Natalizumab In Multiple Sclerosis

Background
Interferon-beta is used to modify the course of Relapsing Multiple Sclerosis.

Despite Interferon-ß therapy, many patients have relapses. Natalizumab, an alpha4 Integrin antagonist, appeared to be safe and effective alone and when added to Interferon-ß-1a in preliminary studies.

Methods
We randomly assigned 1171 patients who, despite Interferon-beta-1a therapy, had had at least one relapse during the 12-month period.

Before randomization to receive continued Interferon-ß-1a in combination with 300 mg of Natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks.

The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years.

Results
Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P=0.02).

Kaplan-Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with Interferon-ß-1a alone.

Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was Interferon-ß-1a alone (0.34 vs. 0.75, P < 0.001) and with fewer new or enlarging lesions on T₂-weighted Magnetic Resonance Imaging (0.9 vs. 5.4, P < 0.001).

Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema.

Two cases of Progressive Multifocal Leukoencephalopathy, one of which was fatal, were diagnosed in Natalizumab-treated patients.

Conclusions
Natalizumab added to Interferon-ß-1a was significantly more effective than Interferon-beta-1a alone in patients with Relapsing Multiple Sclerosis.

Additional research is needed to elucidate the benefits and risks of this combination treatment.

Copyright 2006 Massachusetts Medical Society.

Background
Natalizumab is the first alpha4 Integrin antagonist in a new class of selective Adhesion-Molecule Inhibitors. We report the results of a two-year phase 3 trial of Natalizumab in patients with Relapsing Multiple Sclerosis.

Methods
Of a total of 942 patients, 627 were randomly assigned to receive Natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two years.

The primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale, at two years.

Results
Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77; P < 0.001).

The cumulative probability of progression (on the basis of Kaplan-Meier analysis) was 17 percent in the Natalizumab group and 29 percent in the placebo group.

Natalizumab reduced the rate of clinical relapse at one year by 68 percent (P < 0.001) and led to an 83 percent reduction in the accumulation of new or enlarging HyperIntense lesions.

As detected by T₂-weighted Magnetic Resonance Imaging (MRI), over two years (mean numbers of lesions, 1.9 with Natalizumab and 11.0 with placebo; P < 0.001).

There were 92 percent fewer lesions (as detected by Gadolinium-enhanced MRI) in the Natalizumab group than in the placebo group at both one and two years (P < 0.001).

The adverse events that were significantly more frequent in the Natalizumab group than in the placebo group were fatigue (27 percent vs. 21 percent, P=0.048) and allergic reaction (9 percent vs. 4 percent, P=0.012).

Hypersensitivity reactions of any kind occurred in 25 patients receiving Natalizumab (4 percent), and serious hypersensitivity reactions occurred in 8 patients (1 percent).

Conclusions
Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with Relapsing Multiple Sclerosis.

Adhesion-Molecule Inhibitors hold promise as an effective treatment for Relapsing Multiple Sclerosis.

Copyright 2006 Massachusetts Medical Society.

Natalizumab, an anti-alpha4 Integrin Antibody, significantly reduces the number of visibly enhancing Multiple Sclerosis (MS) lesions.

In this substudy of a 2-year trial of Natalizumab monotherapy versus placebo, contrast-enhanced imaging investigated for subtle Blood Brain Barrier (BBB) leakage in Relapsing/Remitting (RRMS) patients, and whether such leakage is modified by Natalizumab.

After 24 weeks on treatment, 40 patients from 3 centres (27 on Natalizumab and 13 on placebo) were studied.

T₁ weighted images were obtained before and at set timepoints up to 46 minutes after Gadolinium (Gd)-DTPA (0.3mmol/kg to 18 patients, 0.15mmol/kg to 22).

Paired regions of interest were placed around non-enhancing lesions and ContraLateral Normal-Appearing White Matter (NAWM).

BBB leakage was inferred through post-Gd T₁ weighted Signal Intensity (SI) change. SI change was greater in T₂ non-enhancing lesions than paired NAWM at all timepoints (P < 0.005), indicating BBB leakage in lesions.

No significant difference in inferred BBB leakage was observed between treatment arms as measured by SI change of lesions (P > 0.05 for all timepoints, joint test P = 0.24), or in SI change of NAWM (joint test P = 0.37).

T₁ HypoIntense and IsoIntense lesions exhibited similar SI changes (joint test P = 0.12).

There is evidence of a subtle BBB leakage within visibly non-enhancing lesions in RRMS that was not modified by Alpha4 Integrin blockade in this substudy cohort.

Blockade of CD49d-mediated Lymphocyte trafficking has been used therapeutically for certain Autoimmune Diseases, such as Multiple Sclerosis (MS).

In addition to negative effects on the trafficking of mature Lymphocytes to sites of inflammation, CD49d blockade in mice and monkeys rapidly mobilizes Hematopoietic Stem/Progenitor Cells (HSPCs) capable of short- and long-term engraftment.

Here we aimed to ascertain the effects of treatment with AntiFunctional Anti-CD49d AntiBody in humans (MS patients receiving infusions of the CD49d-blocking AntiBody Natalizumab) on levels of circulating HSPCs after a single dose of AntiBody or after long-term treatment.

On average, 6-fold elevated levels of circulating CD34⁺ cells and Colony-Forming Unit-Culture (CFU-C) were achieved within 1 day of the first dose of Natalizumab, and similar levels were continuously maintained under monthly Natalizumab infusions.

The blood of Natalizumab-treated subjects also contained SCID-repopulating cells. The fate of these circulating HSPCs and their clinical relevance for MS patients remains to be determined.

In the pivotal trials of Natalizumab in the treatment of Relapsing/Remitting Multiple Sclerosis (AFFIRM and SENTINEL), a dramatic reduction in relapse rate, new or enlarging T₂-HyperIntense lesions, and mean number of Gadolinium-enhancing lesions was observed.

While both relapses and new MRI lesions were observed in these trials, there has been no comment on the presence of aggressive disease in the face of Natalizumab treatment.

I report a 31-year-old woman with Relapsing/Remitting MS of 12 years duration who developed aggressive DeMyelinating Disease four months after the initiation of Natalizumab.

The clinical worsening was accompanied by a significant increase in new large T₂-HyperIntense signal abnormalities and in both solid and C-shaped Contrast-Enhancing Lesions.

Neither the clinical severity nor the striking MRI abnormalities had been noted earlier in her disease course.

Neutralizing AntiBodies to Natalizumab were not detected. She subsequently responded to combination therapy of pulsed MethylPrednisolone and daily Glatiramer Acetate.

Background
Natalizumab has been recommended for the treatment of Relapsing/Remitting Multiple Sclerosis (RRMS) in patients with insufficient response to Interferon-beta/Glatiramer Acetate (DMT) or aggressive MS.

The pivotal trials were not conducted to investigate Natalizumab monotherapy in this patient population.

Method
Retrospective, multicenter study in Germany and Switzerland.

Five major MS centers reported all RRMS patients who initiated Natalizumab >/=12 months prior to study conduction.

Results
Ninety-seven RRMS patients were included [69% female, mean age 36.5 years, mean Expanded Disability Status Scale (EDSS) 3.4; 93.8% were pre-treated with DMT], mean treatment duration with Natalizumab was 19.3 +/- 6.1 months.

We found a reduction of the annualized relapse rate from 2.3 to 0.2, 80.4% were relapse free with Natalizumab. EDSS improved in 12.4% and 89.7% were progression free (change of >/= 1 EDSS point).

Eighty-six per cent of patients with highly active disease (>/= 2 relapses in the year and >/= 1 Gadolinium (Gd)+ lesion at study entry, n = 20) remained relapse free.

The mean number of Gd enhancing lesions was reduced to 0.1 (0.8 at baseline). Discontinuation rate was 8.2% (4.1% for AntiBody-positivity).

Conclusion
Natalizumab is effective after insufficient response to other DMT and also in patients with high disease activity.

Natalizumab therapy in Multiple Sclerosis has been associated with JC PolyomaVirus-induced Progressive Multifocal Leucoencephalopathy.

We hypothesized that Natalizumab may also lead to reactivation of BK, a related human PolyomaVirus capable of causing morbidity in ImmunoSuppressed groups.

Patients with Relapsing/Remitting Multiple Sclerosis treated with Natalizumab were prospectively monitored for reactivation of BK Virus in blood and urine samples, and for evidence of associated Renal Dysfunction.

In this cohort, JC and BK DNA in blood and urine; CytoMegaloVirus (CMV) DNA in blood and urine; CD4⁺ and CD8⁺

BK subtyping and noncoding control region sequencing was performed on samples demonstrating reactivation.

Prior to commencement of Natalizumab therapy, 3 of 36 patients with Multiple Sclerosis (8.3%) had BK Viruria and BK reactivation occurred in 12 of 54 patients (22.2%).

BK Viruria was transient in 7, continuous in 2 patients, and persistent Viruria was associated with transient Viremia. Concomitant JC and CMV Viral loads were undetectable.

CD4⁺:CD8⁺ ratios fluctuated, but absolute CD4 counts did not fall below normal limits.

In four of seven patients with BK Virus reactivation, transient reductions in CD4⁺ counts were observed at onset of BK Viruria: these resolved in three of four patients on resuppression of BK replication.

No Renal Dysfunction was observed in the cohort. BK Virus reactivation can occur during Natalizumab therapy; however, the significance in the absence of Renal Dysfunction is unclear.

We propose regular monitoring for BK reactivation or at least for evidence of Renal Dysfunction in patients receiving Natalizumab.

Objective
To extend our studies on the prolonged and differential effect of Natalizumab on T-Lymphocyte numbers in the CerebroSpinal Fluid:

We investigated the number and phenotypes of Leukocytes and the expression of Major Histocompatibility Complex (MHC) Classes I and II in Cerebral PeriVascular Spaces (CPVS).

We hypothesized that Natalizumab reduces the number of Antigen Presenting Cells in CPVS.

Design
A case-control study in which inflammatory cell numbers in the CPVS of Cerebral tissue were assessed by ImmunoHistoChemical staining.

Subjects
A patient with Multiple Sclerosis (MS) who developed Progressive Multifocal Leukoencephalopathy (PML) during Natalizumab therapy.

Controls included location-matched Cerebral autopsy material of patients without disease of the Central Nervous System, patients with MS not treated with Natalizumab, and patients with PML not associated with Natalizumab therapy.

Results
The absolute number of CPVS in the patient with MS treated with Natalizumab was significantly lower than in the control groups owing to extensive destruction of the tissue architecture.

The expression of MHC Class II molecules and the number of CD29⁺ Dendritic Cells were significantly decreased in the CPVS of the patient with MS treated with Natalizumab. No CD4⁺ T-Cells were detectable.

Conclusions
Our observations may explain the differential and prolonged effects of Natalizumab therapy on Leukocyte numbers in the CerebroSpinal Fluid.

Published online October 13, 2008 (doi:10.1001/archneur.65.12.noc80051).