ZOLGENSMA (onasemnogene abeparvovec) - Spinal muscular atrophy (SMA)

Reassessment.

Key points

Favourable opinion for reimbursement only in “the treatment of patients with 5q spinal muscular atrophy (SMA) (biallelic mutation in the SMN1 gene):

• in pre-symptomatic patients with up to 3 copies of the SMN2 gene
• with a clinical diagnosis of SMA type 1, 2 or 3”.

What therapeutic improvement?

Therapeutic improvement only in pre-symptomatic patients with 3 copies of the SMN2 gene.

Role in the care pathway?

Due to the complexity of the management of this disease, the decision to initiate ZOLGENSMA (onasemnogene abeparvovec) treatment should be taken on a case-by-case basis at multidisciplinary team meetings within neuromuscular diseases reference and expert centres belonging to the FILNEMUS network. The use of this medicinal product is reserved for hospital neurologists or paediatricians specialising in SMA.

In the absence of a robust comparison versus SPINRAZA (nusinersen) and EVRYSDI (risdiplam), the Committee specifies that the choice between these three treatments should be made taking into account:

• the age of the patients, in a context in which the Committee recalls the importance of starting treatment with ZOLGENSMA (onasemnogene abeparvovec) as quickly as possible and ideally in pre-symptomatic patients,
• the clinical status of patients, insofar as the Committee reiterates the benefit of preservation of respiratory function and the absence of swallowing disorders for administration of treatment,
• patients’ comorbidities in view of the safety profile of each treatment with, for ZOLGENSMA (onasemnogene abeparvovec) a profile characterised by significant hepatic toxicity and a serious risk of thrombotic microangiopathy (TMA) requiring regular appropriate laboratory monitoring,
• the type of SMA and the number of copies of the SMN2 gene,
• the different administration methods of these medicinal products, as well as the choice of families.

The Committee also highlights that, to date, there is no efficacy data with ZOLGENSMA (onasemnogene abeparvovec) in:

• patients with a clinical diagnosis of SMA type 2, in contrast with SPINRAZA (nusinersen) and ERVYSDI (risdiplam),
• patients with SMA type 1 and 1 or 3 copies of the SMN2 gene,
• patients weighing more than 13.5 kg,
• patients treated beyond the age of 6 months,
• patients who would previously have been treated with SPINRAZA (nusinersen) or EVRYSDI (risdiplam).

In addition, although observed in clinical practice, there is a lack of precise information concerning the use of SPINRAZA (nusinersen) or EVRYSDI (risdiplam) in patients previously treated with ZOLGENSMA (onasemnogene abeparvovec).

The Committee also reiterates the importance of complying with the measures specified in the SmPC for ZOLGENSMA (onasemnogene abeparvovec) before and during its administration, and during patient follow-up, in particular the immunological, renal and haematological measures (section 4.2 of the SmPC).

In addition to these measures, the Committee recommends that administration of ZOLGENSMA (onasemnogene abeparvovec) be followed by hospitalisation in a paediatric high-dependency unit for at least 24 hours.

Moreover, it once again stresses the importance of the following in all patients:

• kidney function monitoring (creatinine levels and urine dipstick),
• haematological monitoring (complete blood count in the week following infusion, then at regular intervals),
• testing for haemolysis (schizocytes, haptoglobin and LDH assay),
• a complete kidney function assessment in the event of documented thrombocytopenia, given several cases of serious thrombotic microangiopathy (TMA) reported in the first two weeks following administration of ZOLGENSMA (onasemnogene abeparvovec).

Given the cases of acute liver failure reported, including some fatal cases, the Committee highlights the crucial importance of close monitoring of liver function in the event of any elevation in transaminases, until a return to normal and beyond.

Role of ZOLGENSMA (onasemnogene abeparvovec):

• In pre-symptomatic patients with 1, 2 or 3 copies of the SMN2 gene: it is a first-line treatment in the same way as SPINRAZA (nusinersen), given the suggested efficacy versus the natural course of the disease.
• In patients with SMA type 1: it is a first-line treatment in the same way as SPINRAZA (nusinersen) and EVRYSDI (risdiplam), given the suggested efficacy versus the natural course of the disease.
• In patients with SMA type 2: given the absence of data, but due to the disease continuum between types 1 and 2 in terms of pathophysiology and patient characteristics, and its efficacy deemed to be extrapolable, ZOLGENSMA (onasemnogene abeparvovec) is a therapeutic option in these patients, but SPINRAZA (nusinersen) and EVRYSDI (risdiplam), which have demonstrated an efficacy in these patients, should be favoured.
• In patients with SMA type 3: ZOLGENSMA (onasemnogene abeparvovec) has no role in the care pathway, given the absence of data (in contrast with SPINRAZA (nusinersen) and EVRYSDI (risdiplam)), a non-extrapolable efficacy and a lesser medical need compared to SMA type 1 and 2. 

Special recommendations

Due to the complexity of management of this rare disease and the risks related to administration of ZOLGENSMA (onasemnogene abeparvovec), in addition to the measures indicated in the SmPC, the Committee recommends that:

• the decision to initiate treatment should be taken on a case-by-case basis at multidisciplinary team meetings within neuromuscular diseases reference and expert centres belonging to the FILNEMUS network,
• the use of this medicinal should be reserved for hospital neurologists or paediatricians specialising in SMA,
• administration of ZOLGENSMA (onasemnogene abeparvovec) should be followed by hospitalisation in a paediatric high-dependency unit for at least 24 hours.

Moreover, it once again stresses the importance of the following in all patients:

• kidney function monitoring (creatinine levels and urine dipstick)
• haematological monitoring (complete blood count in the week following infusion, then at regular intervals),
• testing for haemolysis (schizocytes and LDH assay),
• a complete kidney function assessment in the event of documented thrombocytopenia, given several cases of serious thrombotic microangiopathy (TMA) reported in the first two weeks following administration of ZOLGENSMA (onasemnogene abeparvovec).

Given the cases of acute liver failure reported, including some fatal cases, the Committee highlights the crucial importance of close monitoring of liver function in the event of any elevation in transaminases, until a return to normal and beyond.

Avis économique

Ce produit a fait l'objet d'un avis économique rendu par la Commission d'évaluation économique et de santé publique le 21/11/2023.  

L’indication évaluée est restreinte par rapport à l’AMM et porte sur l’indication qui a fait l’objet d’une demande de réévaluation par la Commission de Transparence.

L’évaluation déposée par l’industriel ne permet pas de démontrer l’efficience de ZOLGENSMA (onasemnogene abeparvovec) pour l’indication des patients présymptomatiques atteints d’une SMA avec une délétion bi-allélique du gène SMN1 et jusqu’à 3 copies du gène SMN2 en raison d’une incertitude globale majeure, qui rend les résultats ininterprétables. Les résultats de l’analyse d’impact budgétaire sont en revanche présentés.

> ZOLGENSMA - Avis économique (pdf)