µmol/L and 508.2 µmol/L
respectively, the EU Summary of Product Characteristics (SmPC)
allows for daily doses up to 60mg. The 8-week PRISM-2
double-blind, placebo-controlled, randomized drug discontinuation
trial (RDT) consisted of 86 patients who were randomized to either
remain on Palynziq or receive matching placebo.
The approval was also based on data from an ongoing open-label
extension study at 36 months, where patients being treated with
Palynziq showed a sustained reduction in mean blood Phe over time,
durability of response and an increase in participants reaching
important blood Phe thresholds. Mean blood phenylalanine levels
reduced from 1233 micromol/l at baseline to 565 micromol/l at Month
12 (n=164) and 345 micromol/l at Month 24 (n =90), and these
reductions in mean blood phenylalanine levels were maintained
through Month 36 (341 micromol/l; n =48). At 36 months, 66%
reached Phe levels of ≤360 µmol/L and 72% reached Phe levels of
≤600 µmol/L (the recommended treatment target in the EU).
These results were observed concurrent with a median increase in
protein intake from intact food of 25g over baseline after 36
months on treatment. In addition, the data collected in the Phase 3
trial and extension study was suggestive of an improvement in
inattention and mood symptoms as measured by the inattention
subscale of the investigator-rated Attention Deficient
Hyperactivity Disorder Rating Scale (ADHD-RS IV) and the Profile of
Mood States (POMS) tool that was modified to be specific to PKU
(PKU-POMS).
Phase 3 Study Design
The Phase 3 program consists of two studies. PRISM-1 study
was a Phase 3 open-label, randomized, multi-center study that
enrolled 261 patients, and its primary objective was to
characterize the safety and tolerability of Palynziq during
induction, titration, and maintenance dosing. The secondary
objective of the study was to evaluate blood Phe levels during
induction, titration, and maintenance dosing to achieve a target
dose of Palynziq 20mg/day or 40mg/day.
215 patients who completed PRISM-1 or PAL-003 (Phase 2 long term
extension) enrolled into PRISM-2, which included a randomized,
double-blind, placebo-controlled discontinuation study to evaluate
the efficacy and safety of subcutaneous injections of Palynziq
self-administered by adults with PKU, followed by an open-label
extension. The primary efficacy endpoint is change from the
RDT baseline in blood Phe at eight weeks.
Patients who reached a target dose and achieved ≥20% decrease in
blood Phe from PRISM-1 baseline were randomized into the RDT
portion of the PRISM-2 study to either continue their Palynziq dose
or to start matching placebo. Those participants not reaching
a ≥20% reduction in blood Phe from PRISM-1 baseline did not match
the inclusion criteria for the RDT and enrolled into the open label
extension portion of the study. In the open-label extension,
physicians were allowed to modify dose based on blood Phe response
using a range of doses from 5 mg/day to 60 mg/day. Patients were
evaluated for safety, changes in Phe levels and neurocognitive
assessments focused on inattention and mood symptoms.
About Phenylketonuria
PKU, or PAH deficiency, is a genetic disorder affecting
approximately 50,000 diagnosed patients in the regions of the world
where BioMarin operates and is caused by a deficiency of the enzyme
PAH. This enzyme is required for the metabolism of Phe, an
essential amino acid found in most protein-containing foods. If the
active enzyme is not present in sufficient quantities, Phe
accumulates to abnormally high levels in the blood and becomes
toxic to the brain, resulting in a variety of complications
including severe intellectual disability, seizures, tremors,
behavioral problems and psychiatric symptoms. As a result of
newborn screening efforts implemented in the 1960s and early 1970s,
virtually all individuals with PKU under the age of 40 in countries
with newborn screening programs are diagnosed at birth and
treatment is implemented soon after. PKU can be managed with a
Phe-restricted diet, which is supplemented by low-protein modified
foods and Phe-free medical foods; however, it is difficult for most
adult patients to adhere to the strict diet to the extent needed
for achieving adequate control of blood Phe levels.
To learn more about PKU and PAH deficiency, please visit
www.PKU.com. Information on this website is not incorporated by
reference into this press release.
About Palynziq
Palynziq substitutes the deficient phenylalanine
hydroxylase (PAH) enzyme in PKU with the PEGylated version of the
enzyme phenylalanine ammonia lyase to break down Phe.
Palynziq is administered using a dosing regimen designed to
facilitate tolerability; Palynziq's safety profile consists
primarily of immune-mediated responses, including anaphylaxis, for
which robust risk management measures effective in clinical trials
are in place.
The dosing and administration of Palynziq follows an induction,
titration, and maintenance paradigm. Periodic blood Phe monitoring
is recommended, and patients should be counseled on how to adjust
their dietary intake, as needed, based on blood Phe
concentrations.
U.S. FDA-Approved Indication
PALYNZIQ® (pegvaliase-pqpz) Injection is
a phenylalanine-metabolizing enzyme indicated to reduce blood
phenylalanine concentrations in adult patients with phenylketonuria
(PKU) who have uncontrolled blood phenylalanine concentrations
greater than 600 µmol/L on existing management.
Important Safety Information
BOXED WARNING: RISK OF ANAPHYLAXIS
- Anaphylaxis has been reported after administration of
PALYNZIQ and may occur at any time during treatment with
PALYNZIQ.
- Administer the initial dose of PALYNZIQ under the
supervision of a healthcare provider equipped to manage
anaphylaxis, and closely observe patients for at least 60 minutes
following injection. Prior to self-injection, confirm patient
competency with self-administration, and patient's and observer's
(if applicable) ability to recognize signs and symptoms of
anaphylaxis and to administer auto-injectable epinephrine, if
needed.
- Prescribe auto-injectable epinephrine to all patients
treated with PALYNZIQ. Prior to the first dose, instruct the
patient and observer (if applicable) on its appropriate use.
Instruct the patient to seek immediate medical care upon its use.
Instruct patients to carry auto-injectable epinephrine with them at
all times during treatment with PALYNZIQ.
- PALYNZIQ is available only through a restricted program
under a Risk Evaluation and Mitigation Strategy (REMS) called the
PALYNZIQ REMS. Further information, including a list of
qualified pharmacies, is available at www.PALYNZIQREMS.com or
by telephone 1-855-758-REMS (1-855-758-7367).
WARNINGS AND PRECAUTIONS
Anaphylaxis
- Signs and symptoms of anaphylaxis reported include syncope,
hypotension, hypoxia, dyspnea, wheezing, chest discomfort/chest
tightness, tachycardia, angioedema (swelling of face, lips, eyes,
tongue), throat tightness, skin flushing, rash, urticaria,
pruritus, and gastrointestinal symptoms (vomiting, nausea,
diarrhea).
- Anaphylaxis generally occurred within 1 hour after injection;
however, delayed episodes occurred up to 48 hours after PALYNZIQ
administration.
- Consider having an adult observer for patients who may need
assistance in recognizing and managing anaphylaxis during treatment
with PALYNZIQ. If an adult observer is needed, the observer should
be present during and for at least 60 minutes after administration
of PALYNZIQ, and should be able to administer auto-injectable
epinephrine and call for emergency medical support upon its
use.
- Anaphylaxis requires immediate treatment with auto-injectable
epinephrine. Prescribe auto-injectable epinephrine to all patients
receiving PALYNZIQ and instruct patients to carry auto-injectable
epinephrine with them at all times during treatment with PALYNZIQ.
Prior to the first dose, instruct the patient and observer (if
applicable) on how to recognize the signs and symptoms of
anaphylaxis, on how to properly administer auto-injectable
epinephrine, and to seek immediate medical care upon its
use. Consider the risks associated with auto-injectable
epinephrine use when prescribing Palynziq. Refer to the
auto‑injectable epinephrine prescribing information for complete
information.
- Consider the risks and benefits of readministering PALYNZIQ
following an episode of anaphylaxis. If the decision is made to
readminister PALYNZIQ, administer the first dose under the
supervision of a healthcare provider equipped to manage anaphylaxis
and closely observe the patient for at least 60 minutes following
the dose. Subsequent dose titration of PALYNZIQ should be based on
patient tolerability and therapeutic response.
- Consider premedication with an H1-receptor
antagonist, H2-receptor antagonist, and/or antipyretic
prior to administration of PALYNZIQ based upon individual patient
tolerability.
Other hypersensitivity reactions
- Hypersensitivity reactions other than anaphylaxis have been
reported in 196 of 285 (69%) patients treated with PALYNZIQ.
- Consider premedication with an H1-receptor
antagonist, and/or antipyretic prior to PALYNZIQ administration
based upon individual patient tolerability.
- Management of hypersensitivity reactions should be based on the
severity of the reaction, recurrence of the reaction, and the
clinical judgment of the healthcare provider, and may include
dosage adjustment, temporary drug interruption, drug
discontinuation, or treatment with antihistamines, antipyretics,
and/or corticosteroids.
ADVERSE REACTIONS
- The most common adverse reactions (at least 20% of patients in
either treatment phase) were injection site reactions, arthralgia,
hypersensitivity reactions, headache, generalized skin reaction
lasting at least 14 days, pruritus, nausea, abdominal pain,
oropharyngeal pain, vomiting, cough, diarrhea, and fatigue.
- Of the 285 patients exposed to PALYNZIQ in an
induction/titration/maintenance regimen in clinical trials, 31
(11%) patients discontinued treatment due to adverse reactions. The
most common adverse reactions leading to treatment discontinuation
were hypersensitivity reactions (6% of patients)—including
anaphylaxis (3% of patients) and angioedema (1% of
patients)—arthralgia (4% of patients), generalized skin reactions
lasting at least 14 days (2% of patients), and injection site
reactions (1% of patients)
- The most common adverse reactions leading to dosage reduction
were arthralgia (14% of patients), hypersensitivity reactions (9%
of patients), injection site reactions (4% of patients), alopecia
(3% of patients), and generalized skin reactions lasting at least
14 days (2% of patients)
- The most common adverse reactions leading to temporary drug
interruption were arthralgia (13% of patients), hypersensitivity
reactions (13% of patients), anaphylaxis (4% of patients), and
injection site reactions (4% of patients)
Blood Phenylalanine Monitoring and Diet
- Obtain blood phenylalanine concentrations every 4 weeks
until a maintenance dosage is established.
- After a maintenance dosage is established, periodically monitor
blood phenylalanine concentrations.
- Counsel patients to monitor dietary protein and phenylalanine
intake, and adjust as directed by their healthcare provider.
DRUG INTERACTIONS
Effect of PALYNZIQ on other PEGylated products
- In a single dose study of PALYNZIQ in adult patients with PKU,
2 patients receiving concomitant injections of medroxyprogesterone
acetate suspension (a formulation containing PEG 3350) experienced
hypersensitivity reactions, and 1 of the 2 patients also
experienced anaphylaxis.
- The clinical effects of concomitant treatment with different
PEGylated products is unknown. Monitor patients treated with
PALYNZIQ and concomitantly with other PEGylated products for
hypersensitivity reactions.
USE IN SPECIFIC POPULATIONS
Pregnancy and Lactation
- PALYNZIQ may cause fetal harm when administered to a pregnant
woman.
- If PALYNZIQ is administered during pregnancy, or if a patient
becomes pregnant while receiving PALYNZIQ or within 1 month
following the last dose of PALYNZIQ, healthcare providers should
report PALYNZIQ exposure by calling 1-866-906-6100.
- Monitor blood phenylalanine concentrations in breastfeeding
women treated with PALYNZIQ.
Pediatric use
- The safety and efficacy of PALYNZIQ in pediatric patients have
not been established.
Geriatric Use
- Clinical studies of PALYNZIQ did not include patients aged 65
years and older.
You are encouraged to report side effects to report suspected
adverse events to BioMarin at 1-877-695-8826 and the FDA at
1-800-FDA-1088 or www.fda.gov/medwatch.
Please see
full Prescribing Information, including Boxed Warning, at
PALYNZIQ.com/hcp.
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., including,
without limitation, statements about: the potential benefits and
commercial availability of Palynziq® (pegvaliase injection),
BioMarin continuing to advance the standard of care in PKU and the
data collected in the Phase 3 trial and extension study being
suggestive of an improvement in inattention and mood symptoms.
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, risks related to: uncertainties inherent in research and
development, including unfavorable new clinical data and additional
analyses of existing clinical data; the results and timing of
current and future clinical trials related to Palynziq; the risks
related to commercialization of Palynziq and our ability to
manufacture sufficient quantities of Palynziq; and those other
risks detailed from time to time under the caption "Risk Factors"
and elsewhere in the Company's Securities and Exchange Commission
(SEC) filings including the Current Report on Form 10-Q for the
quarter ended March 31, 2019, and
future filings and reports by the Company. The Company undertakes
no duty or obligation to update any forward-looking statements
contained in this Current Report on Form 8-K as a result of new
information, future events or changes in its expectations.
BioMarin® and Palynziq® are registered trademarks of BioMarin
Pharmaceutical Inc.
I van Wegberg AMJ, MacDonald A, Ahring K, et al. The
complete European guidelines on phenylketonuria: diagnosis and
treatment. Orphanet J Rare Dis. 2017;12(1):162. Published 2017 Oct
12. https://doi.org/10.1186/s13023-017-0685-2. Last accessed:
May 2019
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