1. No category

Evaluation of Multiple Dosing Regimens in Phase 2 Studies of rAvPAL-PEG (BMN 165, Pegvaliase)
for Control of Blood Phenylalanine Levels in Adults with Phenylketonuria
Janet A. Thomas1, Nicola Longo2, Roberto Zori3, Barbara K. Burton4, Melissa Wasserstein5, Dorothy K. Grange6, Jerry Vockley7, Richard Hillman8, Cary Harding9, Natasha Shur10,
Darius Adams11, Gregory M. Rice12, William B. Rizzo13, Chester Whitley14, Kara M. Goodin15, Kim L. McBride16, Celeste Decker17, Markus Merilainen17, Mingjin Li17,
Becky Schweighardt17, David P. Dimmock18
1
University of Colorado, Aurora, CO, USA; 2University of Utah, Salt Lake City, UT, USA; 3University of Florida, Gainesville, FL, USA; 4Ann and Robert Lurie Children’s Hospital of Chicago, Chicago, IL, USA; 5Mount Sinai Hospital, New York, NY, USA; 6St. Louis Children’s Hospital,
St. Louis, MO, USA; 7Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA; 8University of Missouri, Columbia, MO, USA; 9Oregon & Health Science University, Portland, OR, USA; 10Albany Medical College, Albany NY, USA; 11Goryeb Children’s Hospital, Morristown, NJ, USA;
12
University of Wisconsin, Madison WI, USA; 13Nebraska Medical Center, Omaha, NE, USA; 14University of Minnesota, Minneapolis, MN, USA; 15Weisskopf Child Evaluation Center, Louisville, KY, USA; 16Nationwide Children’s Hospital, Columbus, OH, USA;
17
BioMarin Pharmaceutical Inc., Novato, CA, USA; 18Medical College of Wisconsin, Milwaukee, WI, USA
BACKGROUND
RESULTS
PAL-002: Mean Blood Phe Levels and
Weekly Dose Over Time
METHODS
PAL-004: Blood Phe Levels and Weekly
Dose Over Time
• Weekly doses in the PAL-002 study were not adequate to achieve substantial Phe reductions over 16 weeks.
• Error bars represent standard deviation.
• Substantial mean blood Phe reduction (-929 ± 691 µmol/L) was observed at Week 2.
• However, the higher frequency of HAEs compared to PAL-002 led to modified dosages and unsustained Phe reductions in
the majority of subjects.
• Error bars represent standard deviation.
PAL-002: Adverse Events Summary
PAL-004: Adverse Events Summary
Baseline Demographics
SAFETY SUMMARY
•Although AEs and HAEs occurred in all subjects,
most were mild to moderate in severity.
•Two subjects in PAL-002 discontinued pegvaliase
due to AE (grade 1 skin reaction and grade 1
arthralgia) and one subject in PAL-004 discontinued
pegvaliase due to AE (grade 2 angioedema).
Hypersensitivity Adverse Events (HAEs)
Defined per broad algorithmic anaphylactic reaction Standardized MedDRA Query(SMQ)
and modified hypersensitivity SMQ (including arthralgia, arthritis, eye inflammation, eye
irritation, eye pain, joint stiffness, joint swelling, pyrexia, vision blurred, and polyarthritis)
*Related per investigator assessment.
**Grade 3 hypersensitivity and grade 3 dehydration; neither led to discontinuation of study or study drug.
***Identified per High level term (HLT) search of injection site reaction.
PAL-002: Common Drug-Related Adverse Events
Inclusion Criteria
*Related per investigator assessment
**Grade 2 angioedema which resolved, but led to study drug discontinuation.
***Identified per High level term (HLT) search of injection site reaction.
PAL-004: Common Drug-Related Adverse Events
Adverse Events Related to Study Drug in ≥ 10% (≥ 4) of Subjects
Adverse Events Related to Study Drug in ≥ 25% (≥ 4) of Subjects
•Analysis of hypersensitivity AEs using NIAID/FAAN
criteria to identify events consistent with
anaphylaxis revealed 4 events in PAL-002 and 5
events in PAL-004. All of these events resolved
and none led to early drug discontinuation.
•Similar to PAL-002, injection site reactions were
common in PAL-004; however, the most common
AE in PAL-004 was arthralgia in 69% of subjects.
•In both studies, all subjects developed anti-PAL
antibodies and the majority of subjects developed
anti-PEG antibodies.
CONCLUSIONS
•Dose regimens in the early Phase 2 studies
PAL-002 (0.001 to .0.1 mg/kg/week) and PAL-004
(0.06 to 0.8 mg/kg/day), were not adequate to
attain optimal blood Phe reduction.
Related per investigator assessment.
PAL-002: Hypersensitivity Adverse Events
versus Antibody Positivity Incidence Rate
Related per investigator assessment.
PAL-004: Hypersensitivity Adverse Events
versus Antibody Positivity Incidence Rate
Subject Disposition
•Dosing was generally well tolerated in PAL-002,
but the higher starting doses in PAL-004 resulted in
more frequent HAEs requiring dose reductions.
•The majority of subjects from both studies enrolled
in the PAL-003 long-term extension study and later
achieved substantial Phe reduction.
•Results from these studies contributed to the
design of the late Phase 2 study 165-205 with a
fixed induction, titration and maintenance
schedule designed to improve efficacy while
decreasing HAEs.
* PAL-002 discontinuations: 1 due to AE, 1 lost to follow-up, 1 other (went to college);
PAL-004 discontinuation: 1 withdrew consent.
PRESENTED AT THE SIMD ANNUAL MEETING: MARCH 28-31, 2015 SALT LAKE CITY, UTAH
ACKNOWLEDGMENTS
•
•
•
•
All patients developed anti-PAL Ab responses and majority develop anti- PEG Ab responses.
Few patients tested positive for Neutralizing Antibodies (NAb).
No correlation between Ab positivity or titer level and HAE occurrence.
Very few IgE positives and no correlation to hypersensitivity AEs including anaphylaxis.
•
•
•
•
All patients developed anti-PAL Ab responses and majority develop anti- PEG Ab responses.
Few patients tested positive for Neutralizing Antibodies (NAb).
No correlation between Ab positivity or titer level and HAE occurrence.
Very few IgE positives and no correlation to hypersensitivity AEs including anaphylaxis.
• The authors thank the patients and physicians who participated in this
study. BioMarin Pharmaceutical Inc. provided funding for the study,
data analysis, writing, editing, and poster production.
http://www.bmrn.com/pdf/SIMD2015p1.pdf
A Randomized, Placebo-Controlled, Double-Blind Study of Sapropterin to Treat Symptoms of
ADHD and Executive Dysfunction in Children and Adolescents with Phenylketonuria
Mitzie L. Grant1, Jessica L. Cohen-Pfeffer2 (co-first authors), Shawn E. McCandless3, Stephen M. Stahl4, Deborah A. Bilder5, Elaina R. Jurecki2, Shui Yu2, Amarilis Sanchez-Valle6, David Dimmock7
Departments of Psychiatry and Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA; 2Medical Affairs, BioMarin Pharmaceutical Inc., Novato, CA, USA; 3Department of Genetics, Case Western Reserve University, Cleveland, OH, USA;
4
Department of Psychiatry, University of California, San Diego, School of Medicine, La Jolla, CA, USA; 5Medical Division of Child and Adolescent Psychiatry, Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah, USA; 6Department of Pediatrics,
Morsani College of Medicine, Tampa, FL, USA; 7Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
1
PURPOSE
A sub-analysis to determine the impact of sapropterin
therapy on Attention Deficit Hyperactive Disorder (ADHD)
symptoms and Executive Function deficits in a pediatric
PKU population.
B. Burton, et al., A randomized, placebo-controlled, double-blind study of sapropterin to treat ADHD symptoms
and executive function impairment in children and adults with sapropterin-responsive phenylketonuria, Mol.
1
Genet. Metab. (2014), http://dx.doi.org/10.1016/j.ymgme.2014.11.011
Mean Blood Phenylalanine Concentration:
Randomization (Baseline through Week 13) and
Open label Phase
• Percentages are blood Phe change from baseline
• Error bars represent 95% Confidence Intervals
• Sapropterin group N= 42; Placebo group N=40. Patients with missing data for any study visit are omitted (N=3 placebo
group, N=1 sapropterin group)
ADHD-RS Total Score
Mean Change Difference from Baseline to Week 13 and Baseline to Week 26
Mean Change Difference of Sapropterin Group from
Placebo ADHD-RS scores between Baseline and Week 13
Mean Change Difference of Sapropterin Group from
Placebo BRIEF T-scores between Baseline and Week 13
• All patients with a mean reduction of ≥ 20% in blood Phe after beginning sapropterin treatment, calculated as the
difference between the mean of the baseline and screening blood Phe values and the mean of the three lowest blood
Phe concentrations during the first four weeks after initiating sapropterin treatment.
• Insufficient (N=3) non-responders for statistical analysis.
• All patients with a mean reduction of ≥ 20% in blood Phe after beginning sapropterin treatment, calculated as the
difference between the mean of the baseline and screening blood Phe values and the mean of the three lowest blood
Phe concentrations during the first four weeks after initiating sapropterin treatment.
• Insufficient (N=3) non-responders for statistical analysis.
Adverse Events > 5% of Subjects
Week 0 to Week 13 – Blinded Randomized Treatment Period
BRIEF Global Executive Function (GEC)
Mean Change Difference from Baseline to Week 13 and Baseline to Week 26
(T-Score=50 Denotes Normative Group Mean)
NEUROCOGNITIVE ASSESSMENTS
(PARENT REPORT MEASURES)
●●Attention Deficit Hyperactivity Disorder - Rating
Scale (ADHD-RS)
- Total ADHD symptom score, composed of:
•Inattentive subscale
•Hyperactivity subscale
- Higher values represent more severe ADHD symptoms
●●Behavior Rating Inventory of Executive Function
(BRIEF)
- Global Executive Composite (GEC), composed of:
•Behavioral Regulation Index (BRI)
•Metacognition Index (MI)
- Standardized T-scores with mean of 50 (+/- 10)
- Higher scores indicate worse executive function
Shaded Area shows Open Label period, all subjects on sapropterin.
p value is mean change difference from baseline for the differences between placebo and sapropterin.
Mean change difference from placebo (SE); SE = standard error
Shaded Area shows Open Label period, all subjects on sapropterin.
p-value is mean change difference from baseline for the differences between placebo and sapropterin.
ADHD-RS Inattention Score
Mean Change Difference from Baseline to Week 13 and Baseline to Week 26
BRIEF Metacognition Index
Mean Change Difference from Baseline to Week 13 and Baseline to Week 26
(T-Score=50 Denotes Normative Group Mean)
All terms were classified based on MEDRA terminology
CONCLUSIONS
●●Blood Phe was reduced by ≥ 20% in the treatment
group within 4 weeks and Phe response was
maintained throughout 13 week randomization period
●●Parents reported a significant reduction in attention
problems, including significant improvement in
Inattentive and Hyperactivity/Impulsive behaviors
METHODS
●●There was a significant reduction in parent reported
executive function difficulties
●●Improvement in Attention and Executive Function
symptoms were maintained throughout randomization
and open label phase
Shaded Area shows Open Label period, all subjects on sapropterin.
p-value is mean change difference from baseline for the differences between placebo and sapropterin.
Mean change difference from placebo (SE); SE = standard error
Shaded Area shows Open Label period, all subjects on sapropterin.
p-value is mean change difference from baseline for the differences between placebo and sapropterin.
• Blood Phenylalanine measured at baseline and weeks 4,8,13,26
ADHD-RS Hyperactivity
Mean Change Difference from Baseline to Week 13 and Baseline to Week 26
RESULTS
BRIEF Behavioral Regulation Index
Mean Change Difference from Baseline to Week 13 and Baseline to Week 26
(T-Score=50 Denotes Normative Group Mean)
Baseline Characteristics
●●76% of Total Pediatric Sample had ≥ 20%
Phe response
REFERENCES
1.Camp KM, Parisi MA, Acosta PB et al. (2014) Phenylketonuria Scientific Review Conference: state of the
science and future research needs. Mol Genet Metab 112:87-122.
2.Vockley J, Andersson HC, Antshel KM et al. (2014) Phenylalanine hydroxylase deficiency: diagnosis and
management guideline. Genet Med 16:188-200.
3.T.D. Douglas, H.A. Jinnah, D. Bernhard, R.H. Singh, The effects of sapropterin on urinary monoamine
metabolites in phenylketonuria, Mol. Genet. Metab., 109 (2013), pp. 243–250.
4.D.A. White, J.A.V. Antenor-Dorsey, D.K. Grange, T. Hershey, J. Rutlin, J.S. Shimony, R.C. McKinstry, S.E.
Christ, White matter integrity and executive abilities following treatment with tetrahydrobiopterin (BH4) in
individuals with phenylketonuria, Mol. Genet. Metab. 110 (2013) 213-217.
5.S.E. Christ, A.J. Moffitt, D. Peck, D.A. White. The effects of tetrahydrobiopterin (BH4) treatment on brain
function in individuals with phenylketonuria, NeuroImage: Clinical 3 (2013) 539–547.
6.B. Burton, et al., A randomized, placebo-controlled, double-blind study of sapropterin to treat ADHD
symptoms and executive function impairment in children and adults with sapropterin-responsive
phenylketonuria, Mol. Genet. Metab. (2014), http://dx.doi.org/10.1016/j.ymgme.2014.11.011
7.Newcomb TM, Himle MB, Smart AL, et al. Impact of sapropterin dihydrochloride on mood and motor
function in autosomal dominant DOPA-responsive dystonia (AD-DRD): a pilot study. Presented at the
International Congress of Inborn Errors of Metabolism. September 3-6, 2013. Barcelona, Spain.
8.E. Deschênes, L. Ryan, N. Lewis, V. Roy-Girard, L. Leviton, B.K. Burton, J. Cohen-Pfeffer, E.R. Jurecki,
J.J. Mahoney, A. Bradley. Assessments of Executive Function Performance before and after Sapropterin
Treatment in Patients with Phenylketonuria.
ACKNOWLEDGMENTS
*based on ADHD-RS total score at baseline
ADHD = DSM-IV Attention Deficit Hyperactivity Disorder symptoms; Phe = phenylalanine; SD = standard deviation
Mean change difference from placebo (SE); SE = standard error
Shaded Area shows Open Label period, all subjects on sapropterin.
p-value is mean change difference from baseline for the differences between placebo and sapropterin.
PRESENTED AT THE SOCIETY FOR INHERITED METABOLIC DISORDERS MARCH 28 - 31, 2015 SALT LAKE CITY, UTAH
Shaded Area shows Open Label period, all subjects on sapropterin.
p value is mean change difference from baseline for the differences between placebo and sapropterin.
The authors wish to thank all of the PKU-016 Investigators for their
contributions to this study. Funding for this study and poster were
provided by BioMarin Pharmaceutical Inc.
http://www.bmrn.com/pdf/SIMD2015p5.pdf
NEUROPSYCHIATRIC COMORBIDITIES IN ADULTS WITH
PHENYLKETONURIA: A RETROSPECTIVE COHORT STUDY
Deborah A. Bilder1, Joyce A. Kobori2, Jessica L. Cohen-Pfeffer3, Erin M. Johnson3, Elaina R. Jurecki3, Mitzie L. Grant4
1Division of Child and Adolescent Psychiatry, Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah, USA, 2Department of Pediatrics, Kaiser
Permanente, San Jose, CA, USA, 3Medical Affairs, BioMarin Pharmaceutical Inc., Novato, CA, USA, 4Departments of Psychiatry and Pediatrics, Drexel University College of
Medicine, Philadelphia, PA, USA
Cohort Characteristics
(1.49,1.72)
1.70
(1.57,1.85)
Sleep Disturbances
13.43
13.70
6.74
0.98
(0.91,1.05)
1.99
(1.82,2.18)
Migraine / Headache
Movement Disorders /
Parkinsons / Tremors
Epilepsy / Convulsions
8.42
8.12
5.12
1.04
(0.95,1.14)
1.64
(1.47,1.84)
7.36
6.30
3.15
1.17
(1.05,1.3)
2.34
(2.05,2.66)
5.23
4.95
2.33
1.06
(0.93,1.2)
2.24
(1.92,2.62)
Intellectual Disabilities
4.64
0.85
0.66
5.46
(4.1,7.26)
7.03
(5.71,8.66)
Bipolar Disorders
Psychosis /
Schizophrenia
Cognitive and/or
Personality Changes
Secondary to GMC
Eating Disorders
4.27
5.16
3.07
0.83
(0.73,0.93)
1.39
(1.18,1.63)
3.63
3.40
2.02
1.07
(0.92,1.24)
1.80
(1.5,2.15)
3.53
2.63
1.63
1.34
(1.14,1.59)
2.17
(1.79,2.61)
3.34
1.94
0.85
1.72
(1.4,2.12)
3.93
(3.17,4.87)
Dementia
3.26
2.37
2.08
1.38
(1.16,1.63)
1.57
(1.3,1.89)
ADD / ADHD
2.85
2.37
1.59
1.20
(1.01,1.43)
1.79
(1.46,2.2)
Substance Abuse
2.33
3.67
2.45
0.63
(0.55,0.73)
0.95
(0.77,1.18)
Behavioral Conduct
2.09
1.18
0.69
1.77
(1.37,2.28)
3.03
(2.34,3.92)
Alcohol Dependency
1.84
3.13
2.05
0.59
(0.51,0.68)
0.90
(0.71,1.14)
Personality Disorders
1.55
1.31
0.80
1.18
(0.93,1.5)
1.94
(1.46,2.57)
Fatigue / Malaise
1.40
1.09
0.57
1.28
(0.98,1.68)
2.46
(1.81,3.34)
Developmental Disorders
1.18
0.34
0.18
3.47
(2.13,5.64)
6.56
(4.35,9.88)
OCD
PDD (Autism Spectrum
Disorders)
Phobias
1.15
0.52
0.30
2.21
(1.51,3.25)
3.83
(2.66,5.52)
0.86
0.23
0.17
3.74
(2.15,6.49)
5.06
(3.23,7.91)
0.66
0.78
0.39
0.85
(0.61,1.17)
1.69
(1.1,2.59)
Multiple Sclerosis
0.42
0.63
0.33
0.67
(0.47,0.95)
1.27
(0.75,2.15)
Tourettes / Tic Disorders
0.22
0.05
0.06
4.40
(1.45,13.36)
3.67
(1.59,8.47)
Statistically above the control group
Statistically below the control group
References
All Ages
20-29
30-39
40-49
50-59
60-69
70-70
Summary
► Females outnumbered males by 1.6x but this
ratio was kept constant across the 3
populations
► Adults with PKU demonstrated an increased
relative risk of being diagnosed with anxiety,
intellectual
disability
(ID),
movement
disorders,
eating
disorders,
dementia,
ADD/ADHD, behavioral conduct disorders,
developmental disorders, OCD, PDD, and
Tourette’s/Tic disorders, as compared with
both control groups
► Compared with diabetes, adults with PKU had
lower relative risk for medical diagnoses of
substance abuse, alcohol dependency, bipolar
disorders, and multiple sclerosis
► Adults who may have been late-treated (≥50
years old) experienced a higher rate of ID than
young adults, illustrating the success of
newborn screening
[2] K Ahring et al., Blood phenylalanine control in
[1] J Vockley et al., Phenylalanine hydroxylase deficiency:
diagnosis and management guideline, Genetics in Medicine
2014; 16 (2) 188-200
phenylketonuria: a survey of 10 European centres,
European Journal of Clinical Nutrition 2011; 65:275-278
► Anxiety diagnoses were prevalent across the
age cohorts
36.63
15.15
36.28
14.27
3,145
929
77.2
22.8
39.71
16.45
6,304
1,428
81.5
18.5
16,300
8,035
67.0
33.0
All Ages
20-29
30-39
40-49
50-59
60-69
General
1.60
(1.08,1.23)
6.6
27.2
22.1
16.8
14.4
7.7
3.1
2.2
PKU
(0.87,0.97)
1.15
1,609
6,613
5,368
4,079
3,494
1,867
760
545
Diabetics
0.92
9.16
8.7
31.0
25.0
14.9
13.2
5.2
1.3
0.6
General
11.97
13.55
672
2,399
1,935
1,152
1,022
403
100
49
PKU
20.94
15.61
8.8
31.8
23.2
14.6
12.9
5.5
2.1
1.1
Diabetics
19.17
Anxiety
360
1,297
945
593
525
222
86
46
General
Depression
39.5
60.5
PKU
(1.4,1.48)
9,603
14,732
Diabetics
95% CI
1.44
39.3
60.7
General
RR
(0.97,1.01)
3,039
4,693
PKU
95% CI
0.99
38.6
61.4
Diabetics
RR
44.73
General Controls
N
Percent
24,335
100%
1,572
2,502
General
%
64.99
General
%
64.51
Diabetic Controls
N
Percent
7,732
100%
22
20
18
16
14
12
10
8
6
4
2
0
PKU
%
Pain Disorders
22
20
18
16
14
12
10
8
6
4
2
0
Diabetics
PKU / General
Relative Risk
Prevalence (%)
PKU / Diabetes
Relative Risk
PKU
Diabetics
General
PKU
Diabetics
General
PKU
Diabetics
General
PKU
Diabetics
General
PKU
Diabetics
General
PKU
Diabetics
General
PKU
Diabetics
General
PKU
Category
Diabetes General
Controls Controls
PKU
Percent
100%
Prevalence of Anxiety
Prevalence of Intellectual Disabilities
Prevalence (%)
Prevalence and Relative Risks for Medical
Diagnoses of All PKU Patients
N
4,074
PKU
Results
Category
Total Patients
Gender
Male
Female
Age Group
< 20
20 - 29
30 - 39
40 - 49
50 - 59
60 - 69
70 - 79
80+
Age
Mean
Std Dev
Source of Insurance
Employer
Government
Diabetics
• This nested, case-control study used ICD-9 codes from the
MarketScan® insurance claims databases from 2006-2012.
• These databases provide healthcare claims data for USbased employer and government-sponsored health plans.
• Estimated prevalence of the neuropsychiatric comorbidity
diagnoses for adults (≥20 years old in 2012) with PKU were
compared with two comparison groups (diabetes and
general population) matched by age, gender, geographic
location, and insurance type.
• These groups were also stratified by age (20-29, 30-39, 4049, 50-59, 60-69, 70-79) to examine comorbidity prevalence
trends related to age.
General
Adults with phenylketonuria (PKU) have been reported to
experience
neuropsychiatric
symptoms,
including
anxiety, depression, and cognitive functioning problems.
In contrast with the recent ACMG practice guidelines
suggesting that phenylalanine hydroxylase (PAH)
deficiency should be managed throughout life, only an
estimated 30% of adults with PKU are currently followed
in clinic [1,2].
Identifying medical and psychiatric comorbidities
associated with PKU will inform the primary and specialty
care management of adults with PKU.
PKU
Methods
Diabetics
Background
70-70
Conclusions
► Adults with PKU experience higher rates of
intellectual disability, anxiety, autism, and
other neuropsychiatric disorders, when
compared to those with diabetes and the
general population.
► In addition, adults with PKU have higher
rates of depression, sleep disturbances,
migraine, epilepsy/convulsions, bipolar
disorders, phobias, personality disorders,
psychoses/schizophrenia, fatigue/malaise,
and phobias, as compared with the general
population
► These results support the need for
continued
monitoring
of
behavioral,
psychiatric and neurocognitive functioning
across the lifespan
in individuals with PKU.
Acknowledgements
BioMarin Pharmaceutical Inc. provided funding for the study,
data analysis, writing, editing, and poster production.
Presented at the SIMD Annual Meeting: March 28-31, 2015, Salt Lake City, Utah
http://www.bmrn.com/pdf/SIMD2015p4.pdf
Phase 2 Studies Contribute to rAvPAL-PEG (BMN 165, pegvaliase)
Phase 3 Trial Design
Cary Harding1*, Nicola Longo2*, Janet A. Thomas3*, Barbara K. Burton4*, Roberto Zori5*, Deborah A. Bilder2*, John Posner6*, Phil Lieberman7*,
Markus Merilainen8, Zhonghua Gu8, Becky Schweighardt8, Haoling H. Weng8, Harvey Levy9*
1Oregon
Health & Science University, Portland, OR, USA; 2University of Utah, Salt Lake City, UT, USA; 3University of Colorado, Aurora, CO, USA; 4Ann and Robert H. Lurie
Children’s Hospital of Chicago, Chicago, IL, USA; 5University of Florida, Gainesville, FL, USA; 6King's College, London, UK; 7University of Tennessee College of Medicine,
Germantown, TN, USA; 8BioMarin Pharmaceutical Inc., Novato, CA, USA; 9Boston Children's Hospital, Boston, MA, USA
Background
Phenylketonuria (PKU)
Clinical Need
Phase 2 Experience

Inherited metabolic disease in which
phenylalanine (Phe) cannot be
metabolized to tyrosine due to
deficiency of the enzyme phenylalanine
hydroxylase

Characterized by accumulation of Phe
leading to neurocognitive dysfunction

A treatment that will help individuals
with PKU safely achieve lifelong,
reliable control of blood Phe
concentrations and improve functional
outcomes
Pegvaliase

(PEGylated recombinant
Anabaena variabilis
phenylalanine ammonia lyase
[rAvPAL-PEG])
Subcutaneous injectable enzyme
substitution therapy to decrease Phe
levels in patients with PKU

Due to its bacterial origin, rAV-PAL is
PEGylated to reduce immunogenicity
Dosing and Titration Explored in the Phase 2
Clinical Studies of Pegvaliase
Dosing and Titration Conclusions from
the Phase 2 Studies in Adults with PKU
PAL-002
N=40
PAL-004
N=16
165-205
N=24
Weekly weight-based
dosing with 8-week
induction followed by 8week dose titration
5 days/week dosing with
faster titration for 13 weeks
Weekly low-dose induction followed
by titration to max. 375 mg/week
dosed 5 days/week to blood Phe
target ≤ 600 µmol/L for 24 weeks
► The majority of patients can be treated to meaningful blood Phe
reductions with doses of 20 or 40 mg s.c. daily.
Subjects in these 3 studies had option to continue in a long term safety and efficacy study, with further dose
increases and continuation of long-term treatment
PAL-003 Extension Study (N=67)
► Weekly, low-dose introduction of treatment, followed by gradual
increases in dose and frequency, result in fewer hypersensitivity
events.
► Blood Phe reduction appears to be dependent on dose and
duration of treatment. The immune response to the compound is
hypothesized to play a role in blood Phe reduction
► Most Phase 2 subjects entered the long-term extension study, in
which most achieved at least 2 consecutive blood Phe values
≤ 600 µmol/L in 25-40 weeks.
Dosing 1 to 7 times/week with adjustments to
achieve or maintain blood Phe 60 to 600 µmol/L
Phase 3 Study Design
Phase 2 Studies Contribute to Phase 3 Trials
PRISM 301 Trial Design
PRISM 301 Baseline Characteristics
(as of 24 October 2014)†
Phase 2 results defined the induction and titration dosing strategy for the Phase 3 trials
Phase 3 Studies
PRISM 301
PRISM 302
PAL-002
N=40
PAL-004
N=16
165-205
N=24
Weekly weightbased dosing with
8-week induction +
8-week titration
5 days/week dosing
with faster titration
Weekly low-dose
induction followed
by gradual dosage
and frequency
increases
► Doses not adequate to attain optimal blood
Phe reduction
► Lower starting doses well tolerated, but
higher starting doses led to more frequent
hypersensitivity adverse events
Induction
↓
Titration
↓
Maintenance
► Well tolerated
► Blood Phe reduction
dependent on
individual immune
response
Open-label, randomized study to assess safety and tolerability of induction,
titration and maintenance dose regimen of subcutaneous pegvaliase, selfadministered by adults with PKU naïve to pegvaliase treatment
Age at enrollment (years), mean (SD)
Blood Phe
≥600µmol/L
at screening
and on
average in
past 6 months
Screening
New York
Nebraska
Illinois
Massachusetts
New Jersey
Ohio
Colorado
Missouri
40 mg
daily
Induction
Set dose
4 Weeks
Upward Titration
until target dose
achieved from
Week 5 up to Week
34
Double-blind, placebo-controlled, four-arm
randomized discontinuation study (RDT) to evaluate
efficacy and safety of pegvaliase
Primary efficacy
objective:
RDT design:
PRISM 301 and 302 Trial Investigators
ClinicalTrials.gov: NCT01819727
Vanderbilt University Medical Center (Nashville)
Dr. John Phillips III
Weisskopf Child Evaluation Center, Univ. of Louisville
Dr. Kara Goodin
St. Christopher's Hospital for Children (Philadelphia)
Dr. Reena Jethva
Univ. of California, San Diego School of Medicine
Dr. Annette Feigenbaum
University of Florida (Gainesville)
Dr. Roberto Zori*
Wayne State University (Detroit)
Dr. Robert Conway
Oregon Health & Science University
Dr. Cary O. Harding*
University of Kentucky
Dr. Stephen Amato
University of Missouri
Dr. Esperanza Font-Montgomery
Mount Sinai School of Medicine (New York)
Dr. Melissa Wasserstein
Nebraska Medical Center
Dr. William Rizzo
University of Oklahoma
Dr. Klaas Wierenga
Ann & Robert H. Lurie Children's Hospital of Chicago
Dr. Barbara Burton*
Albany Medical Center (New York)
Dr. Natasha Shur
Cooper Health Systems (Camden, NJ)
Dr. Caroline Eggerding
St. Louis Children's Hospital
Dr. Dorothy Grange
Children's Hospital of Pittsburgh
Dr. Gerard Vockley
Goryeb Children’s Hospital (Morristown, NJ)
Dr. Darius Adams
Children's Hospital of Boston
Dr. Harvey Levy
University of South Florida
Dr. Amarilis Sanchez-Valle
Children's Hospital of Orange County (Orange, CA)
Dr. Richard Chang
University of Utah Medical Center
Dr. Nicola Longo*
Children's Hospital Colorado
Dr. Janet Thomas*
Children's Hospital and Research (Oakland, CA)
Dr. Paul Harmatz
Medical College of Wisconsin
Dr. David Dimmock*
Riley Children's Hospital (Indianapolis)
Dr. Mary Stuy
Emory University (Atlanta)
Dr. Hong Li
University of Texas Houston Medical School
Dr. Hope Northrup
University of Washington
Dr. C. Ronald Scott
University Hospitals of Cleveland
Dr. Jirair Bedoyan
* Indicates members of the PRISM 301 and 302 Trials Steering Committee
Secondary
objectives:
28.8 (8.7)
Subjects < 18 years, n (%)
10 (6.3%)
Subjects ≥ 18 years, n (%)
141 (88.7%)
2.5 mg/wk
Oklahoma
Texas
20 mg
daily
40 mg
daily
Maintain
Target Dose
At least 2
weeks
To investigate blood Phe levels at
the end of the 8-week RDT period
82 (51.6%)
Female, n (%)
77 (48.4%)
Weight (kg), mean (SD)
81.08 (22.45)
Blood Phe concentration (µmol/L), mean (SD)
1202.8 (365.1)
Enrollment is ongoing
PRISM 302 Trial Design
20 mg/day
Up to
250
Subjects
from
165-301
or from
PAL-003
Ensures a more homogeneous
population on treatment entering
the placebo-controlled phase
Assessment of the Attention Deficit
Hyperactivity Disorder (ADHD)
inattention subscale and the Profile
of Mood States (POMS) scale.
Male, n (%)
†
PRISM 302 Trial
Oregon
Utah
20 mg
daily
(up to 300
subjects)
PRISM 301 and 302 Trial Investigational Sites
Total Subjects
(n=159)
20 mg/day
Placebo
No study
drug last
week
40 mg/day
40 mg/day
40 mg/day
40 mg/day
40 mg/day
Placebo
Up to 13
Weeks
Screening
20 mg/day
20 mg/day
Part 1
Phe assessment
(open label)
Conclusions
► Data from multiple early-phase clinical studies have informed the design of the
Phase 3 trials for pegvaliase.
► The design of the Phase 3 trials was based on information from Phase 2 studies
using various dosing regimens, which demonstrated the relationships between
dosage, duration of treatment, hypersensitivity reactions, and reduction of blood
Phe concentrations.
8 Weeks
Part 2
Discontinuation
(double-blind);
subjects with blood
Phe reduction
1 Week
Part 3A
Pk/PD
(open-label) vial &
syringe; subjects who
completed Part 2
5 Weeks
Part 3B
(open-label)
prefilled syringe
Subjects who
completed Part 3A
Up to 190
Weeks
Part 4
Extension
(open-label)
Acknowledgments
BioMarin Pharmaceutical Inc. provided
funding for the study, data analysis,
writing, editing, and poster production.
Presented at: SIMD Annual Meeting:
Mar. 28-31, 2015, Salt Lake City, Utah.
http://www.bmrn.com/pdf/SIMD2015p3.pdf
Evaluation of Long-term Safety and Efficacy with rAvPAL-PEG (BMN 165, pegvaliase)
for Control of Blood Phenylalanine Levels in Adults with Phenylketonuria (PKU)
Nicola Longo1, Janet A. Thomas2, Melissa P. Wasserstein3, Barbara K. Burton4, Jerry Vockley5, Dorothy K. Grange6, Richard Hillman7, Cary Harding8, David Dimmock9, Natasha
Shur10, Darius Adams11, William B. Rizzo12, Chester Whitley13, Kara M. Goodin14, Celeste Decker15, Kendra Bolt15, Yinpu Chen15, Becky Schweighardt15, Roberto Zori16
of Utah, Salt Lake City, UT, USA; 2University of Colorado, Aurora, CO, USA; 3Mount Sinai Hospital, New York, NY, USA; 4Ann and Robert Lurie Children’s Hospital of Chicago, Chicago, IL, USA; 5Children's Hospital of
Pittsburgh, Pittsburgh, PA, USA; 6St. Louis Children's Hospital, St. Louis, MO, USA; 7University of Missouri, Columbia, MO, USA; 8Oregon Health and Science University, Portland, OR, USA; 9Medical College of Wisconsin,
Milwaukee, WI, USA; 10Albany Medical College, Albany, NY, USA; 11Goryeb Children’s Hospital, Morristown, NJ, USA; 12Nebraska Medical Center, Omaha, NE, USA; 13University of Minnesota, Minneapolis, MN, USA;
14Weisskopf Child Evaluation Center, Louisville, KY, USA; 15BioMarin Pharmaceutical Inc., Novato, CA, USA; 16University of Florida, Gainesville, FL, USA
1University
Background
Phenylketonuria (PKU)
Clinical Need

Characterized by accumulation of Phe
leading to neurocognitive dysfunction

A treatment that will help individuals
with PKU safely achieve lifelong,
reliable control of blood Phe
concentrations and improve functional
outcomes
(PEGylated recombinant
Anabaena variabilis
phenylalanine ammonia lyase
[rAvPAL-PEG])

Patient Disposition
PAL-003 Phase 2 Extension Study
Inherited metabolic disease in which
phenylalanine (Phe) cannot be
metabolized to tyrosine due to
deficiency of the enzyme phenylalanine
hydroxylase


Pegvaliase
Methods
Open-label, multisite, prospective study evaluating long-term efficacy, safety,
and tolerability of multiple subcutaneous doses of pegvaliase in adults with PKU
Patients entered PAL-003 from one of three Phase 2 parent
studies with various dosing regimens and with previous exposure
to pegvaliase (range: 11 to 24 weeks; mean: 17 weeks).
PAL-002
(N=40)
PAL-004
(N=16)
Potential injectable enzyme substitution
therapy to decrease Phe levels in
patients with PKU
165-205
(N=24)
Due to its bacterial origin, rAV-PAL is
PEGylated to reduce immunogenicityrelated clearance
Enrolled
N=67
PAL-003
N=67

Dose adjustments for safety
and to achieve or maintain
blood Phe 60 to 600 µmol/L

Dosing 1 to 7 times/week

Mean weekly dose:
186 ± 157 mg/week

Study is ongoing: all results
reflect interim data cut of
October 24, 2014

Discontinued
N=14
Treated
N=67
Adverse Event:
Withdrawal of consent:
Lost to Follow-up:
Investigator Decision:
Other:
Efficacy and Safety Analysis
Population
N=67
Up to approximately 4 years
treatment data available
2 (3.0%)
4 (6.0%)
1 (1.5%)
3 (4.5%)
4 ( 6.0%)
Results
Baseline Characteristics
Total Subjects
(n=67)
1800
29 (9)
1500
Subjects ≥ 18 years, n (%)
61 (91%)
Subjects < 18 years, n (%)
6 (9%)
Female, n (%)
39 (58%)
Male, n (%)
28 (42%)
Weight (kg), mean (SD)
1,337
1,052
1200
μmol/L
Age at enrollment (years), mean (SD)
Mean Blood Phe Levels Over Time
900
600
82 (26)
620
300
Blood Phe concentration (µmol/L), mean (SD)
437
1052 (545)
0
67 (100%)
Mild
20 (30%)
Moderate
41 (61%)
Severe
6 (9%)
Serious AE (SAE)
Discontinued treatment due to SAE
(1 arthralgia and peripheral neuropathy,
1 anaphylaxis)
AE requiring dose interruption
17 (25%)
AE leading to withdrawal from study drug
treatment
4 (6%)
62 (93%)
Death
100%
4 (6%)
0
AEs:
Defined per broad algorithmic anaphylactic
reaction Standardized MedDRA
Query(SMQ) and modified hypersensitivity
SMQ (including arthralgia, arthritis, eye
inflammation, eye irritation, eye pain, joint
stiffness, joint swelling, pyrexia, vision
blurred, and polyarthritis)
b Anaphylaxis
* Baseline blood Phe from PAL-002, PAL-004, or 165-205
Error bars represent standard deviation.
Data from interim data cut October 24, 2014.
Total Subjects
(n=67)
Events:
All 4 events resolved without sequelae, with
2 subjects continuing treatment and 2
subjects withdrawing from treatment.
Subjects with at least 2 consecutive blood Phe
levels < 600 µmol/L during PAL-003 study, n (%)
Time to blood Phe < 600 μmol/L, mean (SD)
Skin
54 (81%)
19.5 (20.4) weeks
Time to at least 2 consecutive blood Phe
levels < 600 μmol/L, mean (SD)
25.7 (21.7) weeks
Time to at least 4 consecutive blood Phe
levels < 600 μmol/L, mean (SD)
30.8 (23.8) weeks
0%
* Related per investigator (not sponsor) assessment
0.9 –
52
49
34
0.7 –
4 Years
(N=10)
23
0.2 – 67
0.1 – 67
66
0–
6766
0
50
►
9
35
30
0.5 –
0.4 – 67
67
0.3 –
11
7
IgG PAL
14
53
0.6 –
►
Conclusions
32
0.8 –
40
43
44
44
12
7
14
IgM PAL
19
48
46
NAb
28
25
31
46
44
44
24
13
IgG PEG
33
3113
38
44 38
52
IgE PALPEG
60%
20%
49%
3 Years
(N=22)
Incidence of Antibody Positivity from Baseline of
Phase 2 throughout PAL-003
Time to Blood Phe ≤ 600 μmol/L
National Institute of Allergy and Infectious
Disease/Food Allergy and Anaphylaxis
Network criteria
80%
40%
68%
2 Years
(N=37)
(Numbers on the graph represent the number of patients with antibody data at each time point.)
Adverse Events Related* to Study Drug
in ≥15% of Subjects
Injection site
72%
1 Year
(N=56)
1.0 –
6 (9%)
Anaphylaxis (NIAID/FAAN criteria)b
a Hypersensitivity
Baseline
PAL-003
(N=60)
2 (3%)
AE requiring dose reduction
Hypersensitivity AEa
Percent of Patients
9 (13 %)
Pre-Treatment Baseline*
Antibody Positivity
Adverse event (AE)
65%
-300
Adverse Events Summary
Total Subjects
(N=67)
Mean decrease from
pre-treatment baseline:
424
405
34 34
80
19
32
11
104
IgM PEG
17
17
128
Study Week
100% of patients developed a sustained anti-PAL antibody
response.
67% developed a transient anti-PEG antibody response.
►
►
10
14
156
IgE PAL
75% developed neutralizing antibody at some point.
21% had transient IgE positivity, which had no correlation
with anaphylaxis or HAE.
Acknowledgments
► There was a substantial and persistent decrease in mean blood Phe
levels in adult PKU subjects treated in this Phase 2 extension study
with varying doses of pegvaliase for up to 4 years
The authors thank the patients and physicians who participated in
this study. BioMarin Pharmaceutical Inc. provided funding for the
study, data analysis, writing, editing, and poster production.
► Long-term treatment was well tolerated, with the majority of subjects
experiencing AEs that were mild to moderate.
Presented at: SIMD Annual Meeting: March 28-31, 2015, Salt Lake
City, Utah
http://www.bmrn.com/pdf/SIMD2015p2.pdf