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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03519711
Recruitment Status : Active, not recruiting
First Posted : May 9, 2018
Last Update Posted : September 18, 2020
Sponsor:
Information provided by (Responsible Party):
PTC Therapeutics

Brief Summary:
This study has been designed to demonstrate the safety, pharmacokinetics (PK) and preliminary efficacy of CNSA-001 in reducing blood phenylalanine concentrations in participants with hyperphenylalaninemia due to primary tetrahydrobiopterin (BH4) deficiency.

Condition or disease Intervention/treatment Phase
BH4 Deficiency Hyperphenylalaninemia Drug: CNSA-001 Phase 1 Phase 2

Detailed Description:

BH4 is an essential cofactor for phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase, fatty acid glycerylether oxygenase, and nitric oxide (NO) synthase. Primary tetrahydrobiopterin deficiency (PBD) is caused by deficiency of GTP cyclohydrolase I (GTP-CH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), or sepiapterin reductase (SR) that impairs the biosynthesis of BH4 or by defects in BH4 recycling (pterin-4a-carbinolamine dehydratase [PCD] or dihydropteridine reductase [DHPR] deficiency).

Participants will be randomized into one of 2 cohorts, with each cohort assessing 2 dose levels of CNSA-001 via intra-patient escalation.

Initially, only adult participant(s) (≥18 years) will be enrolled. After the first adult participant(s) have completed the study, a Data Safety Monitoring Board (DSMB) will review safety and pharmacokinetic/pharmacodynamic (PK/PD) data, including preliminary efficacy, for the adult participant(s). If the data display no safety issues and provide for the prospect of clinical benefit in participants ≥12 months to <18 years old, then the eligibility criterion for age at time of enrollment will be expanded to include children (≥12 months).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official 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
Actual Study Start Date : June 24, 2018
Estimated Primary Completion Date : September 30, 2020
Estimated Study Completion Date : November 30, 2020


Arm Intervention/treatment
Experimental: Cohort 1: CNSA-001 2.5 mg/kg/day or 10 mg/kg/day
Participants will receive CNSA-001 suspension 2.5 milligrams (mg)/kilogram (kg)/day (dose divided in 2 for twice daily administration) orally for 7 days in Period 1, undergo a 3- to 4-day washout period, then escalate to 10 mg/kg/day (dose divided in 2 for twice daily administration) administered orally for 7 days in Period 2 (14 days total treatment).
Drug: CNSA-001
CNSA-001 will be administered per dose and schedule specified in arms.
Other Name: Sepiapterin

Experimental: Cohort 2: CNSA-001 5 mg/kg/day or 20 mg/kg/day
Participants will receive CNSA-001 suspension 5 mg/kg/day (dose divided in 2 for twice daily administration) orally for 7 days in Period 1, undergo a 3- to 4-day washout period, then escalate to 20 mg/kg/day (dose divided in 2 for twice daily administration) administered orally for 7 days in Period 2 (14 days total treatment).
Drug: CNSA-001
CNSA-001 will be administered per dose and schedule specified in arms.
Other Name: Sepiapterin




Primary Outcome Measures :
  1. 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 Measures :
  1. 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 ]
  2. Change From Baseline (Day 1) in Plasma phenylalanine Concentration at Day 7 [ Time Frame: Baseline (Day 1, pre-dose); Day 7 ]
  3. 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 ]
  4. 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 ]
  5. 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 ]
  6. 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 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   12 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03519711


Locations
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United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55454
United States, Texas
UT Southwestern
Dallas, Texas, United States, 75390
United States, Utah
University of Utah Hospital
Salt Lake City, Utah, United States, 84132
United States, Wisconsin
Marshfield Clinic
Marshfield, Wisconsin, United States, 54449
Sponsors and Collaborators
PTC Therapeutics
Investigators
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Study Director: Neil Smith, PharmD Censa Pharmaceuticals
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Responsible Party: PTC Therapeutics
ClinicalTrials.gov Identifier: NCT03519711    
Other Study ID Numbers: PBD-001
First Posted: May 9, 2018    Key Record Dates
Last Update Posted: September 18, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Phenylketonurias
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases