ULTOMIRIS (ravulizumab) - Atypical haemolytic uremic syndrome (aHUS)

Opinions on drugs - Posted on May 15 2023

Reason for request

Reassessment

Reassessment.

Key points

Favourable opinion for maintenance of reimbursement in the “treatment of atypical haemolytic uremic syndrome (aHUS)”.

Role in the care pathway?

ULTOMIRIS (ravulizumab) is a first-line therapy in the treatment of patients with a body weight of 10 kg or above with atypical haemolytic uremic syndrome (aHUS) who are complement inhibitor treatment-naïve or have received eculizumab (SOLIRIS) for at least 3 months and have evidence of response to eculizumab. However, in the absence of a direct comparison with eculizumab, the role of ravulizumab cannot be determined compared to this medicinal product.

The Committee highlights that ULTOMIRIS (ravulizumab) has no marketing authorisation in patients not having responded to eculizumab, or in children with a body weight of under 10 kg, in contrast with SOLIRIS (eculizumab), which has an MA from 5 kg.

ULTOMIRIS (ravulizumab) is a complement protein C5 inhibitor that, due to this mechanism of action, increases the patient’s predisposition to infections caused by encapsulated bacteria, in particular meningococcal infection/septicaemia (Neisseria meningitidis). Consequently, its prescription must be combined with vaccination against meningococcal infections using the ACYW conjugated tetravalent vaccine and the serogroup B invasive meningococcal infection vaccine, in accordance with current vaccination schedule guidance.

The Committee recommends that prophylactic antibiotic therapy be implemented for all patients requiring ravulizumab, as for eculizumab, in accordance with the 2021 French national diagnostic and care protocol (PNDS): long-term prophylactic antibiotic therapy with full-dose phenoxymethylpenicillin as two doses per day (or macrolides in the event of allergy) from the start of treatment, to be continued throughout treatment and for 60 days following its discontinuation (until normalisation of CH50 in children). Vaccination of close relatives may be discussed in transplant patients, in whom a weak or nil vaccine response is possible.

Clinical Benefit

Substantial

The clinical benefit of ULTOMIRIS 300 mg/3 ml and 1,100 mg/11 ml (ravulizumab) concentrate for solution for infusion becomes substantial in the MA indication.

Clinical Added Value

no clinical added value

Considering:

the partially met medical need in a disease that is life-threatening in the absence of treatment,
the potential, but not demonstrated, benefit in terms of patients’ quality of life and care pathway, of having access to a treatment making it possible to increase the interval between infusions compared to eculizumab (every 8 weeks or every 4 weeks for children weighing from 10 to under 20 kg, instead of every 2 weeks),
the clinical responses obtained with ravulizumab for a clinically relevant endpoint, complete response in terms of thrombotic microangiopathy (TMA), and the maintenance of these responses up to week 104, in patients naïve to complement inhibitor treatment (60% adult responders and 18/20 responders in the children/adolescents),
maintenance of LDH and haemoglobin levels up to week 104 in children/adolescents treated with ravulizumab having previously responded to at least 3 months of treatment with
eculizumab,

but considering:

the low level of evidence of ravulizumab‘s efficacy demonstration of based on two non-comparative clinical studies and including a small number of patients,
the absence of direct comparative between ravulizumab and eculizumab, another complement C5 inhibitor considered to be the reference first-line treatment for the last ten years,
persistent uncertainties with respect to the long-term efficacy and safety,

the Transparency Committee deems that ULTOMIRIS (ravulizumab) continues to provide no clinical added value (CAV V) compared to current management in the treatment of patients with a body weight of 10 kg or above with atypical haemolytic uremic syndrome (aHUS), which includes SOLIRIS (eculizumab), who are complement inhibitor treatment-naïve or have received eculizumab for at least 3 months and have evidence of response to eculizumab.