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Prescribing Information SmPC

What is MLD?

MLD is a rare, genetic, neurometabolic demyelinating lysosomal storage disorder caused by a deficiency of the arylsulfatase A (ARSA) enzyme due to mutations in the ARSA gene.1,2

MLD is inherited in an autosomal-recessive pattern – the overall carrier frequency being between 1:100 and 1:130.3

The ARSA gene encodes ARSA, a lysosomal enzyme necessary for the metabolism of sulfatides, a major component of the myelin membrane. Patients with MLD inherit two mutant alleles of the ARSA gene and have inadequate ARSA enzyme activity.

Damaging levels of sulfatides accumulate in lysosomes, leading to progressive demyelination that results in missed developmental milestones, regression, and ultimately leading to severe neurological symptoms.2 Patients experience severe motor and cognitive impairment, especially in the most common, early onset forms of the disease (late infantile and early juvenile forms).2

Diagnostic challenge of MLD

Adapted from von Figura K, et al., In: The metabolic and molecular bases of inherited disease, Vol. 3, 8th ed. New York: McGraw-Hill, 2001:3698-37247

Clinical course of MLD

Symptoms, age on onset and disease course vary, but patients progress to dysphagia, severe neurological disability and death.1,2

MLD has a considerable impact on the social, emotional and professional lives of patients and their families, including an average of 17 hours per day spent by families caring for their child with MLD.8

The global incidence of MLD is ~1.6 (range 0.6–2.5)/100,000 live births (for all forms of MLD).9

 

Process of diagnosing MLD

Diagnosing MLD is a challenge for several reasons:10

  • Early symptoms are non-specific and often difficult to identify, leading to delayed referrals to specialist centres.
  • In the rapidly progressive phase, it is often too late for a disease-modifying therapy.
  • Newborn screening is not currently implemented.
  • The neurodevelopmental delay in many other neurodegenerative diseases can mimic MLD, e.g., Saposin B deficiency, Krabbe disease and Angelman syndrome.7 The ideal is to identify pre-symptomatic and early symptomatic patients to expedite the referral process to specialist centres, and start treatment promptly.

 

Recognising early symptoms of MLD

Early identification is critical. The progressive, irreversible nature of MLD demands an understanding of its clinical course and requires immediate, decisive action to prevent patient regression and improve overall outcomes.7

Early symptoms vary depending on whether the condition is late-infantile (LI) or juvenile (JU) MLD.

Most common early signs of late infantile and juvenile MLD reported by caregivers

Adapted from Eichler et al. Initial Signs and Symptoms of MLD: A Caregiver Perspective. Poster presented at the Annual WORLD Symposium, February 8-12 202111

  • Multiple recent studies emphasize the need for early disease identification and intervention for the best chance for successful treatment of MLD.11
  • These data highlight that diagnosis is often delayed, often requiring consultation with multiple specialists, leaving many too far progressed to be suitable candidates for interventional therapies.11
  • Patients present with a constellation of symptoms that ultimately leads to diagnosis.11
  • The majority of late infantile and juvenile patients present with motor symptoms with many juvenile cases also present with cognitive impairments.11
  • It is important to recognize the red flag that these children present with clear caregiver concerns against a background of previously normal development and without a history of peri-natal event.11
  • Lack of developmental progress, when previously reaching milestones normally, i.e., the ‘persistent toddler’ should be recognized as requiring clinical attention.11
  • The insidious nature of “developmental stagnation” demonstrates how onset may be a period of concern rather than a specific point in time.11
  • The findings from this research provide a clear call to action for clinicians across specialties to support broader awareness of MLD and its early indicators in order to direct patients to immediate appropriate specialists and testing.11

Adapted from von Figura K, et al., In: The metabolic and molecular bases of inherited disease, Vol. 3, 8th ed. New York: McGraw-Hill, 2001:3698-37247

Process for diagnosing symptomatic MLD

For HCPs with a symptomatic patient, the following process should be followed:12

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Identifying pre-symptomatic MLD

The earlier patients can be identified, the better the outcomes. This can be achieved by family screening and, ideally, newborn screening.12 Although newborn screening is not yet routinely implemented for MLD, pilot newborn screening studies are under way.

Sibling testing

To allow a timely diagnosis and potential treatment, it is strongly recommended to initiate parallel family testing upon a strong suspicion of an MLD index case.12

Adapted from Parikh et al., Molecular Genetics and Metabolism, 2015: 501-51512

Treating MLD

Before the approval of Libmeldy, there were limited treatment options for patients with MLD.13-16

Standard of care in MLD previously was limited to best supportive care, which involves the palliative treatment of symptoms. The use of allogeneic HSCT is only used in a minority of juvenile MLD patients. For many patients with MLD, particularly those with the late infantile, pre-symptomatic and early symptomatic form of the disease, allogenic HSCT is not recommended due to limited/no efficacy and inherent risks (including the possibility that pre-transplant procedures may even facilitate disease progression).17 Limitations of HSCT may include risk of graft-vs-host disease, limited levels of ARSA produced by the bone marrow HCST-derived microglia, limited donor match availability, and procedure-associated complications. Best supportive care and allogeneic HSCT are summarised below:13-16

Libmeldy is the first autologous haematopoietic stem cell (HST) gene therapy product for early-onset MLD, as well as the first approved treatment.18

Best supportive care vs allogeneic HSCT in MLD

References

  1. Rosenberg JB, et al. J Neurosci Res 2016; 94(11): 1169-1179.
  2. Ferreira CR, Gahl WA. Transl Sci Rare Dis 2017; 2(1-2): 1-71.
  3. Lugowska A et al. PLoS One 2011; 6(6): e20218.
  4. Kreysing J et al. Am J Hum Genet 53: 339-346, 1993.
  5. Zsolt et al. Acta Medica Marisiensis 2015; 61(3): 233–235.
  6. Patil S, Maegawa GHB. Drug Des Devel Ther 2013; 7: 729–745.
  7. von Figura K, et al. J Metachromatic leukodystrophy. 2001 In: The metabolic and molecular bases of inherited disease, Vol. 3, 8th ed. New York, NY: McGraw-Hill, 2001: 3695–372.
  8. Pang T et al. Mol Genet Metab 2020; 129(2): S126.
  9. Kehrer C et al. Dev Med Child Neurol 2011; 53: 850-855.
  10. Wang et al.Wang RY et al. Genet Med 2011; 13(5): 457-484.
  11. Eichler et al. Initial Signs and Symptoms of MLD: A Caregiver Perspective. Poster presented at the Annual WORLDSymposium, February 8-12 2021.
  12. Parikh S et al. Mol Genet Metab 2015 Apr; 114(4): 501-515.
  13. Bredius RGM et al. Bone Marrow Transplant 2007; 39: 309-310.
  14. van Rappard DF et al. Blood 2016a; 127: 3098-3101.
  15. Beschle J et al. Mol Cell Pediatr 2020; 7(1): 12.
  16. Groeschel S et al. JAMA Neurol 2016; 73: 1133-1140.
  17. Laugwitz L, et al. Eur J Paediatri Neurol 2024;49:141–154.
  18. Libmeldy, Summary of Product Characteristics.