Author Of 4 Presentations
P0243 - VISIONARY-MS: A Phase 2 clinical trial of catalytic gold nanocrystals, CNM-Au8, for the treatment of chronic optic neuropathy (ID 431)
Therapies that promote neuroprotection and remyelination are a high priority for multiple sclerosis (MS). CNM-Au8 is an orally delivered suspension of clean-surfaced, faceted gold nanocrystals. CNM-Au8 acts as a nanocatalyst, enhancing cellular bioenergetics, with robust activity in multiple preclinical models of neuroprotection and remyelination. Phase 1 studies identified 15mg and 30 mg per day as well-tolerated doses, with human exposures exceeding those demonstrating preclinical efficacy. No safety issues emerged.
To present the rationale for, and design of, the VISIONARY-MS study (NCT03536559), provide clinical trial baseline demographics and visual characteristics, and report interim, blinded efficacy data.
VISIONARY-MS is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy, safety, and pharmacokinetics of CNM-Au8 (15 mg or 30 mg daily) versus placebo for 24 weeks in stable relapsing multiple sclerosis (RMS) patients with chronic optic neuropathy, currently receiving disease-modifying therapy (DMT). Key inclusion criteria: age 18-55 years, diagnosis of RMS, disease duration £ 15 years, no history of optic neuritis (ON) for 6 months prior to entry (+/- ON prior to that), clinically stable on an approved DMT, Best Corrected Low Contrast Letter Acuity (BC-LCLA) ≤ 20/40 in the affected eye and ≤ 20/32 in the unaffected eye [BC-LCLA ≤ Best Corrected High Contrast Letter Acuity (BC-HCVA) in both eyes], and mean retinal nerve fibre layer thickness ³ 70 mm in both eyes.
Primary endpoint: mean change in BC-LCLA, as measured by 2.5% Sloan letter chart, from baseline to week 24. Key secondary endpoint: mean change in average mf-VEP latency in the mf-VEP affected eye (greatest mf-VEP latency delay at Baseline) from baseline to Week 24.
Other exploratory outcomes: changes in mf-VEP amplitude and latency measures, retinal morphology, nerve fibre layer thickness, magnetic resonance imaging metrics [T1 Black Hole lesion volume, diffusion tensor imaging, magnetization transfer imaging (MTR) and myelin water imaging], EDSS, 25-Foot Timed Walk, Symbol Digit Modality Test, 9-Hole Peg Test and quality of life from baseline to Week 24.
The study commenced in December 2018. Enrolment is ongoing at selected sites in Australia and North America. Baseline demographics and visual characteristics will be presented. Available interim, blinded efficacy data will be presented.
VISIONARY-MS represents the first efficacy study for a completely novel therapeutic catagory. CNM-Au8 is a nanotherapeutic agent providing bioenergetic, catalyitc support to neurons and oligodendroglia precursor cells, resultng in neuroprotection and improved remyelination in an MS population.
P0574 - Expansion of chronic lesions associated with disease progression in RRMS patients. (ID 1062)
It was suggested that slow-burning inflammation isassociated with lesion expansion and leads to progressive loss of axons and disability worsening. However, in vivo evidence linking lesion expansion with biomarkers of disease progression, particularly during relapsing-remitting stage of the disease, is lacking.
To examine the incidence and extent of chronic white matter lesion expansion in relapsing-remitting MS (RRMS) patients followed for 5 yearsand to evaluate its relationship with clinical and imaging biomarkers of disease progression.
Pre- and post-gadolinium T1, FLAIR and diffusion tensor images were acquired from 33 patients. Lesion expansion was analysed between baseline and 48 months using custom-designed software written in Phyton. Percentage brain volume change (PBVC) was calculated using SIENA/FSL. Progression of clinical disability was assessed by EDSS. Progressive tissue damage inside chronic lesions was measured as an increase of Mean Diffusivity (MD).
There were 569 lesions identified as chronic at baseline, of which 261 (46%) were expanding (total volume change:31320 mm3), 236 (42%) were stable (total volume change:1380 mm3) and 72 (12%) were shrinking (total volume change: -2664 mm3). In addition, 139 new free-standing and confluent lesions were detected (total volume:13867).
No association was found between change of volume in chronic lesions and the volume of new lesions (p=0.4). There was a significant increase in total brain lesion volume during the follow-up period (6680+/-5509 vs 7951+/-6315 mm3), the bulk of which was accounted for by an increase of chronic lesions group volume (67.3% or 855+/-1066 mm3), while only 32.7% (or 420+/-633 mm3) was attributable to new lesions.
There was significant negative correlation of chronic lesion volume change with the rate of brain atrophy (r=-0.57, p=0.001) and change of EDSS during the follow-up period (r=0.38, p=0.03). A strong positive correlation was also observed between the rate of chronic lesion volume change and an increase of MD inside the lesions during the follow-up period (r=0.75, p<0.001).
In RRMS patients the expansion of chronic white matter lesions dominates the process of total lesion load accumulation and is a significant contributing factor to the disease progression. Furthermore, our results suggest that low-grade inflammation at the lesion rim associated with significant degree of axonal loss both inside chronic lesions (MD increase) and in NAWM (brain atrophy). In addition, lack of correlation between an expansion of chronic lesion and volume of newly appearing lesions supports the notion that different mechanisms underpin the development of the new lesions and progressive changes in chronic pre-existing lesions.
P0622 - Quanitifying the T1 hypointensity of MS lesions (ID 1063)
Within multiple sclerosis (MS) lesions, T1 weighted hypo-intensity correlates with pathological markers of irreversible damage, including axonal degeneration. Studies have found that T1 “black holes” have a higher correlation with clinical disability than do T2 weighted lesions, and that measurable T1 signal drop out occurs within slowly enlarging lesions or chronic active lesions, as opposed to inactive lesions, suggestive of ongoing axonal degeneration.
To perform this quantitative analysis two pre-processing steps are necessary. The first is correction of low frequency intensity nonuniformity present in image data, also known as bias fields. The second is normalisation of the signal between subjects and timepoints. Both of these steps need to maintain representative contrast between pathological and normal appearing white matter (NAWM) to provide accurate results. Validation of these methods within the MS context is needed to support their use as a biomarker in MS.
To assess the accuracy N34 bias correction on maintaining accurate MS lesion contrast
To assess the accuracy of Freesurfer normalization tool6 in maintaining accurate relative signal intensity
21 relapsing MS and 26 progressive MS subjects had MRI brain scans with 1mm3 3D T1 fast spoiled gradient echo (FSPGR), and 0.6 x 0.46mm2 FLAIR sequences. FLAIR images were resampled and linearly registered to the T1 using FLIRT. MS lesions were segmented from the FLAIR using JIM software.
To calculate an accurate measure of local tissue contrast between MS lesions and surrounding NAWM, the lesion segmentations were dilated and masked for white matter segmentation. The lesion mask was then subtracted from the segmentation to create an edge of NAWM surrounding the lesion. The measure of raw local tissue contrast was taken as the T1 value of
lesion core / lesion edge
N3 bias correction was done with the Freesurfer command mri_nu_correct.mni. Normalization of the T1 sequences was undertaken with Freesurfers mri_normalize which imposes a hard ceiling effect on the white matter peak found, creating an homogenous NAWM intensity of 110 and CSF intensity of ~35.
Correlations of each MS lesion between the bias field corrected and local tissue contrast was explored. Correlations between the bias field corrected and normalized values was explored.
A total of 2401 lesions were analysed. N3 bias corrected T1 images correlated with local tissue contrast of the raw T1 images with an R2 = 0.7556. Normalized T1 images correlated with N3 bias corrected images with an R2 = 0.9415. Average MS lesion normalized T1 intensity was similar between relapsing MS and progressive MS cohorts (82.927 vs 82.793, p = 0.42).
In this analysis T1 intensity was able to be corrected for bias fields and normalized to a set range with reasonable accuracy in maintaining lesion contrast. This supports the use of these methods as a biomarker in quantifying the T1 signal within MS lesions.
P1131 - Pregnancy in a modern day multiple sclerosis cohort: Predictors of postpartum relapse and disability progression (ID 1321)
- W. Yeh
- P. Widyastuti
- J. Stankovich
- M. Gresle
- E. Kubala Havrdová
- D. Horakova
- K. Vodehnalova
- S. Ozakbas
- S. Eichau Madueño
- P. Duquette
- T. Kalincik
- F. Patti
- C. Boz
- M. Terzi
- B. Yamout
- J. Lechner-Scott
- P. Sola
- O. Skibina
- M. Barnett, Md
- M. Onofrj
- M. Sá
- P. McCombe
- P. Grammond
- R. Ampapa
- F. Grand'Maison
- R. Bergamaschi
- D. Spitaleri
- V. Van Pesch
- E. Cartechini
- S. Hodgkinson
- A. Soysal
- A. Saiz
- T. Uher
- D. Maimone
- R. Turkoglu
- R. Hupperts
- M. Amato
- F. Granella
- C. Oreja-Guevara
- A. Altintas
- R. Macdonell
- T. Castillo-Trivino
- H. Butzkueven
- R. Alroughani
- A. Van Der Walt
- T. Msbase Study Group
Disease activity has been investigated in pregnant women with RRMS treated with low-efficacy or no therapy. How newer, more efficacious therapies affect relapse and disability progression risk after pregnancy remains understudied.
To describe disease activity in a modern pregnancy cohort contrasted with historical cohorts. To determine the predictors of postpartum relapse and the predictors of six-month confirmed disability progression events in a contemporary pregnancy cohort.
Data were obtained from the MSBase Registry. Term/preterm pregnancies conceived from 2011-2019 (modern cohort) were compared with those conceived between 2005-2010 and pre-2005. Annualised relapse rates (ARR) were calculated for each pregnancy trimester and 12 months either side. Predictors of time-to-relapse postpartum (1st 3 months) and time to 6-month confirmed disability progression event were determined with clustered Cox regression analyses. Breastfeeding duration and time to DMT reinitiation were modelled as time-varying covariates.
We included 1640 pregnancies from 1452 women (modern cohort). Disease-modifying therapy (DMT) used in the year before conception included interferon-beta (n=597), natalizumab (n=219) and fingolimod (n=147). Continuation of DMT up to conception increased over time (31% pre-2005 vs 54% modern cohort). Preconception ARR decreased across epochs (pre-2005: 0·58 [95% CI 0·49-0·70]; 2005-2010: 0·40 [95% CI 0·36-0·45]; modern: 0·29 [95% CI 0·27-0·32]). In all epochs, ARR decreased during pregnancy to reach similar troughs in the 3rd trimester, and rebounded in the 1st 3-months postpartum. Preconception use of high-efficacy DMT predicted early postpartum relapse (hazard ratio (HR) 2.1 [1.4-3.1]); although those on no DMT were also at risk of postpartum relapse, relative to women on low-efficacy DMT (HR 2.7 [1.2-5.9]). Conception EDSS ≥2, higher preconception and in-pregnancy ARR were also risk factors. DMT reinitiation, particularly of high-efficacy DMT (HR 0.17 [0.07-0.38]), was protective against postpartum relapse. Women who breastfed were less likely to relapse (HR 0.63 [0.42-0.94]). 4.5% of modern pregnancies had confirmed disability progression after delivery. This was predicted by higher pregnancy and postpartum ARR, with postpartum ARR remaining independently predictive in multivariable analysis (HR 1.5 [1.2-2.0]).
The early postpartum period remains a period of vulnerability for disease rebound in women with MS in the modern era. Early DMT reinitiation, particularly with high-efficacy treatment, is protective against postpartum relapse. Confirmed disability progression events after pregnnacy are uncommon in the modern era. Relapse activity is the key driver of these events.