Natalizumab In Multiple Sclerosis

In this open-label drug-interaction trial, we studied 38 patients with Relapsing/Remitting Multiple Sclerosis (MS) who received 3.0 or 6.0 mg/kg of Natalizumab as a single intravenous (i.v.) infusion during stable treatment with intramuscular (i.m.) Interferon-beta-1a 30 microg (IFN-ß-1a; Avonex).

To assess the PharmacoKinetic (PK) interaction of Natalizumab and IFN-ß-1a, Serum concentration-time data for both agents were collected and analyzed.

Biologic response markers of IFN-ß-1a activity, beta2-MicroGlobulin and Neopterin, were also assessed to determine effects of Natalizumab on IFN-ß-1a PharmacoDynamics (PD).

Further, safety and Immunogenicity were evaluated. The combination of drug therapies was well tolerated.

Although Natalizumab Serum concentrations (and corresponding PK exposure measures) appeared to be somewhat elevated in the presence of IFN-ß-1a, when compared to the same dose (6.0 mg/kg).

Administered alone in a concurrent comparator study, the differences were generally small and unlikely to be clinically relevant.

In general, Natalizumab had no apparent clinically relevant effects on the PK or PD properties of IFN-ß-1a. The presence of AntiBodies to IFN-ß-1a and Natalizumab was relatively low.

Overall, the study provided safety, Immunogenicity, PK and PD data to support a combination strategy for the use of Natalizumab and IFN-ß-1a in the treatment of patients with Relapsing/Remitting MS.

A large clinical study is currently in progress to evaluate the efficacy and long-term safety of this combination drug therapy.

Natalizumab [AN 100226, anti-alpha4 Integrin MonoClonal AntiBody, Antegren] is a humanised MonoClonal AntiBody that blocks alpha4ß1 Integrin-mediated Leukocyte migration.

Natalizumab is in Phase III Trials for the treatment of Multiple Sclerosis in North America and the UK, and for the treatment of Crohn's Disease also in the UK. It may have potential in the treatment of other Immune-related Inflammatory Disease.

Elan Corporation intends to examine the potential of Natalizumab in Rheumatoid Arthritis and Ulcerative Colitis.

4ß1 Integrin on circulating Leukocytes binds to Vascular Cell Adhesion Molecule-1, which is expressed at high levels in the blood vessels in the CNS during exacerbations of Multiple Sclerosis.

This allows Leukocytes expressing alpha4ß1 Integrin (Very Late Antigen-4) to move from the peripheral blood into the CNS. Inflammatory proteins and other factors released from Lymphocytes in the Brain lead to the progression of symptoms.

A limitation of Natalizumab is that it must be injected and cannot be administered orally. Scientists have transformed the large anti-alpha4 MonoClonal AntiBody into much smaller, drug-like molecules suitable for oral administration.

Protein Design Labs has granted a worldwide nonexclusive licence under its AntiBody humanisation patents to Elan Pharmaceuticals for Natalizumab.

Biogen Inc. has entered into an agreement with Elan for a worldwide exclusive collaboration to develop, manufacture and commercialise Natalizumab for Multiple Sclerosis and Crohn's Disease and Rheumatoid Arthritis.

Development of Natalizumab is also being funded, in part, by Axogen (acquired by Elan in 1999).

In November 2003, Biogen and IDEC Pharmaceuticals merged to form Biogen Idec. Elan repurchased royalty rights on a package of products, including Natalizumab, from Autoimmune Disease Research Company.

Elan and Genzyme Transgenics Corporation signed an agreement to produce Natalizumab in GTC's genetically engineered goats, which will express the compound in their milk.

Genzyme Transgenics Corporation changed its name to GTC Biotherapeutics in June 2002; it is no longer a subsidiary of Genzyme Corporation.

Following discussions with the US FDA, Elan completed enrolment in a second phase III trial, involving approximately 420 patients with Crohn's Disease.

This Evaluation of Natalizumab as Continuous Therapy-2 (ENACT-2) trial evaluated the effect of Natalizumab on duration of response and remission in patients with Crohn's Disease.

In January 2004, Elan Corporation and Biogen Idec announced that the phase III, ENACT-2 maintenance trial of Natalizumab in Crohn's Disease met the primary endpoint of maintenance of response.

Elan and Biogen Idec will discuss these data with regulatory authorities in both the US and Europe and determine the appropriate path forward for Natalizumab in Crohn's Disease.

An NDA for Antegren in Crohn's Disease was expected to be filed at the end of 2003; however, due to failing to meet the primary endpoint in the induction trial, Elan is unable to predict when and if a regulatory filing will be made.

Earlier, on 23 January 2001, the Wall Street Journal reported that the Biogen CEO expects Antegren to become a blockbuster drug, with sales of at least $US1 billion.

He also predicted that Antegren could be on the market as early as 2003 for the indication of Crohn's Disease and in 2004 for Multiple Sclerosis.

The Journal stated that Biogen is under pressure to develop new drugs since its flagship product Avonex will be losing its US Orphan Drug Act protection in 2003.

Antegren has a different mechanism to that of Avonex and could be used either alone or as a combination therapy.

Background
Relapses in Multiple Sclerosis (MS) can cause significant Neurologic disability.

Natalizumab (Antegren) is a humanized anti-alpha4-Integrin AntiBody that inhibits the trafficking of Leukocytes across Endothelium by blocking binding of alpha4ß1-Integrin to Vascular Cell Adhesion Molecule-1.

Objective
To assess the effects of a single dose of IV Natalizumab administered soon after the onset of MS relapses.

Methods
In this randomized, double-blind, multicenter trial, the effects of a single dose of IV Natalizumab administered soon after the onset of MS relapses were assessed.

MS patients (n = 180) in acute relapse were randomly assigned to receive a single dose of Natalizumab 1 or 3 mg/kg or placebo and were followed for 14 weeks.

Results
There was no difference in Expanded Disability Status Scale (EDSS) score change over time between treatment and placebo groups.

In all three groups, approximately half of patients showed EDSS improvement after 2 weeks, rising to 67% by 8 weeks.

EDSS improved by a mean value of 0.8 point at week 1, 1.2 points at week 4, and 1.6 points at week 8 in the Natalizumab group compared with EDSS improvement of 1.0 point at week 1, 1.6 points at week 4, and 1.6 points at week 8 in the placebo group.

A significant decrease in Gd-enhancing lesion volume was seen in both active treatment groups at weeks 1 and 3 compared with placebo.

Conclusions
A single dose of IV Natalizumab did not hasten clinical recovery after relapse, although a significant decrease in Gd-enhancing lesion volume was observed at 1 and 3 weeks after treatment.

These MRI findings are consistent with prior studies of Natalizumab and support its further investigation as an agent for the treatment of MS.

In patients with either Relapsing/Remitting or Secondary-Progressive Multiple Sclerosis, there were fewer new lesions/patient with Natalizumab (0.7 and 1.1 with Natalizumab 3 and 6 mg/kg every 28 days, respectively) than in the placebo group (9.6 new lesions/patient) over 6 months.

There were also fewer relapses in the Natalizumab groups than the placebo group. However, there were no changes in the Expanded Disability Status Scale scores in any of the groups.

Natalizumab was well-tolerated. Thus, the initial results with Natalizumab treatment over 6 months in Multiple Sclerosis are encouraging.

Circulating B-Cells enter the CNS as part of normal Immune surveillance and in pathologic states, including the common and disabling illness Multiple Sclerosis.

However, little is known about the molecular mechanisms that mediate human B-Cell interaction with the specialized Brain Endothelial Cells comprising the Blood-Brain Barrier (BBB).

We studied the molecular mechanisms that regulate the migration of normal human B-Cells purified ex vivo, across Human adult Brain-Derived Endothelial Cells (HBECs).

We found that B-Cells migrated across HBECs more efficiently than T-Cells from the same individuals.

B-Cell migration was significantly inhibited by blocking Abs to the Adhesion Molecules ICAM and VLA-4, but not VCAM-1, similar to the results previously reported for T-Cells.

Blockade of the Chemokines Monocyte Chemoattractant Protein-1 and IL-8, but not RANTES or IFN-gamma-inducible protein-10, significantly inhibited B-Cell migration.

And, these results were correlated with the Chemokine Receptor expression of B-Cells measured by flow cytometry and by RNase protection assay.

Tissue Inhibitor of MetalloProteinase-1, a natural inhibitor of Matrix MetalloProteinases, significantly decreased B-Cell migration across the HBECs.

A comprehensive RT-PCR comparative analysis of all known Matrix MetalloProteinases and Tissue Inhibitor of MetalloProteinase in human B and T-Cells revealed distinct profiles of expression of these molecules in the different cell subsets.

Our results provide insights into the molecular mechanisms that underlie human B-Cell migration across the BBB.

Furthermore, they identify potential common, and unique, therapeutic targets for limiting CNS B-Cell infiltration and predict how therapies currently developed to target T-Cell migration, such as anti-VLA-4 Abs, may impact on B-Cell trafficking.

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:

1. 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)
2. 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.

Copyright 2003 Massachusetts Medical Society

Antegren (Natalizumab) is a humanized MonoClonal AntiBody directed against alpha 4-Integrin.

This AntiBody binds to the alpha 4 subunit of alpha 4 beta 1-Integrin (VLA-4) and alpha 4 ß 7-Integrin on Leukocytes and blocks the interaction of these Integrins with their Ligands (VCAM and MadCAM).

Disruption of these cell Adhesion Molecule interactions inhibits the migration of Leukocytes through the Blood-Brain Barrier and the trafficking of Leukocytes through the ExtraCellular Matrix.

In clinical studies, short-term treatment of patients with Multiple Sclerosis (MS) with Antegren resulted in a clear reduction of the number of new active Brain lesions on Magnetic Resonance Imaging (MRI).

Antegren was safe and well tolerated. Two large Phase III studies will help to determine the long-term effect of Antegren on MRI and clinical outcome in Relapsing/Remitting MS patients.

Objective
To determine the effect of humanized MonoClonal AntiBody against alpha4 Integrin (reactive with alpha4ß1 Integrin or Very-Late Antigen-4) on MRI lesion activity in MS.

Methods
A randomized, double-blind, placebo-controlled trial in 72 patients with active Relapsing/Remitting and Secondary/Progressive MS was performed.

Each patient received two IV infusions of anti-alpha4 Integrin AntiBody (Natalizumab; Antegren) or placebo 4 weeks apart and was followed up for 24 weeks with serial MRI and clinical assessment.

Results
The treated group exhibited significantly fewer new active lesions (mean 1.8 versus 3.6 per patient) and new enhancing lesions (mean 1.6 versus 3.3 per patient) than the placebo group over the first 12 weeks.

There was no significant difference in the number of new active or new enhancing lesions in the second 12 weeks of the study.

The number of baseline-enhancing lesions (i.e., lesions that enhanced on the baseline scan) that continued to enhance 4 weeks following the first treatment was not significantly different between the two groups.

The number of patients with acute MS exacerbations was not significantly different in the two groups during the first 12 weeks (9 in the treated group versus 10 in placebo).

But, was higher in the treatment group in the second 12 weeks (14 versus 3; p = 0.005).

The study was not, however, designed to look definitively at the effect of treatment on relapse rate. Treatment was well tolerated.

Conclusions
Short-term treatment with MonoClonal AntiBodies against alpha4 Integrin results in a significant reduction in the number of new active lesions on MRI.

Further studies will be required to determine the longer term effect of this treatment on MRI and clinical outcomes.

In recent years antagonists of Very Late Antigen-4 (VLA-4, also known as Integrin alpha(4) ß1) have shown great promise in treating Inflammatory Disorders in a number of animal models.

The most advanced in this endeavor is a humanized anti-alpha(4) AntiBody, Antegren, which is in Phase II clinical trials for Multiple Sclerosis.

The first reported small-molecule VLA-4 AntAgonist to advance into clinical trials is currently in Phase I as an aerosol for treating Asthma.

A number of Peptides, Cyclic Peptides and PeptiDomimetics have been disclosed and are in preliminary stages of development.

Objective
To review the pharmacology, pharmacokinetics, safety, and pivotal clinical trials for Natalizumab in the treatment of Multiple Sclerosis (MS) and Inflammatory Bowel Disease.

Data Sources
A PubMed/MEDLINE search was conducted (1966-June 2005), and information was obtained from Iowa Drug Information Services. Additional data sources included meeting abstracts, bibliographies from identified articles, and information from the manufacturer.

Study Selection And Data Extraction
Studies and review articles examining Natalizumab were evaluated. All published, randomized clinical trials evaluating Natalizumab in MS and IBD were included in this review.

Data Synthesis
Natalizumab is the first drug in a new class of agents called Selective Adhesion Molecule Inhibitors. It has shown promising results in MS and Inflammatory Bowel Disease and appears superior compared with current therapies in reducing relapse rates.

However, 3 recent, confirmed case reports of Progressive Multifocal Leukoencephalopathy (PML) create concern about natalizumab's use in combination with existing therapies or in undefined patient subgroups.

Natalizumab was voluntarily withdrawn from the market in March 2005 while the drug's safety is further evaluated.

Conclusions
Although long-term efficacy and safety of Natalizumab have not been established, available data indicate that it is a novel drug for patients with MS or Inflammatory Bowel Disease.

Analysis of its possible association with PML will determine the risk-benefit evaluation and eventual place in therapy for Natalizumab.

Background
Progressive Multifocal Leukoencephalopathy (PML) was reported to have developed in three patients treated with Natalizumab.

We conducted an evaluation to determine whether PML had developed in any other treated patients.

Methods
We invited patients who had participated in clinical trials in which they received recent or long-term treatment with Natalizumab for Multiple Sclerosis, Crohn's Disease, or Rheumatoid Arthritis to participate.

The clinical history, physical examination, Brain Magnetic Resonance Imaging (MRI), and testing of CerebroSpinal Fluid for JC virus DNA were used by an expert panel to evaluate patients for PML.

We estimated the risk of PML in patients who completed at least a clinical examination for PML or had an MRI.

Results
Of 3417 patients who had recently received Natalizumab while participating in clinical trials, 3116 (91 percent) who were exposed to a mean of 17.9 monthly doses underwent evaluation for PML.

Of these, 44 patients were referred to the expert panel because of clinical findings of possible PML, abnormalities on MRI, or a high plasma viral load of JC virus.

No patient had detectable JC virus DNA in the CerebroSpinal Fluid.

PML was ruled out in 43 of the 44 patients, but it could not be ruled out in one patient who had Multiple Sclerosis and progression of Neurologic Disease because data on CerebroSpinal Fluid testing and follow-up MRI were not available.

Only the three previously reported cases of PML were confirmed (1.0 per 1000 treated patients; 95 percent confidence interval, 0.2 to 2.8 per 1000).

Conclusions
A detailed review of possible cases of PML in patients exposed to Natalizumab found no new cases and suggested a risk of PML of roughly 1 in 1000 patients treated with Natalizumab for a mean of 17.9 months.

The risk associated with longer treatment is not known.

Copyright 2006 Massachusetts Medical Society.

Multiple Sclerosis (MS) is an Autoimmune Inflammatory DeMyelinating Disease of the CNS. In a Phase II clinical trial, Natalizumab was shown to reduce the relapses in patients with Relapsing MS, without improving the disability score.

After 1-year of Phase III clinical trials, Natalizumab was approved by the FDA for use in relapsing MS but was withdrawn 3 months later, due to two reported cases of Progressive Multifocal Leukoencephalopathy (PML).

The completed clinical trials with Natalizumab for Relapsing MS have recently been reported.

In a trial of 1171 subjects with Relapsing MS, Natalizumab alone was shown to reduce the relapse rate and lesions, without causing PML.

Although natalizumab was also shown to reduce the relapse rates and lesions in patients taking IFN-beta, two cases of PML with Natalizumab occurred in these patients.

An assessment of patients who had taken Natalizumab for 1 - 2 years ( approximately 3000), showed the incidence of PML to be 1/1000.

A drug that is useful in Relapsing MS will be used as a long-term therapy in large numbers of patients. For instance, in the 3 months that Natalizumab was registered, 5000 patients commenced taking it.

In the author's opinion, large numbers of patients should not be allowed to take Natalizumab until its safety has been monitored in the long-term use in a clinical trial environment.