A Study of CNSA-001 in Primary Tetrahydrobiopterin (BH4) Deficient Participants With Hyperphenylalaninemia

• Register: ClinicalTrials.gov
• Last refreshed on: 22 November 2021
• Main ID: NCT03519711
• Date of registration: 11/04/2018
• Prospective Registration: Yes
• Primary sponsor: PTC Therapeutics
• Public title: A Study of CNSA-001 in Primary Tetrahydrobiopterin (BH4) Deficient Participants With Hyperphenylalaninemia
• Scientific title: A Phase 1/2, Open-Label, Randomized Parallel Arm, Intra-patient Dose Escalation Study to Evaluate the Safety, Pharmacokinetics and Preliminary Efficacy of CNSA-001(Sepiapterin) in Primary Tetrahydrobiopterin Deficient Patients With Hyperphenylalaninemia
• Date of first enrolment: June 24, 2018
• Target sample size: 6
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT03519711
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1/Phase 2

Countries of recruitment

Germany, United States

Contacts

• Name: Neil Smith, PharmD
• Affiliation: Censa Pharmaceuticals

Key inclusion & exclusion criteria

Inclusion Criteria:

- Male or female participants 18 years old and above and 12 months old and above for the
remaining participants (age reduction pending analysis of safety, PK, and response, in
the adult participant(s) by the DSMB and Food and Drug Administration [FDA])

- Confirmed diagnosis of PBD as evidenced by medical history of biallelic pathogenic
mutations in PTPS or recessive GTP-CH genes, abnormal enzymatic activity of the PTPS
or GTP-CH enzymes, or a cerebrospinal fluid (CSF) biochemical profile indicative of
PTPS or GTP-CH deficiencies

- Informed consent and assent (if necessary) with parental consent

- Females must be either postmenopausal for =1 year, or surgically sterile (tubal
ligation, hysterectomy, or bilateral oophorectomy) for at least 6 months or, if of
childbearing potential and not abstinent, willing to use at least 2 of the following
highly effective methods of contraception (including adolescents 12 to 18 years old)
from screening through 30 days after the last dose of study drug:

- Hormonal contraception (stable dose for 3 months)

- Intrauterine device/intrauterine hormone-releasing System

- Barrier contraceptive method (diaphragm, cervical cap, contraceptive sponge,
condom) with spermicidal foam/gel/cream/suppository Males and females who are
abstinent will not be required to use a second contraceptive method unless they
become sexually active.

- Males with female partners of childbearing potential must agree to use barrier
contraceptive (that is, condom) with spermicidal foam from screening through 90 days
after the last dose of study drug. Males must also refrain from sperm donations during
this time period.

- Females with a negative pregnancy test at screening and on Day 1 prior to dosing

- Creatinine clearance (CrCl) >90 milliliters (mL)/minute (min) as estimated using the
Cockcroft-Gault equation (=18 years) or Schwartz-Lyon equation (=12 months <18 years)

- The participant is clinically stable on therapy for management of their signs and
symptoms of PBD as determined by the investigator.

- The participant is willing and able to comply with the protocol.

- No tobacco use (for example; cigarettes, e-cigarettes, cigars, smokeless tobacco) for
2 weeks prior to the screening visit and willingness to abstain from these products
through the last dose of study drug

Exclusion Criteria:

- PBD caused by biallelic pathogenic mutations in PCD, SR, DHPR, or single dominant
mutations in GTP-CH

- Significant chronic medical illness other than PBD, as determined by the investigator

- Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel
disease, chronic gastritis, peptic ulcer disease, etc.) that could affect the
absorption of study drug

- History of gastric surgery, including Roux-en-Y gastric bypass surgery or an
antrectomy with vagotomy, or gastrectomy

- Inability to tolerate oral medication

- History of allergies or adverse reactions to BH4 or related compounds, or any
excipients in the study drug formulation

- Any clinically significant medical or psychiatric condition or medical history, that
in the opinion of the investigator, would interfere with the participant's ability to
participate in the study or increase the risk of participation for that participant

- Known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or
hepatitis C virus (HCV)

- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) laboratory values
>2 * the upper limit of normal (ULN)

- Any other clinically significant laboratory abnormality unrelated to PBD at the
screening visit or prior to the administration of the first dose of study drug, as
determined by the investigator

- Clinically significant cardiac arrhythmia at screening or prior to the first dose of
study drug

- QTcF (QT with Fridericia's correction) =460 milliseconds (msec) in males and =480 msec
in females (based on the mean of triplicate measurements taken at screening)

- Resting heart rate =40 or =110 beats/minute (bpm) for ages 12 and older, =130 bpm for
ages 3 to 12, =150 bpm for ages 1-2 years, or resting blood pressure <85/40
millimeters of mercury (mmHg) or >150/90 mmHg at screening or prior to the first
administration of study drug

- Current participation in any other investigational drug study or participation within
30 days prior to screening

- History of alcohol or drug abuse within last 6 months prior to screening or current
evidence of substance dependence as determined by the investigator

- Currently taking an antifolate including, but not limited to, methotrexate,
pemetrexed, or trimetrexate

- A female who is nursing or who is pregnant or planning to become pregnant.

- The participant, in the opinion of the investigator, is unwilling or unable to adhere
to the requirements of the study.



Age minimum: 12 Months
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

BH4 Deficiency

Hyperphenylalaninemia

Intervention(s)

Drug: CNSA-001

Primary Outcome(s)

Number of Participants With Treatment-Emergent Adverse Events [Time Frame: From first dose of study drug (Day 1) up to 30 days after last dose of study drug (up to 47 days)]

Secondary Outcome(s)

Elimination Rate Constant (Ke) of Both CNSA-001 and BH4 [Time Frame: Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours (prior to Day 1 evening dose), and 24 hours (prior to Day 2 morning dose) after the first dose of study drug]

Area Under the Plasma Concentration Versus Time Curve (AUC) of Both CNSA-001 and BH4 [Time Frame: Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours (prior to Day 1 evening dose), and 24 hours (prior to Day 2 morning dose) after the first dose of study drug]

Maximum Observed Plasma Concentration (Cmax) of Both CNSA-001 and BH4 [Time Frame: Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours (prior to Day 1 evening dose), and 24 hours (prior to Day 2 morning dose) after the first dose of study drug]

Time to Reach Cmax (Tmax) of Both CNSA-001 and BH4 [Time Frame: Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours (prior to Day 1 evening dose), and 24 hours (prior to Day 2 morning dose) after the first dose of study drug]

Change From Baseline (Day 1) in Plasma phenylalanine Concentration at Day 7 [Time Frame: Baseline (Day 1, pre-dose); Day 7]

Half-Life (t1/2) of Both CNSA-001 and BH4 [Time Frame: Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours (prior to Day 1 evening dose), and 24 hours (prior to Day 2 morning dose) after the first dose of study drug]

Secondary ID(s)

PBD-001

Source(s) of Monetary Support

Please refer to primary and secondary sponsors