PRX-102 in children and adolescents with Fabry disease

ISRCTN	ISRCTN14012649
DOI	https://doi.org/10.1186/ISRCTN14012649
ClinicalTrials.gov (NCT)	NCT06328608
Clinical Trials Information System (CTIS)	2022-503128-29-00/110161
Integrated Research Application System (IRAS)	1010087
Protocol serial number	CLI-06657AA1-01, IRAS 1010087, CPMS 62298
Sponsor	Chiesi (Italy)
Funder	Chiesi Farmaceutici S.p.A

Submission date: 09/05/2024
Registration date: 29/07/2024
Last edited: 27/01/2025

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Nutritional, Metabolic, Endocrine

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Fabry disease is a genetic disorder in which the body does not properly produce an enzyme required to break down a type of fat called Gb3 (for short). If this enzyme is missing or not working properly, Gb3 builds up in cells, which can lead to serious health problems, such as heart disease, kidney failure and strokes. The drug being tested is called pegunigalsidase alfa or PRX-102 which is approved for sale and has shown to be effective in treating adult patients affected by Fabry disease. It is a type of enzyme replacement therapy, meaning that like the natural enzyme, it acts to break down Gb3. It is given by intravenous infusion (through a needle placed in a vein) every 2 weeks. PRX-102 is an investigational drug in children and adolescents, meaning that it is not approved for sale in these age groups and is being studied to see how well it works and how safe it is.

Who can participate?
Children and adolescents aged from 2 to less than 18 years old with Fabry disease

What does the study involve?
This study is being conducted to learn more about the drug that is designed to prevent or reduce the development of health problems caused by this disease. Since the symptoms of Fabry disease appear at a young age and get worse over time, a treatment that would help to slow or stop the irreversible damage that the disease causes to organs would improve patients’ health and quality of life. At this time, not many treatments have been approved for children, so there is an important need to develop new therapies. The goals of this study are to see if this new drug is safe for children and adolescents and to see how well it works. The study is divided into three parts, or “stages”: a dose-finding stage (Stage I), to try and determine the best dose for each age group which will last up to 6 months, a confirmatory stage (Stage II), which will last for up to 12 months; and an optional extension stage. The study will take place in six countries globally including at one UK site and approximately 20-22 participants will be enrolled in the study globally.

What are the possible benefits and risks of participating?
As with all studies, drug treatment and other therapies may involve risks that are known or unknown. Based on previous studies and the experience of other people who have received PRX-102 some side effects may occur.
The most serious possible side effect is an allergic reaction to PRX-102, this has been seen in very few patients receiving PRX-102.
The most commonly reported side effects are:
- Dizziness
- Vertigo
- Asthenia
- Nausea
- Abdominal pain
- Agitation
- Diarrohea
- Vomiting
- Rash
- Erythema
- Pruritus
- Arthralgia
- Musculoskeletal pain
- Chills
- Chest pain
- Generalised pain
- Infusion-related reaction
- Supraventricular extrasystoles (abnormal heartbeat)

Please see protocol/ICF for a full list of side effects.

There may be pain, bleeding, bruising or swelling at the site where the blood samples are taken. The participant may also feel dizzy or faint.
Participants may have to visit the hospital more frequently than normal when taking part in this study.
ECG - During an ECG participants will need to lie still for a few minutes & small electrodes will be attached to their chest with adhesive pads. It may cause slight discomfort when they are being put on / taken off. Male participants may need to have their chest shaved to perform the ECG. Some participants may be sensitive to the adhesive pads resulting in itchy red areas where the patches were placed. This reaction should settle within a few hours.

Where is the study run from?
Chiesi Farmaceutici S.p.A (Italy)

When is the study starting and how long is it expected to run for?
May 2024 to December 2029

Who is funding the study?
Chiesi Farmaceutici S.p.A (Italy)

Who is the main contact?
clinicaltrials_info@chiesi.com

Contact information

Dr Lynsey Kennedy
Public, Scientific

South Country Business Park, Leopardstown
Dublin
Dublin18
Ireland

Email	irasuk@iconplc.com

Dr Anupam Chakrapani
Principal investigator

Great Ormond Street
London
WC1N 3JH
United Kingdom

Email	Anupam.Chakrapani@gosh.nhs.uk

Study information

Primary study design	Interventional
Study design	Multi-centre open-label trial
Secondary study design	Non randomised study
Scientific title	Multi-centre, open-label trial to assess the saFety, pharmacodynamics, efficacy and pharmacokinetics of pegunigaLsidase alfa in patients from 2 years to less than 18 years of age with confirmed FabrY disease (FLY)
Study acronym	FLY
Study objectives	To assess the safety, pharmacodynamics, efficacy and pharmacokinetics of PRX-102 in three different age cohorts in paediatric patients with confirmed Fabry disease.
Ethics approval(s)	Approved 02/07/2024, North of Scotland Research Ethics Committee (Summerfield House, 2 Eday Road, Aberdeen, AB15 6RE, United Kingdom; +44 1224558458; gram.nosres@nhs.scot), ref: 24/NS/0061
Health condition(s) or problem(s) studied	Fabry's disease
Intervention	Arms: Experimental: Single Arm - Pegunigalsidase alfa (PRX-102) For Cohort C, PXR-102 administered every two weeks at 1.0 mg/kg is believed to be the minimum effective dose. For Cohorts A and B, the starting dose will be 1.0 mg/kg every two weeks but it may be adjusted on the outcomes of Stage I, with the support of the Data Safety Monitoring Board. Assigned Interventions: Drug: PRX-102 1 mg/kg every two weeks Drug: PRX-102 1 mg/kg every two weeks Other Names: • pegunigalsidase alfa • Recombinant human alpha galactosidase-A
Intervention type	Drug
Phase	Phase III
Drug / device / biological / vaccine name(s)	Pegunigalsidase alfa
Primary outcome measure(s)	1. Safety Variables will be measured at each study visits, and will be measured using: 1.1. Treatment-emergent adverse events (TEAEs) 1.2. Infusion-related reactions (IRRs) 1.3. Injection site reactions (ISRs) 1.4. Clinical laboratory safety tests 1.5. Physical examination 1.6. Vital signs 1.7. Electrocardiogram (ECG) 1.8. Assessment for the development of anti-drug antibodies (ADA) against PRX-102 1.9. Use of pre-medications to manage infusion-related reactions 1.10. Growth and development (height, weight, and sexual development by Tanner staging) 2. Efficacy Variables will be measured: 2.1.1. For the first patients in Cohorts A and B: at Baseline, Weeks 4, 12, 26 in Stage I, and Weeks 4, 12, 26, 38, 52 in Stage II and quarterly in Stage III 2.1.2. For the first patients in Cohort C: at Baseline, Week 4 in Stage I, Weeks 26, 38 and 52 in Stage II and quarterly in Stage III 2.1.3. For patients entering directly in Stage II: at Baseline, Weeks 26 and 52 in Stage II and quarterly in Stage III 2.2. Efficacy Variables will be measured using: 2.3. Renal function: 2.3.1. eGFR, calculated using the Creatinine-Cystatin C–based 2.3.2. Chronic Kidney Disease in Children (CKiD) (2012). 2.3.3. Albuminuria, as determined by the urine albumin-to-creatinine ratio (uACR) test, and proteinuria, as determined by the urine protein-tocreatinine ratio (UPCR) test. 2.4. Cardiac function: 2.4.1. Echocardiogram 2.4.2. Holter ECG 2.4.3. Cardiac biomarkers: 2.4.3.1. High-sensitivity cardiac troponin T (hs-cTnT) 2.4.3.2. N-terminal pro B-type natriuretic peptide (NTproBNP) 2.5. Fabry disease biomarkers: 2.5.1. Plasma globotriaosylceramide (Gb3) concentration 2.5.2. Plasma globotriaosylsphingosine (lyso-Gb3) concentration 2.5.3. Urine lyso-Gb3 concentration 2.6. Other measures of Fabry disease: 2.6.1. Use of pain medications 2.6.2. Occurrence of Fabry clinical events (FCEs) 2.6.3. Mainz Severity Score Index (MSSI) 2.6.4. Gastrointestinal Symptoms (PedsQL-GI) questionnaire: parent version and age- appropriate subject version 2.6.5. Fabry Specific Pediatric Health and Pain Questionnaire (FPHPQ): age appropriate subject version 2.6.6. PedsQL Pediatric Pain Questionnaire (PedsQL-PPQ): parent version and age- appropriate subject version 2.6.7. EQ-5D-Y questionnaire for assessment of quality of life: parent version and age- appropriate subject version 2.6.8. Measures to be used if a subject reaches the age of 18 years: 2.6.8.1. Gastrointestinal Symptom Rating Scale (GSRS) in place of the PedsQL-GI 2.6.8.2. Brief Pain Inventory - Short Form (BPI-SF) in place of the PedsQL-PPQ 2.6.9. Measures to be used if a subject reaches the age of 18 years: 2.6.9.1. Quality-of-life (EQ-5D-5L) questionnaire in place of the EQ-5D-Y 2.6.9.2. In addition, the FPHPQ will be dropped. The other measures (use of pain medications, occurrence of FCEs, and completion of the MSSI) will remain the same. 3. Pharmacokinetic Assessments will be measured by blood samples at the following time points: 3.1.1. For the first patients in Cohorts A and B: at Baseline, Weeks 2, 4, 12, 26 in Stage I, and Baseline, Weeks 12, 26, 52 in Stage II and every other weeks in Stage III 3.1.2. For the first patients in Cohort C: at Baseline, Weeks 2, 4, 12 in Stage I, Weeks 26 and 52 in Stage II and every other weeks in Stage III 3.1.3. For patients entering directly in Stage II: at Baseline, Weeks 12, 26, 52 in Stage II and every other weeks in Stage III 4. Pharmacodynamic Assessments: Fabry disease is characterised by the progressive accumulation of Globotriaosylceramide (Gb3) and its metabolite Globotriaosylsphingosine (lysoGb3), so concentrations of Gb3 and lyso-Gb3 are biomarkers of the extent of the disease. 4.1. For purposes of determining the dosages of PRX-102 to be used in Stage II for Cohorts A and B, blood samples for measuring the concentration of Gb3 and lyso-Gb3 will be collected in Stage I every 2 weeks from Visits #1 to #9 (baseline to Week 16) and urine samples for measuring lyso-Gb3 will be collected as outlined from Visit #1 to #8 (baseline to Week 12). 4.2. For purpose of assessing efficacy, additional blood samples for the measurement of Gb3 and lyso-Gb3 and urine samples for the measurement of lyso-Gb3 will be collected at specified time points during the study in all cohort. 4.3. PD will be measured at the following time points: 4.3.1. For the first patients in Cohorts A and B: at Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 26 in Stage I, and Weeks 12, 26, 38, 52 in Stage II and quarterly in Stage III 4.3.2. For the first patients in Cohort C: at Baseline, Weeks 2, 4, 12 in Stage I, Weeks 26, 38 and 52 in Stage II and quarterly in Stage III 4.3.3. For patients entering directly in Stage II: at Baseline, Weeks 12, 26, 52 and (54) in Stage II and quarterly in Stage III
Key secondary outcome measure(s)	There are no secondary outcome measures
Completion date	31/12/2029

Eligibility

Participant type(s)	Patient
Age group	Child
Lower age limit	2 Years
Upper age limit	17 Years
Sex	All
Target sample size at registration	22
Key inclusion criteria	1. Male or female aged 2 to 7 years (Cohort A), 8 to 12 years (Cohort B), or 13 to <18 years (Cohort C) 2. A documented diagnosis of Fabry disease, as determined by the following: 2.1. Males: Plasma and/or leukocyte alpha-galactosidase-A (α-GAL-A) activity (by activity assay) that is ≤ 5% of mean normal laboratory levels, or, if the enzymatic activity is above the 5% limit but still under the normal level, a confirmed disease-causing mutation of the α-GAL-A (GLA)gene. 2.2. Females: Historical genetic test results consistent with Fabry mutations, or, in the case of novel mutations, a first-degree male relative with Fabry disease. 2.3. All subjects: At least one of the following characteristic features of Fabry disease: neuropathic pain, cornea verticillata, and/or clustered angiokeratoma. 3. History of Fabry pain: 3.1. Episodic crises (Fabry crises) characterised by agonizing burning pain originating in the extremities and radiating inwards to the limbs and other parts of the body, OR 3.2. Chronic pain characterised by burning and tingling paraesthesia 4. Clinical condition that, in the opinion of the Investigator, requires treatment with enzyme replacement therapy (ERT).
Key exclusion criteria	1. Estimated glomerular filtration rate (eGFR) at screening < 80 mL/min/1.73 m2, calculated using the Creatinine Cystatin C-based Chronic Kidney Disease in Children (CKiD) equation (2012). 2. History of type I hypersensitivity reactions (anaphylactic or anaphylactoid life-threatening reaction) to other ERT treatment for Fabry disease or to any component of the study drug. 3. Initiation of treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB), or a change of dose in ongoing treatment, in the 4 weeks prior to screening. 4. Subject with urine protein to creatinine ratio (UPCR) > 0.5 g/g (0.5 mg/mg or 500 mg/g) if not treated with an ACE inhibitor or ARB. 5. Currently taking another investigational drug for any condition. 6. Carry only known non-pathogenic Fabry mutations. 7. History of acute kidney injury in the 12 months prior to screening, including specific kidney diseases (e.g., acute interstitial nephritis, acute glomerular and vasculitic renal diseases); non-specific conditions (e.g., ischaemia, toxic injury); or extrarenal pathology (e.g., prerenal azotaemia, acute postrenal obstructive nephropathy). 8. History of renal dialysis or kidney transplantation. 9. History of or current malignancy requiring treatment. 10. Severe cardiomyopathy or significant unstable cardiac disease within 6 months prior to screening. 11. A positive test for Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) within 3 months prior to screening, using a validated molecular assay or antigen assay. 12. Presence of any medical, emotional, behavioural, or psychological condition that in the judgement of the Investigator could interfere with the subject’s compliance with the requirements of the study. 13. Additional Exclusion Criteria for Subjects Enrolled in Stage I:For subjects enrolled in Stage I (targeting up to 9 subjects total) these specific exclusion criteria, in addition to those above, apply: a) Female b) Non-classic form of Fabry disease c) Receipt of treatment for Fabry disease within 6 months prior to screening d) Positive for anti-PRX-102 antibodies at screening 14. Additional Exclusion Criteria for Subjects in Stage II: a) Unwilling to discontinue current ERT treatment for Fabry disease at least 14 days, or chaperone therapy at least 3 days, before baseline. 15. Additional Exclusion Criteria for Subjects in Stage II: Females: Pregnant or lactating, or of childbearing potential with a fertile male partner and/or unwilling to undergo pregnancy testing as outlined and to use a highly reliable method of contraception from the informed consent signature until 30 days after the last infusion. Note: Before the start of treatment, the Investigator will decide whether or not pregnancy testing and contraception counselling are necessary. Since over the course of the study, pre-pubertal girls may reach menarche and adolescents of either gender may become sexually active, the Investigator must periodically check on the status of these issues and implement pregnancy testing and/or contraception counselling if required. A female subject is considered of childbearing potential, i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 16. Note: Inclusion and Exclusion criteria will be assessed at the screening visit and verified at the baseline visit.
Date of first enrolment	30/04/2025
Date of final enrolment	29/09/2027

Locations

Countries of recruitment

United Kingdom
England
Austria
France
Norway
Spain
United States of America

Study participating centre

Great Ormond Street Hospital

Great Ormond Street
London
WC1N 3JH
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not expected to be made available
IPD sharing plan	The datasets generated during and/or analysed during the current study are not expected to be made available due to the Clinical trial transparency policy - Patient-level data will not be shared from rare disease trials since the risk of re-identification is too high and the Sponsor values the privacy rights of its patients.

Editorial Notes

27/01/2025: The recruitment start date was changed from 15/01/2025 to 30/04/2025.
20/09/2024: The recruitment start date was changed from 29/09/2024 to 15/01/2025.
21/08/2024: The ethics approval was added.
02/08/2024: Internal review.
27/07/2024: ISRCTN received notification of combined HRA/MHRA approval for this trial on 27/07/2024.
09/05/2024: Study's existence confirmed by Health Research Authority (HRA) (UK).