PBD-001

Principal Investigator: Nicola Longo
Keywords: primary tetrahydrobiopterin deficiency (PBD) , recessive guanosine triphosphate cyclohydrolase 1 (GTP-CH) deficiency , 6-pyruvoyl-tetrahydropterin synthase (PTPS) , CNSA-001 , Censa , sepiapterin Department: Pediatric Genetics
IRB Number: 00110412 Co Investigator:  
Specialty: Pediatric Genetics
Sub Specialties: Medical Genetics
Recruitment Status: Not yet recruiting

Contact Information

Carrie Bailey
carrie.bailey@hsc.utah.edu
8015873605

Brief Summary

The primary objective of this study is:

To assess the safety and tolerability of 4 dose levels of CNSA-001 in primary tetrahydrobiopterin deficiency (PBD) patients with 6-pyruvoyl-tetrahydropterin synthase (PTPS) or recessive guanosine triphosphate cyclohydrolase 1 (GTP-CH) deficiency

The secondary objectives of the study are: 

• To assess the pharmacokinetic profile of CNSA-001 and its effect on tetrahydrobiopterin (BH4), phenylalanine (Phe), and tyrosine (Tyr) in PBD patients with PTPS or recessive GTPCH deficiency.


• To evaluate the preliminary efficacy of CNSA-001 in reducing blood Phe levels in adult and adolescent PBD patients with PTPS or recessive GTP-CH deficiency after 7 days of treatment.

The Exploratory Objectives of the study are: 

To assess the change from baseline in other exploratory biomarkers of this disease such as serum prolactin, whole blood serotonin, and urine sepiapterin, BH4, and neopterin levels.

To assess the change from baseline in a CANTAB test battery including the Reaction Time (RTI), the Spatial Span (SSP), the Spatial Working Memory (SWM) and Rapid Visual Information Processing (RVP).

Inclusion Criteria

1. Male or Female patients 18 years old and above and 12 years old and above for the remaining patients (age reduction pending analysis of safety, PK, and response, in the adult patient(s) by the DSMB and FDA)

2. Confirmed diagnosis of PBD as evidenced by medical history of biallelic pathogenic mutations in PTPS or recessive GTP-CH

3. Blood Phenylalanine (Phe) level > 360 μmol/L during the Screening or BH4 Washout Periods

4. Informed consent and assent (if necessary) with parental consent

5. 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:
     o Hormonal contraception (stable dose for 3 months)
     o IUD/IU Hormone-releasing System
     o 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 2nd contraceptive method unless they become sexually active.

6. Males with female partners of childbearing potential must agree to use barrier contraceptive (i.e., 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.         

7. Females with a negative pregnancy test at Screening and on Day 1 prior to dosing

8. Creatinine clearance (CrCl) >90 mL/min as estimated using the Cockcroft-Gault equation (Appendix 2)

9. The patient is clinically stable on therapy for management of their signs and symptoms of PBD as determined by the Investigator

10. The patient is willing and able to comply with the protocol                           

11. No tobacco use (e.g., 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

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

2. Significant chronic medical illness other than PBD, as determined by the Investigator

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

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

5. Inability to tolerate oral medication 

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

7. Any clinically significant medical or psychiatric condition or medical history, that in the opinion of the Investigator, would interfere with the patient’s ability to participate in the study or increase the risk of participation for that patient 

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

9. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) laboratory values >2 × the upper limit of normal (ULN) 

10. 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 

11. Clinically significant cardiac arrhythmia at Screening or prior to the first dose of study drug 

12. QTcF (QT with Fredericia’s correction) ≥460 msec in males and ≥480 msec in females (based on the mean of triplicate measurements taken at Screening) 

13. Resting heart rate ≤40 or ≥110 bpm or resting blood pressure <90/40 mmHg or >150/90 mmHg at Screening or prior to the first administration of study drug 

14. Current participation in any other investigational drug study or participation within 30 days prior to Screening 

15. History of alcohol or drug abuse within last 6 months prior to Screening or current evidence of substance dependence as determined by the Investigator

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

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

18. The patient, in the opinion of the Investigator, is unwilling or unable to adhere to the requirements of the study