Efficacy and Safety of Orally Administered Engineered Probiotics (CBT102-A) for the Treatment of Children With Phenylketonuria

Efficacy and Safety of Orally Administered Engineered Probiotics (CBT102-A) for the Treatment of Children With Phenylketonuria：a Randomized, Double-blind, Placebo-controlled, Parallel-group Clinical Study

This is a randomized, double-blind, placebo-controlled, parallel-group study. A total of 15 children with phenylketonuria(PKU) age 3 to 17 years will be randomized to two groups. Experimental group of 10 children will intervene engineered probiotics (CBT102-A) for 20 days and 5 children will intervene placebo. The goal of this study is to determine whether CBT102-A is an effective and safe treatment for PKU.

Due to an increased blood phenylalanine (Phe) concentration, untreated children with PKU will develop progressively intellectual disability. Engineered probiotics can metabolize Phe into other products in the intestine by expressing related exogenous proteins in the Phe metabolic pathway, thereby reducing Phe concentration in the intestine and blood.

Animal experiments have confirmed the efficacy and safety of CBT102-A. This study will enroll children with PKU age 3 to 17 years according to a strict inclusion and exclusion criteria. Subjects who meet the requirements will be randomly assigned on Day 1 and start the study administration. The administration period of both groups is 20 days (Day 1~Day 20), in which the experimental group receives CBT102-A with 4 dose levels, and the control group receives placebo administration, with the same mode, frequency, time, cycle and dose as the experimental group. All subjects will be observed for 3 days (Day 21~Day 23) without intervene in hospital and will be followed up weekly for 4 consecutive weeks after discharge（Day 51）.

Change of blood Phe concentration and occurrence of Treatment-Emergent Adverse Events(TEAE) with PKU will be used to evaluate the efficacy and safety of the CBT102-A.

Inclusion Criteria:

• Blood phe ≥ 600μmol/L at newborn screening;
• Blood phe ≥ 600μmol/L at least 3 times in the last 1 year before screening, and the blood Phe ≥ 600μmol/L in the last 1 time;
• Screening laboratory evaluations (e.g., chemistry panel, complete blood count, urinalysis, creatinine clearance, CRP) within normal limits or judged to be not clinically significant by the investigator;
• Stable diet for at least 60 days prior to screening;
• Able to produce at least 2 bowel movements per week on average without using any form of laxatives;
• Adolescents and children's guardians can voluntarily complete the whole process of informed consent, including stool, urine and blood collection, adherence to diet control, hospital monitoring, follow-up and oral trial drug compliance, and sign informed consent.

Exclusion Criteria:

• The standard percentile values of height and weight of Chinese children aged 0 to 18 years were evaluated with weight less than P3 or weight greater than P97；
• History of active or chronic passage of 3 or more loose stools per day；
• Have any medical conditions or medications that may affect the absorption of medications or nutrients；
• History of or current immunodeficiency disorder including autoimmune disorders；
• Subjects with obvious influenza-like symptoms caused by COVID-19 or other viral infections during screening；
• Hepatitis B surface antigen and/or hepatitis C antibodies and/or treponema pallidum antibodies positive；
• Subjects who are dependent on drugs and alcohol；
• Received gene therapy related to PKU；
• Intolerant or allergic to Escherichia coli Nissle 1917 (EcN)；
• Active gastrointestinal bleeding or a proven history of gastrointestinal bleeding within 60 days prior to screening；
• Antibiotics within 28 days before the planned first dose of investigational product (IP), or anticipated during the study period；
• Take probiotic supplements within 28 days before the planned first dose of IP, or anticipated during the study period；
• A history of fever, confirmed bacteremia, or other active infection within 30 days prior to the planned first dose of IP；
• Drugs that use of the digestive system has been used within 30 days prior to the planned first dose of IP;
• Drugs that may affect gastrointestinal function has been used within 30 days prior to the planned first dose of IP;
• Major survery performed within 90 days before the anticipated first dose of IP or planned surgery or hospitalization during the study period；
• Take sapropterin (KUVAN®) within 1 week before the planned first dose of IP；
• Use pegylated recombinant phenylalanine ammonia lyase (PALYNZIQ™) within 30 days before the planned first dose of IP；
• History of severe immune adverse reactions to PALYZIQ；
• Participated in an interventional clinical trial and used the investigational drug within 60 days or 5 half-lives before the planned first dose of IP；
• Subjects who may not be able to complete the study for other reasons.