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

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

Trial completion • Metabolic Disorders • CD14

GONADAL TOXICITY AND PREMATURE OVARIAN INSUFFICIENCY AFTER HEMATOPOIETIC STEM CELL GENE-THERAPY IN FEMALE PATIENTS WITH METACHROMATIC LEUKODYSTROPHY (EBMT 2026) - "Atidarsagene autotemcel (arsa-cel) is an ex vivo autologous hematopoietic stem-cell gene therapy and it is infused intravenously following single agent busulfan conditioning. In our analysis POI is a frequent adverse effect associated with busulfan, consistent with previous reports. Sub-myeloablative exposure does not appear reducing the incidence of gonadal dysfunction compared with myeloablative regimen. Longitudinal hormonal assessments demonstrate early impairment of ovarian reserve, and the need to offer fertility preservation before arsa-cel and to initiate HRT when indicated."

Clinical • Gene therapy • Endocrine Cancer • Endocrine Disorders • Gene Therapies • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases • Women's Health

GALLBLADDER ABNORMALITIES IN METACHROMATIC LEUKODYSTROPHY: PRELIMINARY ANALYSIS IN PATIENTS TREATED WITH HEMATOPOIETIC STEM CELL GENE THERAPY AND UNTREATED PATIENTS (EBMT 2026) - "Atidarsagene autotemcel (arsa-cel), an autologous transplantation of CD34+ cells transduced ex vivo with a lentiviral vector encoding the ARSA gene, represents the only approved treatment for pre-symptomatic late-infantile and early-juvenile MLD, or early-symptomatic early-juvenile MLD forms... Our analysis confirms early and frequent gallbladder involvement across all MLD forms. Gallbladder wall thickening emerged as the earliest alteration and may represent the first precursor to more complex abnormalities such as polyps. The detection of ultrasound abnormalities as well as cases of cholecystectomy in patients before neurological symptom onset—including those with late-onset forms— suggests that visceral involvement may serve as an early diagnostic disease indicator."

Clinical • Gene therapy • CNS Disorders • Gene Therapies • Metabolic Disorders • CD34

A CASE OF LACK OF ENGRAFTMENT OF GENE-CORRECTED CELLS AFTER LENTIVIRAL HEMATOPOIETIC STEM CELL GENE THERAPY FOR METACHROMATIC LEUKODYSTROPHY: AN INTEGRATED CLINICAL AND IMMUNOLOGICAL INVESTIGATION (EBMT 2026) - "Background: Atidarsagene autotemcel (arsa-cel) is an autologous lentiviral haematopoietic stem cell (HSC) gene therapy indicated for the treatment of early-onset metachromatic leukodystrophy (MLD)...Mobilization, CD34⁺ cell yield, drug-product characteristics and busulfan exposure were comparable to that in other patients successfully treated with arsa-cel... This case represents the first failure of engraftment of gene-corrected cells after arsa-cel administration secondary to immune response. A null ARSA genotype (absence of baseline tolerance), in the presence of active infection along with a pro-inflammatory context, sustained ARSA-specific CD4⁺ T cell responses and humoral activation support a potential multifactorial, T-cell-driven rejection of transduced cells. Individual genetic predisposition, potentially including specific HLA backgrounds, may modulate the risk of immune rejection and warrants comparative analyses with other treated patients."

Clinical • Gene therapy • CNS Disorders • Eosinophilia • Gene Therapies • Human Immunodeficiency Virus • Infectious Disease • Metabolic Disorders • CD34 • CD8 • IFNG

LONG-TERM CLINICAL OUTCOMES OF ATIDARSAGENE AUTOTEMCEL, AUTOLOGOUS HEMATOPOIETIC STEM CELL GENE THERAPY (HSC-GT) FOR EARLY-ONSET METACHROMATIC LEUKODYSTROPHY, WITH UP TO 13 YEARS OF FOLLOW-UP (EBMT 2026) - P1/2, P2, P3 | "With up to 13 years of follow-up, arsa-cel continues to show a favourable benefit–risk profile, exhibiting a durable effect in slowing progression and preventing severe motor and cognitive impairment in most treated patients."

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

ATIDARSAGENE AUTOTEMCEL IN METACHROMATIC LEUKODYSTROPHY: SAFETY CONSIDERATIONS FROM REAL-WORLD PRACTICE (EBMT 2026) - "Mobilised peripheral blood (G-CSF + plerixafor) was used as the CD34⁺ source in all cases, with a median collection of 37.6×10⁶ CD34⁺ cells/kg (range 19.2–62.9). All patients underwent myeloablative single-agent busulfan conditioning... The robust engraftment, sustained ARSA reconstitution and early outcomes seen in most patients in this real-world cohort of 12 patients with MLD treated with arsa-cel are consistent with those seen in the clinical development programme; however, this cohort highlights the critical importance of systematic, long-term post-therapy monitoring for the continued evaluation of the risk–benefit profile in the real world setting."

Clinical • Real-world • Real-world evidence • Acute Lymphocytic Leukemia • Gene Therapies • Hematological Disorders • Hematological Malignancies • Hepatology • Leukemia • Metabolic Disorders • Rare Diseases • Thrombocytopenia • CD34

GONADAL TOXICITY AND PREMATURE OVARIAN INSUFFICIENCY AFTER HEMATOPOIETIC STEM CELL GENE-THERAPY IN FEMALE PATIENTS WITH METACHROMATIC LEUKODYSTROPHY (EBMT 2026) - "Atidarsagene autotemcel (arsa-cel) is an ex vivo autologous hematopoietic stem-cell gene therapy and it is infused intravenously following single agent busulfan conditioning. In our analysis POI is a frequent adverse effect associated with busulfan, consistent with previous reports. Sub-myeloablative exposure does not appear reducing the incidence of gonadal dysfunction compared with myeloablative regimen. Longitudinal hormonal assessments demonstrate early impairment of ovarian reserve, and the need to offer fertility preservation before arsa-cel and to initiate HRT when indicated."

Clinical • Gene therapy • Endocrine Cancer • Endocrine Disorders • Gene Therapies • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases • Women's Health

A CASE OF LACK OF ENGRAFTMENT OF GENE-CORRECTED CELLS AFTER LENTIVIRAL HEMATOPOIETIC STEM CELL GENE THERAPY FOR METACHROMATIC LEUKODYSTROPHY: AN INTEGRATED CLINICAL AND IMMUNOLOGICAL INVESTIGATION (EBMT 2026) - "Background: Atidarsagene autotemcel (arsa-cel) is an autologous lentiviral haematopoietic stem cell (HSC) gene therapy indicated for the treatment of early-onset metachromatic leukodystrophy (MLD)...Mobilization, CD34⁺ cell yield, drug-product characteristics and busulfan exposure were comparable to that in other patients successfully treated with arsa-cel... This case represents the first failure of engraftment of gene-corrected cells after arsa-cel administration secondary to immune response. A null ARSA genotype (absence of baseline tolerance), in the presence of active infection along with a pro-inflammatory context, sustained ARSA-specific CD4⁺ T cell responses and humoral activation support a potential multifactorial, T-cell-driven rejection of transduced cells. Individual genetic predisposition, potentially including specific HLA backgrounds, may modulate the risk of immune rejection and warrants comparative analyses with other treated patients."

Clinical • Gene therapy • CNS Disorders • Eosinophilia • Gene Therapies • Human Immunodeficiency Virus • Infectious Disease • Metabolic Disorders • CD34 • CD8 • IFNG

GALLBLADDER ABNORMALITIES IN METACHROMATIC LEUKODYSTROPHY: PRELIMINARY ANALYSIS IN PATIENTS TREATED WITH HEMATOPOIETIC STEM CELL GENE THERAPY AND UNTREATED PATIENTS (EBMT 2026) - "Atidarsagene autotemcel (arsa-cel), an autologous transplantation of CD34+ cells transduced ex vivo with a lentiviral vector encoding the ARSA gene, represents the only approved treatment for pre-symptomatic late-infantile and early-juvenile MLD, or early-symptomatic early-juvenile MLD forms... Our analysis confirms early and frequent gallbladder involvement across all MLD forms. Gallbladder wall thickening emerged as the earliest alteration and may represent the first precursor to more complex abnormalities such as polyps. The detection of ultrasound abnormalities as well as cases of cholecystectomy in patients before neurological symptom onset—including those with late-onset forms— suggests that visceral involvement may serve as an early diagnostic disease indicator."

Clinical • Gene therapy • CNS Disorders • Gene Therapies • Metabolic Disorders • CD34

LONG-TERM CLINICAL OUTCOMES OF ATIDARSAGENE AUTOTEMCEL, AUTOLOGOUS HEMATOPOIETIC STEM CELL GENE THERAPY (HSC-GT) FOR EARLY-ONSET METACHROMATIC LEUKODYSTROPHY, WITH UP TO 13 YEARS OF FOLLOW-UP (EBMT 2026) - P1/2, P2, P3 | "With up to 13 years of follow-up, arsa-cel continues to show a favourable benefit–risk profile, exhibiting a durable effect in slowing progression and preventing severe motor and cognitive impairment in most treated patients."

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

PRICE ANALYSIS OF GENE THERAPIES AUTHORIZED BY THE U.S. FOOD AND DRUG ADMINISTRATION (ISPOR 2026) - "The inflation-adjusted WAC (adj-WAC) ranged from $253,121 (revakinagene taroretcel) to $4,395,213 (atidarsagene autotemcel)...Tisagenlecleucel had different prices for two indications and onasemnogene abeparvovec for two routes of administration/patient populations... When adjusted for inflation, prices remained relatively constant over time. Prices varied depending on therapeutic class, patient population, and duration of therapy. Gene therapies had similar WAC and ASP."

Gene therapy • Gene Therapies

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 | Recruiting ➔ Active, not recruiting

Enrollment closed • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

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

A Safety and Efficacy Study of Cryopreserved OTL-200 for Treatment of Metachromatic Leukodystrophy (MLD) (clinicaltrials.gov) - P2 | N=10 | Recruiting | Sponsor: Orchard Therapeutics Limited | Phase classification: P3 ➔ P2

Phase classification • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

A Safety and Efficacy Study of Cryopreserved OTL-200 for Treatment of Metachromatic Leukodystrophy (MLD) (clinicaltrials.gov) - P3 | N=10 | Recruiting | Sponsor: GlaxoSmithKline

New P3 trial • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

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: Aug 2028 ➔ Apr 2028 | Trial primary completion date: Aug 2022 ➔ Apr 2022

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

Newborn Screening for Metachromatic Leukodystrophy: A Combined Method of Analysis (ACMG 2026) - "A major advancement in the treatment of MLD, an FDA approved autologous, hematopoietic stem cell transplantation (Lenmeldy), has increased interest in early disease detection via newborn screening... The combined method met or exceeded the standard criteria for linearity, precision, and accuracy. Additionally, the combined method performed similarly to assays currently in use. The combined method multiplexes the evaluation of MLD with other five conditions and requires no additional DBS specimens, sample preparations, or analyses, facilitating integration into routine screening algorithms."

Bone Marrow Transplantation • Genetic Disorders • Hurler Syndrome • Metabolic Disorders • Pompe Disease • IDUA

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