UPLIZNA (inébilizumab) - Neuromyélite optique

Key points

Approval of reimbursement as monotherapy for the treatment of neuromyelitis optica spectrum disorders (NMOSD) in adult patients seropositive for anti-aquaporin 4 immunoglobulin G (AQP4-IgG).

Therapeutic improvement?

Therapeutic improvement in the care pathway excluding rituximab.

Role in therapeutic strategy?

As per the 2021 national diagnosis and treatment protocol (PNDS) for NMOSD, the treatment of an attack of neuromyelitis optica (NMO) is a therapeutic emergency, due to the risk of incapacitating sequelae and, besides its potential functional outcomes, its potentially life-threatening nature. In parallel, long-term treatment (background therapy) is key in reducing the risk of attacks, the recurrence of which is liable to result in severe functional sequelae.

The initial treatment for attacks is based on high-dose methylprednisolone (1g/day) intravenous corticosteroid therapy for 5 to 10 days, followed by long-term oral treatment (1 mg/kg/day) and plasma exchanges for severe attacksErreur ! Signet non défini..

The basic treatments used in practice (off-label) and recommended to prevent relapses are the following immunosuppressant treatments:

• rituximab, an anti-CD20 therapy, administered by IV every 6 months (beneficial effect on episode prevention, significant reduction in annualised rate of attacks),
• azathioprine, in association with corticosteroid therapy administered orally for the first six months (decrease in annualised rate of attacks),
• mycophenolate mofetil, in association with corticosteroid therapy administered orally for the first six months (decrease in annualised rate of attacks),
• mitoxantrone (reduction in annualised rate of attacks).

Other medicinal products such as cyclophosphamide and ciclosporin are also used to a more limited extent.

The treatments used in MS (interferons, glatiramer acetate, natalizumab or fingolimod) appear to be ineffective or even harmful.

Tocilizumab, an anti-IL6 therapy, is also used off-label for conventional immunosuppressant-refractory NMOSD.

Two monoclonal antibodies were recently granted marketing authorisations for the treatment of NMOSD in adult patients exhibiting anti-aquaporin 4 (AQP4) antibodies;

• anti-complement protein C5 antibody, SOLIRIS (eculizumab) indicated for adults for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in patients exhibiting anti-aquaporin 4 (AQP4) antibodies with the recurrent form of the disease 
• anti-interleukin 6 antibody, ENSPRYNG (satralizumab) indicated as monotherapy or in association with an immunosuppressant treatment (IST) for the treatment of neuromyelitis optica spectrum disorders (NMOSD) in adult patients and adolescents from 12 years, who are seropositive for anti-aquaporin-4 IgG (AQP4IgG)”

The Transparency Committee assessed these two proprietary medicinal products on 16 September 2020 (SOLIRIS) and 17 January 2022 (ENSPRYNG), respectively, and approved reimbursement within a restricted scope of their respective marketing authorisations reserved for patients with recurrent forms of the disease and failing to respond to conventional immunosuppressant treatments.

Role of the medicinal product

Considering:

• the evidence of the superiority of inebilizumab monotherapy versus placebo assessed in a double-blind randomised study on the time to relapse (clinically relevant primary outcome measure) and on reduced worsening of incapacity following the 6.5-month double-blind phase (adjusted secondary outcome measure),
• that the large majority of the patients included in this study (93%) were seropositive for anti-aquaporin-4 IGG,
• the similarity of the mechanism of action of inebilizumab to that of rituximab, predominantly used as a first-line approach,

and despite,

• the limited percentage of treatment-naive patients (34%) at the time of inclusion in the study,
• the lack of direct comparative data versus the immunosuppressant treatments used in practice (off-label), of which rituximab, or treatments with a marketing authorisation (satralizumab, eculizumab) reserved for recurrent forms as a second-line approach, the latter having been developed concomitantly,
• the uncertainties around long-term efficacy and safety and around the optimal treatment duration in a context in which the mechanism of action of the medicinal product exposes the patient to a risk of hypogammaglobulinaemia and severe associated infections,

UPLIZNA (inebilizumab) monotherapy is a first-line treatment for NMOSD in adult patients seropositive for anti-aquaporin 4 immunoglobulin G (AQPA-IgG).

The Committee stresses that, in the absence of comparative data, it is not possible to specify the role of UPLIZNA (inebilizumab) in relation to rituximab based on the data available.

Moreover, despite the similarity of their mechanism of action, the Committee points out the uncertainties around a potential risk of hypogammaglobulinaemia when treated with UPLIZNA (inebilizumab) associated with its additional action on plasmablasts and certain plasmocytes and in a context in which severe infection and three deaths, including two associated with infections, have been reported. Unlike the current follow-up available on the use of rituximab, the follow-up on the safety of UPLIZNA (inebilizumab) is limited (open-label extension phase up to a median follow-up period of 3.15 years).

In this context, in accordance with the SPC, particular attention must be placed on the risk of infection and the need for full blood count monitoring (including leukocyte and immunoglobulin counts) prior to commencing treatment, during treatment, and after discontinuing treatment until B-cell repopulation has been achieved. The summary of product characteristics (SPC) and the Risk Management Plan (RMP) must be adhered to.

Special recommendations

The Committee recommends that UPLIZNA (inebilizumab) treatment be administered in a multiple sclerosis expert centre or a centre of the MIRCEM network (rare inflammatory brain and bone marrow disease), with prescription restricted to neurologists within the framework of multidisciplinary review meetings, justified with regard to the risk of UPLIZNA (inebilizumab) use beyond the scope defined by the Committee, especially use for patients with no anti-AQP4 antibodies (off-label).