Autor:innen:
L. Laugwitz (Tübingen, DE)
S. Gröschel (Tübingen, DE)
F. Fumagalli (Mailand, IT)
V. Calbi (Mailand, IT)
J. Dalle (Paris, FR)
M. Essing (München, DE)
P. van Hasselt (Utrecht, NL)
S. Jones (Manchester, GB)
P. Lang (Tübingen, DE)
C. Sevin (Le Kremlin-Bicêtre, FR)
C. Lindemans (Utrecht, NL)
N. Wolf (Amsterdam, NL)
R. Wynn (Manchester, GB)
A. Aiuti (Mailand, IT)
Background
MLD is an ultra-rare, autosomal-recessive lysosomal disorder caused by deficiency of arylsulfatase A. Atidarsagene autotemcel (“arsa-cel”, Libmeldy®), an ex vivo autologous CD34+ haematopoietic stem and progenitor cell gene therapy, was approved by EMA in 2020 to treat children with late infantile[LI] and early juvenile [EJ] MLD without clinical manifestations of the disease, and children with the early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline. Here, we report long-term outcome of treated patients and share our German treatment experience.
Methods
The clinical trial program for arsa-cel, conducted at SR-TIGET, included 39 patients with early-onset MLD (19 LI, 20 EJ) compared to a historical cohort of 43 early-onset MLD subjects followed prospectively at the same centre (NHx) to assess the safety and efficacy of arsa-cel; all studies used comparable schedules of assessments and endpoints.
Results
Results from 39 patients followed for up to 12 years (median f/u 6.76 years, range 0.64-12.19) post-treatment demonstrated a favourable benefit-risk profile of arsa-cel: it has been generally well tolerated with no treatment-related SAEs, signs of insertional mutagenesis or replication-competent lentivirus to date. The risk of experiencing severe motor impairment or death was significantly reduced in the pre-symptomatic (PS)-LI (p < 0.001), PS-EJ (p=0.042), and early symptomatic (ES)-EJ (p < 0.001) treated subgroups versus NHx. Compared with NHx, arsa-cel treatment resulted in substantial improvements in motor and cognitive outcomes, particularly among patients treated before symptom onset. Over 95% (25/26) of patients treated while PS retained the ability to walk at last follow-up and maintained normal or near-normal cognitive development. Arsa-cel must be administered in a qualified treatment centre with experience in HSCT for neurometabolic disorders in children. Based on these requirements, Tübingen has become one of 5 European treatment centers. To date, one patient has been treated commercially with Libmeldy® in Tübingen, and 3 cases of MLD have been identified in a German newborn screening pilot study. One of these cases has been referred for treatment with Libmeldy with the other two pending clinical assessment.
Discussion
Long-term data confirm the favourable safety profile and sustained efficacy of arsa-cel in preventing severe motor and cognitive impairment and slowing disease progression in early-onset MLD patients. In the absence of a systematic newborn screening, timely detection and referral to a specialist centre is crucial to allow treatment in the ideal time-window before patients are too progressed. Ultimately, inclusion of MLD into the national newborn screening programs will allow diagnosis and treatment in the pre-symptomatic stage and enable best treatment outcomes for patients with early-onset MLD.