Lenmeldy (atidarsagene autotemcel) / GSK, Kyowa Kirin - LARVOL DELTA

TIGET-MLD: Gene Therapy for Metachromatic Leukodystrophy (MLD) (clinicaltrials.gov) - P1/2 | N=20 | Completed | Sponsor: Orchard Therapeutics | Active, not recruiting ➔ Completed

Trial completion • Gene Therapies • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

Promises past and future - Gene therapy and the actualisation of future expectations. (PubMed, Soc Sci Med) - "The advent of gene therapies such as Zolgensma, Libmeldy, and Luxturna has given rise to new treatment options for several rare conditions, drastically changing the expectations of affected patients...Similarly marginalised issues include for instance assumptions of effectiveness that do not acknowledge the long-term uncertainty of treatment outcomes; and assumptions of profitability that run counter to real-life examples of business failure. As a revolutionary future becomes reality for some patients, such questions are becoming harder to ignore - but are crucially often omitted from discussion about projected change."

Journal • Gene Therapies

Atidarsagene autotemcel (autologous hematopoietic stem cell gene therapy) preserves cognitive and motor development in early-onset metachromatic leukodystrophy with up to 12 years follow-up (SSIEM 2023) - "After myeloablative busulfan conditioning, arsa-cel was administered intravenously. With up to 12 years follow-up, arsa-cel shows a favorable safety profile and sustained efficacy, preventing severe motor and cognitive impairment and slowing disease progression in early-onset MLD patients."

Gene therapy • Alzheimer's Disease • Cardiovascular • Cognitive Disorders • Gene Therapies • Metabolic Disorders • CD34

Unveiling myeloid-mediated enzymatic correction of ARSA-deficient neural cells in hematopoietic stem cell gene therapy for Metachromatic Leukodystrophy. (ESGCT 2024) - "More than ten years of robust safety and efficacy data culminated in the full marketing authorization of this HSC-GT approach for MLD (atidarsagene autotemcel, “arsa-cel”) in Europe, UK and USA...Delving deeper into the mechanism of myeloid-to-neural enzymatic cross-correction, we showed that transgenic ARSA enzyme is post-transcriptionally modified through the phosphorylation of mannose-6 residues and its uptake by MLD neural cells is partly mediated by the mannose-6-phosphate receptor. Our findings underscore the consistent occurrence of myeloid-mediated enzymatic cross-correction of ARSA-deficient neurons and glial cells within a clinically relevant HSC-GT framework, offering profound insights into the therapeutic potential of this approach for genetic neurological diseases."

Gene therapy • CNS Disorders • Gene Therapies • Immunology • Inflammation • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

Atidarsagene autotemcel (autologous hematopoietic stem cell gene therapy) preserves cognition, language, and speech and slows brain demyelination and atrophy in early-onset metachromatic leukodystrophy (ESGCT 2024) - P1/2, P2 | "Atidarsagene autotemcel (arsa-cel) consists of autologous CD34+ cells transduced ex vivo with a lentiviral vector encoding the human ARSA cDNA with constitutive expression driven by a human PGK promoter, infused intravenously after busulfan conditioning. Additionally, several patients (1 PSLI, 2 PSEJ, 1 ESEJ) showed slight decreases in brain MRI scores after treatment that can be attributed to improved brain myelination. With up to 12 years follow-up, arsa-cel shows benefits to treated patients’ QoL by preserving cognition, language abilities, and speech, supported by evidence from brain MRI."

Gene therapy • Alzheimer's Disease • Cognitive Disorders • Gene Therapies • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases • CD34

Atidarsagene autotemcel (lentiviral hematopoietic stem cell gene therapy) for late juvenile metachromatic leukodystrophy: preliminary results from a phase III clinical trial (ESGCT 2024) - P3 | "Atidarsagene autotemcel (arsa-cel) is a hematopoietic stem cell (HSC) gene therapy (GT) and consists of autologous CD34+ cells transduced ex vivo with a lentiviral vector (LV) encoding for the human ARSA gene, infused after intravenous myeloablative busulfan conditioning. This analysis demonstrates that the preliminary results on safety of this LV based HSC GT strategy and pharmacodynamics efficacy in LJ-MLD were similar to those reported in early-onset MLD. Longer follow-up is needed to assess clinical efficacy."

Clinical • Gene therapy • P3 data • P3 data: top line • Gene Therapies • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases • Thrombocytopenia • CD34

Biological properties and clonality of engineered hematopoietic stem/progenitor cells persisting long-term after gene therapy (ESGCT 2024) - "In this project we are comprehensively studying the functional properties, clonality and maintenance of stemness properties of LV transduced HSPC in long-term GT treated (LT-GT) patients with Wiskott-Aldrich Syndrome (WAS, n=6) and Metachromatic Leukodystrophy (MLD, n=10 HSC-GT known as atidarsagene autotemcel) reaching a follow-up of >8 years post-treatment...These data will be complemented with ongoing in vitro and in vivo functional studies and recently developed methods to retrieve multi-omic data at single-cell level, including transcriptome, chromatin accessibility, integration sites and mitochondrial DNA (mtDNA) diversity, allowing the collection of unprecedented information on the behavior of HSPC clones and subclones. Overall, the information generated from these studies will increase our knowledge on human HSPC properties and on the capability of engineered HSPC to maintain a functional and safe long-term graft, ultimately validating the hypothesis of HSC-GT..."

Gene therapy • Gene Therapies • Immunology • Metabolic Disorders • Primary Immunodeficiency

Cell-based device provides effective therapeutic strategy to treat the metachromatic leukodystrophy (ESGCT 2024) - "Currently, Libmeld"

Gene Therapies • Inflammation • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

Kyowa Kirin and Orchard Therapeutics Announce OTL-200 Granted Orphan Regenerative Medicine Product Designation for Early-onset MLD in Japan (Yahoo Finance) - "Kyowa Kirin is currently preparing the potential initiation of a clinical trial for OTL-200 in children with PSLI, PSEJ, and ESEJ MLD in Japan."

Orphan drug • Lysosomal Storage Diseases • Metabolic Disorders

Encapsulated cells as an enzyme replacement therapy for metachromatic leukodystrophy. (PubMed, J Control Release) - "Libmeld"

Journal • Gene Therapies • Inflammation • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

TIGET-MLD: Gene Therapy for Metachromatic Leukodystrophy (MLD) (clinicaltrials.gov) - P1/2 | N=20 | Active, not recruiting | Sponsor: Orchard Therapeutics | Trial completion date: Mar 2025 ➔ Sep 2025

Trial completion date • Gene Therapies • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

OTL-200 in Patients With Late Juvenile Metachromatic Leukodystrophy (MLD) (clinicaltrials.gov) - P3 | N=6 | Active, not recruiting | Sponsor: Orchard Therapeutics | Trial primary completion date: Mar 2025 ➔ Jan 2026

Trial primary completion date • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

Lenmeldy (atidarsagene autotemcel) for individuals with early metachromatic leukodystrophy (MLD): A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG). (PubMed, Genet Med Open) - No abstract available

Journal • Gene Therapies • Metabolic Disorders

BIOLOGICAL PROPERTIES AND CLONALITY OF ENGINEERED HEMATOPOIETIC STEM/PROGENITOR CELLS PERSISTING LONG-TERM AFTER GENE THERAPY (EHA 2025) - "Aims: We are studying the functional features, clonality and maintenance of stemness properties of LV transduced HSC in long-term GT treated (LT-GT) patients with Wiskott-Aldrich Syndrome (WAS, n=6 treated with etuvetidigene autotemcel) and Metachromatic Leukodystrophy (MLD, n=10 treated with atidarsagene autotemcel) reaching a follow-up of >8 years post-GT... Our preliminary data have shown maintenance of stable gene-corrected HSPC compartment displaying in vitro multilineage properties. Moreover, we provided evidence that the engrafted pool of engineered HSPC retain self-renewal properties preserving their number and clonality up to 10 years post-GT. Finally, scRNAseq data suggest that primitive HSC from LT-GT patients express molecular signature associated with stemness.Overall, this study will shed light on human engineered HSPC to maintain a functional and safe long-term graft."

Gene therapy • Gene Therapies • Immunology • Metabolic Disorders • Pediatrics • Primary Immunodeficiency

Treatment effect of atidarsagene autotemcel (arsa-cel) in age-matched treated vs. untreated sibling pairs with early-onset metachromatic leukodystrophy (MLD) (ASGCT 2025) - P1/2, P2 | "Given the stark difference in motor outcomes between the treated and untreated sibling pairs, this analysis reinforces the importance of early diagnosis through newborn screening to enable all early-onset patients to have the opportunity for pre-symptomatic treatment, not just the younger siblings of symptomatic patients. Clinical trial registration: NCT01560182, NCT03392987, EudraCT 2009-017349-77, EudraCT 2017-001730-26 Disease Focus of Abstract:Storage/Lysosomal Disorders"

CNS Disorders • Gene Therapies • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases • CD34

Lentiviral hematopoietic stem cell gene therapy (atidarsagene autotemcel) for late juvenile Metachromatic leukodystrophy (MLD): Interim analysis of a Phase III trial (ASGCT 2025) - P3 | "Stem cell source was mobilized peripheral blood collected after 6-8 doses of G-CSF and administration of Plerixafor 6-8 hours before leukapheresis...All patients received myeloablative conditioning with busulfan as a single agent, with a cumulative target area under the curve of 85 mg×h/L...Conclusion This interim analysis suggests that the drug product characteristics, short-term safety profile, and pharmacodynamic efficacy of arsa-cel in LJ-MLD align with previous studies in early-onset MLD. Further follow-up is ongoing to assess brain imaging, clinical efficacy endpoints, and long-term safety Disease Focus of Abstract:Inherited Neurological Disorders"

Gene therapy • P3 data • P3 data: top line • CNS Disorders • Gene Therapies • Lysosomal Storage Diseases • Metabolic Disorders • Oncology • Rare Diseases • CD34

Encapsulated cell therapy demonstrated therapeutic efficacy in metachromatic leukodystrophy and sustained ARSA production in NHP (ASGCT 2025) - "Libmeld"

Clinical • CNS Disorders • Gene Therapies • Inflammation • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

Diversity, Equity, and Inclusion in Gene and Cell Therapies Clinical Trials (ISPOR 2025) - "The lowest enrollment was for atidarsagene autotemcel (7 participants), while sipuleucel-T had the highest (512 participants)...White participants were disproportionately represented, particularly in sipuleucel-T (90.0%) and talimogene laherparepvec (97.9%)... The findings revealed persistent racial disparities in gene and cell therapy clinical trials, with minority populations underrepresented and White participants comprising the majority. Achieving DEI in clinical trials remains a challenge, underscoring the need for greater efforts to address these disparities."

Clinical • Gene Therapies • Oncology

Effects of atidarsagene autotemcel gene therapy on peripheral nerves in late-infantile metachromatic leukodystrophy. (PubMed, Brain) - "In addition to the potential role of early age at treatment in the preservation of myelin, supraphysiological ARSA levels may slow demyelination of the DPN and other peripheral nerves. Arsa-cel may exert a stronger effect on NCV than allogeneic hematopoietic stem cell transplantation due to its greater ARSA expression."

Journal • Bone Marrow Transplantation • Gene Therapies • Metabolic Disorders • Pain • Transplantation

Treatment of leukodystrophies: Advances and challenges. (PubMed, Eur J Paediatr Neurol) - "Gene therapy has become a viable option, with ex vivo approaches like atidarsagene autotemcel providing promising outcomes for early-onset MLD...Despite these advances, challenges remain, including the ultrarare nature of most leukodystrophies, limited natural history data, high treatment costs, and barriers to accessibility. Future developments, including newborn screening and close international collaboration, aim to enhance early diagnosis, refine treatment timing, and expand access to innovative therapies."

Journal • Review • Bone Marrow Transplantation • CNS Disorders • Gene Therapies • Genetic Disorders • Metabolic Disorders • Rare Diseases • Transplantation

Long-Term Effects of Atidarsagene Autotemcel for Metachromatic Leukodystrophy. (PubMed, N Engl J Med) - P1/2, P2 | "Among patients with presymptomatic late-infantile or early-juvenile MLD and those with early-symptomatic early-juvenile MLD, the risk of severe motor impairment or death was significantly lower among those who received treatment with arsa-cel than in a natural history cohort that did not receive treatment. (Funded by Orchard Therapeutics and others; ClinicalTrials.gov numbers, NCT01560182 and NCT03392987.)."

Journal • Febrile Neutropenia • Gene Therapies • Hematological Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Neutropenia • Oncology • Rare Diseases

TREATMENT EFFECT OF ATIDARSAGENE AUTOTEMCEL (ARSA-CEL) IN AGE-MATCHED TREATED VS. UNTREATED SIBLING PAIRS WITH EARLY-ONSET METACHROMATIC LEUKODYSTROPHY (MLD) (EBMT 2025) - P1/2, P2 | "The results for the subset of sibling pairs align with the previously presented data from the presymptomatic LI and EJ CDP population vs. the NHx cohort. Given the stark difference in motor outcomes between the treated and untreated sibling pairs, this analysis reinforces the importance of early diagnosis through newborn screening to enable all early-onset patients to have the opportunity for pre-symptomatic treatment, not just the younger siblings of symptomatic patients."

CNS Disorders • Gene Therapies • Genetic Disorders • Metabolic Disorders

TREATMENT EFFECT OF ATIDARSAGENE AUTOTEMCEL (ARSA-CEL) IN AGE-MATCHED TREATED VS. UNTREATED SIBLING PAIRS WITH EARLY-ONSET METACHROMATIC LEUKODYSTROPHY (MLD) (EBMT 2025) - P1/2, P2 | "The results for the subset of sibling pairs align with the previously presented data from the presymptomatic LI and EJ CDP population vs. the NHx cohort. Given the stark difference in motor outcomes between the treated and untreated sibling pairs, this analysis reinforces the importance of early diagnosis through newborn screening to enable all early-onset patients to have the opportunity for pre-symptomatic treatment, not just the younger siblings of symptomatic patients."

CNS Disorders • Gene Therapies • Genetic Disorders • Metabolic Disorders

Orchard Therapeutics Announces Reimbursement Agreement in Spain (PRNewswire) - "Orchard Therapeutics...announced it has recently reached an agreement with the Interministerial Commission for the Pricing of Medicines of the Directorate of Common Portfolio of Services of the Spanish National Health System (SNS) which will result in reimbursed access to Libmeldy (atidarsagene autotemcel) for all eligible children with pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile (PSEJ) or early symptomatic early juvenile (ESEJ)—collectively referred to as early-onset—metachromatic leukodystrophy (MLD)."

Reimbursement • Metabolic Disorders

A Safety and Efficacy Study of Cryopreserved OTL-200 for Treatment of Metachromatic Leukodystrophy (MLD) (clinicaltrials.gov) - P2 | N=10 | Active, not recruiting | Sponsor: Orchard Therapeutics | Trial completion date: Apr 2028 ➔ Jan 2026

Trial completion date • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases