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AAN Abstract Analysis Continued

• The Safety and Tolerability of Natalizumab: Results from the Safety-Extension Study in Patients with Multiple Sclerosis: This abstract regarding the post-marketing study of Tysabri (prior to it being pulled) reveals little detail, but the talk should be very interesting. This study will include discussions of the GLANCE trial that combined Tysabri with Copaxone.
  
  "OBJECTIVE: To report safety results from multiple sclerosis (MS) patients who received extended dosing with natalizumab (TYSABRI) as part of an open-label extension study. RESULTS: A total of 1,561 patients with MS were enrolled. The mean age of patients at enrollment was 40.1 years...71% were female... the median EDSS score was 2.0. The study was stopped early due to 2 cases of PML (one of which occurred during this study); a recently completed safety analysis showed no new cases of PML. The final safety and clinical efficacy data will be presented. CONCLUSIONS/RELEVANCE: This safety-extension study will provide valuable data regarding the longer-term safety and tolerability of natalizumab in MS patients."

• The Incidence and Clinial Significance of Antibodies to Natalizumab over 2 Years of Treatment in Patients with Multiple Sclerosis: Nothing new here-- about 6% of Tysabri patients form antibodies to the drug, which makes the drug generally ineffective as well as increases the risk of adverse reactions. The good news is that this resistance makes itself apparent very quickly-- within the first year, and does not seem to develop over time.
  
  "OBJECTIVE: To report the incidence and clinical impact of antibodies to natalizumab (Tysabri) in patients with relapsing multiple sclerosis (MS) in AFFIRM and SENTINEL... RESULTS: Over the course of 2 years in AFFIRM, 6% of patients were persistently positive for anti-natalizumab antibodies; antibodies developed by 6 months in >95% of those who became persistently positive. No patient developed persistent antibodies during the second year of therapy. Persistently positive patients were shown to have lost the clinical benefit of natalizumab by 6 months. Another 3% of patients were transiently positive at 3 months; these patients had a temporary diminution of efficacy that was regained with continued dosing concomitant with reversion to antibody-negative status. Persistently positive patients also had a higher incidence of infusion-related adverse events. Two-year data from SENTINEL were consistent with those of AFFIRM."

• Natalizumab Reduces Loss of Visual Function in Patients with Relapsing Multiple Sclerosis. This is a clever, focussed new study that shows Tysabri is effective in reducing visual damage due to Multiple Sclerosis.
  
  "OBJECTIVE: To report data on the effects of natalizumab on loss of visual function in patients with relapsing multiple sclerosis (MS) in the AFFIRM and SENTINEL studies... CONCLUSIONS/RELEVANCE: Natalizumab reduces loss of visual function in patients with relapsing MS. Low-contrast letter acuity is a sensitive visual function outcome for MS trials."

• Natalizumab Improves Health-Related Quality of Life in Patients with Relapsing Multiple SclerosisNothing extraordinary here; an effective treatment should generally be expected to improve patient's quality of life.
  
  " OBJECTIVE: To report data on the effects of natalizumab on health-related quality of life (QoL) in patients with relapsing multiple sclerosis (MS) from the AFFIRM and SENTINEL studies... CONCLUSIONS/RELEVANCE: Natalizumabs effects on disability and relapse in MS are associated with a significant improvement in health-related QoL in patients with MS."

• Immune Surveillance in Multiple Sclerosis Patients Treated with Natalizumab: This one is critical. We know Tysabri has been seen with PML, but we don't know exactly how and why. The exceedingly important questions that this study helps to answer: If Tysabri were to be re-introduced on the market, how would we determine who could reasonably take the therapy, and how would we monitor those that are on it to ensure PML does not develop? The study shows that a treated patient's CD4:CD8 ratio, which is an indicator of the overall level of immune suppression (the lower, the more the system is suppressed), can look like that of an HIV patient (and PML is most often seen with HIV patients... perhaps a connection). The abstract does not explain how pervasive this is, or whether there are thresholds to watch out for. What we can glean is that the CD4:CD8 ratio should be monitored closely while under therapy, and if it starts to approach a critical number, therapy might be discontinued or additional monitoring indicated. We simply cannot tell from this limited, but highly valuable information.
  
  "OBJECTIVE: To test whether treatment of multiple sclerosis (MS) with natalizumab, an antibody against VLA-4, interferes with central nervous system immune surveillance, leukocyte cell numbers and cellular phenotypes in cerebrospinal fluid (CSF) and peripheral blood (PB)...RESULTS: CSF total leukocyte counts, CD4+ and CD8+ T cells, CD19+ B cells and CD138+ plasma cells were significantly lower in natalizumab-treated MS patients compared with Other Neurological Disease (OND) patients and untreated MS patients. Natalizumab therapy decreased the CD4:CD8 ratio in the CSF to levels similar to that of HIV-infected patients. JCV DNA was not detected in natalizumab-treated patients. Six months after cessation of therapy, low lymphocyte counts in the CSF persisted, whereas the CD4:CD8 ratio normalized. The patient with the highest total leukocyte, CD4+ and CD8+T cell counts in the CSF experienced a clinical relapse. CONCLUSIONS/RELEVANCE: These data suggest that a low CSF CD4:CD8 ratio in natalizumab-treated patients may confer an increased risk of developing PML in these patients."