In 8-week Placebo-Controlled Portion No Benefit
in Inattention or Mood Scores Were Observed
BioMarin announced today that the pivotal Phase 3 PRISM-2 study
(formerly referred to as 165-302) of pegvaliase met the primary
endpoint of change in blood Phe compared with placebo (p<0.0001)
in preliminary results. During the 8 week PRISM-2
double-blind, placebo-controlled, randomized drug discontinuation
trial (RDT), 86 patients were randomized to either remain on
pegvaliase or receive matching placebo. The pegvaliase
treated group maintained mean blood Phe levels at 527.2 umol/L
compared to their RDT baseline of 503.9 umol/L, whereas the placebo
treated group mean blood Phe levels increased to 1385.7 umol/L
compared to their RDT baseline of 536.0 umol/L . (see Table 1) The
treatment effect demonstrated in this study represents an
approximately 62% improvement in blood Phe compared to
placebo.
This is the first placebo controlled study demonstrating the
ability to improve Phe levels in PKU patients who at baseline do
not have to follow a Phe-restricted diet. Typically, a
Phe-restricted diet does not allow any protein intake outside of
medical food. Patients in the trial were estimated to be
eating 75% of the daily recommended allowance for protein intake
for a healthy adult.
In the secondary endpoints of the 8 week RDT, no benefit in
inattention or mood scores were observed in patients treated with
pegvaliase compared to placebo. In an exploratory sub study
of cognitive function in 9 patients, the Cambridge
Neuropsychological Test Automated Battery (CANTAB) showed trends of
improvement favoring pegvaliase. (see Table 2)
In contrast to the short term results of the RDT, supportive
evidence of the association of reduced blood Phe and improvement in
inattentiveness comes from two long term evaluations in the PRISM-1
and PRISM-2 studies. In these studies, ADHD-RS assessments
were obtained prior to treatment and at various times thereafter
(scale range 0-27 points, higher score indicating greater
impairment). In the open label PRISM-1 study (formerly
referred to as 165-301 or feeder study), 49 patients had baseline
inattention scores greater than 9 (defining patients with
inattentive symptoms at baseline). Of the 35 patients whose
Phe was reduced during PRISM-1 by greater than 20%, the mean
improvement in inattention was 7.3 points, while the 14 patients
whose Phe was reduced by less than 20% only showed an improvement
of 3.7. (see Table 3).
In the PRISM-2 study, the 72 patients were evaluated regardless
of the baseline scores. Among those who completed 41 weeks in
the open-label extension, patients were divided into quartiles
based on the magnitude of their Phe reduction from baseline.
The quartile of patients having the largest Phe reductions (to
values lower than ≥ 1,296 umol/L) had mean improvements in their
ADHD-RS inattention score of 7.5 while the patients with the
smallest Phe reductions (to values no less than <289 umol/L) had
mean improvements in the inattention score of 3.2. (See Table
4).
Practice guidelines issued by the American College of Medical
Genetics and Genomics (ACMG) support the need for lifelong
management of Phe levels in patients with phenylketonuria or
PKU. The guidelines state that the treatment goal for PKU
patients should be blood levels of phenylalanine (Phe) for all
patients between 120-360 umol/L. The Long Term open label portion
of the PRISM-2 study demonstrated sustained and substantial
reductions in Phe levels. Of the 90 patients who had been
treated for at least 41 weeks in this portion of PRISM-2, 40% had
achieved a Phe level of 120 umol/L or less (120 umol/L is
considered the upper limit of normal), 60% had achieved a Phe level
of 360 umol/L or lower (the target Phe level according to the ACMG
guidelines) and 79% had achieved a Phe level reduction of 20% or
greater.
PRISM-1 and PRISM-2 studies are the phase 3 studies evaluating
blood Phe in PKU patients treated with pegvaliase. PRISM-1
was an open-label study which enrolled and randomized pegvaliase
naïve adult PKU patients to a target dose of pegvaliase 20mg/day or
40mg/day. Patients were treated in an induction, titration,
maintenance dosing regimen to achieve stable, reduced blood Phe
levels. Patients who met a pre-specified reduction in blood
Phe of at least 20% (based on two consecutive assessments) from
their pre-treatment baseline in the PRISM-1 feeder study were
eligible to enter the RDT of the PRISM-2 study, where patients were
randomized to continue on their target dose of pegvaliase or to
receive matching placebo.
In the PRISM-2 RDT, no subjects discontinued study drug due to
adverse events and pegvaliase was generally well tolerated compared
to placebo. Pegvaliase treated patients had more
hypersensitivity adverse events (39%) as compared to placebo
(14%). During the 8 week RDT phase there were no
anaphylaxis events as defined by the broad National Institute of
Allergy and Infectious Disease and the Food Allergy and Anaphylaxis
Network (NIAID/FAAN) (Sampson’s) criteria. The most frequent
adverse events were arthralgia (pegvaliase 14% vs placebo 10%),
headache (pegvaliase 12% vs placebo 24%), fatigue (pegvaliase 11%
vs placebo 10%). In the PRISM-2 long term open label
extension, the most common adverse events were arthralgia (28%),
headache (24%), and injection site reaction (23%).
In PRISM-1, hypersensitivity adverse events and anaphylaxis as
defined by the broad NIAID/FAAN criteria were higher during the
initial treatment phase and then decreased over time as patients
reached stable dosing. Across the entire Phase 3 program,
including the PRISM-1 and the PRISM-2 studies, 8% of patients had
anaphylaxis by the broad NIAID/FAAN criteria. 48% of patients
with anaphylaxis were safely rechallenged and continued dosing with
pegvaliase without further anaphylaxis episodes.
The safety data set for all pegvaliase trials includes
approximately 550 patient years of treatment, 300 of which are from
the Phase 3 program. Approximately 190 patients have been
treated with pegvaliase for more than a year, 105 patients have
been treated for more than two years and 46 have been treated more
than three years.
These studies will be presented at the Society of Inherited
Metabolic Disorders in April of 2016.
BioMarin intends to submit a marketing application by the end of
the year subject to further discussions with the FDA.
“We are pleased that the double-blind, randomized,
placebo-controlled part of the PRISM-2 trial demonstrated strong
blood Phe reduction in pegvaliase treated patients whose dietary
protein intake was unrestricted at baseline and maintained
throughout the study. We are committed to the global PKU
community and to bringing them a medicine that has the potential to
treat PKU adult patients,” said Hank Fuchs, M.D., Chief Medical
Officer at BioMarin. “We look forward to sharing this data
with the regulatory authorities in the US and Europe to continue
the process of bringing an important therapy to patients.”
“Treatment with pegvaliase has resulted in dramatic Phe
decreases down to within normal levels which have not been
achievable in the past with other PKU treatment options. We
are grateful to the patients who participated in this important
trial. Blood Phe reductions at this level have the potential
to have a meaningful impact on the lives of PKU patients,” said
Cary Harding, M.D. Professor of Molecular and Medical Genetics and
Pediatrics at Oregon Health & Science University and
investigator for the pegvaliase Phase 3 program.
“A therapy in development that shows such a substantial
reduction in Phe levels could mean that for the first time, PKU
patients who cannot comply with dietary protein restriction, can
achieve targeted blood Phe levels,” said Barbara Burton, M.D.,
Professor of Pediatrics-Genetics, Birth Defects and Metabolism at
Northwestern School of Medicine and investigator for the pegvaliase
Phase 3 program. “This pegvaliase study represents an
important advance for PKU adult patients and a potentially
meaningful treatment.”
Table 1: Observed Blood Phe Concentration at
Treatment Naïve Baseline, Start and End of RDT (mITT
Population)
|
Treatment Naïve Baseline |
RDT Baseline |
RDT Week 8 |
|
|
|
Active |
Placebo |
N |
86 |
86 |
|
|
Mean (µmol/L) |
1306.9 |
514.3** |
527.2 |
1385.7 |
p-value* |
|
|
< 0.0001 |
|
mITT: modified intent-to-treat; Phe:
phenylalanine; RDT: randomized discontinuation trial. * P-value
from the mixed-effect model repeated measure (MMRM) model for
comparison of change in blood Phe concentration from RDT baseline
to Week 8 between the pooled active arm and the pooled placebo arm.
RDT Week 4 assessments were included in the modeling.
Table 2: Summary of Secondary Efficacy Endpoints
in RDT and Efficacy Endpoints in Exploratory Sub Study of Cognitive
Function
Study |
Efficacy Endpoints* |
Results (Active – Placebo)
|
|
|
N(Active/Placebo) |
Difference in LS Mean (95% CI) |
p-value |
RDT**(Part 2 of
165-302) |
ADHD-RS Inattention Subscale Scores(Treatment Naïve Baseline >
9) |
26 / 11 |
2.74 (-0.27, 5.75) |
0.0734 |
|
ADHD-RS Inattention Subscale Scores |
58 / 28 |
0.71 (-1.21, 2.62) |
0.4634 |
|
PKU POMS Confusion Subscale Scores |
58 / 28 |
-0.37 (-1.46, 0.73) |
0.5074 |
|
PKU POMS TMD Scores |
58 / 28 |
-0.28 (-6.05, 5.49) |
0.9226 |
|
POMS Self-rated TMD Scores |
58 / 28 |
2.87 (-10.10, 15.84) |
0.6606 |
|
|
|
|
|
Sub Study***(165-303 |
Rapid Visual Processing (RVP) Mean Response Latency |
6 / 3 |
-72 (-145, 1) |
0.0719 |
|
Stop Signal Task (SST) Stop Signal Reaction Time (ms)
|
6 / 3 |
-64 (-122, -6) |
0.0497 |
|
Spatial Working Memory (SWM)Between Errors 4-8 Boxes |
6 / 3 |
-9 (-21, 3) |
0.1377 |
ADHD-RS: attention deficit hyperactivity disorder rating scale;
CI: confidence interval; LS: least square; PKU: phenylketonuria;
POMS: profile of mood states; RDT: randomized discontinuation
trial; TMD: total mood disturbance. * Lower is
better for all efficacy endpoints. ** P-value from the
mixed-effect model repeated measure (MMRM) model for comparison of
change from RDT baseline to Week 8 between the pooled active arm
and the pooled placebo arm. RDT Week 4 assessments were included in
the modeling. *** Pooled active had a mean increase in blood Phe of
75 umol/L vs. pooled placebo had a mean increase of 1,201
umol/L.
Table 3: Change in ADHD-RS Inattention in PRISM 1
and PRISM 2 Part 1 in Subjects with Naïve Baseline Inattention
>9
|
Sample Size |
PRISM 1 BaselineMean (SD) |
PRISM 1 End of Study/PRISM 2 Part 1Mean (SD) |
Change from baseline to end of studyMean (SD) |
Patients with >20% reduction in blood Phe in PRISM-1 |
35 |
15.5 (4.18) |
8.1 (4.45) |
-7.3 (6.16) |
Patients without 20% Phe reduction in PRISM-1 |
14 |
14.0 (4.30) |
10.3 (6.27) |
-3.7 (5.01 |
Table 4: Correlation of Change from Naïve Baseline
to Open Label Extension at Week 41 between Blood Phe Concentration
and ADHD Inattention Subscale Score in PRISM 2
Reduction in Value* from Treatment Naïve
Baseline to Open Label Extension at Week
41 |
Blood Phe Concentration (µmol/L)
by Quartile (range) |
|
|
Quartile
1>1,296More
reduction |
Quartile 2(837 to 1,295) |
Quartile 3(290 to 836) |
Quartile 4<
289Less Reduction |
ADHD Inattention Subscale Score |
N = 72 |
|
|
|
|
|
Mean |
7.5 |
6.5 |
5.4 |
3.2 |
|
Min, Max |
-1, 19 |
-2, 17 |
-6, 21 |
- 7, 10 |
ADHD-RS: attention deficit hyperactivity disorder rating scale.
* Numbers with a minus sign indicate increase in value from
treatment naïve baseline to Part 4 Week 41.
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 pegvaliase 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 pegvaliase 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 pegvaliase
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 study to either continue their pegvaliase dose or to
start matching placebo. Those participants not reaching a
≥20% reduction in blood Phe from PRISM-1 baseline skipped 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 10 mg/day to 60 mg/day. Patients were evaluated for
changes in Phe levels and inattention and mood symptoms.
About Pegvaliase
Pegvaliase is an investigational study drug that substitutes the
PAH enzyme in PKU by breaking down Phe. It is being developed as a
potential treatment for adults with inadequately controlled blood
Phe levels
For additional information regarding the investigational product
pegvaliase, please contact BioMarin Medical Information at
medinfo@bmrn.com.
About Phenylketonuria or Phenylalanine Hydroxylase
Deficiency
Phenylketonuria (PKU) or phenylalanine hydroxylase (PAH)
deficiency is a genetic disorder affecting approximately 50,000
diagnosed patients in the developed world 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 or PAH deficiency under
the age of 40 in developed countries are diagnosed at birth and
treatment is implemented soon after. PAH deficiency can be managed
with a Phe-restricted diet, which is supplemented by low-protein
modified foods and Phe-free medical foods; however, the strict diet
is difficult for most patients to adhere 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.
Some of the signs and symptoms of high blood Phe include:
- For infants and children: severe intellectual disability and
developmental delay, skin rash (eczema), light-colored skin, eyes
and hair (hypopigmentation)
- For teens and adults: lower intelligence, psychological and
psychiatric symptoms like anxiety, depression and phobias, problems
with memory and performing tasks (executive function), poor
concentration and irritable mood among other things.
- For pregnant women: increased risk for the baby's growing
brain, including risk of intellectual disability, increased risk
for a small head (microcephaly) and other problems such as a heart
malformation (congenital heart defect) and poor overall growth
(intrauterine growth retardation). This teratogenic effect of Phe
on the developing fetus is called Maternal PKU syndrome.
About ACMG Guidelines
Practice guidelines issued by the American
College of Medical Genetics and Genomics (ACMG) support the need
for lifelong management of Phe levels in patients with
phenylketonuria or PKU. The new diagnosis and management
guidelines were published online in Genetics In Medicine’s Advance
Online Publication (AOP) service and provide the first update to
recommendations for therapy of PKU since the 2001 National
Institutes of Health Consensus statement.
The guidelines state that treatment of PKU
should be initiated as early as possible and must be continued
throughout adulthood and “lifelong,” with a goal of maintaining
blood levels of Phe for all patients between 120-360 umol/L.
Patients treated from the early weeks of life with initial good
metabolic control, but who lose that control in later childhood or
adult life, may experience both reversible and irreversible
neuropsychiatric consequences.
According to the guidelines “the primary goal of
therapy is to lower blood Phe, and any interventions, including
medications, or combination of therapies that help to achieve that
goal in an individual, without other negative consequences, should
be considered appropriate therapy.”
Evidence for the guidelines are drawn from two
previous independent review processes from the National Institutes
of Health (2001) and the Agency for Health Research and Quality
(2012). The guidelines can be accessed online at:
https://www.acmg.net/docs/Phenylalanine_Hydrosylase_Deficiency_Practice_Guideline_AOP_Jan_2013.pdf
Conference Call Details
BioMarin will host a conference call and live
audio webcast today at 5:30am PDT/8:30am EDT to discuss Phase 3
results with pegvaliase. The live audio webcast will be
available via the Investors and Media section of the BioMarin
Pharmaceutical website at www.BMRN.com. Interested parties
may now access the PowerPoint presentation that will be used for
the call at the same URL. A replay will be available for one
week following the call.
U.S. / Canada Dial-in Number: (877)
303-6313International Dial-in Number: (631) 813-4734Conference ID:
71342573
Replay Dial-in Number: (855) 859-2056Replay
International Dial-in Number: (404) 537-3406Conference ID:
71342573
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: BioMarin's development
programs for pegvaliase generally, and specifically about the
results of the Phase 3 pivotal trial and an ongoing extension study
of pegvaliase. 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 PRISM 1 and PRISM 2 trial
data; results and timing of current and planned clinical trials of
pegvaliase; the content and timing of decisions by the U.S. Food
and Drug Administration, the European Medicines Agency and other
regulatory authorities; our ability to manufacture sufficient
quantities of pegvaliase for clinical trials, commercial launch and
other preapproval requirements; 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, as amended, and the factors contained in BioMarin's reports
on Form 8-K. 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 trademarks 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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