Objective To investigate potential neuroprotective and pro-remyelinating effects of alemtuzumab in multiple sclerosis (MS), using the visual pathway as a model.
Methods We monitored clinical, multifocal visual evoked potential (mfVEP) and MRI outcomes in 30 patients commencing alemtuzumab for relapsing MS, and a reference group of 20 healthy controls (HCs), over 24 months. Change in mfVEP latency was the primary endpoint; change in optic radiation (OR) lesion diffusion metrics and Mars letter contrast sensitivity over the course of the study were secondary endpoints.
Results In patients, we observed a mean shortening of mfVEP latency of 1.21 ms over the course of the study (95% CI 0.21 to 2.21, p=0.013), not altered by correction for age, gender, disease duration or change in OR T2 lesion volume. Mean mfVEP latency in the HC group increased over the course of the study by 0.72 ms (not significant). Analysis of chronic OR T2 lesions (patients) showed an increase in normalised fractional anisotropy and axial diffusivity between baseline and 24 months (both p<0.01). Mean Mars letter contrast sensitivity was improved at 24 months vs baseline (p<0.001), and driven by an early improvement, in both patients and HC.
Conclusion We found evidence of partial lesion remyelination after alemtuzumab therapy, indicating either natural restoration in the context of a ‘permissive’ local milieu; or potentially an independent, pro-reparative mechanism of action. The visual system presents a unique opportunity to study function-structure specific effects of therapy and inform the design of future phase 2 MS remyelination trials.
- multiple sclerosis
Data availability statement
All data relevant to the study are included in the article or uploaded as supplemental information.
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Contributors MHB, CW and AK conceived the study. CW and YB developed the imaging protocols. KK and LL performed MRI analysis. AK and JB developed the electrophysiological protocols and analysed the mfVEP and OCT data. MHB, SWR, JB, HB and MT collected and analysed all clinical data. CW performed statistical testing. H-PH and all authors made significant contributions to data analysis and interpretation, and drafting and revision of the manuscript.
Funding This study is funded by a Sanofi-Genzyme Research Grant: VisMS (Vision in MS: GZ-2015-11423). CW is supported by the Nerve Research Foundation, University of Sydney and Multiple Sclerosis Research Australia.
Competing interests CW has received research fellowship support from Multiple Sclerosis Research Australia, Nerve Research Foundation at the University of Sydney, and is an employee at Sydney Neuroimaging Analysis Centre (SNAC). JB has received honoraria for talks and advisory boards and support for scientific meetings from Sanofi-Genzyme, Novartis, Teva, Merck and Biogen. KK and LL are employees at SNAC. YB is a consulting neuroradiologist for SNAC. HB has received honoraria for presentations and advisory boards; and has received educational travel support from Biogen, Genzyme, Merck, Novartis and/or Roche. SWR has received institutional support from Baxter, Bayer Schering, Biogen Idec, CSL, Genzyme, Grifols, Octapharma, Merck, Novartis, Roche, Sanofi Aventis Genzyme, Servier and TEVA; and is a co-founder of Medical Safety Systems/RxMx. MHB reports grants from Genzyme-Sanofi, during the conduct of the study; grants from Genzyme-Sanofi, Novartis, Biogen and Merck outside the submitted work; and is a co-founder of RxMx, which provides automated laboratory monitoring for patients with MS prescribed immunotherapies; and research director of SNAC. H-PH has received fees for serving on steering and data monitoring committees from Bayer Healthcare, Biogen, Celgene BMS, CSL Behring, GeNeuro, MedImmune, Merck, Novartis, Octapharma, Roche, Sanofi Genzyme, TG Therapeutics and Viela Bio; fees for serving on advisory boards from Biogen, Sanofi Genzyme, Merck, Novartis, Octapharma and Roche; and lecture fees from Biogen, Celgene BMS, Merck, Novartis, Roche and Sanofi Genzyme. MT and AK have nothing to disclose.
Provenance and peer review Not commissioned; externally peer reviewed.
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