Therapeutic lag after natalizumab

Therapeutic lag affects brain atrophy: major implications for NEDA-4 and progressive trial duration. #MSBlog #MSResearch 

“This study below supports my therapeutic lag hypothesis that inflammation in the last 2 years drives disability progression, or its biomarker brain atrophy, over the next two years. To have a robust impact on disability progression you need to look beyond 2 years. This is particularly relevant in progressive MS trials were the main pathway, the lower limb motor function, is used as the primary outcome in trials (EDSS and timed-25-ft-walk).”

“In the study below brain atrophy rates in MSers treated with natalizumab were greater in year 1 and year 2 in MSers who had active MRI scans at baseline, i.e. the presence of Gd-enhancing lesions, but was not in year 3. I suspect axons damaged by inflammation take up to 2 years to die and degenerate and this process is complete by 2 years. This is study is very important in how we think about end-organ damage and incorporating it into our definition of no evident disease activity and clinical trials. If we do include normalising brain atrophy rates into our treat-2-target approach, we will need to re-baseline brain volume at 24 months to overcome this therapeutic lag in terms of brain atrophy.”

Epub: Sastre-Garriga et al. Brain atrophy in natalizumab-treated patients: A 3-year follow-up. Mult Scler. 2014 Nov 12.

BACKGROUND: A pseudoatrophy effect has been held responsible for the lack of net impact of natalizumab on brain volume outcomes in 2-year trials, but no data are available beyond 24 months.

OBJECTIVE: We aimed to investigate brain volume dynamics in natalizumab-treated MSers in up to 3 years after therapy initiation with clinical correlations.

METHODS: MSers on natalizumab for at least 3 years were clinically assessed 3-monthly. Magnetic resonance imaging scans were performed at baseline and yearly. Brain volume changes were obtained with SIENA. Multivariate models were used to investigate the association between baseline inflammation and changes in brain volume and disability.

RESULTS: Sixty-two MSers with multiple sclerosis were analysed. Mean age and disease duration were 34.7 (SD: 8.3) and 10.4 (SD: 6.6) years. Presence of gadolinium enhancement at baseline was not associated with Expanded Disability Status Scale changes (p=0.468), but was associated with larger brain volume decreases (p=0.005) in the first (p=0.024) and second year (p=0.019) but not in the third year (p=0.863). Brain volume changes at 12 and 36 months were marginally associated with disability status at month 12 (p=0.094) and 36 (p=0.084), respectively.

CONCLUSIONS: Baseline inflammation affects brain volume measures up to 24 months after natalizumab initiation. A marginal association of brain volume changes with disability is present.

CoI: multiple

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