CompletedPhase 1ACTRN12622000523707

A Phase 1, Randomized, Open-Label, Crossover Study to Evaluate the Relative Oral Bioavailability of 2 Formulations of PTC923 and the Food Effect on the Phase 3 Formulation When Administered as a Single Dose to Healthy Subjects

Sponsor

PTC Therapeutics Inc.

Enrollment

32 participants

Start Date

Nov 22, 2021

Study Type

Interventional

Conditions

Phenylketonuria (PKU)

Summary

The study is intended to assess the relative bioavailability of the analytes BH4 and sepiapterin following a single oral dose of 2 formulations of PTC923 (PTC923 Phase 3 powder for oral use in water [Formulation B] vs. PTC923 Phase 1/2 powder for oral suspension in Medisca oral mix [Formulation A]) under fed conditions in male and female adult healthy volunteers. Medisca oral mix is used for Formulation A to be consistent with the way in which the Phase 1 and Phase 2 studies were conducted previously. The current powder for oral use PTC923 formulation has been used in the Phase 1/2 studies in healthy volunteers and PKU and/or PBD patients.

Eligibility

Sex: Both males and femalesMin Age: 18 YearssMax Age: 55 Yearss

Inclusion Criteria10

Individuals eligible to participate in this study include those who meet all of the following
Males or females aged between 18 and 55 years old and have a Body Mass Index between 18.5 and 30.0 kg/m squared
Subjects must understand the nature of the study and must provide signed and dated written informed consent before the conduct of any study-related procedures.
Women of childbearing potential must have a negative pregnancy testing at Screening and agree to abstinence or the use of effective forms of contraception (with a failure rate of less than 1% per year when used consistently and correctly. Highly effective contraception or abstinence must be continued for the duration of the study and for up to 30 days after the last dose of study drug.
Males with female partners of childbearing potential must agree to use barrier contraceptive and their female partners must use a highly effective method of contraception from Screening through 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 after the procedure. Same-sex couples are not required to use contraception.
Females with a negative pregnancy test at Screening and on Day -1
Willing and able to comply with the protocol
Have not used tobacco products of any kind (eg, cigarettes, e-cigarettes, cigars, smokeless tobacco) for at least 2 weeks prior to the Screening Visit and are willing to abstain from these products through end of study.
Part A only: Subject must be willing and able to consume the entire low-fat breakfast in the designated timeframe.
Part B only: Subject must be willing and able to consume the entire high-fat breakfast in the designated timeframe.

Exclusion Criteria28

Individuals are not eligible to participate in this study if they have met or meet any of the
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
History of fat malabsorption
Dietary restrictions that preclude participation
Inability to tolerate oral medication
History of allergies or adverse reactions to BH4 or related compounds or to any excipients in the study drug formulation
Any clinically significant medical or psychiatric condition or medical history, that in the opinion of the investigator or the medical monitor, would interfere with the subject’s ability to participate in the study or increase the risk of participation for that subject
Alanine aminotransferase or aspartate aminotransferase laboratory values greater than 1.5× the
upper limit of normal (ULN)
Serum creatinine greater than or equal to 1.5× ULN at Screening
Any other clinically significant laboratory abnormality at the Screening Visit or prior to the administration of the first dose of study drug. 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. The investigator may repeat laboratory testing one time in the event of an out-of-range laboratory value to confirm eligibility.
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, current evidence of substance dependence or self-reported alcoholic intake greater than 10 standard drinks/week
A female who is nursing or who is planning to become pregnant
QTcF (QT with Fredericia’s correction) greater than or equal to 450 msec in males and greater than or equal to 470 msec in females
(based on the mean of triplicate measurements taken at Screening)
Resting heart rate less than or equal to 45 or greater than or equal to 100 beats per minute
Resting blood pressure less than 90/50 mmHg or greater than 150/95 mmHg at Screening
Subject is, in the opinion of the investigator, unwilling or unable to adhere to the requirements of the study
Major surgery within the 90 days prior to Screening
Use of an antifolate including, but not limited to, methotrexate, within 1 week prior to Screening and through discharge from clinic
Use of sapropterin dihydrochloride within 1 week prior to Screening and through discharge from clinic
Use of melatonin within 1 week prior to Screening and through discharge from clinic
Positive test for human immunodeficiency virus, hepatitis B, or hepatitis C
Positive screen for drugs with a high potential for abuse or positive screen for EtOH at
Screening and Check-in
Blood donation of greater than or equal to 450 mL of blood within the 90 days prior to Screening

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Interventions

This is a Phase 1, open-label, randomized, single dose, crossover study consisting of 2 independent parts: a relative bioavailability study of 2 formulations (Formulation A and Formulation B) and 2 doses of PTC923 (Part A); and a food effect study of Formulation B (Part B) in in healthy adult subjects. Subjects are permitted to participate in one study part (Part A or Part B) only. Part A is a cross over study between Formulation A and Formulation B. Part A and Part B are independent of each other. Part B is a cross over study between fasted and fed of Formulation B. Mode of administration: Oral suspension. Formulation B is a powder mixed with water and Formulation A is a powder mixed with ‘Medisca Oral Mix’ oral suspension. Ingestion will be under clinical monitoring. Subjects are inpatients at CMAX. Laboratory tests for PK will also confirm ingestion. Part A Subjects will be randomized into the 2 treatment sequences of PTC923 in a 1:1 ratio. Each treatment is a single dose, and each treatment will be separated from the next by a minimum of 3-day washout period. Sequence 1: 20 mg/kg Formulation A PTC923, 20 mg/kg Formulation B PTC923, 60 mg/kg Formulation A PTC923, and 60 mg/kg Formulation B PTC923 -all administered concurrent with a low-fat meal. Sequence 2: 20 mg/kg Formulation B PTC923, 20 mg/kg Formulation A PTC923, 60 mg/kg Formulation B PTC923, and 60 mg/kg Formulation A PTC923 -all administered concurrent with a low-fat meal. Part B Subjects will be randomized into the 2 treatment sequences of PTC923 in a 1:1 ratio. Each treatment is a single dose, and each treatment will be separated from the next by a minimum of 3-day washout period. Subjects will only receive Formulation B PTC923 in this study part. Sequence 3: 20 mg/kg Formulation B PTC923 fasted, 20 mg/kg Formulation B PTC923 high-fat fed, 60 mg/kg Formulation B PTC923 fasted, and 60 mg/kg Formulation B PTC923 high-fat fed Sequence 4: 20 mg/kg Formulation B PTC923 high-fat fed, 20 mg/kg Formulation B PTC923 fasted, 60 mg/kg Formulation B PTC923 high-fat fed, and 60 mg/kg Formulation B PTC923 fasted. Formulation B is a powder mixed with water and Formulation A is a powder mixed with ‘Medisca Oral Mix’ oral suspension. Low fat is a 400-500 calorie meal with 25% of the calories from fat. An example of a low fat meal is one boiled egg, one packet of instant oatmeal made with water and one cup of low fat milk – with the whole meal containing approximately 25% fat. High fat is a 800-1000 calorie meal with 60% of the calories from fat. An example of a high fat meal is two eggs fried in butter, two strips of bacon, two slices of toast with butter, four ounces of hash brown potatoes and eight ounces of whole milk – with the whole meal containing approximately 60% fat. Fasting is for 10 hours overnight fast. Formulation B is provided 30 minutes after the high fat meal is consumed. The fasting is an overnight fast of 10 hours with up to 240 mL of water allowed during the fast. Water (except water provided with each dosing) will be restricted 1 hour prior to and 1 hour after each study drug administration. After the dose subjects may consume water ad libitum from 1 hour a snack from 4 hours post dose, if desired.