OTL-203 / Ospedale San Raffaele, Kyowa Kirin - LARVOL DELTA

Hematopoietic stem cell-based gene therapy in Mucopolysaccharidosis type I Hurler (OTL-203): focus on skeletal damage and cross-correction mechanisms (ESGCT 2024) - P1/2 | "Finally, the histological analyses of the osteomedullary biopsies of MPSIH patients before HSC-GT revealed vacuolation of the enthesis tissue, which was completely rescued after HSC-GT. These findings obtained by in vitro, in vivo and ex vivo studies suggest a beneficial effect of HSC-GT on characteristic MPSIH skeletal disease-associated features."

Gene therapy • Bone Marrow Transplantation • Gene Therapies • Hurler Syndrome • Lysosomal Storage Diseases • Metabolic Disorders • Orthopedics • Rare Diseases • IDUA • SOX9

Hematopoietic Stem Cell Gene Therapy for Hurler Syndrome (OTL-203): interim skeletal, neurological and systemic outcomes (ESGCT 2024) - P1/2, P3 | "This interim analysis indicates an early beneficial effect of OTL-203 on MPSIH-typical skeletal, neurological, CC, cardiac and CTS manifestations up to 4-year after treatment, together with biochemical detoxification in urine and CSF. A randomized multicenter Phase III trial (NCT06149403) sponsored by Orchard Therapeutics evaluating the safety and efficacy of autologous HSC-GT OTL-203 compared to allo-HSCT is in progress."

Gene therapy • Bone Marrow Transplantation • Gene Therapies • Hurler Syndrome • Musculoskeletal Pain • IDUA

Non-neurological, non skeletal outcomes after hematopoietic stem and progenitor cell-gene therapy -OTL-203- for Hurler syndrome. (PubMed, Mol Ther) - P1/2 | "No HSPC-GT patients developed severe cardiomyopathy or valvular disease, while in the HSCT cohort 4/9 patients experienced progression of valvular insufficiency although not requiring valve replacement. Our results indicate a favorable effect of HSPC-GT on MPSIH multisystemic manifestations up to 4-year after treatment; long-term, prospective comparative studies are warranted for definitive conclusions."

Journal • Bone Marrow Transplantation • Cardiomyopathy • Cardiovascular • Gene Therapies • Hurler Syndrome • Musculoskeletal Pain • Oncology • Otorhinolaryngology • Transplantation

TigetT10_MPSIH: Gene Therapy With Modified Autologous Hematopoietic Stem Cells for the Treatment of Patients With Mucopolysaccharidosis Type I, Hurler Variant (clinicaltrials.gov) - P1/2 | N=8 | Active, not recruiting | Sponsor: IRCCS San Raffaele | Trial completion date: Jan 2025 ➔ Mar 2028 | Trial primary completion date: Jan 2025 ➔ Mar 2028

Trial completion date • Trial primary completion date • Gene Therapies • Hurler Syndrome • IDUA

Extensive detoxification and favorable effects on systemic clinical outcomes after Hematopoietic Stem Cell Gene Therapy for Mucopolysaccharidosis Type I-Hurler (OTL-203) (ASGCT 2025) - P1/2 | "Long-term comparative studies are warranted for definitive conclusions. Disease Focus of Abstract:Metabolic Disease"

Clinical • Clinical data • Gene therapy • Bone Marrow Transplantation • Gene Therapies • Hurler Syndrome • Metabolic Disorders • Musculoskeletal Pain • IDUA

EXTENSIVE DETOXIFICATION AND FAVORABLE EFFECTS ON SYSTEMIC CLINICAL OUTCOMES AFTER HEMATOPOIETIC STEM CELL GENE THERAPY FOR MUCOPOLYSACCHARIDOSIS TYPE I-HURLER (OTL-203) (EBMT 2025) - P1, P1/2 | "Our results indicate sustained engraftment of gene-corrected cells, extensive detoxification and an early favorable effect of OTL-203 on MPS-IH multi-systemic clinical manifestations up to 5-years after treatment. Long-term comparative studies are warranted for definitive conclusions. Clinical Trial Registry: NCT03488394EudraCT 2017-002430-23"

Clinical • Clinical data • Gene therapy • Bone Marrow Transplantation • Gene Therapies • Hurler Syndrome • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Pediatrics • IDUA

HURCULES: A Study to Investigate the Efficacy and Safety of OTL-203 in Subjects with MPS-IH Compared with Standard of Care with Allogeneic HSCT (clinicaltrials.gov) - P3 | N=41 | Active, not recruiting | Sponsor: Orchard Therapeutics | Recruiting ➔ Active, not recruiting

Enrollment closed • Bone Marrow Transplantation • Hurler Syndrome • Transplantation

Orchard Therapeutics Announces Multiple Data Presentations and Publications (GlobeNewswire) - "Ten presentations (three oral and seven posters) from across its hematopoietic stem cell (HSC) gene therapy portfolio will be featured at the European Society of Gene and Cell Therapy (ESGCT) 31st Annual Congress taking place October 22-25...Featured data include several accepted abstracts and encore presentations detailing clinical, biochemical and other functional outcomes from across the company’s commercial- and clinical-stage neurometabolic portfolio in metachromatic leukodystrophy (MLD), the Hurler subtype of mucopolysaccharidosis type I (MPS-IH), and mucopolysaccharidosis type IIIA (MPS-IIIA), also known as Sanfilippo syndrome type A....An oral presentation of preclinical proof-of-concept data showing the therapeutic potential of OTL-104 for NOD2-deficient Crohn’s disease, a severe and treatment-refractory form of the condition; A poster presentation outlining the potential of HSC gene therapy as a mechanism to deliver therapeutic antibodies..."

Clinical • Preclinical • Crohn's disease • Hurler Syndrome • Immunology • Inflammatory Bowel Disease • Metabolic Disorders • Multiple Sclerosis

DESIGN OF A RANDOMIZED PHASE 3 CLINICAL TRIAL (HURCULES) EVALUATING THE SAFETY AND EFFICACY OF OTL-203 IN PATIENTS WITH MPS-IH VERSUS STANDARD OF CARE WITH ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (SSIEM 2024) - P1/2 | "Discussion/Conclusion The design of this Phase 3 study is informed by preliminary data from the Phase 1/2 study and feedback from key stakeholders and aims to evaluate the potential impact of OTL-203 to address significant unmet needs associated with alloHSCT. Palavras-chave : gene therapy, mucopolysaccharidosis type I, randomized clinical trial, clinical trial design, allogeneic hematopoietic stem cell transplantation"

Clinical • P3 data • Bone Marrow Transplantation • CNS Disorders • Gene Therapies • Hurler Syndrome • Transplantation • IDUA

HEMATOPOIETIC STEM CELL GENE THERAPY FOR HURLER SYNDROME: INTERIM SKELETAL OUTCOME AND SKELETAL CROSS-CORRECTION MECHANISMS (SSIEM 2024) - P1/2 | "Here we report interim results from a Phase I/II clinical trial (NCT03488394) on the skeletal outcome of 8 MPSIH patients treated with autologous ex vivo hematopoietic stem cell gene therapy (HSC-GT; OTL-203) up to 4 years after treatment... Clinical, functional, radiological and biological parameters indicate an early beneficial effect of HSCGT on MPSIH-typical skeletal features."

Gene therapy • Bone Marrow Transplantation • Gene Therapies • Hurler Syndrome • Orthopedics • IDUA

INTERIM ANALYSIS ON NEUROLOGICAL OUTCOMES IN HURLER SYNDROME PATIENTS TREATED WITH AUTOLOGOUS EX-VIVO HAEMATOPOIETIC STEM CELL GENE THERAPY (SSIEM 2024) - P1/2 | "The neurological outcomes of 8 MPSIH patients enrolled in a phase I/II study (NCT03488394) of autologous ex-vivo hematopoietic stem cell gene therapy (HSC-GT, also known as OTL-203) were evaluated up to 4 years after treatment... This preliminary neurological analysis suggests biochemical detoxification and initial clinical response in the CNS. A longer follow-up and a prospective comparison with HSCT are needed to draw definitive conclusions on the effect of HSC-GT on the neurological manifestations of MPSIH."

Gene therapy • Preclinical • Bone Marrow Transplantation • Gene Therapies • Hurler Syndrome • IDUA

NON-NEUROLOGICAL, NON-SKELETAL OUTCOMES AFTER AUTOLOGOUS HEMATOPOIETIC STEM CELL GENE (SSIEM 2024) - P1/2 | "Background: In a phase I/II clinical trial (NCT03488394), exvivo hematopoietic stem cell-gene therapy (HSC-GT; also known as OTL-203) demonstrated extensive metabolic correction; however, its effects on multiple disease manifestations such as corneal clouding (CC), hearing loss (HL), carpal tunnel syndrome (CTS) and cardiac involvement have not been reported... Our results indicate stability or improvement of CC, HL, cardiac manifestations and CTS in MPSIH patients after HSC-GT up to 4 years after treatment. Longer follow-up is needed to draw definitive conclusions on the effects of HSC-GT on these clinical outcomes."

Bone Marrow Transplantation • Cardiomyopathy • Cardiovascular • Gene Therapies • Hurler Syndrome • Musculoskeletal Pain • Otorhinolaryngology

Interim Analysis on Neurological Outcomes in Hurler Syndrome Patients Treated with Autologous Ex Vivo Hematopoietic Stem Cell Gene Therapy (ASGCT 2024) - P1/2 | "The neurological outcomes of 8 MPSIH patients enrolled in a phase I/II study (NCT03488394) of autologous ex vivo hematopoietic stem cell gene therapy (HSC-GT, also known as OTL-203) were evaluated up to 4 years after treatment... This preliminary neurological analysis suggests biochemical detoxification in the CSF and initial clinical response in terms of motor and cognitive abilities up to 4 years after treatment, except for one patient with behavioral issues preventing him from demonstrating his full neurocognitive abilities, determined to be unrelated to treatment. CSF detoxification suggests migration of gene-modified cells across the blood brain barrier and local engraftment in the CNS. Neuroradiological modifications are consistent with biochemical and clinical outcomes."

Gene therapy • Preclinical • Bone Marrow Transplantation • Gene Therapies • Hurler Syndrome • Transplantation • IDUA

Hematopoietic Stem Cell Gene Therapy for Hurler Syndrome: Interim Skeletal Outcome and Skeletal Cross-Correction Mechanisms (ASGCT 2024) - P1/2 | "Here we report interim results from a Phase I/II clinical trial (NCT03488394) on the skeletal outcome of 8 MPSIH patients treated with HSC-GT (OTL-203) up to a median follow-up of 4 years... Clinical, functional and radiological parameters indicate an early beneficial effect of HSC-GT on MPSIH-typical skeletal features. A longer follow-up and a direct comparison with HSCT are needed to draw definitive conclusions on the impact of HSC-GT on skeletal dysplasia. Biological studies aimed at unveiling skeletal correction mechanisms after HSC-GT will be key to advance the treatment of MPSIH patients."

Gene therapy • Bone Marrow Transplantation • Gene Therapies • Hurler Syndrome • Musculoskeletal Diseases • Orthopedics • Transplantation • IDUA

DESIGN OF A RANDOMIZED PHASE 3 CLINICAL TRIAL (HURCULES) INVESTIGATING THE SAFETY AND EFFICACY OF OTL-203 IN MPS-IH VERSUS ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANTATION (EBMT 2024) - P1/2, P3 | "To ensure efficient engraftment of cells, all patients will undergo a myelo- and lympho-ablative conditioning regimen with busulfan and fludarabine prior to infusion of OTL-203 or allo-HSCT. The design of this Phase 3 study is informed by preliminary data from the Phase 1/2 proof-of-concept study and incorporates feedback from clinical experts, regulators, patient advocacy groups, and payers. This study aims to characterize the potential clinical impact of OTL-203 to address the significant unmet medical needs associated with the current SoC allo-HSCT"

Clinical • P3 data • Bone Marrow Transplantation • Gene Therapies • Hurler Syndrome • Lysosomal Storage Diseases • Metabolic Disorders • Musculoskeletal Diseases • Rare Diseases • Transplantation • CD34 • IDUA

INTERIM ANALYSIS ON NEUROLOGICAL OUTCOMES IN HURLER SYNDROME PATIENTS TREATED WITH EX-VIVO HAEMATOPOIETIC STEM CELL GENE THERAPY (EBMT 2024) - P1/2 | "The neurological outcomes of 8 MPSIH patients enrolled in a phase I/II study (NCT03488394) of autologous ex-vivo haematopoietic stem cell gene therapy (HSC-GT, also known as OTL-203) were evaluated up to 4 years after treatment... This preliminary neurological analysis suggests biochemical detoxification in the CSF and initial clinical response in terms of motor and cognitive abilities up to 4 years after treatment, except for one patient with cognitive delay and behavioural disturbance determined to be unrelated to treatment. CSF detoxification suggests migration of gene-modified cells across the blood brain barrier and local engraftment in the CNS. Neuroradiological modifications correspond well with biochemical and clinical outcomes."

Gene therapy • Preclinical • Bone Marrow Transplantation • CNS Disorders • Developmental Disorders • Gene Therapies • Hurler Syndrome • Transplantation • IDUA

HAEMATOPOIETIC STEM CELL GENE THERAPY FOR HURLER SYNDROME: CLINICAL SKELETAL OUTCOME DATA AND STUDY OF THE SKELETAL CROSS-CORRECTION MECHANISMS (EBMT 2024) - P1/2 | "Here we report the interim results from a Phase I/II clinical trial (NCT03488394) on the skeletal outcome of 8 MPSIH patients treated with HSC-GT (OTL-203) up to a median follow-up of 4 years... Clinical, functional and radiological parameters indicate an early beneficial effect of HSC-GT on MPSIH-typical skeletal features. A longer follow-up and direct comparison with HSCT are needed to draw definitive conclusions on HSC-GT impact on skeletal dysplasia. Biological studies aimed at unveiling skeletal correction mechanisms after HSC-GT will be key to advance the treatment of MPSIH patients"

Clinical • Gene therapy • Bone Marrow Transplantation • Gene Therapies • Hurler Syndrome • Musculoskeletal Diseases • Orthopedics • Pediatrics • Transplantation • IDUA

NON-NEUROLOGICAL, NON-SKELETAL OUTCOMES AFTER HAEMATOPOIETIC STEM AND PROGENITOR CELL-GENE THERAPY IN HURLER PATIENTS: RETROSPECTIVE COMPARISON WITH ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANTATION (EBMT 2024) - P1/2 | "Clinical Trial Registry: NCT03488394 (https://www.clinicaltrials.gov/study/NCT03488394) Background: Preliminary results of a phase I/II study (NCT03488394) of ex-vivo haematopoietic stem and progenitor cells gene therapy (HSC-GT, also known as OTL-203) in 8 Mucopolysaccharidosis type I Hurler syndrome (MPSIH) patients have demonstrated superior metabolic correction compared to allogeneic haematopoietic stem cell transplantation (HSCT)... Our results indicate stability or improvement of CC, HL, cardiac manifestations and CTS in MPSIH patients after HSC-GT up to 4 years after treatment. A longer follow-up and a prospective comparison with HSCT patients are required to draw definitive conclusions on the efficacy of HSC-GT in addressing these disease burdens"

Gene therapy • Retrospective data • Bone Marrow Transplantation • Cardiomyopathy • Cardiovascular • Gene Therapies • Hurler Syndrome • Musculoskeletal Pain • Otorhinolaryngology • Transplantation

DESIGN OF A RANDOMIZED PHASE 3 CLINICAL TRIAL (HURCULES) INVESTIGATING THE SAFETY AND EFFICACY OF OTL-203 IN MPS-IH VERSUS ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANTATION (EBMT 2024) - P1/2, P3 | "To ensure efficient engraftment of cells, all patients will undergo a myelo- and lympho-ablative conditioning regimen with busulfan and fludarabine prior to infusion of OTL-203 or allo-HSCT. The design of this Phase 3 study is informed by preliminary data from the Phase 1/2 proof-of-concept study and incorporates feedback from clinical experts, regulators, patient advocacy groups, and payers. This study aims to characterize the potential clinical impact of OTL-203 to address the significant unmet medical needs associated with the current SoC allo-HSCT"

Clinical • P3 data • Bone Marrow Transplantation • Gene Therapies • Hurler Syndrome • Lysosomal Storage Diseases • Metabolic Disorders • Musculoskeletal Diseases • Rare Diseases • Transplantation • CD34 • IDUA

Design of a Multi-Center Randomized Active Controlled Phase 3 Clinical Trial (HURCULES) Evaluating the Safety and Efficacy of OTL-203 in Patients with MPS-IH Versus Standard of Care with Allogeneic Hematopoietic Stem Cell Transplantation (TCT-ASTCT-CIBMTR 2024) - P1/2 | "Patients will be followed-up on the study for 5 years post-treatment and invited to enroll in a long-term follow-up study for a total of 15 years."

Clinical • P3 data • Bone Marrow Transplantation • CNS Disorders • Gene Therapies • Hurler Syndrome • Lysosomal Storage Diseases • Metabolic Disorders • Musculoskeletal Diseases • Ophthalmology • Rare Diseases • Transplantation • IDUA

Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency. (PubMed, Nat Med) - P, P2 | "Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort...These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT03478670 ."

Gene therapy • Journal • Real-world • Real-world evidence • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Oncology • Primary Immunodeficiency • Transplantation • CD34

HURCULES: A Study to Investigate the Efficacy and Safety of OTL-203 in Subjects With MPS-IH Compared With Standard of Care With Allogeneic HSCT (clinicaltrials.gov) - P3 | N=40 | Recruiting | Sponsor: Orchard Therapeutics | Not yet recruiting ➔ Recruiting

Enrollment open • Bone Marrow Transplantation • Hurler Syndrome • Transplantation

HURCULES: A Study to Investigate the Efficacy and Safety of OTL-203 in Subjects With MPS-IH Compared With Standard of Care With Allogeneic HSCT (clinicaltrials.gov) - P3 | N=40 | Not yet recruiting | Sponsor: Orchard Therapeutics

New P3 trial • Bone Marrow Transplantation • Hurler Syndrome • Transplantation

INTERIM ANALYSIS OF FIRST IN HUMAN PHASE I-II CLINICAL TRIAL OF EX-VIVO GENE THERAPY FOR HURLER SYNDROME: AN UPDATE AT 3 YEAR FOLLOW-UP (EHA 2023) - P1/2 | "Aims: Here we report an update of interim results of a first-in-human phase I/II clinical trial (NCT03488394) of 8 MPSIH pediatric patients treated with autologous hematopoietic stem and progenitor cells transduced ex vivo with an α- L-iduronidase (IDUA)-encoding lentiviral vector after a busulfan/fludarabine-based conditioning regimen at 3-year follow-up. These data show extensive metabolic correction and initial clinical response after GT and a favorable safety profile, highlighting its therapeutic potential for MPSIH treatment. A longer follow-up is needed to draw definitiveconclusions on the impact of GT on MPSIH manifestations in the long term. Stem cell gene therapy, Gene therapy"

Gene therapy • P1/2 data • Preclinical • Bone Marrow Transplantation • Gene Therapies • Hurler Syndrome • Lysosomal Storage Diseases • Metabolic Disorders • Pediatrics • Rare Diseases • Transplantation

"Growth patterns in children with mucopolysaccharidosis type I-Hurler after hematopoietic stem cell transplantation: Comparison with untreated patients". (PubMed, Mol Genet Metab Rep) - "Despite a progressive decrease after HSCT when estimated with reference to the WHO growth charts, median height SDS showed a progressive and statistically significant increase when comparing the stature recorded at each timepoint in our population to the curves of untreated MPS-IH individuals (from -0.39 SDS at t to +1.35 SDS 5 years after HSCT, p value < 0.001 and to +3.67 SDS at the age of 9 years, p value < 0.0001). In conclusion, though not efficient enough to restore a normal growth pattern in MPS-IH patients, we hereby demonstrate that HSCT positively affects growth and provides transplanted patients with a remarkable height gain compared to untreated gender- and age- matched individuals."

Clinical • Journal • Bone Marrow Transplantation • Hurler Syndrome • Transplantation