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LIVTENCITY (maribavir) - CMV

Opinions on drugs - Posted on Mar 10 2023

Reason for request

Inclusion

First assessment.

Key points

Favourable opinion for reimbursement in “the treatment of cytomegalovirus (CMV) infection and/or disease that are refractory (with or without resistance) to one or more prior therapies, including ganciclovir, valganciclovir, cidofovir or foscarnet in adult patients who have undergone a haematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT)”.

Role in the care pathway?

LIVTENCITY (maribavir) is a last-resort option for the treatment of CMV infection and/or disease that are refractory (with or without resistance) to one or more prior therapies, including ganciclovir, valganciclovir, cidofovir or foscarnet in adult patients who have undergone a haematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT).

The use of this anti-CMV antiviral agent should only be considered as a last resort, i.e. when the available options are not feasible for reasons of toxicity (particularly haematological or nephrological), drug interaction or virological failure (viral strain refractory or resistant to conventional treatments). A second anti-CMV antiviral agent may be combined with maribavir in the event of life-threatening disease.

The Committee specifies that, despite an overall favourable effect observed in the SOLSTICE study, the benefit in terms of virological improvement appears to be inferior in the refractory population without resistance to prior treatment compared to that in the refractory population with resistance.

Due to its low diffusion, maribavir is not recommended in the event of neurological or ocular damage due to CMV infection and/or disease. In the latter case, a combination containing ganciclovir and foscarnet will be favoured.

Special recommendations

The Committee recommends the performance of resistance genotyping (testing for UL97 resistance) before initiating treatment with maribavir, particularly in patients previously treated with
ganciclovir/valganciclovir and liable to present a maribavir resistance mutation. Treatment should be discontinued if resistance to maribavir is detected (see Section 4.4 Special warnings and precautions for use in the SmPC). The performance of genotyping does not prevent treatment from being initiated.


Clinical Benefit
Substantial

The clinical benefit of LIVTENCITY (maribavir) 200 mg film-coated tablets is substantial in the MA indication.

Clinical Added Value
minor

Considering:

  • the unmet medical need in adult patients who have undergone a haematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT) and with CMV infection and/or disease refractory (with or without resistance) to one or more prior therapies, including ganciclovir, valganciclovir, cidofovir or foscarnet;
  • the effect size of LIVTENCITY (maribavir) in terms of confirmed CMV viremia clearance rate at week 8 of 33% and maintenance of the response at week 16 of 10% (SOLSTICE study);
  • the effect of maribavir as a salvage therapy in patients initially treated with conventional anti-CMV therapies and who achieved confirmed CMV viremia clearance after 8 complete weeks of treatment in 50% of cases (N = 11);
  • an acceptable safety profile but marked by adverse events such as mild to moderate dysgeusia, generally resolving spontaneously, and the risk of increases in plasma levels of certain immunosuppressants in the event of co-administration;

But:

  • a benefit that appears to be inferior in terms of virological improvement in the refractory population without resistance to prior treatment;
  • the low percentage of patients in whom the response was maintained at week 16 following a complete 8-week treatment and the absence of data concerning the duration of treatment beyond 8 weeks;
  • the fact that the majority of the population included had asymptomatic CMV infection (91.8%), which limits the transposability to the curative treatment of patients with CMV disease (3.7% in the study);
  • the risk of the emergence of resistance among patients with RAS to anti-CMV treatment or maribavir at baseline (PRS or MRS population), with 20% of them having developed RAS to maribavir after 8 weeks of treatment with maribavir;

the Transparency Committee deems that LIVTENCITY (maribavir) 200 mg film-coated tablets provides a minor clinical added value (CAV IV) in the current care pathway for patients who have undergone a haematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT) and with CMV infection and/or disease refractory (with or without resistance) to one or more prior therapies, including ganciclovir, valganciclovir, cidofovir or foscarnet.

Avis économique

Ce produit a fait l'objet d'un avis économique rendu par la Commission d'évaluation économique et de santé publique le 29/08/2023. 

L’avis économique porte sur une indication superposable à celle demandée au remboursement, à savoir les patients adultes atteints de l’infection et/ou de la maladie à cytomégalovirus (CMV) réfractaire (avec ou sans résistance) à un ou plusieurs traitements antérieurs, y compris le ganciclovir, le valganciclovir, le cidofovir ou le foscarnet après avoir reçu une greffe de cellules souches hématopoïétiques (GCSH) ou une greffe d’organe solide (GOS). 

La Commission évaluation économique et de santé publique conclut que :  

  • Au prix revendiqué et selon les hypothèses retenues dans la modélisation, la comparaison de LIVTENCITY au bras mixte composé du ganciclovir, valganciclovir, foscarnet et cidofovir (GVFC), aboutit à un RDCR de 135 570 €/QALY (194 608 €/AVG) sur 10 ans. 
  • Le choix visant à faire dépendre du traitement reçu jusqu’à la semaine 20 la survenue des récidives cliniquement significatives pourrait conduire à sous-estimer le RDCR. 
  • Les choix et hypothèses de modélisation s’appuyant sur des données de faible niveau de preuves scientifiques (i.e. avis d’experts et études rétrospectives), des incertitudes demeurent concernant :  
    • la durée à partir de laquelle l’immunité naturelle est retrouvée chez les patients ; 
    • le risque de retransplantation chez les patients post-greffe d’organe solide ; 
    • l’estimation des scores d’utilité associés aux états de santé. 
  • Une incertitude demeure quant à la transposabilité des résultats chez les patients atteints de la maladie à CMV. 

> LIVTENCITY - Avis économique (pdf)

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