Amendment A • Following the Paediatric Committee within the European Medicines Agency (PDCO) request and available results from the HEP001 study: o The evaluation of the primary objective was based on biochemical parameters rather than functional parameters (ammonia). The primary and secondary objectives and endpoints were updated accordingly as well as the procedures (laboratory assessments), the rationale for sample size and the planned statistical analysis. o The rational for the new schedule of administration (4 infusions spread over a 2-month period) was updated. • Based upon the results from the HEP001 study which suggested a better efficacy in younger patients, the inclusion was restricted to patients aged below 12 years old. • Following the ANSM (French national competent authority) comments, o The total dose to be administered was clarified. o The differences between the 2 possible methods to administer HepaStem (PAC and transient transhepatic catheter) were clarified in term of procedures and study duration. More specifically, the procedures for each method, including the specification of the catheter to be used were provided. o The study population was redefined (inclusion and exclusion criteria). o The laboratory tests to be performed as well as the time points at which they should be performed were have been updated. o The qualification and training to be followed by the investigators were specified. • The importance to accurately document the evolution of the UCD metabolic condition of each patient throughout the study duration, and to standardise documentation of evaluation was emphasised. • The definition of the pre and post-infusion time windows were clarified.

Amendment B The amendment followed a consultation of the EMA Scientific Advice Committee (CHMP) where Promethera Biosciences was seeking advice on the development of HepaStem for paediatric patients with UCDs. Additionally, several physicians expert in metabolic disease were consulted. Main major changes are summarised below: • Although based on available data, the benefit risk of the study was positive; a stopping rule was introduced to protect the paediatric patients. The DSMB was to review the efficacy and safety data of the first 5 patients treated till FU visit 3 before recruiting the subsequent patients. • The primary and secondary objectives and, primary and secondary endpoints, were updated because ammonia has been shown not to be a robust primary endpoint. o The primary endpoint was thus defined as ureagenesis improvement at 6 months post first infusion and was evaluated using the absolute 13C blood urea AUC0-120 min quantified with the 13C tracer method. o The secondary objectives/endpoints were adapted following the changes in the primary endpoints. • A DRC was appointed in order to get an objective evaluation of the patients. The members of this committee reviewed the clinical and biological parameters related to the secondary objectives. • The study design was adapted and was divided in 4 periods. A screening period was defined to allow for screening of the patients and for optimising their treatment, if needed. A BL period was also defined. • BL procedures were updated. They included 3 visits (therefore 3 evaluation of the BL ureagenesis) and collect data in a prospective way over 3 months in order to assess intra-patient variability and get a robust BL evaluation. • The request to increase the daily total protein dose adjusted to BW at each visit as of FU visit 3 and the monitoring of diet was strengthened. This was to allow for assessing if the diet could be improved without worsening of the other clinical parameters.

Amendment C • Stopping rules were adapted to take into account the possibility that some patients may not be eligible or would not complete the baseline period. • Some procedures were clarified: o Protein electrophoresis (following recurrent question raised by the study centres). o Use of the concomitant treatment related to study procedure (clarification of timepoints for tacrolimus and of procedures for ACT measurement in the context of bivalirudin use). o Time window for PAC placement and update regarding the choice of the catheter to be used. • The laboratory performing the 13C analyses was specified, included its localisation, in order to be compliant with ethical practice and EU directive on data privacy.

This amendment was only submitted in Spain as study recruitment was stopped and only Spain still had patients participating in the study at that date. • The investigational product shipment procedure was updated. • The pharmacovigilance activities had been outsourced and the contact details for AE reporting were then updated. • A long-term safety registry had replaced the foreseen long-term FU study (SAF001) in the aim of unifying data collection with standardised outcome data across all indications targeted by HepaStem therapy. The protocol was updated accordingly.