This study has been transitioned to CTIS with ID 2023-509229-31-00 check the CTIS register for the current data. Primary:• To evaluate the long-term safety of PTC923 in subjects with phenylketonuria (PKU)• To evaluate changes from baseline in…
ID
Source
Brief title
Condition
- Protein and amino acid metabolism disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety is a primary endpoint: Safety of long-term treatment with PTC923 will be
measured by number of treatment-emergent adverse events (TEAEs), including
assessment of severity of TEAEs, clinical laboratory tests, vital signs, and
physical examinations.
The primary efficacy endpoint is the change from baseline in dietary
Phe/protein consumption measured during Dietary Phe Tolerance Assessment period:
• Dietary Phe tolerance evaluated at Baseline and every 2 weeks over the course
of 26 weeks assessment period
Secondary outcome
Secondary measures will be evaluated at 6-month intervals starting at M8D1 and
will include the following:
• Changes from baseline in QOL using PKU-QOL questionnaire in the subset of
subjects who are able to complete the PKU-QOL (ie, subjects whose primary
language is English [British or American], Turkish, Dutch, German, Spanish,
Italian, Portuguese, or French) (ages 6 to 8 years Parent PKU-QOL; ages 9 to 11
years Child PKU-QOL; ages 12 to 17 years Adolescent PKU-QOL; ages >=18 years
Adult PKU-QOL)
• Changes from baseline in QOL using the EQ-5D (EQ-5D-Y Proxy Version 1 [3 to 7
years]; EQ-5D-Y [8 to 15 years]; EQ-5D-5L ([>=16 years])
• PK assessment of sepiapterin and BH4 concentrations in plasma following
dosing of sepiapterin
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 individualswith 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 Phecontrol
(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 registration study to assess the efficacy
of PTC923 in reducing blood Phe levels in subjects with PKU. All subjects who
successfully complete a PTC Therapeutics (PTC)-sponsored Phase 3 study in PKU,
including Study PTC923-MD-003-PKU, will be eligible for the PTC923-MD-004-PKU
study as feeder subject. Additionally, subjects with PKU who have not completed
a feeder study (non-feeder subjects) will be considered eligible if they
fulfill the inclusion and exclusion criteria. This open-label study will
provide important long-term safety data in subjects who will receive PTC923 for
a minimum of 12 months or until PTC923 is authorized and commercially available
in the specific country.
Study objective
This study has been transitioned to CTIS with ID 2023-509229-31-00 check the CTIS register for the current data.
Primary:
• To evaluate the long-term safety of PTC923 in subjects with phenylketonuria
(PKU)
• To evaluate changes from baseline in dietary phenylalanine (Phe)/protein
consumption
Secondary:
• To evaluate PTC923 effect on quality of life (QOL) using the
Phenylketonuria-quality of life (PKU-QOL) questionnaire in the subset of
subjects who are able to complete the PKU-QOL (ie, subjects whose primary
language is English [British or American], Turkish, Dutch, German, Spanish,
Italian, Portuguese, or French) (ages 6 to 8 years Parent PKU-QOL; ages 9 to 11
years Child PKU-QOL; ages 12 to 17 years Adolescent PKU-QOL; ages
>=18 years Adult PKU-QOL)
• To evaluate PTC923 effect of QOL using the European Quality of Life 5
Dimensions (EQ-5D) (EQ-5D for Youth [EQ-5D-Y] Proxy Version 1 [3 to
7 years]; EQ-5D-Y [8 to 15 years]; EQ-5D-5 Levels (EQ-5D-5L) ([>=16 years])
• To evaluate the pharmacokinetics (PK) of sepiapterin and tetrahydrobiopterin
(BH4) following PTC923 dosing
Exploratory:
• To evaluate changes in blood Phe and tyrosine (Tyr) over time
• To assess the taste, palatability, and acceptability of PTC923 (non-feeder
subjects <18 years)
Study design
This is a Phase 3 open-label study of PTC923 for subjects with PKU. Eligible
subjects are:
- Feeder subjects: those who have completed a Phase 3 PTC Therapeutics
(PTC)-sponsored feeder study (including Study PTC923-MD-003-PKU.
At select sites only, the following subjects are eligible:
- Non-feeder controlled subjects: those who have not completed a feeder study
and have blood Phe levels <360 µmol/L at study entry
- Non-feeder uncontrolled subjects: those who have not completed a feeder study
and have blood Phe levels >=360 µmol/L at study entry
All potential non-feeder subjects will undergo screening procedures. After
successful screening, for subjects who have not completed a feeder study and
have controlled blood Phe levels (<360 µmol/L), a protein loading test will be
performed to test for PTC923 responsiveness (responsiveness defined as >=15%
reduction in blood Phe levels at any timepoint (1, 8, or 24 hours) post- PTC923
dose compared to pre-PTC923 dose baseline). These subjects will be classified
as responsive and should continue into the study immediately or within 14 days
of determination of ascertainment of responsiveness.
For all the subjects, the treatment phase of the study consists of open-label
treatment with PTC923 administered orally once a day for a minimum of 12 months
or until subject experiences lack of efficacy, adverse events (AEs) that lead
to discontinuation, withdraws from treatment, or PTC923 is authorized and
commercially available in the specific country.
Upon entry to the study, subjects will be eligible for the following age-based
dose escalation:
• 0 to <6 months of age: up to 7.5 mg/kg/day
• 6 to <12 months of age: up to 15 mg/kg/day
• 12 months to <2 years of age: up to 30 mg/kg/day
• >=2 years old of age: up to 60 mg/kg/day
All subjects will provide blood Phe samples at M1D5, 10, 14, 19, 24, and 28.
During this period, all subjects will continue their usual diet and will
maintain 3-day diet records once every 2 weeks. To determine qualification for
the 26-week concurrent Dietary Phe Tolerance Assessment, subjects* mean blood
Phe concentrations averaged from M1D5, M1D10, and M1D14 will be analyzed (if
only 2 values are available, these will be averaged; and if only 1 value is
available, this will be used) and provided to the clinical site prior to the
in-clinic M2D1 visit. If on M2D1 there are no blood Phe values from M1D5, M1D10
or M1D14, then the determination of the subject*s participation into the
Dietary Phe Tolerance Assessment will be made upon receipt of the initial
post-PTC923 treatment M1 blood Phe value and the subject will begin
participation in the Dietary Phe Tolerance Assessment at the earliest
convenience for the site and subject, but no later than M3D1.
During the Dietary Phe Tolerance Assessment, dietary Phe adjustments will be
performed in 2-week intervals for 26 weeks. Once participation in the Dietary
Phe Tolerance Assessment concludes, subjects will revert to monthly blood
sampling (samples will be collected on Day 1 of each month, where possible),
and subjects or parent(s)/legal guardian(s) will complete a 3-day diet record
quarterly (the week prior to the scheduled quarterly visit).
Intervention
The test product is PTC923 Powder for Oral Use. All subjects will receive
PTC923 (administered with food) daily:
• 7.5 mg/kg/day for subjects 0 to <6 months of age
• 15 mg/kg/day for subjects 6 to <12 months of age
• 30 mg/kg/day for subjects 12 months to <2 years of age
• 60 mg/kg/day for subjects >=2 years of age
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).
Side effects of PTC923 are: Constipation, Diarrhea, Abdominal Pain, Vomiting,
Gas, Stomach discomfort, Worsening ofgastrointestinal 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;
- physcial examination;
- ECG;
- Questionnaires;
- Venous blood draw, including PK and Phe/Tyr samples.
Subjects or subject's legal representative will be asked to maintain a 3-days
diet diary in study which will be collected 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
Individuals are eligible to participate if they meet all the following
inclusion criteria:
1. Informed consent and assent (if necessary, at the investigator*s discretion
[ie, for children]) with parental/legal guardian consent
2. Male or female subjects of any age.
3. Clinical diagnosis of PKU with hyperphenylalaninemia (HPA) documented by
past medical history of at least 2 blood Phe measurements >=600 µmol/L
4. Women of childbearing potential, as defined in (CTFG 2020), must have a
negative
pregnancy test at study entry 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).
5. 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.
6. Willing and able to comply with the protocol and study procedures
7. Willing to continue current diet unchanged while participating in the study
(unless specifically instructed to change diet during the study by the
investigator)
Exclusion criteria
Individuals are not eligible to participate if they meet any of the following
exclusion criteria:
1. The individual, in the opinion of the investigator, is unwilling or unable
to adhere to
the requirements of the study
2. Inability to tolerate oral medication
3. A female who is pregnant or breastfeeding, or considering pregnancy
4. 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
5. Past medical history and/or evidence of renal impairment and/or condition
including
moderate/severe renal insufficiency (glomerular filtration rate [GFR] <60
mL/min as
estimated most recently during qualifying participation in a feeder study)
and/or under
care of a nephrologist
6. Any other condition 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
7. Requirement for concomitant treatment with any drug known to inhibit folate
synthesis
(eg, methotrexate)
8. Concomitant treatment with BH4 supplementation (eg, sapropterin
dihydrochloride,
KUVAN) or pegvaliase-pqpz (PALYNZIQ)
Additional criteria for subjects who did not participate in a feeder study:
9. 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
10. History of gastric surgery, including Roux-en-Y gastric bypass surgery or
an antrectomy with vagotomy, or gastrectomy
11. History of allergies or adverse reactions to synthetic BH4 or sepiapterin
12. Current participation in any other investigational drug study or use of any
investigational agent within 30 days prior to Screening
13. 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
14. Any abnormal physical examination and/or laboratory findings indicative of
signs or symptoms of renal disease, including calculated GFR <60 mL/min/1.73 m2.
In subjects >=18 years of age, the Modification of Diet in Renal Disease
Equation should be used to determine GFR.
In subjects <18 years of age, the Bedside Schwartz Equation should be used to
determine GFR.
15. 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-alpha-carbinolamine dehydratase genes
16. Major surgery within the prior 90 days of screening
17. 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 |
|---|---|
| EU-CTR | CTIS2023-509229-31-00 |
| EudraCT | EUCTR2021-000497-28-NL |
| ClinicalTrials.gov | NCT05166161 |
| CCMO | NL82363.042.22 |