Lentiviral (LV) Gene Therapy for Adenosine Deaminase (ADA) Deficiency

Phase I/II, Historical Controlled, Open-label, Non-randomised, Single-centre Trial to Assess the Safety and Efficacy of EF1αS-ADA Lentiviral Vector Mediated Gene Modification of Autologous CD34+ Cells From ADA-deficient Individuals

This is a historically controlled, non-randomized Phase I/II clinical trial to assess the safety and efficacy of autologous transplantation of CD34+ hematopoietic stem/progenitor cells (HSPCs), obtained from infants affected by ADA-SCID, following transduction of the HSPCs with a lentiviral vector (LV) carrying the human ADA complementary DNA (cDNA) under the control of the elongation factor 1 alpha shortened (EFS) promoter. Subjects treated in the trial receive the infusion of autologous, transduced cells following marrow cytoreduction with busulfan. The outcomes are compared to those observed in a historical control group of patients who received an allogeneic hematopoietic stem cell transplant (HSCT).

This Phase I/II clinical trial will be performed at Great Ormond Street Hospital (GOSH), London, United Kingdom.

Study Overview

• Status: Completed
• Conditions: Adenosine Deaminase Deficiency; Severe Combined Immunodeficiencies (SCID)
• Intervention / Treatment: Drug: Busulfan; Genetic: Infusion of autologous EFS-ADA LV CD34+ cells; Drug: Peg-Ada; Other: Haematopoietic Stem Cell Transplantation (HSCT)

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital For Children NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 13 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Gene Therapy (On Trial)

Inclusion Criteria:

1. Diagnosis of ADA-SCID confirmed by DNA sequencing or by confirmed absence of <3% of ADA enzymatic activity in peripheral blood (or for neonates) in umbilical cord blood erythrocytes and/or leukocytes or in cultured fetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of Polyethylene glycol-modified ADA (PEG-ADA) replacement therapy
2. Patients who lack a fully Human leukocyte antigen (HLA)-matched family donor
3. Patients (male or female) <5 years of age OR Patients (male or female) ≥ 5 years to 15 years of age who have preserved thymic function as evidenced by presence of >10 % naïve T cells (CD4+45RA+27+ cells)
4. Parental/guardian signed informed consent

Exclusion Criteria:

1. Cytogenetic abnormalities on peripheral blood
2. Evidence of active malignant disease
3. Known sensitivity to busulfan
4. If applicable, confirmed pregnancy (to be tested in patients above 12 years old)

Gene Therapy (CUP)

A group of patients were treated under CUP (GOSH special license) either because the study was not yet open and patients needed urgent treatment, or because they were outside of the inclusion/exclusion criteria or received Investigational Medicinal Product (IMP) followed a different process (ie, received in two infusions). Patients followed the same protocol steps and study visits.

Historical Control Group

Inclusion Criteria:

1. Diagnosis of ADA-SCID confirmed by DNA sequencing OR by confirmed absence of <3% of ADA enzymatic activity in peripheral blood or (for neonates) in umbilical cord blood erythrocytes and/or leucocytes or in cultured foetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of PEG-ADA replacement therapy
2. Patients (male or female) between 0-18 years at time of treatment
3. Patient treated with allogeneic haematopoietic stem cell transplantation since 2000

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Gene Therapy; Infusion of autologous EFS-ADA LV CD34+ cells	Drug: Busulfan; Busulfan is used for non-myeloablative conditioning; Genetic: Infusion of autologous EFS-ADA LV CD34+ cells; Autologous EFS-ADA LV CD34+ cells (OTL-101*) are infused intravenously; Other Names: OTL-101*; Drug: Peg-Ada; Peg-Ada enzyme replacement therapy is discontinued at Day +3- (-3/+15 days) after successful engraftment
Other: Historical Control Group; Historical data from ADA-SCID patients who were treated with Hematopoietic Stem Cell Transplantation (HSCT)	Other: Haematopoietic Stem Cell Transplantation (HSCT); Historical data from a database of ADA-SCID patients treated with allogeneic HSCT from GOSH will be collected as comparator group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)	Overall survival is defined as the percentage of subjects alive at 12 months post- treatment with OTL-101* or HSCT	12 months
Event-free Survival (EvFS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)	Event-free survival is defined as the percentage of subjects alive with no "event", an "event" being the resumption of PEG-ADA ERT or the need for a rescue allogenic Hematopoietic Stem Cell Transplant (HSCT), or death.	12 months
Vector Copy Number (VCN) in Granulocytes Fraction (Neutrophils)	Engraftment of transduced cells was assessed using vector gene marking in granulocytes (neutrophils)	36 months
VCN in Peripheral Blood Mononuclear Cells (PBMCs)	Engraftment of transduced cells was assessed using vector gene marking in PBMCs	36 months
VCN in CD3+ T Cells	Engraftment of transduced cells was assessed using vector gene marking	36 months
VCN in CD19+ B Cells	Engraftment of transduced cells was assessed using vector gene marking in CD19+ B Cells	36 months
Change From Baseline in CD3+ T Cell Counts (1 Year)	Immune reconstitution was assessed by change in CD3+ T Cell counts over time.	12 months
Change From Baseline in CD3+ T Cell Counts (3 Years)	Immune reconstitution was assessed by change in CD3+ T Cell counts over time.	36 months
ADA Activity in Erythrocytes	ADA enzyme activity was assessed as a measure of successful engraftment of genetically modified Hematopoietic stem progenitor cells (HSPCs), as it marks sustained gene expression from the normal ADA transgene.	36 months
Reduction in Deoxyadenosine Triphosphate (dATP) in Erythrocytes	Decreased dATP levels coincide with increased ADA enzyme activity, detoxification was used as a marker of correction of the defective ADA gene. The threshold for detoxification was <100 μmol/L.	36 months
Frequency of Vector Integration Into Known Protooncogenes (3 Years)	Vector Integration Site Analysis (VISA) allowed determination of the distribution of vector integration sites in each subject's genome, as well as the relative clonal abundance. VISA was to be considered abnormal for a subject if, in 2 or more instances during the course of follow-up, a single integration site was found to represent >30% of the total integration sites detected. There were no instances of clonal proliferation in the course of the 36 month follow-up for on-study and CUP subjects; hence, a detailed analysis of the frequency of clonal expansion associated with vector integration near proto-oncogenes was not generated.	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years)	Overall survival (OS) is defined as the percentage of subjects alive at 36 months post- treatment with OTL-101* or HSCT	36 months
EvFS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years)	Event-free survival is defined as the percentage of subjects alive with no "event", an "event" being the resumption of PEG-ADA ERT or the need for a rescue allogenic Hematopoietic Stem Cell Transplant (HSCT), or death.	36 months
Infection Rate	The infections of interest in this study were severe infections or opportunistic infectious episodes, defined as infections requiring hospitalization or prolonging hospitalization and/or documented infections by opportunistic pathogens.	36 months

Collaborators and Investigators

• Sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust
• Collaborators: Orchard Therapeutics
• Investigators: Principal Investigator: Claire Booth, Dr, Great Ormond Street Hospital NHS Foundation Trust

Publications and helpful links

General Publications

• Kohn DB, Booth C, Shaw KL, Xu-Bayford J, Garabedian E, Trevisan V, Carbonaro-Sarracino DA, Soni K, Terrazas D, Snell K, Ikeda A, Leon-Rico D, Moore TB, Buckland KF, Shah AJ, Gilmour KC, De Oliveira S, Rivat C, Crooks GM, Izotova N, Tse J, Adams S, Shupien S, Ricketts H, Davila A, Uzowuru C, Icreverzi A, Barman P, Campo Fernandez B, Hollis RP, Coronel M, Yu A, Chun KM, Casas CE, Zhang R, Arduini S, Lynn F, Kudari M, Spezzi A, Zahn M, Heimke R, Labik I, Parrott R, Buckley RH, Reeves L, Cornetta K, Sokolic R, Hershfield M, Schmidt M, Candotti F, Malech HL, Thrasher AJ, Gaspar HB. Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency. N Engl J Med. 2021 May 27;384(21):2002-2013. doi: 10.1056/NEJMoa2027675. Epub 2021 May 11.

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2012
• Primary Completion (Actual): December 23, 2019
• Study Completion (Actual): December 23, 2019

Study Registration Dates

• First Submitted: June 23, 2011
• First Submitted That Met QC Criteria: June 23, 2011
• First Posted (Estimate): June 27, 2011

Study Record Updates

• Last Update Posted (Actual): September 16, 2021
• Last Update Submitted That Met QC Criteria: August 20, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: ADA-SCID; Gene therapy; Lentiviral vector; Hematopoietic stem and progenitor cells
• Additional Relevant MeSH Terms: Metabolic Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; DNA Repair-Deficiency Disorders; Primary Immunodeficiency Diseases; Severe Combined Immunodeficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Busulfan
• Other Study ID Numbers: 10-MI-29

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No