simoladagene autotemcel (OTL-101) / Kyowa Kirin - LARVOL DELTA

A Clinical Study to Enable Process Validation of Commercial Grade OTL-101 (clinicaltrials.gov) - P2/3; N=3; Recruiting; Sponsor: Orchard Therapeutics

Clinical • New P2/3 trial • Gene Therapies • Genetic Disorders • Primary Immunodeficiency

Lentiviral Gene Therapy with Autologous Hematopoietic Stem and Progenitor Cells (HSPCs) for the Treatment of Severe Combined Immune Deficiency Due to Adenosine Deaminase Deficiency (ADA-SCID): Results in an Expanded Cohort (ASH 2019) - P1/2; "Single dose busulfan (4 mg/kg) was administered prior to infusion of OTL-101...One of 30 OTL-101 subjects (3%) did not engraft and was restarted on ERT; the subject was withdrawn from the study at 5.9 mo and subsequently received a rescue HSCT, whereas 42% of HSCT patients required rescue HSCT, PEG-ADA ERT or died... Based on sustained gene correction and restoration of immune function in all subjects who engrafted, treatment of ADA-SCID with OTL-101 has a favorable benefit-risk profile. Key correlates of engraftment were consistent across the expanded cohort. Importantly, higher rates of OS and EvFS compared with HSCT (with or without an MRD) were observed."

CD34

Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID (clinicaltrials.gov) - P1/2 | N=13 | Completed | Sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust | Active, not recruiting ➔ Completed

Preclinical • Trial completion • Viral vector • Genetic Disorders • Immunology • Primary Immunodeficiency

A Clinical Study to Enable Process Validation of Commercial Grade OTL-101 (clinicaltrials.gov) - P2/3 | N=0 | Withdrawn | Sponsor: University of California, Los Angeles | Terminated ➔ Withdrawn

Preclinical • Trial withdrawal • Gene Therapies • Genetic Disorders • Immunology • Primary Immunodeficiency

A Clinical Study to Enable Process Validation of Commercial Grade OTL-101 (clinicaltrials.gov) - P2/3; N=3; Terminated; Sponsor: Orchard Therapeutics; Trial completion date: Feb 2022 ➔ Aug 2021; Suspended ➔ Terminated; Recruitment on hold for business reasons

Clinical • Preclinical • Trial completion date • Trial termination • Gene Therapies • Genetic Disorders • Immunology • Primary Immunodeficiency

Autologous CD34+ Hematopoietic Stem Cells Transduced ex Vivo With Elongation Factor 1 Alpha Shortened (EFS) Lentiviral Vector Encoding for the Human ADA Gene (clinicaltrials.gov) - P1/2; N=46; Completed; Sponsor: Orchard Therapeutics; N=20 ➔ 46

Enrollment change • Preclinical • Genetic Disorders • Immunology • Primary Immunodeficiency • Transplantation

Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID (clinicaltrials.gov) - P1/2; N=13; Active, not recruiting; Sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust; Recruiting ➔ Active, not recruiting; N=10 ➔ 13

Enrollment change • Enrollment closed • Genetic Disorders • Immunology • Primary Immunodeficiency

[VIRTUAL] Autologous Ex Vivo Lentiviral Gene Therapy for the Treatment of ADA-SCID (ASGCT 2021) - "An investigational gene therapy (GT) consisting of autologous CD34+ hematopoietic stem cell progenitors (HSPCs) transduced ex vivo using a self-inactivating lentiviral vector (LV) encoding the human ADA cDNA sequence under the control of a shortened human elongation factor 1α gene promoter (EFS-ADA LV) was studied in trials in the US and EU. Fifty patients with ADA-SCID (30 in the US and 20 in the EU) were treated with lentiviral gene therapy following non-myeloablative busulfan conditioning. An analysis was conducted integrating two US studies (using fresh and cryopreserved formulations of OTL-101) at 24-months’ follow-up alongside an EU study (fresh formulation) with 36-months’ follow-up. Overall survival was 100% for all analyses up to 24 and 36 months... Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high rates of overall and event-free survival, with sustained ADA gene expression, metabolic correction, and functional immune reconstitution."

Preclinical • Gene Therapies • Genetic Disorders • Graft versus Host Disease • Immunology • Primary Immunodeficiency • Transplantation • CD34

A Clinical Study to Enable Process Validation of Commercial Grade OTL-101 (clinicaltrials.gov) - P2/3; N=3; Suspended; Sponsor: Orchard Therapeutics; Trial completion date: Feb 2021 ➔ Feb 2022; Trial primary completion date: Aug 2020 ➔ Aug 2021

Clinical • Trial completion date • Trial primary completion date • Gene Therapies • Genetic Disorders • Immunology • Primary Immunodeficiency

[VIRTUAL] EX VIVO RETROVIRAL GENE THERAPY FOR THE TREATMENT OF SEVERE COMBINED IMMUNODEFICIENCY DUE TO ADENOSINE DEAMINASE DEFICIENCY (ADA-SCID): LONG-TERM (UP TO 18 YEARS) FOLLOW-UP (ESID 2020) - No abstract available

Immunology • Primary Immunodeficiency

ADA Gene Transfer Into Hematopoietic Stem/Progenitor Cells for the Treatment of ADA-SCID (clinicaltrials.gov) - P2; N=12; Completed; Sponsor: Orchard Therapeutics; N=18 ➔ 12

Enrollment change • Gene Therapies • Human Immunodeficiency Virus • Immunology

A Clinical Study to Enable Process Validation of Commercial Grade OTL-101 (clinicaltrials.gov) - P2/3; N=3; Suspended; Sponsor: Orchard Therapeutics; Recruiting ➔ Suspended

Clinical • Trial suspension • Gene Therapies • Genetic Disorders • Immunology • Primary Immunodeficiency

Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID (clinicaltrials.gov) - P1/2; N=10; Recruiting; Sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust; N=20 ➔ 10

Clinical • Enrollment change • Gene Therapies • Genetic Disorders • Primary Immunodeficiency

Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID (clinicaltrials.gov) - P1/2; N=20; Recruiting; Sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust; N=10 ➔ 20; Trial completion date: Mar 2021 ➔ Jul 2022; Trial primary completion date: Dec 2020 ➔ Jul 2021

Clinical • Enrollment change • Trial completion date • Trial primary completion date

Lentiviral (LV) Gene Therapy for Adenosine Deaminase (ADA) Deficiency (clinicaltrials.gov) - P1/2; N=36; Completed; Sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust; Active, not recruiting ➔ Completed; N=10 ➔ 36; Trial completion date: Dec 2018 ➔ Dec 2019; Trial primary completion date: Dec 2018 ➔ Dec 2019

Clinical • Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Gene Therapies • Genetic Disorders • Immunology • Primary Immunodeficiency

Autologous Cryopreserved CD34+ Hematopoietic Cells Transduced With EFS-ADA Lentivirus for ADA SCID (clinicaltrials.gov) - P1/2; N=10; Completed; Sponsor: Orchard Therapeutics; Active, not recruiting ➔ Completed

Trial completion

Strimvelis Registry Study to Follow-up Patients With Adenosine Deaminase Severe Combined Immunodeficiency (ADA-SCID) (clinicaltrials.gov) - P=N/A; N=50; Enrolling by invitation; Sponsor: Orchard Therapeutics; Recruiting ➔ Enrolling by invitation

Clinical • Enrollment status

ADA Gene Transfer Into Hematopoietic Stem/Progenitor Cells for the Treatment of ADA-SCID (clinicaltrials.gov) - P2; N=18; Completed; Sponsor: Orchard Therapeutics; Active, not recruiting ➔ Completed

Trial completion

An Observational LTFU Study for Patients Previously Treated With Autologous ex Vivo Gene Therapy for ADA-SCID (clinicaltrials.gov) - P; N=70; Enrolling by invitation; Sponsor: Orchard Therapeutics

New trial

Orchard Therapeutics Reports 2018 Financial Results and Reviews Recent Business Highlights (GlobeNewswire, Orchard Therapeutics Limited) - "Upcoming Data Presentations & Remaining 2019 Milestones: Release engraftment data in 10 patients from a cryopreserved formulation clinical trial of OTL-101 for ADA-SCID...Design and engage regulators on the registrational trial for OTL-102 for patients with X-CGD...During 2018, the company recognized $2.1 million in net product sales from Strimvelis....Research and development expenses were $205.3 million in 2018...The increase was primarily driven by the acquisition of Strimvelis...Selling, general and administrative expenses were $31.4 million in 2018...due to personnel costs to support public company operations, as well as costs to market Strimvelis..."

P1/2 data • Regulatory • Sales

Autologous Ex Vivo Lentiviral Gene Therapy for the Treatment of Severe Combined Immune Deficiency Due to Adenosine Deaminase Deficiency Improves B Cell Function (CIS 2019) - "...Prior to, and often after, treatment with allogeneic hematopoietic stem cell (HSC) transplant (HSCT) or autologous ex vivo HSC gene therapy (GT), patients are managed with enzyme replacement therapy (ERT) and immunoglobulin (Ig) replacement therapy (IgRT)...Genetically modified cells were administered after conditioning with single dose busulfan (4 mg/kg)... GT with autologous HSCs transduced ex vivo with EFSADA LV resulted in B cell reconstitution, as evidenced by doubled IgA and IgM production at 18 months, cessation of IgRT in 90% of patients by 24 months, and protective specific antibody responses to tetanus vaccine in patients that were evaluated. Grant Support: Supported by a research grant from the NIAID, NIH (U01 AI100801), the National Gene Vector Biorepository (5P40HL116242), the California Institute for Regenerative Medicine (CL1-00505-1.2, FA1-00613-1), Medical Research Council (MR/K015427/1), and the National Institute for Health Research Biomedical..."

Preclinical

Autologous Ex Vivo Lentiviral Gene Therapy for the Treatment of Severe Combined Immune Deficiency Due to Adenosine Deaminase Deficiency (CIS 2019) - "...Historically, ADA-SCID has been treated using enzyme replacement therapy (ERT) followed by allogeneic hematopoietic stem cell (HSC) transplant (HSCT) from a matched related donor (MRD) or, if none is identified, a non-MRD (matched/mismatched unrelated or mismatched related donor)...Busulfan was administered at a single dose (4 mg/kg) prior to infusion of OTL-101...Over 24 months, none of the GT subjects required PEG-ADA ERT reinstitution and 90% were able to stop receiving immunoglobin replacement therapy (IgRT), whereas 38% HSCT patients required rescue HSCT or reinstitution of PEG-ADA ERT, and 52% were able to stop receiving IgRT (Table)... Treatment with lentiviral GT for ADA-SCID is well tolerated and has a favorable benefit-risk profile at 24 months based on sustained gene correction and restoration of immune function, as well as improved OS and EvFS compared with HSCT (MRD or non-MRD) at 24 months. Grant Support: Supported by a research grant from the NIAID, NIH..."

Preclinical

Orchard Therapeutics presents two year follow-up data versus historical control from registrational trial of OTL-101 for the treatment of ADA-SCID (GlobeNewswire) - P1/2, N=20; NCT01852071; Sponsor: Orchard Therapeutics; "Orchard Therapeutics...will present two-year follow-up data in 20 patients from the registrational trial evaluating OTL-101...for the treatment of severe combined immune deficiency due to adenosine deaminase deficiency (ADA-SCID) during the President’s Symposia at the 2019 Transplantation and Cellular Therapy Meetings of ASBMT and CIBMTR in Houston...results demonstrate that by engrafting autologous, gene-modified, long-term repopulating hematopoietic stem cells, we are able to see durable recovery of the immune system. With 100% overall survival and 100% event free survival in this trial maintained at 24 months...BLA filing in 2020..."

BLA • P1/2 data

Autologous Ex Vivo Lentiviral Gene Therapy for the Treatment of Severe Combined Immune Deficiency Due to Adenosine Deaminase Deficiency (ADA-SCID) (TCT-ASBMT-CIBMTR 2019) - "Subjects received single conditioning IV busulfan (4 mg/kg) and a fresh formulation of OTL-101 was infused after transduction. At 24 mo, overall survival (OS) and event-free survival (EvFS, defined as survival in the absence of ERT reinstitution or rescue allogeneic HSCT) were greater in the GT group than in the HSCT group (Figure). Successful engraftment of genetically modified HSC was observed in all GT subjects at 6 mo and persisted over 24 mo, based on vector gene marking in granulocytes (median 0.085 copies/cell, [range 0.04-2.50] at 24 mo) and peripheral blood mononuclear cells (median 0.843 copies/cell, [range 0.13-1.86] at 24 mo), and was associated with red blood cell ADA enzyme activity and metabolic detoxification from deoxyadenosine nucleotides.Over 24 mo, none of the GT subjects reinstituted PEG-ADA ERT and 90% stopped immunoglobin replacement therapy (IgRT), whereas 38% HSCT patients required rescue HSCT or PEG-ADA ERT and 52% stopped IgRT. Nine GT..."

Late-breaking abstract • Preclinical

Orchard Therapeutics announces acceptance of late-breaking abstracts of OTL-101 for ADA-SCID and OTL-102 for X-CGD at the 2019 Transplantation and Cellular Therapy Meetings of ASBMT and CIBMTR (GlobeNewswire) - "Orchard Therapeutics...announced that new clinical data for OTL-101 and OTL-102 will be presented in oral and poster presentations at the Transplantation and Cellular Therapy (TCT) Meetings of the American Society of Blood and Marrow Transplantation (ASBMT) and Center for International Blood and Marrow Transplant Research (CIBMTR) to be held on February 20-24, 2019 in Houston, TX."

Clinical data • P1/2 data