Primary:• To evaluate the efficacy of PTC923 in reducing blood phenylalanine (Phe) levels in subjects with phenylketonuria (PKU) as measured by mean change in blood Phe levels from baseline to Weeks 5 and 6 (ie, the average of each respective…
ID
Source
Brief title
Condition
- Protein and amino acid metabolism disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy measure will be reduction in blood Phe levels in subjects
with PKU as measured by mean change in Phe levels from baseline to Part 2 Weeks
5 and 6 (ie, the average of the 2-week period at the target dose of
double-blind treatment). Baseline blood Phe level will be the mean of Day -1
and Day 1 blood Phe levels.
Secondary outcome
The secondary efficacy endpoints are the proportion of subjects with baseline
Phe levels >=600 µmol/L who achieve Phe levels <600 µmol/L at the end of the
double-blind treatment period and the change from baseline in mean blood Phe
levels at each PTC923 dose level (ie, each 2-week period in Part 2).
Safety endpoints:
Safety and tolerability of PTC923 as measured by severity and number of
treatment-emergent adverse events (TEAEs), clinical laboratory tests, vital
signs, physical examinations, and electrocardiograms (ECGs) will be compared to
placebo.
Pharmacokinetics endpoints:
Depending on the number of samples obtained, the following PK parameters of
sepiapterin and BH4 for a given subject may be calculated using
noncompartmental methods: Cmax, Tmax, T1/2, area under the plasma
concentration-time curve from time zero to 24 hours (AUC0-24h),
area under the plasma concentration-time curve from time zero to infinity
(AUC0-inf), apparent total clearance of the drug from plasma following oral
administration (CL/F), and apparent volume of distribution during terminal
phase after non-intravenous administration (Vz/F).
Additionally, depending on the number of samples collected and subject
demography, a population PK analysis will be performed using all PK samples
collected in the study to further characterize the PK of sepiapterin and BH4 to
examine potential source of PK variability, such as age, and to explore the
relationship between exposure and response.
The exploratory efficacy endpoint is the change from baseline in blood Tyr over
time, including the Phe:Tyr ratio.
Background summary
Phenylketonuria (PKU) is an autosomal-recessive inborn error of metabolism
characterized by deficiency of the enzyme phenylalanine hydroxylase (PAH),
which metabolizes phenylalanine (Phe). Gene mutations of PAH result in
decreased catalytic activity leading to hyperphenylalaninemia (HPA). High
levels of Phe are toxic to the brain and are associated with cognitive
dysfunction, memory impairment, and can lead to psychiatric and behavioral
problems. If left untreated, severe and irreversible intellectual disability
can occur. Phenylketonuria is diagnosed at birth with the near universal
adoption of newborn screening. Phenylketonuria has been described in all ethnic
groups, and its incidence worldwide varies widely, but is estimated to occur in
approximately 1 in every 23930 births.
Currently, there is no cure for PKU. Initial treatment consists of prompt
institution of stringent Phe dietary restriction supplemented with specifically
designed medical foods. Dietary control is considered the standard of care
(SoC). The restriction in protein requires exclusion of natural
foods such as meat, fish, milk, cheese, bread, nuts, and many other common food
items. Even the intake of vegetables is limited.
The success of dietary control, however, comes at high personal cost to
affected individuals and their families. Compliance with a restrictive diet and
Phe monitoring can be difficult for older children, adolescents, and adults and
it is accepted that dietary burden does not improve with age. Lifelong
management of Phe levels is critical to avoid neurocognitive decline and other
comorbidities.
Synthetic tetrahydrobiopterin (BH4) (eg, sapropterin dihydrochloride), is
commercially available as an approved drug for the treatment of HPA in PKU.
However, international experts concluded that most people with PKU have little
or no benefit from sapropterin dihydrochloride, and evidence of long-term
clinical improvements was lacking. They further concluded that *new drugs that
are safe, efficacious, and impacting a larger proportion of individuals with
PKU are needed*.
PALYNZIQ (pegvaliase-pqpz) is a commercially available product that was
recently approved for the treatment of adult patients with PKU (aged 16 years
and older in the European Union [EU]) who have inadequate blood Phe control
(blood Phe levels greater than 600 µmol/L) despite prior management with
available treatment options including sapropterin. While effective at helping
lower blood Phe levels to <600 µmol/L, it requires a daily injection and
patients in clinical studies experienced significant adverse reactions to
PALYNZIQ treatment (e.g. anaphylactic reaction, hypersensitivity, etc.).
PALYNZIQ is not indicated for patients <=18 years of age in the United States
and <=16 years of age in the EU, and accordingly does not address the unmet need
for new medications that are safe and efficacious for children and adolescents.
PTC923 is a new molecular entity and synthetic form of sepiapterin. Sepiapterin
serves as a substrate for de novo synthesis of BH4 via the pterin salvage
pathway, making sepiapterin a naturally occurring precursor for BH4.
Tetrahydrobiopterin is an essential cofactor for enzymes including PAH and
tyrosine (Tyr) hydroxylase. Following oral administration, PTC923 is rapidly
converted to BH4 intracellularly, the natural cofactor of PAH, and is intended
to restore BH4 to physiological levels in patients who lack endogenous BH4,
increase BH4 levels in patients who have lower than normal physiological levels
of BH4, or enhance the chaperone effect on PAH in PAH-deficient patients by
providing pharmacological levels of BH4 while also directly enhancing the
thermal stability of PAH.
Study PTC923-MD-003-PKU is a Phase 3 study to assess the efficacy of PTC923 in
reducing blood Phe levels in subjects with PKU. It is anticipated that a
greater reduction in Phe will be observed in subjects with PKU who receive
PTC923 versus those who receive placebo. This Phase 3 study is designed to
support registration of PTC923 in subjects with PKU.
Study objective
Primary:
• To evaluate the efficacy of PTC923 in reducing blood phenylalanine (Phe)
levels in subjects with phenylketonuria (PKU) as measured by mean change in
blood Phe levels from baseline to Weeks 5 and 6 (ie, the average of each
respective treatment dose 2-week period of double-blind treatment).
Secondary:
• To evaluate the proportion of subjects with baseline Phe levels >=600 µmol/L
who achieve Phe levels <600 µmol/L at the end of the double-blind treatment
period.
• To evaluate the effect of PTC923 dose response on reducing blood Phe levels
in subjects with PKU.
• To evaluate the pharmacokinetics (PK) of PTC923 in subjects with PKU.
• To assess the safety of PTC923 in subjects with PKU.
Exploratory Objectives:
• To evaluate changes in blood tyrosine (Tyr) overtime, including the Phe:Tyr
ratio.
Study design
Study PTC923-MD-003-PKU is a phase 3, double-blind, randomized study that
compares PTC923 plus
SoC to placebo plus SoC. Standard of care in PKU is a Phe-restricted diet.
The study is set up in 2 parts and lasts in total 122 days.
During Part 1 (the open-label Responsiveness Test), subjects with PKU will be
enrolled and receive PTC923 for 14 days to identify subjects with >=15%
reduction from baseline in blood Phe levels.
Subjects will receive the following doses of PTC923 for 14 days:
- Subjects 0 to <6 months of age - 7.5 mg/kg
- Subjects 6 to <12 months of age - 15 mg/kg
- Subjects 12 months to <2 years of age - 30 mg/kg
- Subjects >=2 years - 60 mg/kg
Subjects who experience <15% reduction in blood Phe levels will be classified
as nonresponsive and will be contacted to schedule an Early
Termination Visit (ETV) (on or between Day 28 to Day 35 of last dose).
Subjects <2 years of age who experience a >=15% reduction in blood Phe levels
will be offered
the option to enroll directly into an open-label extension study.
PTC923-responsive subjects >=2 years of age will be entered into Part 2.
Part 2 (double-blind, randomized (1:1), placebo controlled):
Subjects in the PTC923 treatment arm will receive:
- PTC923 20 mg/kg daily for 14 days,
- PTC923 40 mg/kg daily for 14 days and
- PTC923 60 mg/kg daily for 14 days.
As dosing is weight-based and to maintain the blind, subjects in the placebo
arm will receive equivalent quantities of placebo to match the 20 to 40 to 60
mg/kg dose escalation of the PTC923 treatment arm.
After 6 weeks of treatment with either PTC923 or placebo, subjects will be
offered the option to enter an open-label extension study.
Intervention
PTC923 is a powder for oral use and will be suspended in water or apple juice
prior to administration.
In part 1 (open label) of the study the subjects will receive PTC923 once daily
for 2 weeks:
- Subjects 0 to <6 months of age - 7.5 mg/kg
- Subjects 6 to <12 months of age - 15 mg/kg
- Subjects 12 months to <2 years of age - 30 mg/kg
- Subjects >=2 years - 60 mg/kg
In part 2 (double-blind, randomized) of the study the subjects will receive:
- PTC923 20 mg/kg daily for 14 days,
- PTC923 40 mg/kg daily for 14 days and
- PTC923 60 mg/kg daily for 14 days.
As dosing is weight-based and to maintain the blind, subjects in the placebo
arm will receive equivalent quantities of placebo to match the 20 to 40 to 60
mg/kg dose escalation of the PTC923 treatment arm.
Study burden and risks
Currently, there is no cure for PKU. Initial treatment consists of prompt
institution of stringent
Phe dietary restriction supplemented with specifically designed medical foods.
Dietary control is
considered the standard of care (SoC).
Study PTC923-MD-003-PKU is a Phase 3 study to assess the efficacy of PTC923 in
reducing blood Phe levels in subjects with PKU. It is anticipated that a
greater reduction in Phe will be observed in subjects with PKU who receive
PTC923 versus those who receive placebo.
PTC923 is provided as a powder for suspension in water or apple juice.
Side effects of PTC923 are: Constipation, Diarrhea, Abdominal Pain, Vomiting,
Gas, Stomach discomfort, Worsening of gastrointestinal reflux disease, Painful
periods, Fatigue, Decreased appetite, Conjunctivitis (pink eye), Headache,
Dizziness
Risks associated to study assessments:
- Blood draws can cause pain, bruising, inflammation and swelling of the vein,
bleeding or even an infection at the puncture site.
- ECG: Skin reactions to the sticky pads may occur, such as redness, itching or
discomfort. Some hair loss may be associated with the glue at the placement
sites of the ECG pads.
The following procedures are performed:
- measurement of vital signs, part 1 - day 1, part 2 - day 1 and 42 and at the
Early termination visit (part 1 and 2 - day 1 pre- and post-dose);
- physcial examination at screening, part 1 - day 1, part 2 - day 1 and 42 and
at the Early termination visit;
- ECG at part 1 - day 1, part 2 - day 42 and Early termination visit. For
subjects in the PK sub-study ECGs will be performed on part 1 - day 1 at 2, 4,
6 and 8 hours post-dose as well;
- Questionnaires to be completed on day 1 of part II: PKU Quality of Life
(subjects as of age 6 years) and EQ-5D (subjects as of age 3 years).
- Venous blood draw: at screening, part 1 day 1, part 2 - days 1 and 42 or
early termination visit.
Blood samples will be collected for PK analysis from subjects participating PK
sub-study at the following timepoints. In Part 1, subjects >=2 years, samples
will be collected at Part 1 Day 1 (predose, and 0.5, 1, 2, 4, 6, 8, and 24
hours postdose).
In Part 1, subjects <2 years, samples will be collected at Part 1 Day 1
(predose and 4 hours postdose), Part 1 Day 14 (2 and 6 hours postdose).
In Part 2 (all ages), samples will be collected pre-dose and 4 hours post dose
on Day 1, Part 2 Day 14, Part 2 Day 28 , Part 2 Day 42.
For subjects participating in the PK sub-study, additional, blood Phe and Tyr
samples will be collected at all timepoints from the PK samples prior to plasma
harvesting in Part 1.
- Dried blood spot for participants <2 years:
- screening: 1 time 0.12 mL and/or 3 times 0.12 mL (washout period);
- part 1: 8 times 0.12 mL and/or 4 times 0.25 mL (in case of PK-substudy);
- part 2: 11 times 0.12 mL
- Dried blood spot for participants >= 2 years <12 years:
- screening: 1 time 0.12 mL and/or 3 times 0.12 mL (washout period);
- part 1: 8 times 0.12 mL and/or 8 times 0.25 mL (in case of PK-substudy);
- part 2: 11 times 0.12 mL
- Dried blood spot for participants >= 12 years:
- screening: 1 time 0.12 mL and/or 3 times 0.12 mL (washout period);
- part 1: 8 times 0.12 mL and/or 8 times 0.25 mL (in case of PK-substudy);
- part 2: 11 times 0.12 mL
Subjects or subject's legal representative will be asked to maintain a 3-days
diet diary every week in study which will be collected every week by the site
staff for review by a dietician.
Corporate Court 100
South Plainfield NJ 07080
US
Corporate Court 100
South Plainfield NJ 07080
US
Listed location countries
Age
Inclusion criteria
Informed consent and assent (if necessary, at the investigator*s discretion
[ie, for
children and/or subjects who are mentally impaired secondary to disease]) with
parental/legal guardian consent
2. Male or female subjects of any age
3. Uncontrolled blood Phe level >=360 µmol/L on current therapy anytime during
Screening and uncontrolled blood Phe level >=360 µmol/L on current therapy when
taking the average of the 3 most recent Phe levels from the subject*s medical
history
(inclusive of the Screening value)
4. Clinical diagnosis of PKU with hyperphenylalaninemia (HPA) documented by past
medical history of at least 2 blood Phe measurements >=600 µmol/L
5. Women of childbearing potential, as defined in (CTFG 2020), must have a
negative
pregnancy test at Screening and agree to abstinence or the use of at least one
highly
effective form of contraception (with a failure rate of <1% per year when used
consistently and correctly):
• Combined (estrogen- and progestogen-containing) hormonal contraception
associated with inhibition of ovulation:
* Oral
* Intravaginal
* Transdermal
• Progestogen-only hormonal contraception associated with inhibition of
ovulation:
* Oral
* Injectable
* Implantable
• Intrauterine device
• Intrauterine hormone-releasing system
• Bilateral tubal occlusion
• Vasectomized partner with confirmed azoospermia
Highly effective contraception or abstinence must be continued for the duration
of the
study and for up to 90 days after the last dose of the study drug.
All females will be considered of childbearing potential unless they are
postmenopausal (at least 12 months consecutive amenorrhea in the appropriate age
group without other known or suspected cause) or have been permanently
sterilized surgically
(eg, hysterectomy, bilateral salpingectomy, bilateral oophorectomy).
6. Males who are sexually active with women of childbearing potential who have
not had
a vasectomy must agree to use a barrier method of birth control during the
study and
for up to 90 days after the last dose of study drug. Males must also refrain
from sperm
donations during this time period.
Males who are abstinent will not be required to use a contraceptive method
unless they
become sexually active. Males who have undergone a vasectomy are not required to
use a contraceptive method if at least 16 weeks post procedure.
7. Willing and able to comply with the protocol and study procedures
8. Willing to continue current diet unchanged while participating in the study
Exclusion criteria
1. The individual, in the opinion of the investigator, is unwilling or unable
to adhere to
the requirements of the study
2. Gastrointestinal disease (such as irritable bowel syndrome, inflammatory
bowel
disease, chronic gastritis, and peptic ulcer disease, etc.) that could affect
the absorption
of study drug
3. History of gastric surgery, including Roux-en-Y gastric bypass surgery or an
antrectomy with vagotomy, or gastrectomy
4. Inability to tolerate oral medication
5. History of allergies or adverse reactions to synthetic BH4 or sepiapterin
6. Current participation in any other investigational drug study or use of any
investigational agent within 30 days prior to Screening
7. Any clinically significant laboratory abnormality as determined by the
investigator. In
general, each laboratory value from Screening and baseline chemistry and
hematology
panels should fall within the limits of the normal laboratory reference range,
unless
deemed not clinically significant by the investigator
8. A female who is pregnant or breastfeeding, or considering pregnancy
9. Serious neuropsychiatric illness (eg, major depression) not currently under
medical
control, that in the opinion of the investigator or sponsor, would interfere
with the
subject*s ability to participate in the study or increase the risk of
participation for that
subject
10. Past medical history and/or evidence of renal impairment and/or condition
including
moderate/severe renal insufficiency (glomerular filtration rate [GFR] <60
mL/min)
and/or under care of a nephrologist
11. Any abnormal physical examination and/or laboratory findings indicative of
signs or
symptoms of renal disease, including calculated GFR <60 mL/min/1.73m2.
In subjects >=18 years of age, the Modification of Diet in Renal Disease Equation
should be used to determine GFR.
In subjects <18 years, the Bedside Schwartz Equation should be used to determine
GFR.
12. Requirement for concomitant treatment with any drug known to inhibit folate
synthesis
(eg, methotrexate)
13. Confirmed diagnosis of a primary BH4 deficiency as evidenced by biallelic
pathogenic
mutations in 6-pyruvoyltetrahydropterin synthase, recessive GTP cyclohydrolase
I,
sepiapterin reductase, quinoid dihydropteridine reductase, or
pterin-4-alphacarbinolamine
dehydratase genes
14. Major surgery within the prior 90 days of screening
15. Concomitant treatment with BH4 supplementation (eg, sapropterin
dihydrochloride,
KUVAN) or pegvaliase-pqpz (PALYNZIQ)
16. Unwillingness to washout from BH4 supplementation (eg, sapropterin
dihydrochloride,
KUVAN) or pegvaliase-pqpz (PALYNZIQ)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-000474-29-NL |
| ClinicalTrials.gov | NCT05099640 |
| CCMO | NL77504.042.22 |