Natalizumab in the treatment of multiple sclerosis: appropriate patient selection

Multiple sclerosis ( MS ) is a chronic disabling disease of the central nervous system ( CNS ), affecting more than 2 million people worldwide.
The disease usually starts in early adulthood, but the age range for disease onset is wide, with both pediatric cases and new onset of disease above the age of 50 years; 85%–90% of people with multiple sclerosis experience relapses and remissions of neurologic symptoms ( relapsing–remitting multiple sclerosis [ RRMS ] ), particularly early in the disease, and clinical events are usually associated with areas of CNS inflammation.
Over time, the majority of untreated patients develops a pattern of progressive worsening with or without superimposed relapses; after 20–25 years, approximately 90% of untreated RRMS patients will have secondary progressive multiple sclerosis.
Compared to the normal population, life expectancy is reduced by 8–12 years in the MS population untreated with a disease-modifying therapy.

The unpredictable disease course, as well as the progressive nature of the disease with ongoing physical and mental impairment, significantly impacts patients’ quality of life, social and family lives, and employment status.
Although quality-of-life reduction occurs in parallel with increasing physical disability, invisible symptoms of multiple sclerosis such as fatigue, as well as cognitive and affective disorders, may contribute significantly to a decrease in quality of life early in the disease course.

Interferons and Glatiramer acetate were approved for RRMS in the mid-1990s in the US and Europe on the basis of prospective, randomized, placebo-controlled trials.
Treatment response, as measured by relapse rate, disability progression, and magnetic resonance imaging ( MRI ) parameters, varies considerably among patients. However, approximately 30% of patients have an excellent response to Interferon or Glatiramer acetate.
In contrast, occurrences of relapses and MR activity within the first 12–18 months after treatment initiation are good predictors for future increase in Expanded Disability Status Scale ( EDSS ) scores in patients treated with Interferon beta.

Natalizumab, a humanized monoclonal antibody, was approved by the US Food and Drug Administration ( FDA ) in 2004 on the basis of interim analysis of two phase III studies, Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis ( AFFIRM ) and Safety and Efficacy of Natalizmab in Combination with Avonex ( IFNbeta-1a ) in Patients with Relapsing-Remitting MS ( SENTINEL ).

The introduction of Natalizumab into the market in 2004 was a milestone in multiple sclerosis therapy. Its profound suppression of clinical and MR activities led to the introduction of a new goal in MS therapy, namely, freedom from disease activity and therefore induced a paradigm shift in MS therapy with lower tolerance to MS activity in patients treated with disease-modifying agents.

However, only 3 months after its first approval, Natalizumab was temporarily withdrawn from the market after the occurrence of three progressive multifocal leukoencephalopathy ( PML ) cases, two in phase III MS trials and one in a patient with inflammatory bowel disease.

In 2006, Natalizumab was reintroduced into the US market and released in the European Union, together with a Global Risk Managment Plan, to be carried out mandatorily in the US ( TOUCH: TYSABRI Outreach: Unified Commitment to Health ) and voluntary in the remaining parts of the world ( TYGRIS: TYSABRI Global Observation Program in Safety ).

Currently, 13 disease-modifying therapies have been approved by the European Medicines Agency ( EMA ) and the FDA, including three oral preparations ( Fingolimod [ Gilenya ], Dimethyl fumarate [ Tecfidera ] and Teriflunomide [ Aubagio ] ) as well as Alemtuzumab [ Lemtrada ] given as an intravenous 5 day course in year 1 and a 3 day course in year 2.
The increasing armamentarium of approved MS therapeutics makes treatment decisions more complex, both to clinicians and to patients.

Natalizumab: safety

The most serious adverse events reported under therapy with Natalizumab are progressive multifocal leukoencephalopathy ( PML ), infections, and hypersensitivity.

The risk of progressive multifocal leukoencephalopathy is the major limiting factor in Natalizumab therapy. Progressive multifocal leukoencephalopathy is an opportunistic CNS infection, caused by the John Cunningham virus ( JCV ).
Three major risk factors for Natalizumab-associated progressive multifocal leukoencephalopathy have been identified: 1) positive serostatus for anti-JCV antibodies; 2) prior use of immunosuppressants; and 3) duration of Natalizumab therapy.

As of December 3, 2014, the overall PML incidence in Natalizumab-treated patients was 3.78 cases per 1,000 patients ( 95% CI: 3.46–4.12 per 1,000 patients ), with the highest risk in JCV-positive patients who have received prior immunosuppression and who have exceeded treatment duration of 24 months ( 11.2/1,000; 95% CI: 8.6–14.3 ).
The overall PML incidence in a recently published prospective open-label study was 3.73 cases per 1,000 patients ( TOP ), which is consistent with the most recently reported PML risk in the postmarketing setting.

MRI ( magnetic resonance imaging ) is the most sensitive paraclinical tool in the detection of PML lesions, which can be present up to months before clinical symptoms occur.

Although progressive multifocal leukoencephalopathy is usually diagnosed during Natalizumab therapy, it has also been reported to occur up to 109 days after Natalizumab suspension for reasons other than suspected or laboratory-proven PML.

Natalizumab-associated progressive multifocal leukoencephalopathy is usually treated with plasma exchange and is often complicated by the occurrence of immune reconstitution inflammatory syndrome ( IRIS ).

While Natalizumab-associated progressive multifocal leukoencephalopathy is fatal in approximately 20% of cases, most patients survive with significant morbidity and irreversible disability.

Early detection of progressive multifocal leukoencephalopathy, or even detection of PML in clinically asymptomatic patients, leads to better functional outcomes and reduced mortality.

Infections, reported in 3.2% of patients receiving Natalizumab monotherapy, comprised the most frequently reported serious adverse event in the phase III trial, compared to 2.6% of patients on the placebo arm.

The risk of infection was also assessed in the phase IV open-label studies. Infections, including urinary tract infections and pneumonia, were reported to occur in 1.9–4% of patients.
Opportunistic infections other than progressive multifocal leukoencephalopathy were found with an incidence of 0.2% in TOP, which is in line with the reported risk of less than 1% in phase III trials.

The most common reported opportunistic infections other than PML were associated with herpes virus ( herpes zoster and herpes meningitis ).

Serious hypersensitivity reactions ( 0.5% ) and anaphylaxis or anaphylactic shock ( 0.2% ) occurred with a lower incidence in the long-term open-label studies as compared to the phase III trials ( 1.3% and 0.8%, respectively ).

Natalizumab: patient selection

Against the background of an increasing spectrum of MS therapeutics, selection of the appropriate drug for an individual patient at a given time point during the disease course is complex.

Early and effective disease control has been shown to delay long-term consequences of multiple sclerosis. On the basis of the available evidence on Interferon beta, estimates indicate a 20–40% reduction of disability progression with the early use of Interferon beta.
The observed reduction of MS-associated mortality rates in the Interferon beta-1b extension study supports the long-term benefits of Interferon beta.

Although the disease course is highly unpredictable, some indicators of early accrual of disability have been identified. A high relapse frequency within the first years after disease onset, a short first interattack interval, and a short interval to reach EDSS score of 3.0 increase the probability of early conversion to secondary progressive multiple sclerosis.
As current immune therapies are only modestly effective in the progressive phase of the disease, it is important to avoid conversion to secondary progressive multiple sclerosis.
High T2 lesion load and rapid increase of MR burden correlate with disability 20 years later, although with a high variance.
Conversely, patients with a low T2 lesion load and fewer new T2 lesions show significantly less disability progression over 10 years. Timely implementation of an effective treatment in patients at risk for early disability may therefore improve patients’ long-term outcome.

Natalizumab is highly effective in preventing relapses, disease progression, and MR activity and further has a positive impact on patients’ quality of life.
Natalizumab wide use is limited by the risk of progressive multifocal leukoencephalopathy.

Natalizumab is indicated in patients with one or more relapses during the previous year and nine or more T2 lesions or one contrast-enhancing lesion on MRI despite treatment with Interferon beta or Glatiramer acetate.
In patients with two or more relapses and increase of T2 lesion load or at least one contrast-enhancing lesion on brain MRI, Natalizumab may be prescribed independent of the pretreatment.

Assessment of prior immunosuppressive therapy and treatment duration, as well as JCV antibody testing, is performed in order to stratify for the Natalizumab-associated PML risk. However, this risk stratification does not allow a precise prediction of the individual PML risk. More recently, it has been suggested that patients with low JCV antibody titers carry a lower Natalizumab-associated PML risk than patients with high titers.
Further immunologic markers for the prediction of the individual PML risk, such as leukocyte cell membrane markers or JCV-specific activated T effector memory cells, are currently discussed.
Despite the implementation of risk stratification, the PML incidence has not decreased since 2010. The reasons for this are currently unknown.

In JCV-negative patients, the PML risk is considered to be negligible ( 0.1/1,000; 95% CI: 0.01–0.35 ), irrespective of treatment duration, and the benefit of effective disease control outweighs the risk.
The reported prevalence of JCV seropositivity in the general MS population is 57.6% and is increasing with age.
The conversion rate per year during Natalizumab therapy is approximately 3%,but this was higher ( 14.5% ) in a recent report.
It is unknown to what extent treatment duration in patients who convert from seronegativity to seropositivity during Natalizumab therapy increases the PML risk.
In contrast, it is generally advised to stop Natalizumab treatment in patients who display all three PML risk factors, ie, JCV seropositivity, prior immunosuppressant use, and treatment duration of more than 2 years, in whom the PML risk is 1:90.

JCV-positive patients with high disease activity may receive Natalizumab at least for 24 months, since during this period, the PML risk appears to be low ( 0.7/1,000; 95% CI: 0.5–1.0 in patients without prior immunosuppression ).
However, after 24 months of treatment, the PML risk increases significantly ( 5.2/1,000; 95% CI: 4.4–6.2 ) and treatment continuation or cessation on the basis of a risk–benefit analysis has to be discussed again.
In case of treatment continuation, MR monitoring every 3–6 months has been advised. The MRI appearance of Natalizumab-associated PML is heterogeneous and fluctuating and may also involve cortical gray matter.
Fluid-attenuated inversion recovery is the most sensitive sequence for detection of PML lesions. Diffusion-weighted imaging may allow detection of active demyelination in PML lesions.

Keeping in mind the limited treatment period due to the increasing PML risk after 24 months, and thus, the need for sequential therapies, the unknown consequences of sequential immune therapies, and the uncertainty with respect to the individuals’ response to another compound, alternative effective options in patients with highly active MS may be considered. ( Xagena )

Kornek B, Patient Prefer Adherence 2015; 9: 675–684



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