Safety and Efficacy of Encapsulated Allogeneic MPS-1 Therapy

Study Overview
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Brief Summary
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SIG-005-121 is a FIH, Phase 1/2, multi-centre, open-label, sequential dose-escalating study to assess the safety, tolerability, and preliminary efficacy of SIG-005 in adults with MPS-1. The study will evaluate up to three ascending dose levels of SIG-005 in male and female patients with attenuated MPS-1 (Scheie or Hurler-Scheie), 18 years of age or greater, who received Enzyme Replacement Therapy (ERT) for a minimum of 12 months prior to the study entry. Each cohort will include 3 patients.

Official Title
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A Phase 1/2 Open-Label, Sequential Dose-Escalation, Safety, Tolerability and Efficacy Study of SIG-005 in Adult Patients With Mucopolysaccharidoses 1 (MPS-1)

Conditions
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MPS I, MPS1-S, MPS1-HS

Intervention / Treatment
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* Combination Product: SIG-005 (hIDUA Producing Spheres)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to provide informed consent Male or female aged 18 or older Diagnosis of attenuated MPS-1 (Hurler-Scheie or Scheie) Alpha-L-iduronidase enzyme activity level of less than 10% of the lower limit of the normal range Prior treatment with ERT Willing to transition from ERT to SIG-005 Female patients of childbearing potential with negative pregnancy test Use of highly effective method of contraception if applicable Exclusion Criteria: A diagnosis of severe MPS-1 Previous haematopoietic stem cell transplantation (HSCT) History of elevated total (IgG) anti-IDUA antibody Use of assistive respiratory devices Unable to walk independently History of allergic reaction or anaphylaxis to recombinant hIDUA Body mass index (BMI) ≥35 History of abdominal adhesions, medical history of Crohn's disease, inflammatory bowel disease or any disease that increases the risk of post-operative abdominal adhesions Significant underlying disease or comorbidities that are a contraindication for general anaesthesia or laparoscopic procedure Pregnant or lactating patients Prior administration of a gene therapy product Participation in another investigational medicine or device study Abnormal laboratory values as defined in the protocol Active alcoholism or drug addiction during the 12 months before the screening visit Active malignancy or history of malignancy in the 5 years prior to study entry Recent COVID-19 infection: within 60 days of recovery from infection Vaccination(s) within the last 60 days (including vaccines for SARS-CoV-2/COVID- 19)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SIG-005<br>SIG-005 is comprised of human native alpha-L-iduronidase enzyme (hIDUA) producing spheres | Combination Product: SIG-005 (hIDUA Producing Spheres)<br>* Laparoscopic administration of SIG-005 spheres, an encapsulated allogeneic cell therapy genetically modified with a non-viral vector to produce hIDUA<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with clinically significant changes from baseline in physical examination | Safety and tolerability will be assessed by evaluating the number of patients with clinically significant changes from baseline in physical examination as assessed by an assessment of general appearance (head, eyes, ears, nose, and throat), as well as review of cardiovascular, dermatologic, gastrointestinal, genitourinary, lymphatic, musculoskeletal, neurologic and respiratory systems. Directed physical examinations at protocol-specified visits will be based on the patient's clinical status and will include general appearance, cardiovascular, gastrointestinal, neurologic, and respiratory assessments. Clinically significant changes from baseline will be captured as AEs. | Baseline up to 5 years | 
| Number of patients with clinically significant changes in vital signs from baseline | Safety and tolerability will be assessed by evaluating the number of patients with clinically significant changes from baseline in vital signs, including temperature, respiratory rate, seated blood pressure, and pulse. | Baseline up to 5 years | 
| Number of patients with clinically significant changes in total (IgG) IDUA antibody titres from baseline | Safety and tolerability will be assessed by evaluating the number of patients with clinically significant changes from baseline in total (IgG) antibody titres against IDUA | Baseline up to 5 years | 
| Number of patients with clinically significant changes in clinical laboratory tests from baseline | Safety and tolerability will be assessed by evaluating the number of patients with clinically significant changes from baseline in clinical laboratory tests, including hematology, serum chemistry, and urinalysis. | Baseline up to 5 years | 
| Number of patients with clinically significant changes in treatment-emergent adverse events (TEAE) from baseline, as assessed by CTCAE v5.0. | Safety and tolerability will be assessed by evaluating the number of patients with clinically significant changes from baseline in TEAEs as assessed by CTCAE v5.0. | Baseline up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate and Characterize effect of SIG-005 in levels of α-L-iduronidase (IDUA) in blood after administration of SIG-005 | To evaluate and characterize levels of IDUA and leukocyte count in blood plasma from time of baseline up to 5 years post-administration of SIG-005. | Baseline up to 5 years | 
| To evaluate and Characterize effect of SIG-005 on glycosaminoglycans (GAG) levels in urine following administration of SIG-005. | Total GAG, HS and DS levels in urine and any clinically significant changes will be assessed from time of baseline up to 5 years post-administration of SIG-005. | Baseline up to 5 years | 
| To evaluate and Characterize effect of SIG-005 MRI images of liver and spleen volume | Non-contrast MRI of the liver and spleen will be performed to determine any clinically significant changes in liver or spleen volume from time of baseline up to 5 years post-administration of SIG-005. | Baseline up to 5 years | 
| To evaluate and Characterize effect of SIG-005 on cardiac measurements via electrocardiogram (ECG) | Resting 12-lead ECG assessments will be performed to determine any clinically significant changes in cardiac measurements from time of baseline up to 5 years post-administration of SIG-005. | Baseline up to 5 years |