In an integrated data set, 29 children with MLD (16 late infantile, 13 early juvenile) aged 7.6‒139.9 months were treated with Libmeldy. They were compared with 31 untreated children with MLD (19 late infantile, 12 early juvenile). The median duration of follow-up was 3.16 years (range 0.64-7.51 years). The aim of the study was to determine the efficacy and safety of Libmeldy hematopoietic stem cell (HSC) gene therapy. Of the 29 patents included (who were given the fresh formulation (OTL0200-f), 20 were from Study 201222 (Registrational study), 1 was from CUP 207394 (Compassionate Use Programme), 3 were from HE 205029 (Hospital exemption) and 5 were from SUP 206258 (Compassionate Use Programme).1
Summary of demographic characteristics by symptomatic status at time of gene therapy and by disease subtype (Integrated efficacy set)
Libmeldy Summary of Product Characteristics.2
The co-primary endpoints were, at 2 years post-treatment:3,4
An improvement of 10% of the total GMFM-88 score in treated patients compared to natural history.
A significant (≥2 SD) increase of ARSA activity from pre-treatment values in PBMCs.
At year 3, an interim safety and efficacy analysis was planned and, at year 8, an efficacy and safety follow-up was planned.
The safety of Libmeldy was evaluated in 35 patients with MLD. The median duration of follow-up in the integrated safety data set, which included 29 patients treated with the fresh (investigational) formulation, was 4.51 years (range: 0.64 to 8.85 years). The median duration of follow-up in the 6 patients treated with the cryopreserved (commercial) formulation was 0.87 years (range: 0.0 to 1.47 years).
Adverse reactions attributed to Libmeldy
Anti-ARSA antibodies: AAA were reported in 5 patients during clinical development; titers were generally low and resolved spontaneously or after treatment with rituximab. No impacts on the clinical efficacy or safety outcomes were observed.
Risk of insertional oncogenesis: There is a theoretical risk of leukaemia or lymphoma after treatment with Libmeldy.
The long-term efficacy and safety of Libmeldy are unknown. Patients are asked to enrol in a follow up study for up to 15 years to better understand the long-term effects of Libmeldy.
Treatment with Libmeldy is preceded by medical interventions, namely haematopoietic stem cell collection through bone marrow harvest or peripheral blood mobilisation with G-CSF with or without plerixafor followed by apheresis, and myeloablative conditioning (preferably using busulfan) which are associated to well characterized but potentially serious risks.
Normalised ARSA activity in peripheral blood mononuclear cells
Reconstitution of ARSA achieved normal to supraphysiologic levels within 3-6 months post‐treatment. Patients treated with Libmeldy showed stable reconstitution of ARSA levels at 24 months after treatment. Reconstitution of ARSA levels maintained up to 7 years after treatment administration in late infantile patients.1
Survival benefit with Libmeldy vs. natural history group in late infantile (LI) MLD2
100% survival in LI patients treated with Libmeldy, with the longest follow-up of 8.7 years post treatment vs. 36.8% survival (7/19) in untreated late infantile patients in the natural history cohort at the time of the analysis.2
LI: late infantile
Statistically and clinically significant improvements in Gross Motor Function1
Patients treated with Libmeldy showed statistically and clinically significant improvements in Gross Motor Function measure at 24 months after treatment; when compared to natural history patients, results significantly exceed the pre-defined threshold of 10%.
Statistically significant differences were maintained at 3 years.1
Adapted from Libmeldy Summary of Product Characteristics.2
The Gross Motor Function Measure at 2 years after treatment was a co-primary endpoint of the registrational clinical study.
Note: Analysis of covariance adjusting for treatment and age. P-values are from a two-sided 5% hypothesis test with null hypothesis of 10% difference.
Gross Motor Function Measure (GMFM) is the most common functional outcome measure for gross motor functioning in children with neurologically based conditions.3 It is designed to measure gross motor function over time for children with disabilities, from 5 months to 16 years of age.2 The GMFM-88 test contains 88 questions grouped into five dimensions:3 lying and rolling (17), sitting (20), crawling and kneeling (14), standing (13), and walking, running and jumping (24). Percentage scores are calculated within each dimension and averaged to obtain a total score that ranges from 0 to 100. Higher scores indicate better capacity.3
Qualified treatment centres (QTCs) have the required infrastructure and experience in haematopoietic stem cell transplantation and the management of leukodystrophies to ensure the consistency and quality of treatment. For more details, see treatment process.
▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions
GMFM, gross motor function measurement; PBMC, peripheral blood mononuclear cells; CI, confidence interval; EJ, early juvenile; GMFM, gross motor function measurement; GT, gene therapy; HSC, haematopoietic stem cell; LI, late infantile; MLD, metachromatic leukodystrophy
Fumagalli F, et al. Lentiviral hematopoietic stem cell gene therapy (HSC-GT) for metachromatic leukodystrophy (MLD) provides sustained clinical benefit; Presented at: 2019 Annual Symposium of the Society for the Study of Inborn Errors of Metabolism (SSIEM); September 3-6, 2019; Rotterdam, The Netherlands.
Libmeldy, Summary of Product Characteristics. March 2021
Alotaibi M, et al Disabil Rehabil. 2014; 36(8): 617–627.