Background

Magnetic resonance imaging (MRI) can supplement clinical diagnostic criteria for multiple sclerosis (MS) by increasing diagnostic sensitivity and predicting the onset of clinically definite MS (CDMS).

Objectives

To determine whether the number of gadolinium-enhanced (Gd⁺) lesions and T2 volume at baseline (BL) may be predictors of CDMS.

Methods

RENEW (NCT01721161) was a randomised, double-blind, placebo-controlled study of participants with a first episode of acute optic neuritis who were treated with opicinumab 100 mg/kg once every 4 weeks (6 doses) and followed-up to week 32. Eligible participants were enrolled in RENEWED (NCT02657915), a 1-day follow-up (Day 1) at 2 years, to study the long-term electrophysiologic and clinical outcomes of treatment with opicinumab vs. placebo. Severity of disease using brain MRI was a secondary efficacy endpoint. In a post hoc analysis of brain MRI lesions, the number of Gd⁺ lesions and volume of T2 lesions at BL in RENEW were assessed for predicting CDMS at Day 1 of RENEWED for the intention-to-treat (ITT) and per protocol (PP) populations. Primary analyses were performed in the PP population.

Results

The numbers of RENEW participants who completed RENEWED were 52/82 in the ITT population (opicinumab, n=28; placebo, n=24) and 47/69 in the PP population (opicinumab, n=24; placebo, n=23). In the PP population, 40/47 (85%) did not have CDMS prior to enrollment in RENEW; 24/40 at-risk participants (opicinumab n=12; placebo n=12) developed CDMS from enrollment in RENEW up to Day 1 in RENEWED. Median time to CDMS diagnosis after enrollment in RENEW was 909.5 days in the opicinumab group and 386.0 days in the placebo group. CDMS developed in participants with Gd⁺ lesions and enlarged T2 volumes at RENEW baseline. The hazard ratios (95% CI; p-value) of MRI measures at BL were: presence of Gd⁺ lesions, 11.52 (2.20, 60.25; p<0.001); number of Gd⁺ lesions, 6.78 (1.97, 23.35; p=0.0024); and T2 volume, 1.80 (1.34, 2.43; p=0.0001). Participants who did not develop CDMS had no Gd⁺ lesions at BL and had lower T2 volumes compared with participants who developed CDMS. Results were comparable in the ITT population. No differences were found in the risk of converting to CDMS in participants treated with opicinumab vs. placebo in either the ITT or PP populations.

Conclusions

The number of Gd⁺ lesions and T2 volume at BL may predict the onset of CDMS. A limitation of this study is its small sample size.

Supported by: Biogen

Background

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.

Objectives

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.

Methods

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).

Results

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).

Conclusions

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.

Background

The placebo-controlled phase 2 RENEW study (NCT01721161) assessed efficacy and safety of opicinumab (anti-LINGO-1) at 100 mg/kg dosed every 4 weeks for 24 weeks in patients with first-episode acute optic neuritis (AON). Thirty-nine of 82 subjects participated in the multifocal visual evoked potential (mfVEP) sub-study. The pre-specified per-protocol (PP) population showed better recovery with opicinumab versus placebo on VEP latency, which was more pronounced in mfVEP.

Objectives

The objective of the current study was to assess long-term post-treatment mfVEP outcomes in previous RENEW participants.

Methods

RENEWED (NCT02657915) was a 1-day follow-up study 2 years (+up to 12 months) after the last or projected last study visit (Week 32). mfVEP sub-studies were conducted in both RENEW and RENEWED.

Results

Nineteen (48.7%) participants in the RENEW mfVEP sub-study completed RENEWED (opicinumab n=10, placebo n=9). At Day 1 of RENEWED, the difference in latency between affected eye versus baseline of the fellow eye was 8.2±8.5 ms in the opicinumab group and 23.9±16.5 ms in the placebo groups (p=0.01, Student t-test).

Average latency recovery in the affected eye, calculated as difference between latency at RENEW baseline and RENEWED Day 1, was 14.9±11.2 ms (max 35 ms) in the opicinumab group and 6.0±5.8 ms (max 13 ms) in the placebo group (p=0.05). In the opicinumab group, there was a linear relationship between the degree of latency delay at baseline and the latency recovery at RENEWED Day 1 (r²=0.72, p=0.004, Pearson). Conversely, the magnitude of mfVEP latency recovery was limited in the placebo group and did not correlate with initial degree of latency delay (p=0.2), which was consistent with the “natural history” study results of spontaneous optic nerve remyelination following episode of AON¹. Finally, between the last visit of RENEW study (24 or 32 weeks) and Day 1 of RENEWED study, mfVEP latency demonstrated a trend for better recovery in the opicinumab group vs placebo group (8.4±7.3 and 2.7±5.6 ms respectively, p=0.07, t-test).

Conclusions

While acknowledging the small sample size of the mfVEP sub-study, the effect of opicinumab on enhanced mfVEP latency recovery was sustained over 2 years ofthe post-treatment period. In addition, a close association between baseline latency delay and degree of latency recovery in opicinumab group suggests that the remyelinating effect of opicinumab treatment may be proportional to the initial degree of demyelination.

Background

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.

Objectives

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.

Methods

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).

Results

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).

Conclusions

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.

Background

The placebo-controlled phase 2 RENEW study (NCT01721161) assessed efficacy and safety of opicinumab (anti-LINGO-1) at 100 mg/kg dosed every 4 weeks for 24 weeks in patients with first-episode acute optic neuritis (AON). Thirty-nine of 82 subjects participated in the multifocal visual evoked potential (mfVEP) sub-study. The pre-specified per-protocol (PP) population showed better recovery with opicinumab versus placebo on VEP latency, which was more pronounced in mfVEP.

Objectives

The objective of the current study was to assess long-term post-treatment mfVEP outcomes in previous RENEW participants.

Methods

RENEWED (NCT02657915) was a 1-day follow-up study 2 years (+up to 12 months) after the last or projected last study visit (Week 32). mfVEP sub-studies were conducted in both RENEW and RENEWED.

Results

Nineteen (48.7%) participants in the RENEW mfVEP sub-study completed RENEWED (opicinumab n=10, placebo n=9). At Day 1 of RENEWED, the difference in latency between affected eye versus baseline of the fellow eye was 8.2±8.5 ms in the opicinumab group and 23.9±16.5 ms in the placebo groups (p=0.01, Student t-test).

Average latency recovery in the affected eye, calculated as difference between latency at RENEW baseline and RENEWED Day 1, was 14.9±11.2 ms (max 35 ms) in the opicinumab group and 6.0±5.8 ms (max 13 ms) in the placebo group (p=0.05). In the opicinumab group, there was a linear relationship between the degree of latency delay at baseline and the latency recovery at RENEWED Day 1 (r²=0.72, p=0.004, Pearson). Conversely, the magnitude of mfVEP latency recovery was limited in the placebo group and did not correlate with initial degree of latency delay (p=0.2), which was consistent with the “natural history” study results of spontaneous optic nerve remyelination following episode of AON¹. Finally, between the last visit of RENEW study (24 or 32 weeks) and Day 1 of RENEWED study, mfVEP latency demonstrated a trend for better recovery in the opicinumab group vs placebo group (8.4±7.3 and 2.7±5.6 ms respectively, p=0.07, t-test).

Conclusions

While acknowledging the small sample size of the mfVEP sub-study, the effect of opicinumab on enhanced mfVEP latency recovery was sustained over 2 years ofthe post-treatment period. In addition, a close association between baseline latency delay and degree of latency recovery in opicinumab group suggests that the remyelinating effect of opicinumab treatment may be proportional to the initial degree of demyelination.