Revisión sistemática

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Does risk stratification decrease the risk of natalizumab-associated PML? Where is the evidence?

Año 2014
Autores Cutter GR , Stüve O
Revista Multiple sclerosis (Houndmills, Basingstoke, England)
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The use of natalizumab has likely been limited by its association with progressive multifocal leukoencephalopathy (PML), an infection caused by the human polyomavirus John Cunningham (JC). Three factors were recently identified that contribute to the overall risk of natalizumab-associated

PML:

(1) Positive serostatus for anti-JCV antibodies, (2) prior use of immunosuppressants, and (3) duration of natalizumab therapy. This risk stratification algorithm has not led to a reduction in the incidence of PML in natalizumab-treated patients with multiple sclerosis between April 2010 and February 2014. This observation may appear perplexing, as treatment duration and JCV serostatus are modifiable risk factors. Potential reasons for the lack of success of companion diagnostics that determine the overall risk of natalizumab-associated PML are discussed.

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Revisión sistemática

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[Efficacy and safety of natalizumab for multiple sclerosis and Crohn's disease: a meta analysis].

Año 2010
Autores Li YY , Li YP , Sun X , Wang L , Wen J , Cheng L
Revista Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae
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OBJECTIVE:

To systematically evaluate the safety and efficacy of natalizumab in treating multiple sclerosis (MS) and Crohn's disease(CD).

METHODS:

Literatures from 1998 to 2009 were searched in databases including MEDLINE,EMBASE,The Cochrane Library, and CBM for randomized controlled trials (RCTs) and quasi-randomization controlled trials. Quality assessment and data extraction were conducted using the Cochrane Collaboration's RevMan 5.0 software and then a Meta analysis was performed. The main indicators included the rate of adverse reactions, the rate of serious adverse reactions,response rate,and remission rate.

RESULTS:

Thirteen trials entered the final analysis. The main findings in the MS trials included: the rate of serious and general adverse effects were no significantly different among different groups (P>0.05). The new lesions rate was not significantly different within 3 months after treatment [RR=0.99, 95%CI (0.82, 1.18), P=0.87], but was significantly lower in 6 months in the treatment group [RR=0.45, 95%CI (0.33, 0.60), P<0.00001], and such advantage was maintained till 2 years later [RR=0.49, 95%CI (0.45, 0.53), P<0.00001]. The 2-year relapse rate was also significantly lower in the treatment group [RR=0.51, 95%CI (0.38, 0.69), P<0.0001]. The main findings in CD trials were as follows: The incidences between serious reactions and general adverse reactions were not significantly different (P>0.05). The remission rate was not significantly different between treatment group and control group in the 2nd week [RR=4.67, 95%CI (0.65, 33.26), P=0.12], but became significantly higher in the treatment group after 12 weeks [RR=1.46, 95%CI (1.26, 1.70), P<0.00001]. The response rate was significantly higher in the treatment group [RR=1.53, 95%CI (1.15, 2.03), P=0.004].

CONCLUSIONS:

The rates of serious and general adverse reactions are not remarkably increased after natalizumab treatment for both MS and CD. The new lesions rate and 2-year relapse rate of MS as well as the response rate and remission rate of CD are all improved after natalizumab treatment,especially after long-term administration. Although severe adverse effect such as progressive multifocal leukoencephalopathy may occur,its clinical application can be further promoted after cautiously balancing the benefits and risks.

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Estudio primario

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Natalizumab para inducción y la terapia de mantenimiento para la enfermedad de Crohn.

Traducción colaborativa
Año 2005
Revista The New England journal of medicine
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Este artículo está incluido en 11 Revisiones sistemáticas Revisiones sistemáticas (11 referencias) 2 Síntesis amplias Síntesis amplias (2 referencias)

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ANTECEDENTES:

Natalizumab, un anticuerpo monoclonal humanizado contra la integrina alfa 4, inhibiendo la adhesión y migración de leucocitos en el tejido inflamado.

MÉTODOS:

Se realizaron dos ensayos controlados para evaluar Natalizumab como tratamiento de inducción y de mantenimiento en pacientes con Enfermedad de Crohn activa. En el primer ensayo, 905 pacientes fueron asignados al azar para recibir 300 mg de natalizumab o placebo en las semanas 0, 4 y 8. El resultado primario fue la respuesta, definida por una disminución en el Índice de Actividad de la Enfermedad de Crohn (CDAI) de al menos 70 puntos, en la semana 10. En el segundo ensayo, 339 pacientes que presentaron una respuesta al Natalizumab en el primer ensayo fueron reasignados aleatoriamente para recibir 300 mg de Natalizumab o placebo cada cuatro semanas hasta la semana 56. El resultado primario fue una respuesta sostenida hasta la semana 36. Un resultado secundario en ambos ensayos fue de remisión de la enfermedad (una puntuación CDAI inferior a 150).
Resultados: En el primer ensayo, los grupos tratados con Natalizumab y placebo tuvieron tasas similares de respuesta (56 por ciento y 49 por ciento, respectivamente, p = 0,05) y remisión (37 por ciento y 30 por ciento, respectivamente, p = 0,12) a las 10 semanas. Continuando con natalizumab en el segundo juicio dio lugar a mayores tasas de respuesta sostenida (61 por ciento vs 28 por ciento, P <0,001) y remisión (44 por ciento vs 26 por ciento, p = 0,003) en la semana 36 que ha de cambiar a placebo. Los eventos adversos graves se produjeron en el 7 por ciento de cada grupo en el primer ensayo y en el 10 por ciento del grupo placebo y el 8 por ciento del grupo con natalizumab en el segundo juicio. En un estudio de extensión de etiqueta abierta, un paciente tratado con Natalizumab murió de leucoencefalopatía multifocal progresiva, asociada al virus JC, un poliomavirus humano.

CONCLUSIONES:

La terapia de inducción con Natalizumab para la enfermedad de Crohn no tiene mejoras significativas y remisión. Los pacientes que tuvieron una respuesta habían aumentado significativamente las tasas de respuesta y remisión sostenida si Natalizumab se continuó cada cuatro semanas. El beneficio de Natalizumab se deben sopesarse contra el riesgo de eventos adversos graves, incluyendo la leucoencefalopatía multifocal progresiva. (ClinicalTrials.gov numbers, NCT00032786 and NCT00032799.)

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Estudio primario

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A controlled trial of natalizumab for relapsing multiple sclerosis.

Año 2003
Revista The New England journal of medicine
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Este artículo está incluido en 1 Síntesis amplia Síntesis amplias (1 referencia) 1 Revisión sistemática Revisiones sistemáticas (1 referencia)

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BACKGROUND:

In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis.

METHODS:

In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being.

RESULTS:

There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram).

CONCLUSIONS:

In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.

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Estudio primario

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The cost effectiveness and budget impact of natalizumab for formulary inclusion.

Año 2010
Revista Journal of medical economics
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BACKGROUND:

Crohn's disease (CD) and multiple sclerosis (MS) are debilitating autoimmune diseases, which represent a substantial cost burden in the context of managed care. As a corollary, there is an unmet pharmacotherapeutic need in patient populations with relapsing forms of MS, in addition to populations with moderately to severely active CD with evidence of inflammation who have experienced an inadequate response to other mainstream therapies. The purpose of this study was to analyze the clinical and economic data associated with natalizumab (Tysabri) and to determine the potential impact of its formulary inclusion in a hypothetical health plan.

FINDINGS:

Regarding MS, the implemented cost-effectiveness and budget-impact models demonstrated an anticipated reduction in relapse rate of 67% over 2 years, and a total therapy cost of $72,120 over 2 years, equating to a cost per relapse avoided of $56,594. With respect to the model assumptions, the market share of natalizumab would experience an increase to 8.5%, resulting in a total per-member, per-month healthcare cost increase of $0.003 ($0.002 for pharmacy costs and $0.001 for medical costs). Regarding CD, over a 2-year period outlined by the model, natalizumab produced the highest average time in remission, steroid-free remission, and remission or response in comparison to the other agents. The mean total costs associated with the initiation of natalizumab, infliximab, and adalimumab were $68,372, $62,090, and $61,796, respectively. Although natalizumab's costs were higher, the mean time spent in remission while on this medication was 4.5 months, as opposed to 2.4 months for infliximab and 2.9 months with adalimumab. This shift in market share was used to estimate the change in total costs (medical + pharmacy), and the per-member per-month change for the model's base case was calculated to be $0.035.

LIMITATIONS:

The aforementioned cost-effectiveness results for natalizumab in the treatment for CD and MS were limited by the model's predetermined assumptions. These assumptions include anticipated reduction in relapse rate after 2 years of therapy and acquisition costs in the MS model, as well as assuming a certain percentage of patients were primary and secondary failures of TNFalpha inhibitor therapy in the CD model.

CONCLUSION:

The evidence presented here demonstrates that natalizumab provides clinical practitioners with another tool in their fight against both MS and CD, albeit by way of a different mechanism of action. After a thorough review of the evidence, the authors find that natalizumab has been shown to be relatively cost effective in the treatment of both conditions from a payer perspective; the therapy adds a new option for those patients for whom conventional treatment was unsuccessful.

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Estudio primario

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Progressive multifocal leukoencephalopathy in a patient treated with natalizumab.

Año 2005
Revista The New England journal of medicine
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Este artículo está incluido en 1 Síntesis amplia Síntesis amplias (1 referencia)

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We describe the clinical course of a patient with multiple sclerosis in whom progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the central nervous system, developed during treatment with interferon beta-1a and a selective adhesion-molecule blocker, natalizumab. The first PML lesion apparent on magnetic resonance imaging was indistinguishable from a multiple sclerosis lesion. Despite treatment with corticosteroids, cidofovir, and intravenous immune globulin, PML progressed rapidly, rendering the patient quadriparetic, globally aphasic, and minimally responsive. Three months after natalizumab therapy was discontinued, changes consistent with an immune-reconstitution inflammatory syndrome developed. The patient was treated with systemic cytarabine, and two months later, his condition had improved.

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Estudio primario

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Infusion-related hypersensitivity reactions during natalizumab treatment.

Año 2006
Revista Neurology
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Resumen estructurado de revisiones sistemáticas

No clasificado

Natalizumab for multiple sclerosis - horizon scanning review

Año 2003
Autores NHSC
Revista HTA Database
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RECORD STATUS:

This is a bibliographic record of a published health technology assessment from a member of INAHTA. No evaluation of the quality of this assessment has been made for the HTA database.

CITATION:

NHSC. Natalizumab for multiple sclerosis - horizon scanning review. Birmingham: National Horizon Scanning Centre (NHSC). 2002

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Revisión sistemática

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Natalizumab in multiple sclerosis: discontinuation, progressive multifocal leukoencephalopathy and possible use in children.

Año 2015
Revista Expert review of neurotherapeutics
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In the early 1990s, attention was drawn to the migration of immune cells into the central nervous system via the blood-brain barrier. The literature showed that lymphocytes binding to the endothelium were successfully inhibited by an antibody against α4β1 integrin. These biological findings resulted in the development of a humanized antibody to α4 integrin - natalizumab (NTZ) - to treat multiple sclerosis (MS). Here, we provide a systematic review and meta-analysis on the efficacy and safety of natalizumab, trying to answer the question whether its use may be recommended both in adult and in pediatric age groups as standard MS treatment. Our results highlight the improvement of clinical and radiological findings in treated patients (p < 0.005), confirming NTZ efficacy. Nevertheless, if NTZ is shown to be efficient, further studies should be performed to evaluate its safety and to target the MS profile that could benefit from this treatment.

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Estudio primario

No clasificado

A safety and pharmacokinetic study of intravenous natalizumab in patients with MS.

Año 1999
Revista Neurology
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A phase 1, randomized, placebo-controlled, five-level dose escalation safety and tolerability and pharmacokinetic study of a single IV dose of natalizumab was performed. Doses of 0.03 to 3.0 mg/kg natalizumab or placebo were studied in 28 stable relapsing-remitting or secondary-progressive MS. All doses were safe and well tolerated in MS. Serum concentrations of natalizumab are detectable for 3 to 8 weeks after a single 1- or 3-mg/kg IV dose and justify controlled efficacy studies.

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