Tysabri Abstracts from the American Academy of Neurology

[xo++]

Here are a number of abstracts on Tysabri from AAN conference. I found the first study particularly interesting. Basically the study found that even among those who progressed in the study, the people on Tysabri enjoyed benefits relative to placebo.

[P05.090] Impact of Sustained Disability Progression and Relapses on Visual Outcomes in the AFFIRM Trial

Laura Balcer, Steven Galetta, Philadelphia, PA, Richard Rudick, Cleveland, OH, Paul W. OConnor, Toronto, ON, Canada, Eva Havrdova, Praha 2, Czech Republic, Michael Hutchinson, Dublin, Ireland, Ludwig Kappos, Basel, Switzerland, David Miller, J. Theodore Phillips, Dallas, TX, Chris Polman, Amsterdam, Netherlands, Fred Lublin, New York, NY, Gavin Giovannoni, London, United Kingdom, Andrzej Wajgt, Katowice-Ligota, Poland, Frances Lynn, Michael Panzara, Cambridge, MA, for the AFFIRM Investigators.
OBJECTIVE: To determine the relation of sustained disability progression and relapses on visual outcomes in the AFFIRM trial.

BACKGROUND: Low-contrast letter acuity testing as a tertiary outcome in the AFFIRM trial demonstrated reduced probabilities of sustained visual loss and lower degrees of worsening from baseline in the natalizumab group compared with placebo.

DESIGN/METHODS: AFFIRM was a randomized, double-blind, placebo-controlled multicenter phase 3 trial of natalizumab in 942 patients with relapsing MS. Visual function testing was performed binocularly at low-contrast levels of 2.5% and 1.25%. Disability progression was defined as 1-point worsening in EDSS score, sustained over 12 weeks; sustained visual loss was pre-defined as 2-line [10-letter] worsening of low-contrast acuity score, sustained over 12 weeks.

RESULTS: Among patients with sustained disability progression (n=104 natalizumab, 84 placebo), those treated with natalizumab had lower probabilities of sustained visual loss compared with placebo (Hazard ratios [natalizumab/placebo]: 2.5% contrast: 0.45 [95% CI 0.22, 0.94], p=0.03; 1.25% contrast: 0.46 [0.25, 0.85], p=0.01, Cox proportional hazards models). Those with 1 or more relapses during the study period (n=176 natalizumab, 170 placebo) showed treatment differences in favor of natalizumab that reached or approached significance (Hazard ratios: 2.5% contrast: 0.51 [0.29, 0.91], p=0.02; 1.25% contrast: 0.67 [0.42, 1.06], p=0.09).

Treatment group differences were less pronounced in patients without sustained EDSS progression and in those with no relapse; the highest probabilities of sustained visual loss were noted for placebo group patients who had progression or relapses.

CONCLUSIONS/RELEVANCE: Even in patients who appear to be treatment failures according to established criteria, a meaningful therapeutic effect may be present that should be taken into consideration in treatment decisions. The sensitivity of low-contrast letter acuity to treatment effects supports its use in future clinical trials of relapsing MS.

Supported by: Biogen Idec and Elan Pharmaceuticals, Inc.Category - MS and Related DiseasesSubCategory - Clinical Science

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[P06.082] The Efficacy of Natalizumab Monotherapy over 3 Years of Treatment in Patients with Relapsing Multiple Sclerosis

Paul W. OConnor, Toronto, ON, Canada, Andrew Goodman, Rochester, NY, Ludwig Kappos, Basel, Switzerland, Fred Lublin, New York, NY, David Miller, London, United Kingdom, Chris Polman, Amsterdam, Netherlands, Richard Rudick, Elizabeth Fisher, Cleveland, OH, Frances Lynn, Michael Panzara, Cambridge, MA.

OBJECTIVE: To report the 3-year efficacy of natalizumab monotherapy in patients with relapsing multiple sclerosis (MS).

BACKGROUND: The efficacy of natalizumab was demonstrated in a randomized, placebo-controlled, 2-year study (AFFIRM). Patients who completed AFFIRM were eligible to receive natalizumab in an open-label safety-extension study. The primary objective of the safety-extension study was to assess safety of extended natalizumab treatment. Relapses and sustained progression were also measured.

DESIGN/METHODS: In the safety-extension study, all patients received natalizumab 300 mg intravenously every 4 weeks. Relapse data included relapses reported at unscheduled visits and as adverse events. Expanded Disability Status Scale (EDSS) score was assessed every 6 months. The study was stopped early due to natalizumab dosing suspension in February 2005, and patients received an MRI as part of the ensuing safety evaluation; brain parenchymal fraction (BPF) was assessed from these MRI scans.

RESULTS: Data from all patients randomized in AFFIRM (natalizumab, n=627 [531 dosed in safety-extension]; placebo, n=315 [259 dosed in safety-extension]) were included in this ITT analysis. Median total duration of natalizumab exposure was 2.72 years (min, max: 0.10, 3.15) in AFFIRM natalizumab patients and 0.60 years in AFFIRM placebo patients (min, max: 0.23, 0.93).

In natalizumab patients, annualized relapse rate (ARR) was 0.23 and the proportion relapse free was 67% (Kaplan-Meier analysis) over the 3-year period; yearly ARRs were 0.26 in Year 0-1, 0.20 in Year 1-2, and 0.15 in Year 2-3. In placebo patients, the ARR in Year 2-3 after switching to natalizumab was 0.27 (the 2-year ARR in AFFIRM was 0.73). Kaplan-Meier estimates of the proportions of patients with 6-month sustained disability progression were 13% at 3 years in natalizumab patients and 23% at 2 years in placebo patients. BPF data will be reported.

CONCLUSIONS/RELEVANCE: Natalizumabs effects on relapses and disability progression may be sustained beyond 2 years.

Supported by: Biogen Idec and Elan Pharmaceuticals, Inc.Category - MS and Related DiseasesSubCategory - Clinical Science


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[P01.045] Live Imaging of Natalizumab Mediated Effect on Human Lymphocyte Interaction with the Blood-Brain Barrier In Vivo

Caroline Coisne, Tardent Heidi, Britta Engelhardt, Bern, Switzerland.

OBJECTIVE: Investigate the effect of natalizumab on human leukocyte recruitment across the blood-brain barrier (BBB) in vivo.

BACKGROUND: In multiple sclerosis (MS), and in its animal model, experimental autoimmune encephalomyelitis (EAE), circulating leukocytes gain access to the central nervous system (CNS) and cause inflammation, BBB breakdown and demyelination, which all set the stage for the development of the clinical manifestations of MS.

Thus, inflammatory cell recruitment across the BBB has been recognized as a major pathophysiological hallmark of MS and blocking leukocyte/endothelial interactions especially alpha 4-integrins by the anti-alpha 4-integrin antibody natalizumab (marketed as Tysabri by BiogenIdec/Elan) have proven beneficial for the treatment of MS. Nevertheless, direct in vivo evidence for the inhibition of T-cell interaction with the BBB endothelium by natalizumab in vivo is still lacking.

DESIGN/METHODS: In order to investigate the effect of natalizumab on human leukocyte interaction with the BBB in vivo, we have performed intravital fluorescence videomicroscopy using a spinal cord window preparation in mouse, which enables us to directly visualize CNS white matter microcirculation.

Fluorescently labeled human T-cells were incubated with natalizumab (170g/400L) or vehicle control in vitro before injection into TNF-alpha stimulated mice. To assess permanent T-cell adhesion, several areas of the spinal cord microvasculature were scanned at different period of time after cell injection.

RESULTS: Adherence of T-cells to the inflamed BBB was reduced by approximately 50% in the natalizumab treated sample compared with controls.

CONCLUSIONS/RELEVANCE: This study provides the first in vivo evidence that natalizumab interferes with the adhesion of human mononuclear cells with the BBB in vivo. Although these findings do not preclude the possibility that natalizumab can have additional immunomodulatory effects, our data support the notion that a major aspect of the therapeutic efficacy of natalizumab is due to the inhibition of leukocyte recruitment across the BBB.

Supported by: The Swiss and the American National Multiple Sclerosis Society and BiogenIdec.Category - MS and Related DiseasesSubCategory - Basic Science

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[P02.053] Clinical and MRI Characteristics of Progressive Multifocal Leukoencephalopathy (PML): Comparison with Relapsing-Remitting Multiple Sclerosis (RRMS)

Aaron Boster, Detroit, MI, Christina Endress, Stephanie Hreha, Fen Bao, Imad Zak, Basil Shah, Christina Caon, Alexandros Tselis, Kenneth Tyler, Denver, Michael Racke, Columbus, Omar Khan, Detroit.

OBJECTIVE: To describe the clinical and MRI presentations of PML, and identify characteristics that may help in differentiating PML from RRMS.

BACKGROUND: There is renewed interest in PML after the development of PML in three natalizumab-treated patients. PML is known to occur in immunocompromised hosts. The potential risk of developing PML associated with natalizumab has created the need for identifying patients at the earliest stages of PML. Furthermore, it also requires the neurologist to distinguish PML from RRMS, for which natalizumab is approved . Clinical and MRI characteristics of PML compared to RRMS is timely information for the neurologists.

DESIGN/METHODS: We conducted a retrospective chart review of all PML cases at three urban teaching hospitals in Detroit from 1980 to date. Analysis from one hospital was completed at the time of this submission and ongoing at other hospitals.

RESULTS: At the time of this submission, 39 cases PML (90% HIV+) cases were identified, confirmed by JCV CSF PCR (31%), brain biopsy (67%), and rarely autopsy. Polysymptomatic presentations were common although monosymptomatic onset with hemiplegia (28%) and mental status changes (18%) were also seen. Brain MRI showed most HIV+ PML lesions to be confluent, granular, and hyperintense on T2W images without gadolinium enhancement.

However, crescent shaped cerebellar lesions, transcallosal banding pattern, and gadolinium enhancement were identified in non-HIV PML patients. PML case identification including MRI analysis is underway at two additional urban teaching hospitals at the time of this submission. Furthermore, Brain MRI with PML will be compared with RRMS.

CONCLUSIONS/RELEVANCE: Confluent granular lesions on dual-echo MRI images may be a distinct feature of PML in HIV while gadolinium enhancement and unusual T2 lesions may be more common in non-HIV PML. Non-HIV PML brain MRI may be more similar to RRMS. Further clinical and image analysis including regional and global atrophy is underway.

Supported by: Partners Multiple Sclerosis Fellowship Program.Category - MS and Related DiseasesSubCategory - Clinical Science

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[S22.002] Sustained Disability Progression Using Scores from the Multiple Sclerosis Functional Composite

Chris Polman, Amsterdam, Netherlands, Richard A. Rudick, Laura Balcer, Philadelphia, PA, Jeffrey Cohen, Cleveland, OH, Christian Confavreux, Lyon, France, Michael Hutchinson, Dublin, Ireland, Fred Lublin, Aaron Miller, New York, NY, Paul W. OConnor, Toronto, ON, Canada, Steven Schwid, Rochester, NY, Frances Lynn, Michael Panzara, Alfred Sandrock, Cambridge, MA.
OBJECTIVE: To develop a measure of sustained disability progression using the Multiple Sclerosis Functional Composite (MSFC).

BACKGROUND: The MSFC is a relatively new disability measure in MS. Change from baseline to study exit is a sensitive measure of treatment interventions, but the clinical relevance of a statistically significant change is not readily apparent. Change in MSFC was a prespecified endpoint in the phase 3 study of natalizumab monotherapy (AFFIRM). AFFIRM data were used to explore prespecified degrees of sustained worsening from baseline MSFC scores as clinically relevant endpoints.

DESIGN/METHODS: AFFIRM patients received natalizumab 300 mg (n=627) or placebo (n=315) intravenously once every 4 weeks for 116 weeks. The MSFC consists of a 25-timed walk, nine-hole peg test, and 3-second Paced Auditory Serial Addition Test (PASAT3). MSFC was performed at baseline and every 12 weeks.

Kaplan-Meier analyses determined the proportion of patients with 10% and 20% worsening from baseline MSFC scores sustained for 12 weeks. Because PASAT3 scores have notable practice effects with repeated testing, the analyses were also conducted with a 2-part composite, excluding PASAT3.

RESULTS: Using 20% worsening in MSFC, estimates of the proportion of patients with progression at 2 years were 5% with natalizumab and 9% with placebo (hazard ratio=0.49, 95% confidence interval [CI]: 0.28,0.84; P=0.01). With the 10% criterion, proportions with MSFC progression were higher; 11% natalizumab vs. 19% placebo (hazard ratio=0.53, 95% CI: 0.37,0.76; P<0.001). Results for both 20% and 10% MSFC worsening were slightly more robust after excluding PASAT3.

Data on the optimal cut-point, which categorizes patients into those with no disease activity vs disease activity during the 2-year study, will be presented.

CONCLUSIONS/RELEVANCE: Sustained MSFC worsening has the potential to demonstrate treatment effects in clinical studies. Defining the optimal cut-point for sustained MSFC worsening could improve the clinical interpretation of results in future studies.

Supported by: Biogen Idec and Elan Pharmaceuticals, Inc.Category - MS and Related DiseasesSubCategory - Clinical Science

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[P05.089] Health-Related Quality of Life in Multiple Sclerosis: Effects of Natalizumab

Richard Rudick, Deborah Miller, Cleveland, OH, Michael Hutchinson, Dublin, Ireland, Peter Calabresi, Baltimore, MD, Christian Confavreux, Lyon, France, Steven Galetta, Philadelphia, PA, Gavin Giovannoni, Eva Havrdova, Praha 2, Czech Republic, Ludwig Kappos, Fred Lublin, New York, NY, David Miller, London, United Kingdom, Paul W. OConnor, Toronto, ON, Canada, J. Theodore Phillips, Dallas, TX, Chris Polman, Amsterdam, Netherlands, Ernst-Wilhelm Radue, Basel, Switzerland, William Stuart, Atlanta, GA, Andrzej Wajgt, Katowice-Ligota, Poland, Bianca Weinstock-Guttman, Buffalo, NY, Daniel Wynn, Northbrook, IL, Frances Lynn, Michael Panzara, Cambridge, MA, for the AFFIRM and SENTINEL Investigators.

OBJECTIVE: To report the relationship between disease activity and health-related quality of life (HRQoL) in patients with relapsing multiple sclerosis (MS), and the impact of natalizumab.

BACKGROUND: MS is associated with reduced HRQoL. In a phase 3 clinical study (AFFIRM study), natalizumab monotherapy reduced the risk of sustained disability progression by 42% and annualized relapse rate by 68% in relapsing MS. To determine if clinical benefits extend to improved quality of life, HRQoL measures were included in natalizumab clinical studies (AFFIRM and SENTINEL).

DESIGN/METHODS: Patients in AFFIRM received natalizumab 300mg (n=627) or placebo (n=315); patients in SENTINEL were randomized to receive interferonb-1a plus natalizumab 300mg (n=589), or interferonb-1a plus placebo (n=582). The Short Form-36 (SF-36) and a subject global assessment visual analog scale (VAS) were administered at baseline, Weeks 24, 52, and 104. The odds ratio of a clinically meaningful improvement or worsening, defined as a 0.5-SD change, on the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the SF-36 were analyzed using logistic regression controlling for treatment and baseline score.

RESULTS: Baseline SF-36 scores were significantly lower than the general US population. Lower SF-36 scores were correlated with higher EDSS scores, sustained progression of disability, relapses, and increased volume of MRI lesions, indicating that SF-36 scores reflected severity and progression of MS. In both studies, natalizumab-treated patients were significantly more likely to experience clinically important improvement on the PCS at Week 104 (AFFIRM: odds ratio [OR]=1.54, 95% confidence interval [CI], 1.06-2.23; SENTINEL: OR=1.47, 95% CI, 1.08-2.03), and less likely to experience clinically important worsening than placebo or interferonb-1a patients, respectively (AFFIRM: OR=0.63, 95% CI, 0.45-0.88; SENTINEL: OR=0.64, 95% CI, 0.47-0.87). Similar trends were observed on the MCS.

CONCLUSIONS/RELEVANCE: HRQoL scores correlated with neurologic and MRI measures of disease severity and activity, and improved significantly with natalizumab therapy.

Supported by: Biogen Idec and Elan Pharmaceuticals, Inc.Category - MS and Related DiseasesSubCategory - Clinical Science

[Jules A]

Thanks Mark.

[MS Mommy]

Thank you, Mark.

I am one of the people who has seen remarkable improvement in the 5 months that I have been on Tysabri.

Interferons did nothing to slow my progression. I feel like T has literally stopped it dead in it's tracks. I didn't believe anything would work for me.

I am enjoying my new lease on life. With all of the drugs now available to help us, plus everything that is on it's way, I am very optimistic and hopeful.

Choices in treatment are a great luxury that I am grateful to have available to our MS community.

[msladyinca]

How wonderful for you MS Mommy...thank you to you and Mark for posting the data on Tysabri...,

Much continued and sustained improvements for you Mommy :)

(((((hugs)))))