LIBMELDY (population autologue enrichie en cellules CD34+ qui contient des cellules souches progénitrices hématopoïétiques transduites ex vivo avec un vecteur lentiviral codant le gène de l’arylsulfatase A humaine)

Key points

Favourable opinion for reimbursement in the treatment of metachromatic leukodystrophy (MLD) only in asymptomatic children without clinical manifestations of the disease in terms of motor, cognitive and/or behavioural functional impairment, with late infantile (onset before 30 months of age) or early juvenile (onset from 30 months to 6 years of age inclusive) forms.

Unfavourable opinion for reimbursement in the treatment of metachromatic leukodystrophy (MLD) in symptomatic children with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline, with the early juvenile form (onset from 30 months to 6 years of age inclusive).

What therapeutic improvement?

Therapeutic improvement in the management of metachromatic leukodystrophy (MLD) in asymptomatic children with late infantile (onset before 30 months of age) or early juvenile (onset from 30 months to 6 years of age inclusive) forms.

 Role in the care pathway?

The care pathway for metachromatic leukodystrophy (MLD) is currently based on symptomatic treatment.

Allogeneic haematopoietic stem cell transplantation (HSCT) is a currently available alternative to correct the enzyme deficiency, generally reserved for milder forms of MLD corresponding to the juvenile and adult forms. Current results for the efficacy of allogeneic HSCT in patients with juvenile forms are heterogeneous, however, and relate to small patient cohorts or case studies. It has been suggested that transplantation would have more impact in the event of early use, at the very start of the disease rather than at an advanced stage. However, allogeneic grafts are ineffective to prevent progression of the disease in aggressive forms, such as late infantile forms or early forms with evident neurological symptoms; that is because the rapid progression of the disease at these stages is incompatible with the very gradual nervous system microglia and macrophage replacement time associated with central reconstitution of arylsulfatase A (ARSA) enzymatic activity following transplantation.

Finally, phase 1/2 and 2 trials are currently ongoing with the following new treatment methods, being investigated in MLD:

• enzyme replacement therapy, with the administration of human recombinant ARSA by intravenous or intrathecal injections;
• gene therapy:
  • direct intracerebral administration of adeno-associated viral vector.
  • direct intracerebral administration of lentiviral vector.
  • administration of autologous CD34+ cells transduced ex vivo using a lentiviral vector encoding the ARSA/ABCD1 gene, including the product assessed in this opinion.

 Role of the medicinal product in the care pathway

Considering:

• the observed efficacy:
• in terms of motricity on the GMFM score after 2 years, with a difference of 65.1% in asymptomatic patients with the infantile form (onset before 30 months of age) and 52.4% in asymptomatic patients with the early juvenile form (onset from 30 months to 6 years of age inclusive) compared to the natural history cohort,
• on the observed increase in ARSA activity after 2 years (second co-primary efficacy endpoint):
  • with an activity multiplied by 8.6 (CI95% = [3.9; 19.2]) in children with a late infantile form,
  • with an activity multiplied by 7.3 (CI95% = [3.6; 14.9]) in children with an early juvenile form

• on cognitive function, assessed using IQ scales in asymptomatic patients with the late infantile form (onset before 30 months of age) or early juvenile form (onset from 30 months to 6 years of age inclusive),
• but with less benefit in symptomatic children with the early juvenile form.
• limited short-term safety data with signals relative to immunisation, and the important potential risk identified in the RMP on malignancy associated with insertional mutagenesis,
• limitations related to the manufacturing and administration circuit with, in particular, adverse events related to busulfan conditioning,

LIBMELDY is a therapeutic option in metachromatic leukodystrophy (MLD) only in asymptomatic children without clinical manifestations of the disease in terms of motor, cognitive and/or behavioural functional impairment, with late infantile (onset before 30 months of age) or early juvenile (onset from 30 months to 6 years of age inclusive) forms.

In the other children covered by the scope of the MA for LIBMELDY corresponding to the treatment of metachromatic leukodystrophy (MLD) in symptomatic children with early clinical manifestations of the disease who still have the ability to walk independently and before the onset of cognitive decline, with the early juvenile form (onset from 30 months to 6 years of age inclusive), the Committee considers that LIBMELDY has no role in the care pathway.

The Summary of Product Characteristics (SPC) and the Risk Management Plan (RMP) must be complied with. Special monitoring during and after treatment is required.

According to the SPC, patients should undergo regular monitoring of anti-ARSA antibodies (AAA) before treatment and for up to 15 years post-treatment. The theoretical risk of leukaemia or lymphoma after treatment with LIBMELDY should also be monitored.

Special recommendations

The Committee highlights the benefit to patients and their carers of having access to appropriate information on the complexity of the gene therapy procedure and the risks to patients, in particular:

• the uncertainties relative to maintenance of efficacy in the medium and long term,
• the uncertainties relative to safety, including the potential risk of immunisation and insertional mutagenesis in a context in which the median duration of follow-up after LIBMELDY treatment is 4.5 years on a limited patient population,
• the impact on fertility of LIBMELDY treatment, related to administration of busulfan during the conditioning phase.

Considering the complexity of the gene therapy procedure with LIBMELDY, its use strictly limited to a small population of patients with MLD and uncertainties in terms of the maintenance of its efficacy and its long-term safety:

• The decision to treat a patient with LIBMELDY should be discussed at a multidisciplinary team (MDT) meeting attended by professionals from a reference centre experienced in allogeneic bone marrow transplantation and gene therapy in metachromatic leukodystrophy.
• The prescription of LIBMELDY and its administration should be reserved for qualified reference centres, by physicians experienced in HCST and in the treatment of metachromatic leukodystrophy, in accordance with the requirements of the SPC and according to expert opinion.

In this context, the Committee highlights the importance of overall care (in particular including travel and local accommodation near healthcare facilities, where required).

The Committee will reassess LIBMELDY within a maximum period of 3 years, on the basis of the data requested, including the interim analyses of studies not completed on this date.