Development of Tysabri for Multiple Sclerosis

(Ted Yednock, Elan Pharmaceuticals, Inc.)

Case study: Inhibition of immune cell infiltration for treating multiple sclerosis (MS)

  • Developed at Elan Pharmaceuticals, currently co-marketed by Elan and Biogen Idec for MS and Crohn’s disease

Strong preclinical data derived from a mechanism-driven approach

  • Use of the experimental autoimmune encephalomyelitis (EAE) mouse model for studies
    • Replicates the fundamental pathological features of MS – immune cell infiltration of the CNS and resulting myelin damage
  • Main hypothesis – Inhibition of immune cell infiltration would slow disease progression
  • Approach – Identify immune cell adhesion molecules that mediate attachment to inflamed CNS endothelium
    • Simple functional assays for immune cell adhesion to exposed vascular endothelium in fresh brain sections and cultured TNF-stimulated endothelial cells

By screening a large number of antibodies, a4b1 integrin was identified as a key molecule for immune cell adhesion to CNS endothelium.

  • An anti-a4 integrin antibody tested in vivo in a guinea pig EAE model demonstrated >90% inhibition of mononuclear cell infiltration into the spinal cord.
    • Further preclinical studies with the antibody demonstrated efficacy in inhibiting demyelination, reversing EAE clinical score, reversing immune cell accumulation and establishing a permissive environment for re-myelination.
  • No notable toxicity observed in a 6 month primate study.

Natalizumab (Tysabri) was developed as a humanized anti-a4 integrin antibody.

  • Elan initiated clinical development in 1995; after two phase III MS trials, Tysabri went on the market in 2004.
  • In clinical trials, the antibody was as effective in preventing immune cell infiltration and decreasing new lesions as was predicted in preclinical animal studies (See REF – Miller).
    • Treated MS patients had significantly decreased disease activity (number of lesions), reduced risk of relapse and reduced risk of sustained disability progression.
  • Time to FDA approval: 15 years from conception, 10 years of clinical testing with 4000 patients (with no serious side effects).

Three months after FDA approval, three Tysabri-treated patients developed Progressive Multifocal Leukoencephalopathy (PML) which led to the withdrawal of the drug.

  • PML is a rare opportunistic infection of the brain by JC virus that leads to death or severe disability.
  • About a year after the withdrawal, after a safety evaluation and a FDA advisory committee, Tysabri was re-approved for MS but with highly regulated distribution and monitoring (e.g. black box warning for PML).
  • Incidence rate for PML in Tysabri-treated patients is ~1/1000.
  • PML likely results from a convergence of risk factors including the presence of JC virus, mutations in the virus that enhance CNS penetration and compromised immune function (which is affected by length of Tysabri treatment, prior use of immunosuppresants, genetics).

Risk can be stratified by measuring JC virus exposure in patients.

  • A two-step ELISA assay was developed to detect serum antibodies to JC virus. The assay is currently in clinical development and not commercially available.
    • In multiple studies, roughly half of MS patients tested positive for JC virus; prevalence is not affected by length of Tysabri exposure.
    • All 22 previous PML cases resulting from Tysabri were positive for JC virus.
  • Ongoing work to establish best clinical response to PML as well as to identify factors associated with increased risk.
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