ZOLGENSMA (onasemnogene abeparvovec)

Key points

Favourable opinion for reimbursement in the treatment of patients with 5q spinal muscular atrophy (SMA) with a bi-allelic mutation in the SMN1 gene and a clinical diagnosis of SMA Type 1 and 2 or pre-symptomatic SMA, with up to 3 copies of the SMN2 gene.

Unfavourable opinion for reimbursement in the treatment of patients with 5q spinal muscular atrophy (SMA) with a bi-allelic mutation in the SMN1 gene and a clinical diagnosis of SMA Type 3.

What therapeutic improvement?

Therapeutic improvement, in the same way as SPINRAZA (nusinersen), in the management of symptomatic patients with 5q spinal muscular atrophy (SMA) with a bi-allelic mutation in the SMN1 gene and a clinical diagnosis of SMA Type 1 as well as in pre-symptomatic patients with 1 to 2 copies of the SMN2 gene.

No clinical added value in the therapeutic strategy for symptomatic patients with 5q spinal muscular atrophy (SMA) with a bi-allelic mutation in the SMN1 gene and a clinical diagnosis of SMA Type 2 as well as in pre-symptomatic patients with 3 copies of the SMN2 gene.

Role in the care pathway?

Patients with SMA must be treated as early as possible, particularly in the event of types 1 and 2 in order to anticipate respiratory complications. Current management consists of:

• Symptomatic treatment, with a multidisciplinary approach, with the aim of improving quality of life. This includes, in particular, physiotherapy, occupational therapy and respiratory assistance, with, in certain cases, non-invasive ventilation and gastrostomy.
• SPINRAZA (nusinersen), an antisense oligonucleotide administered intrathecally, which increases functional SMN protein production by acting on splicing of the SMN2 Before the arrival of ZOLGENSMA (onasemnogene abeparvovec), SPINRAZA (nusinersen) was the only treatment with an MA in 5q spinal muscular atrophy.

According to the Committee opinions of 2018 and 2020, SPINRAZA (nusinersen) is a first-line treatment reserved for patients:

• with type 1 SMA whose symptoms began before the age of 3 months,
• with type 2 SMA,
• as well as in pre-symptomatic infants and children with genetically diagnosed SMA with 2 to 3 copies of the SMN2

The decision to prescribe the drug must nonetheless be discussed on a case-by-case basis:

• in severe type 1 SMA having started before the age of 3 months, taking into account, in particular, the existence of restrictive respiratory syndrome,
• and in early type 3 SMA, taking into account the walking capacity.

SPINRAZA (nusinersen) has no role in the care pathway for the management of type 4 SMA.

Role of the medicinal product in the care pathway

Considering:

• the efficacy of single IV administration of ZOLGENSMA (onasemnogene abeparvovec) observed in 3 non-randomised, open-label clinical studies, in symptomatic patients with type 1 SMA (with 2 copies of the SMN2 gene) and in pre-symptomatic patients (with 2 or 3 copies of the SMN2 gene), particularly in terms of survival without permanent ventilation and the acquisition of the main motor milestones,
• results that suggest a marked improvement compared to the natural course of the disease after 2 years in symptomatic patients but without recovery (persistence of motor and respiratory disability) and with uncertainties with respect to maintenance of the effect of treatment and the longer-term outcome for these patients,
• the significant limitations of the indirect comparison with SPINRAZA (nusinersen), the only other medicinal product with an MA in this indication having been the subject of concomitant development, meaning that it is not possible to accurately determine the role of ZOLGENSMA (onasemnogene abeparvovec) in the care pathway of patients with type I SMA compared to this drug,
• and an efficacy that appears to be extrapolable to patients with a clinical diagnosis of type 2 SMA given the clinical continuum between types 1 and 2 and the pathophysiology of the disease, the mechanism of action of the medicinal product, and despite the absence of data in these patients,

ZOLGENSMA (onasemnogene abeparvovec) is a first-line treatment, in the same way as SPINRAZA (nusinersen), to be used in symptomatic patients with type 1 SMA or pre-symptomatic patients with up to 3 copies of the SMN2 gene.

In symptomatic patients with type 2 SMA, the Committee considers that ZOLGENSMA (onasemnogene abeparvovec) is a therapeutic option but that SPINRAZA (nusinersen) should be favoured pending data in these patients.

In the absence of data and given a lesser medical need and a non-extrapolable efficacy, ZOLGENSMA (onasemnogene abeparvovec) has no role in the care pathway of patients with type 3 SMA.

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. In addition, in accordance with the SPC, treatment must be initiated and administered in a hospital environment and supervised by a physician experienced in the treatment of patients with SMA.

In the absence of a robust comparison (direct or indirect) compared to SPINRAZA (nusinersen), and pending the results from the national SMA registry (see paragraph 10 of this opinion), the Committee specifies that the choice of these two treatments should be made taking into account:

• the age of the patients, in a context in which the Committee recalls the need to start treatment with ZOLGENSMA (onasemnogene abeparvovec) as quickly as possible and if possible 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 and, in particular, the significant hepatic toxicity of ZOLGENSMA (onasemnogene abeparvovec),
• the different administration methods of these medicinal products,
• the available data for these two medicinal products and their level of evidence,
• as well as the choice of families.

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

• patients with a clinical diagnosis of type 2 SMA, in contrast with SPINRAZA (nusinersen),
• patients with type I SMA and 1 or 3 copies of the SMN2 gene,
• patients weighing more than 13.5 kg,
• patients treated beyond the age of 6 months,
• and patients who would not previously have been treated with SPINRAZA (nusinersen).

Considering laboratory evidence of liver injury observed in clinical studies and cases of serious clinical hepatitis reported in the literature and by experts, the Committee recommends prior performance of a liver function assessment, as well as close monitoring of liver function and hospitalisation for at least 24 hours in a paediatric high-dependency unit following the administration of ZOLGENSMA (onasemnogene abeparvovec).

Following publication of cases of thrombotic microangiopathy in patients treated with ZOLGENSMA (onasemnogene abeparvovec), the Committee recommends the implementation of kidney function monitoring in all patients (creatinine levels and urine dipstick) as well as testing for haemolysis (schizocytes, haptoglobin and LDH assay) in the event of documented thrombocytopenia.

Longer-term monitoring of patients in the context of a registry (see section 10 of this opinion) is essential to assess the medium to long-term effect of ZOLGENSMA (onasemnogene abeparvovec) on respiratory, motor and cognitive functions, and on mortality and quality of life, as well as its safety.

Finally, the Committee points out that, although observed in clinical practice, the use of SPINRAZA (nusinersen) in patients previously treated with ZOLGENSMA (onasemnogene abeparvovec) has not been assessed in clinical studies and has not been validated by an MA.

Special recommendations

Due to the complexity of management of this rare disease and the risks related to administration of ZOLGENSMA (onasemnogene abeparvovec), 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 product be reserved for hospital physicians specialising in SMA,
• close monitoring of liver function be put in place given the laboratory evidence of liver injury observed in clinical studies and cases of serious clinical hepatitis reported in the literature and by experts,
• kidney function monitoring be implemented in all patients (creatinine levels and urine dipstick) as well as testing for haemolysis (schizocytes, haptoglobin and LDH assay) in the event of documented thrombocytopenia, given the cases of thrombotic microangiopathy (TMA) reported in patients treated with ZOLGENSMA (onasemnogene abeparvovec),
• and that administration of ZOLGENSMA (onasemnogene abeparvovec) be followed by hospitalisation in a paediatric high-dependency unit for at least 24 hours.

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