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.