EVRYSDI 0,75 mg/ml (risdiplam)

Key points

Favourable opinion for reimbursement in the treatment of 5q spinal muscular atrophy (SMA) in patients 2 months of age and older, with a clinical diagnosis of SMA type 1, type 2 or type 3.

Unfavourable opinion for reimbursement in patients with SMA with a clinical diagnosis of SMA type 4 and in pre-symptomatic patients.

What therapeutic improvement?

Therapeutic improvement in the management of the disease in patients with 5q spinal muscular atrophy (SMA) with a clinical diagnosis of:

• SMA type 1, in the same way as SPINRAZA (nusinersen) and ZOLGENSMA (onasemnogene abeparvovec),
• SMA type 2, in the same way as SPINRAZA (nusinersen), and
• non-ambulant SMA type 3.

No clinical added value in the therapeutic strategy for ambulant symptomatic patients with SMA type 3.

Role in the care pathway?

According to the treatment guidelines, treatment should be started as early as possible - at the pre-symptomatic stage if possible - in order to anticipate complications, in particular 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.
• The curative treatments currently available:
  • ZOLGENSMA (onasemnogene abeparvovec), a viral vector using the capsid of a non-replicating, recombinant adeno-associated serotype 9 virus, in which the DNA has been replaced by the cDNA of the human survival of motor neuron (SMN) gene and enabling the expression of the deficient SMN protein, as a single intravenous injection;
  • SPINRAZA (nusinersen), an antisense oligonucleotide administered intrathecally, which increases functional SMN protein production by acting on splicing of the SMN2 gene, and;
  • Now EVRYSDI (risdiplam), an oral SMN2 gene splicing modifier that has had a European MA since 26 March 2021.

According to the opinions of the Committee of January 2018 and July 2020 for SPINRAZA (nusinersen) and of December 2020 for ZOLGENSMA (onasemnogene abeparvovec):

• In type 1 SMA and in pre-symptomatic patients with up to 3 copies of the SMN2 gene, SPINRAZA and ZOLGENSMA are first-line treatments. In the absence of a robust comparison, the choice between these two treatments should be made on the basis of the patient’s age, clinical condition and comorbidities, the administration methods and the preferences of the family, as well as the available data and their level of evidence. For patients with severe type 1 SMA having started before the age of 3 months, the decision to prescribe SPINRAZA should be discussed on a case-by-case basis, taking into account, in particular, the existence of restrictive respiratory syndrome. It should be noted that the experts currently recommend treatment of patients diagnosed at the pre-symptomatic stage with 4 copies of the SMN2 gene;
• In type 2 SMA, SPINRAZA is the treatment to be favoured, whereas ZOLGENSMA is a treatment option pending data in these patients;
• In type 3 SMA, SPINRAZA is the only treatment option available and the decision to prescribe it should be discussed on a case-by-case basis, taking into account the date of onset of the symptoms and the patient’s capacity to walk. The Committee considered that ZOLGENSMA had no role in the care pathway for these patients;
• In type 4 SMA, no treatments are currently recommended. In fact, ZOLGENSMA is not indicated in this clinical type and the Committee considered that SPINRAZA had no role in the care pathway.

Role of the medicinal product in the care pathway

Considering:

• the medical need to have access to alternative treatments, mainly in patients with a clinical diagnosis of SMA type 1 or 2, but also in patients with type 3 (including ambulant) due to the administration methods, as reported by patient and user associations and experts;
• the efficacy of risdiplam administered daily by the oral route demonstrated in two phase 2/3 clinical studies (FIREFISH and SUNFISH) in patients with a laboratory diagnosis of SMA and a clinical diagnosis of SMA type 1, type 2 or type 3 (non-ambulant patients);
• exploratory results that suggest a marked improvement compared to the natural course of the disease after two 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 methodological limitations of the adjusted indirect comparisons made versus SPINRAZA (nusinersen) and ZOLGENSMA (onasemnogene abeparvovec) due to their concomitant development, in patients with SMA type 1 and 2, meaning that it is not possible to accurately determine the role of EVRYSDI (risdiplam) in the care pathway, and;
• an efficacy deemed to be extrapolable to ambulant patients with a clinical diagnosis of SMA type 3 given the clinical continuum and the pathophysiology of the disease, the mechanism of action of the medicinal product, and despite the absence of data in these patients;

EVRYSDI (risdiplam) is a first-line treatment, to be used:

• in symptomatic patients with SMA type 1, in the same way as SPINRAZA (nusinersen) and ZOLGENSMA (onasemnogene abeparvovec),
• in patients with SMA type 2 and 3, in the same way as SPINRAZA (nusinersen).

In the absence of data and given an efficacy that it is difficult to extrapolate, EVRYSDI (risdiplam) has no role in the care pathway for pre-symptomatic patients with SMA and up to 4 copies of the SMN2 gene.

Due to the complexity of the management of this disease, the decision to initiate EVRYSDI (risdiplam) 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 by a physician experienced in the treatment of patients with SMA.

In the absence of a robust comparison (direct or indirect) versus SPINRAZA (nusinersen) and ZOLGENSMA (onasemnogene abeparvovec), and pending the results from the national SMA registry (see paragraph 10 of this opinion), the Committee specifies that the choice between the treatments available should be made taking into account:

• the age of the patients; a context in which the Committee highlights the need to start treatment as soon as possible and, if possible, in pre-symptomatic patients;
• the patient’s general condition;
• patients’ comorbidities in view of the safety profile of each treatment and, in particular, the serious risk of thrombotic microangiopathy (TMA) with ZOLGENSMA (onasemnogene abeparvovec);
• the different administration methods of these medicinal products insofar as the Committee highlights the fact that the daily oral administration of EVRYSDI (risdiplam) may be an interesting option compared to the other administration methods available but that it is not necessarily an advantage in young children for treatment compliance reasons;
• the available data for these three medicinal products and their level of evidence;
• as well as the choice of families and patients.

The Committee also highlights that, to date, there is no data with EVRYSDI (risdiplam) in:

• patients with type 1 SMA and 1 or 3 copies of the SMN2 gene;
• ambulant patients with a clinical diagnosis of SMA type 3;
• and efficacy data in patients who would previously have been treated with SPINRAZA (nusinersen) or ZOLGENSMA (onasemnogene abeparvovec).

As with the alternatives previously analysed by the Committee, longer-term follow-up of patients in the context of a registry is essential to assess the medium and long-term effect of EVRYSDI (risdiplam) on respiratory, motor and cognitive functions, and on mortality and quality of life, as well as its safety.

Special recommendations

Due to the complexity of the management of this rare disease, the Committee recommends that the treatment decision 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 and that the use of this medicinal product be reserved for physicians specialising in SMA.

Avis économique

Ce produit a fait l'objet d'un avis économique rendu par la Commission d'évaluation économique et de santé publique le 14 septembre 2021  . 

La demande de remboursement correspond à l’indication de l’AMM obtenue le 26 mars 2021 en procédure centralisée. L’évaluation porte sur la partie de l’indication pour laquelle une ASMR III est revendiquée. De ce fait, le périmètre de l’évaluation économique est plus restreint que la demande de remboursement. 

La Commission d’évaluation économique et de santé publique conclut que l’évaluation déposée par l’industriel ne permet pas de démontrer l’efficience de risdiplam pour les indications pour lesquelles  il demande le remboursement  en raison  d’une  incertitude globale majeure, qui rend le résultat ininterprétable. 

Selon les choix et hypothèses de l’industriel, l’introduction de risdiplam entraine, pour son prix revendiqué (indemnité ATU), un impact budgétaire cumulé sur 5 ans représentant une augmentation de 26,7% par rapport au scénario n’incluant pas risdiplam  pour une population cible de 1 116 patients en année 5.

> EVRYSDI - Avis économique (pdf)