An Efficacy and Safety Study of AVR-RD-02 Compared to Enzyme Replacement Therapy for Treatment of Gaucher Disease Type 3

NCT05815004 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: AVRO-RD-02-301
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of autologous hemotopoietic stem cell (HSC) gene therapy, AVR-RD-02, compared to enzyme replacement therapy, for the treatment of Gaucher disease Type 3 in male and female participants aged 2 to 25 years. The study will consist of 2 parts - Core (Part 1) followed by the ERT-crossover (Part 2)

Conditions

Gaucher Disease, Type 3

Keywords

Gaucher Disease; Gaucher Disease, Type 3; Neuronopathic Gaucher Disease; GD3

Outcome Measures

Primary Outcomes (1)

• Change from baseline in a multidomain endpoint as assessed by Global Statistical Test (GST)

  The multidomain endpoint consists of the following 4 domains: I. Change in modified Scale for Assessment and Rating of Ataxia total score (mSARA) II. Percent change in diffusing capacity of the lung for carbon monoxide (DLco) for the assessment of interstitial lung disease (ILD) III. Percent change in spleen volume by Magnetic Resonance Imaging (MRI) IV. Percent change in a liver volume by MRI

  Baseline to 52 weeks post AVR-RD-02 infusion (AVR-RD-02 arm) or Baseline to 52 weeks (ERT arm)

Secondary Outcomes (10)

• Change from Baseline in Lyso-Gb1 level in cerebrospinal fluid (CSF) as assessed by liquid chromatography tandem mass spectrometry (LC/MS/MS)

  Baseline to 52 weeks post AVR-RD-02 infusion (AVR-RD-02 arm) or Baseline to 52 weeks (ERT arm)

• Change from baseline in clinical improvement as assessed by Clinical Global Impression -Improvement (CGI-I scale)

  Baseline to 52 weeks post AVR-RD-02 infusion (AVR-RD-02 arm) or Baseline to 52 weeks (ERT arm)

• Change from baseline in pain as assessed by Brief Pain Inventory-Short Form (BPI-SF) questionnaire scores

  Baseline to 52 weeks post AVR-RD-02 infusion (AVR-RD-02 arm) or Baseline to 52 weeks (ERT arm)

• Vector Copy Number (VCN) - Engraftment of genetically-modified hematopoietic stem cells (HSCs) in peripheral blood leukocytes (PBL) as assessed by droplet digital polymerase chain reaction (ddPCR)

  Baseline to 52 weeks post AVR-RD-02 infusion

• Vector Copy Number (VCN) - Engraftment of genetically-modified hematopoietic stem cells (HSCs) in bone marrow as assessed by digital droplet polymerase chain reaction (ddPCR)

  Baseline to 52 weeks post AVR-RD-02 infusion

Study Arms (2)

AVR-RD-02 Arm

EXPERIMENTAL

Participants will have been on a stable prescribed ERT dose for at least 6 consecutive months at the time of Screening and willing to remain on the same ERT dose until 2 weeks prior to gene therapy infusion.

Drug: Gene therapy

ERT Control Arm

ACTIVE COMPARATOR

Participants on stable prescribed ERT dose for at least 6 consecutive months at the time of Screening. Participants will have the opportunity to receive a gene therapy infusion of AVR-RD-02 after week 52 of Part 1.

Drug: Gene therapy; Drug: Enzyme Replacement Agent

Interventions

Gene therapy DRUG

AVR-RD-02 Drug product: active substance is autologous CD34+ enriched hematopoietic stem cells (HSCs) that have been genetically modified ex vivo with a lentiviral vector (LV) to contain a ribonucleic acid (RNA) transcript that, after reverse transcription, results in codon-optimized, complementary deoxyribonucleic acid (cDNA) that, upon its integration into human genome, encodes for functional human glucocerebrosidase (GCase)

Also known as: AVR-RD-02

AVR-RD-02 Arm; ERT Control Arm

Enzyme Replacement Agent DRUG

A hydrolytic lysosomal glucocerebrosidase-specific enzyme

Also known as: Imiglucerase, velaglucerase, taliglucerase alfa

ERT Control Arm

Eligibility Criteria

• Age: 2 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Participant and/or parent, caregiver, or legal representative must be willing and able to provide written informed consent/assent for the study in accordance with applicable regulations and guidelines and to comply with all study visits and procedures, including the use of any data collection device(s) that may be used to directly record participant data.
• Participant is ≥2 to ≤ 25 years old, at the time of providing informed consent or assent.
• Participant has a confirmed diagnosis of Gaucher disease Type 3 based on all of the following:
• Biallelic GBA1 gene mutation
• Deficient GCase enzyme activity in blood
• Clinical phenotype with the presence of gaze palsy, predominantly horizontal and with slow or absent saccades
• Participant has the presence of one or both of the following within 3 months of screening:
• Ataxia (score ≥1) based on the modified scale for the assessment and rating of ataxia total score (mSARA)
• Interstitial lung disease (to be confirmed by radiological imaging)
• Participant has the presence of one or both of the following within 3 months of screening:
• Hepatomegaly
• Splenomegaly
• Participant is on stable prescribed ERT dose for ≥6 consecutive months at the time of Screening.
• Participant has not received SRT or chaperone therapy for Gaucher disease during the 6 months immediately preceding Screening.
• Participant is willing to attend all study visits and comply with all study procedures and assessments.

You may not qualify if:

• Participant has a diagnosis of Gaucher disease Type 1 or Type 2.
• Participant has any one of the following:
• Hemoglobin value of \<9.0 g/dL
• Platelet count of \<70 × 109/L
• Pulmonary hypertension
• Bone crisis attributable to osteonecrosis and/or pathological fractures within 3 months prior to Screening
• Treatment refractory epilepsy
• Progressive myoclonic epilepsy
• Participant has had or is scheduled to undergo a partial or total splenectomy.
• Participant requires use of invasive ventilatory support.
• Participant requires use of noninvasive ventilator support while awake for longer than 12 hours daily.
• Participant has a contraindication to ERT, including a prior anaphylactic or anaphylactoid reaction of any severity to ERT.
• Busulfan is contraindicated for the participant.
• Participant has a history of sensitivity to dimethyl sulfoxide.
• Participant presents with iron, folic acid, and/or vitamin B12 deficiency anemia during Screening.

Sponsors & Collaborators

• AVROBIO: lead

MeSH Terms

Conditions

Gaucher Disease

Interventions

Genetic Therapy; imiglucerase; Velaglucerase alfa, human; taliglucerase alfa

Condition Hierarchy (Ancestors)

Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Intervention Hierarchy (Ancestors)

Biological Therapy; Therapeutics; Genetic Engineering; Genetic Techniques; Investigative Techniques

Study Officials

• Milena Veselinovic, MD, PhD

  AVROBIO, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Participants, who are randomized to the ERT control arm, will have the opportunity to cross over and receive AVR-RD-02 gene therapy.

Study Record Dates

• First Submitted: April 3, 2023
• First Posted: April 18, 2023
• Study Start: October 1, 2023
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: August 9, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will share