Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID

NCT02999984 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: OTL-101-4
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

This is a prospective, non-randomized, single-cohort, longitudinal, single-center, clinical study designed to assess the efficacy and safety of a cryopreserved formulation of OTL-101 (autologous CD34+ hematopoietic stem/progenitor cells transduced ex vivo with EFS (Elongation Factor 1α Short form) Lentiviral Vector (LV) encoding for the human ADA gene) administered to ADA-SCID subjects between the ages of 30 days and 17 years of age, who are not eligible for an Human Leukocyte Antigen (HLA) matched sibling/family donor and meeting the inclusion/exclusion criteria. The OTL-101 product is infused after a minimal interval of at least 24 hours following the completion of reduced intensity conditioning. For subjects who successfully receive the OTL-101 product, pegademase bovine (PEG-ADA) Enzyme Replacement Therapy (ERT) is discontinued at Day+30 (-3/+15) after the transplant. After their discharge from hospital, the subjects will be seen at regular intervals to review their history, perform examinations and draw blood samples to assess immunity and safety.

Conditions

Severe Combined Immunodeficiency Due to ADA Deficiency

Keywords

gene therapy; hematopoietic and progenitor cells; lentiviral vector; ADA-SCID

Outcome Measures

Primary Outcomes (3)

• Percentage of Participants With Treatment Efficacy After Treatment With OTL 101 (6 Months)

  Efficacy of OTL-101 treatment at 6 months post OTL-101 infusion based on the following parameters and thresholds: 1. ADA enzyme activity in erythrocytes above baseline/pretreatment level (i.e., \>0 units). ADA enzyme activity is measured to assess the amount of functional gene product produced from the normal ADA transgene delivered by EFS-ADA LV. 2. Absolute CD3+ T cell counts ≥200 cells/μL. Increase in CD3+ T cell counts is a marker of immune reconstitution. 3. Granulocyte samples positive for vector sequences by quantitative Polymerase Chain Reaction (PCR) (≥1/10,000 cells). Vector copy number (VCN) in the Peripheral Blood (PB) Granulocytes fraction that was T cell depleted, is a surrogate for amount of engrafted genetically modified Hematopoietic stem cell (HSC) that are producing granulocytes every 3-5 days.

  6 months

• 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 cryopreserved OTL-101.

  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 allogeneic Hematopoietic Stem Cell Transplant (HSCT), or death.

  12 Months

Secondary Outcomes (7)

• OS of Subjects Treated With Investigational Medicinal Product (IMP) (2 Years)

  24 months

• EvFS of Subjects Treated With Investigational Medicinal Product (IMP) (2 Years)

  24 months

• Change From Baseline in CD3+ T Cell Counts (2 Years)

  24 months

• Severe Infections Excluding First 3 Months After Treatment

  24 months

• Change From Baseline in Quality of Life Measures (2 Years)

  24 months

Study Arms (1)

Gene Therapy

EXPERIMENTAL

Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells

Genetic: Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101); Drug: busulfan; Drug: PEG-ADA ERT

Interventions

Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101) GENETIC

autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101) are infused intravenously

Also known as: OTL-101

Gene Therapy

busulfan DRUG

Busulfan is used for non-myeloablative conditioning

Gene Therapy

PEG-ADA ERT DRUG

PEG-ADA ERT is discontinued at Day +30 (-3/+15 days) after successful engraftment

Gene Therapy

Eligibility Criteria

• Age: 30 Days - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Provision of written informed consent prior to any study related procedures. In this study consent must be provided by the parents/legal guardians and, where applicable according to local laws, a signed assent from the child,
• Subjects ≥30 days and \<18 years of age,
• With a diagnosis of ADA-SCID based on:
• Evidence of ADA deficiency, defined as:
• i. Decreased ADA enzymatic activity in erythrocytes, leukocytes, skin fibroblasts, or in cultured fetal cells to levels consistent with ADA-SCID as determined by the reference laboratory, or ii. Identified mutations in ADA alleles consistent with a severe reduction in ADA activity,
• Evidence of ADA-SCID based on either:
• i. Family history of a first order relative with ADA deficiency and clinical and laboratory evidence of severe immunologic deficiency, or ii. Evidence of severe immunologic deficiency in subjects prior to the institution of immune restorative therapy, based on
• Lymphopenia (absolute lymphocyte count (ALC) \<400 cells/µL) OR absence or low number of T cells (absolute CD3+ count \< 300 cells/µL), or
• Severely decreased T lymphocyte blastogenic responses to phytohemagglutinin (either \<10% of lower limit of normal controls for the diagnostic laboratory, or \<10% of the response of the normal control of the day, or stimulation index \<10), or
• Identification of SCID by neonatal screening revealing low T cell Receptor Excision Circle (TREC) levels.
• Ineligible for matched family allogeneic Bone Marrow (BM) transplantation, defined as the absence of a medically eligible HLA-identical sibling or family donor, with normal immune function, who could serve as an allogeneic bone marrow donor.
• Females of child-bearing age will be required to provide a negative pregnancy test 30 days prior to Visit 2.
• Subjects and their parents/legal guardians must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period and willing to return to the clinic for the follow up evaluation as specified in the protocol.

You may not qualify if:

• Ineligible for autologous Hematopoietic Stem Cell Transplantation (HSCT) as per clinical site criteria.
• Other conditions which in the opinion of the Principal Investigator and/or Co Investigators, contraindicate the harvest of bone marrow, the administration of Busulfan and the infusion of transduced cells, or which indicate an inability of the subject or subject's parent/legal guardian to comply with the protocol.
• Hematologic abnormality, defined as:
• Anemia (Hb \<8.0 g/dl).
• Neutropenia (ANC \<500/mm3). Note: ANC \<500 with absence of myelodysplastic syndrome on bone marrow aspirate and biopsy and normal marrow cytogenetics are acceptable for eligibility.
• Thrombocytopenia (platelet count \<50,000/mm3, at any age).
• Prothrombin time or international normalized ratio (INR) and partial thromboplastin time (PTT) \>2 x upper limit of normal (ULN) (subjects with a correctable deficiency controlled on medication will not be excluded).
• Cytogenetic abnormalities on peripheral blood or bone marrow or amniotic fluid (if available).
• Prior allogeneic HSCT with cytoreductive conditioning.
• Pulmonary abnormality, defined as:
• Resting O2 saturation by pulse oximetry \<90% on room air.
• Chest X-ray indicating active or progressive pulmonary disease. Note: Chest X ray indicating residual signs of treated pneumonitis is acceptable for eligibility.
• Cardiac abnormality, defined as:
• Abnormal ECG indicating cardiac pathology.
• Uncorrected congenital cardiac malformation with clinical symptoms.

Sponsors & Collaborators

• University of California, Los Angeles: lead
• California Institute for Regenerative Medicine (CIRM): collaborator
• Orchard Therapeutics: collaborator

Study Sites (1)

University of California, Los Angeles

Los Angeles, California, 90095, United States

Location

Related Publications (2)

• Carbonaro DA, Zhang L, Jin X, Montiel-Equihua C, Geiger S, Carmo M, Cooper A, Fairbanks L, Kaufman ML, Sebire NJ, Hollis RP, Blundell MP, Senadheera S, Fu PY, Sahaghian A, Chan RY, Wang X, Cornetta K, Thrasher AJ, Kohn DB, Gaspar HB. Preclinical demonstration of lentiviral vector-mediated correction of immunological and metabolic abnormalities in models of adenosine deaminase deficiency. Mol Ther. 2014 Mar;22(3):607-622. doi: 10.1038/mt.2013.265. Epub 2013 Nov 20.

  PMID: 24256635 BACKGROUND

• 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.

  PMID: 33974366 BACKGROUND

Related Links

• Pre-clinical activity and safety data

MeSH Terms

Conditions

Severe combined immunodeficiency due to adenosine deaminase deficiency

Interventions

Busulfan

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Results Point of Contact

• Title: Orchard Medical Information
• Organization: Orchard Therapeutics (Europe) Ltd

medinfo@orchard-tx.com

+44 (0) 203 808 8286

Study Officials

• Donald B. Kohn, MD

  University of California, Los Angeles

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 19, 2016
• First Posted: December 21, 2016
• Study Start: December 16, 2016
• Primary Completion: October 11, 2018
• Study Completion: September 26, 2019
• Last Updated: August 3, 2022
• Results First Posted: July 22, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)