Interpretation of the latest basic and clinical research on ECTRIMS 2021 in multiple sclerosis

On October 13-15, 2021, the 37th European Multiple Sclerosis (MS) Treatment and Research Committee Conference (ECTRIMS 2021) will be held online.
The discussion on the progression of MS disease and the treatment of advanced MS are still the same.
The major theme of the conference that has attracted much attention
.

Doctors and patients have different perceptions of cognitive impairment in progressive MS.
Patients with progressive MS have a heavy burden of cognitive impairment and have not received enough attention1
.

About 34%-65% of MS patients will experience cognitive impairment (CI)
.

Although it is more common in SPMS patients, CI can occur in the early stages of MS
.

CI not only has a negative impact on the quality of life of MS patients, the cognitive status of MS patients is also related to their work ability, and can predict the progression of disease and disability
.

CI usually has different performances, which can affect the speed of information processing, causing memory problems and difficulty concentrating
.

This conference released a retrospective cross-sectional analysis study based on the Adelphi Multiple Sclerosis Disease Specific Programme (MS-DSP), which analyzed the MS by investigating neurologists and corresponding patients.
The prevalence of CI among patients and the differences in the assessment of CI by doctors and patients
.

The neurologists surveyed provided data on 25,374 MS patients, of which 11,220 completed the forms filled out by the patients themselves, and 4,817 provided information about cognitive and emotional symptoms
.

The study found that compared with RRMS patients, SPMS patients reported a higher percentage of cognitive or emotional symptoms, and a relatively higher percentage of moderate or extreme symptoms
.

62% of MS patients reported having CI symptoms in the past two weeks; however, the proportion of corresponding neurologist reports was only 27%, indicating that there is a big difference in the assessment of CI between doctors and patients2
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Sinimod is currently the first and only oral disease-modifying drug that can delay the progression of disability.
At the 37th ECTRIMS conference, there is also a core highlight.
Data release: Mechanism of action Sinimod can promote oligodendrocytes in vitro Differentiation and myelination3
.

Preclinical evidence shows that Sinimod can effectively inhibit demyelination in MS, but its clear pharmacological mechanism is still unclear
.

In order to verify whether Sinimod inhibits demyelination by affecting the differentiation and migration of oligodendrocytes, and myelination mediated directly or indirectly by astrocytes, Farina Windener et al.
used Siniimo Germany and other S1P receptor modulators treat human-derived induced pluripotent stem cells (iPSC) derived oligodendrocytes (hiOL), astrocytes (astrocytes, hA) and human brain For human brain organoids, it was found that both Sinimod and other S1P receptor modulators can effectively promote the differentiation of hiOL, but only Sinimod has the effect of promoting remyelination
.

Sinimod treatment can increase the myelin content of MS patients and promote nerve repair4
.

Magnetic resonance myelin water imaging (MWI) and its specific parameters Myelin water fraction (MWF) is a potential surrogate marker of myelin content, which can be used as a myelin integrity and nerve repair in MS patients In vivo biomarkers
.

Researchers conducted long-term MRI follow-up on 24 patients with relapsing remitting multiple sclerosis (RRMS) who received sinimod treatment, and assessed the trend of MWF change and its relationship with the progression of disability
.

The white matter MWF of normal control participants at baseline was 0.
230±0.
007.
The MWF of normal white matter, diffuse abnormal white matter and T2 lesions in RRMS patients were 0.
219±0.
009, 0.
184±0.
014, and 0.
148±0.
052, respectively, which were significantly lower than those of normal controls
.

With an average follow-up of 5.
8 years, 69% of patients in the RRMS cohort maintained stable EDSS, 9% showed improvement; 65% of patients did not relapse
.

The increase of MWF was moderately correlated with the improvement of EDSS
.

Clinical research chapter The proportion of super-response patients in the Sinimod EXPAND study is as high as 78%.
Will patients with different clinical characteristics show different benefits on different evaluation scales? Yes! The disability progression of 5MS patients is multifaceted, and the commonly used disability progression indicator EDSS in clinical research cannot fully reflect the disability progression
.

EXPAND’s post-event analysis study evaluated the effects of sinimod treatment on EDSS, 9-hole peg test (9HPT), and timed 25-foot walk test (ambulation) in patients with secondary progressive multiple sclerosis (SPMS).
Using the timed-25-fooot walk test (T25FWT) and the influence of the results of the single digit modalities test (SDMT), the proportion of super-responders and their baseline characteristics were analyzed
.

Studies have shown that compared with placebo, Sinimod can significantly reduce the progress of clear disability for 3 months, with EDSS, SDMT, 9HPT and T25FWT reduced by 21%, 25%, 14 and 5%, respectively
.

It was found that the proportion of super-response patients was as high as 78% (cut-off value 21%-55%) (Figure 3)
.

The improvement of the disability progression of super-response patients at 3 months was more significant, the reduction ratio was between 44% and 61%, and the survival of patients was also significantly improved
.

The baseline characteristics (baseline variables) of responding patients assessed by different indicators are related to each outcome (Table 1)
.

For EDSS evaluation, the baseline variables for predicting high response to treatment are age, enhanced lesions, baseline EDSS score, recurrence before enrollment, etc.
, while for SDMT evaluation, the baseline variables for predicting high response to treatment are gender, 25 feet walk test, duration, T1 / T2 ratio
.

This result supports the concept that different pathophysiological processes drive responses to different outcomes, and may be related to the dual mechanism of action of Sinimod targeting inflammation and neurodegenerative pathophysiological processes
.

This study emphasizes the relevance of evaluating the treatment response in different aspects of MS, and the feasibility of applying innovative methods to define the characteristics of super patient responders, as a step towards optimizing and personalized treatment methods for the management of MS
.

Long-term treatment of Sinimod for up to 7 years can continue to delay the progression of disability in SPMS patients6
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The EXPAND study is a global multicenter, event-driven, and exposure-driven, double-blind, randomized phase 3 clinical study 7 evaluating the effectiveness and safety of Sinimod.
In the EXPAND extended study, subjects in the placebo group were converted to Sini Modder treatment makes it impossible for researchers to directly evaluate the efficacy of Sinimod compared with long-term placebo treatment
.

Bruce et al.
used rank preserving structural failure time models (RPFST) to analyze that compared with the model simulated virtual placebo (LTVP) and placebo-to-sinimod treatment (LTPS) groups, continuous use of Western medicine The Nimod treatment (LTCS) group was based on the 6-month confirmed disability progression (6mCDP) risk and the difference in progression time assessed by EDSS, and subgroup analysis was performed according to disease activity
.

The results showed that the continuous use of sinimod therapy significantly reduced the risk of 6mCDP, significantly delayed the progression time, and the efficacy lasted up to 7 years
.

Compared with LTVP, the risk of 6mCDP in the LTCS group was reduced by 33%, and the time to progression was prolonged by 62% (p<0.
0001); among them, 42% and 79% of disease-active patients and 20% and 44% of inactive patients were respectively
.

This analysis confirmed the continuous effectiveness of Sinimod for up to 7 years
.

Switching from other disease-modifying drugs to sinimod therapy, with good tolerability and safety8
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At this conference, the interim results of the EXCHANGE study were released
.

EXCHANGE is a phase 3b study aimed at investigating the safety and tolerability of switching from other DMTs treatment to sinimod treatment immediately
.

The study is a 6-month prospective, multi-center, open-label, single-arm trial, and 50% of patients have been enrolled
.

The included patients were patients with progressive RMS aged 18-65, EDSS 2.
0-6.
5, and continuous oral/injection of DMTs for ≥3 months at the time of enrollment
.

The primary endpoint of the study was an adverse event suspected to be related to sinimod for more than 6 months of treatment.
The secondary endpoint was any adverse event or hospitalization, and the change in heart rate from baseline examination to 6 hours after the first administration
.

The study included 163 patients from 42 centers in the United States, and 65% completed the study
.

The most common oral and injectable DMTs were fingolimod (30.
7%), glatiramer acetate/IFNB (27.
7%), dimethyl fumarate (20.
9) and teriflunomide (17.
2%)
.

Results of the study: Only 31.
3% of patients reporting AEs or more may be related to sinimod treatment; in the overall population or subgroups stratified by previous DMTs, including switching from fingolimod to sinimod In subjects who did not undergo dose titration, when sinimod was started, there was no evidence that there was a significant reduction in heart rate
.

The interim analysis suggested that immediate conversion from other DMTs to sinimod has acceptable safety and tolerability, and no unexpected adverse events
.

Sinimod treatment significantly inhibits the thinning of the inner layer of the retina9
.

The inner layer of the retina of MS patients, including the retinal nerve fiber layer (RNFL) and the combined ganglion cell and inner plexiform layers (GCIPL), will become thinner over time.
Reflects the loss of nerve axons
.

Thinning of the retinal layer is associated with MS-related disability and brain atrophy, and is more pronounced in progressive MS than in recurrent MS
.

The EXPAND OCT (optical coherence tomography, OCT) sub-study was performed on some EXPAND participants (10%, 55 in the placebo group and 104 in the Sinimod group) at the time of screening at 3, 12, 24, and 36 months.
Optical coherence tomography detection
.

The results of the study found that compared with the placebo group, the sinimod group had significantly lower thinning of the inner retinal layer at 12 and 24 months and GCIPL at 24 months; RNFL thinning was significantly lower at 12 months
.

Expert comment on expert profileProfessor Xu Yan, Chief Physician, Master's Tutor, Deputy Leader of the Neuroimmunology Group, Chinese Medical Association Neurology Branch, Member of the Chinese Rare Diseases Alliance Neurological Rare Disease Professional Committee Member of the Chinese Society of Immunology Neuroimmunology Branch Standing Committee of the Chinese Medical Doctor Association Neuroimmunology Member of the Subcommittee, Standing Committee of the Neuroimmune Branch of the Chinese Stroke Society, Standing Committee of the Beijing Neurology Association, Neuroinfection and Immunity Professional Committee, Standing Committee of the Chinese Society of Immunology, Neuroimmunity Branch, Postdoctoral Fellow at the Yale University School of Medicine in the United States from 2005 to 2007, and has been engaged in multiple sclerosis Clinical and basic research work on demyelinating diseases of the central nervous system such as optic neuromyelitis, optic neuritis, myelitis, acute disseminated encephalomyelitis, etc.
, published more than 60 articles, participated in the compilation of 7 parts, independently undertaken or mainly involved There are 6 items from the National Natural Science Foundation of China, the Beijing Municipal Natural Science Foundation, and the University Fund
.

Pathology, imaging, evaluation, and treatment of disease progression in multiple sclerosis have been the subject of increasing attention in recent years
.

Although little is known about the cognitive impairment of MS and its impact on individuals with MS and their families, the cognitive function of MS has not been paid attention to, nor has it been routinely evaluated or optimally treated.
It is one of the symptoms that have a great impact on life.
First, patients' perception of cognitive impairment far exceeds that of doctors, which deserves clinical attention
.

Sinimod is a highly effective disease-modifying drug that can delay the progression of disability.
Its mechanism for promoting remyelination and repair may be closely related to its targeting of neurodegenerative pathophysiological processes
.

In clinical terms, we are more concerned about what kind of clinical characteristics patients can maximize benefit from such drugs? The baseline variable analysis of the Sinimod super-response patients this time gave us the answer and also provided us with a good idea for individualized treatment in the future
.

In addition, we have also seen the benefits of long-term treatment of Sinimod for up to 7 years in patients with continuous delaying of the progression of disability, especially for SPMS patients with active disease, as well as from the EXCHANGE study.
The immediate conversion of other DMTs to sinimod has acceptable safety and tolerability, which also provides a good methodological reference for patients who need to be converted in the clinic
.

Retinal thickness is a potential biomarker of MS neurodegeneration.
The EXPAND sub-study disclosed in this conference shows that Sinimod can also significantly inhibit the thinning of the retinal fiber layer, which may also be affected by Sinimod in the mechanism.
The neurodegenerative process may be related to the promotion of remyelination
.

References: 1.
Iris-KatharinaPenner, et al.
Discordance Between Neurologists and People Living With Multiple Sclerosis on the Perception of the Presence and Burden of Cognitive Impairment.
ECTRIMS 20212.
Pontieri, et al.
Demographic and clinical characteristics of treated and untreated patients with secondary progressive multiple sclerosis --analysis from three European registries.
ECTRIMS 20213.
Farina Windener, et al.
Sphingosine-1-receptor-modulators promote directly the differentiation of human iPSC-derived oligodendrocytes.
ECTRIMS 20214.
Long-term myelin water imaging in treated relapsing remitting MS patients.
ECTRIMS 20215.
Francesca Bovis, et al.
Estimating the profile of responders to treatment: Do different patients show benefits on different outcomes? ECTRIMS 20216.
Bruce AC Cree, et al.
Estimating Long-Term Effect of Siponimod on Disability Progression versus Virtual Placebo in SPMS Using RPSFT Model: EXPAND Data Up to 7 Years.
ECTRIMS 20217.
Ludwig Kappos, Amit Bar-Or, Bruce AC Cree, et al.
Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study.
Lancet.
2018 Mar 31;391(10127):1263-1273.
8.
Amit Bar-Or, et al.
Safety and Tolerability of Conversion to Siponimod With and Without Titration in Patients with Advancing Forms of RMS: Interim Results of the Phase 3b EXCHANGE Study.
ECTRIMS 2021.
9.
Patrick Vermersch, et al.
Effect of Siponimod on Retinal Thickness, a Potential Marker of Neurodegeneration, in Patients with SPMS: Findings from the EXPAND OCT Substudy.
ECTRIMS 2021.
EXPAND Data Up to 7 Years.
ECTRIMS 20217.
Ludwig Kappos, Amit Bar-Or, Bruce AC Cree, et al.
Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study.
Lancet.
2018 Mar 31;391(10127):1263-1273.
8.
Amit Bar-Or, et al.
Safety and Tolerability of Conversion to Siponimod With and Without Titration in Patients with Advancing Forms of RMS: Interim Results of the Phase 3b EXCHANGE Study.
ECTRIMS 2021.
9.
Patrick Vermersch, et al.
Effect of Siponimod on Retinal Thickness, a Potential Marker of Neurodegeneration, in Patients with SPMS: Findings from the EXPAND OCT Substudy.
ECTRIMS 2021.
EXPAND Data Up to 7 Years.
ECTRIMS 20217.
Ludwig Kappos, Amit Bar-Or, Bruce AC Cree, et al.
Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study.
Lancet.
2018 Mar 31;391(10127):1263-1273.
8.
Amit Bar-Or, et al.
Safety and Tolerability of Conversion to Siponimod With and Without Titration in Patients with Advancing Forms of RMS: Interim Results of the Phase 3b EXCHANGE Study.
ECTRIMS 2021.
9.
Patrick Vermersch, et al.
Effect of Siponimod on Retinal Thickness, a Potential Marker of Neurodegeneration, in Patients with SPMS: Findings from the EXPAND OCT Substudy.
ECTRIMS 2021.
phase 3 study.
Lancet.
2018 Mar 31;391(10127):1263-1273.
8.
Amit Bar-Or, et al.
Safety and Tolerability of Conversion to Siponimod With and Without Titration in Patients with Advancing Forms of RMS: Interim Results of the Phase 3b EXCHANGE Study.
ECTRIMS 2021.
9.
Patrick Vermersch, et al.
Effect of Siponimod on Retinal Thickness, a Potential Marker of Neurodegeneration, in Patients with SPMS: Findings from the EXPAND OCT Substudy.
ECTRIMS 2021.
phase 3 study.
Lancet.
2018 Mar 31;391(10127):1263-1273.
8.
Amit Bar-Or, et al.
Safety and Tolerability of Conversion to Siponimod With and Without Titration in Patients with Advancing Forms of RMS: Interim Results of the Phase 3b EXCHANGE Study.
ECTRIMS 2021.
9.
Patrick Vermersch, et al.
Effect of Siponimod on Retinal Thickness, a Potential Marker of Neurodegeneration, in Patients with SPMS: Findings from the EXPAND OCT Substudy.
ECTRIMS 2021.
Findings from the EXPAND OCT Substudy.
ECTRIMS 2021.
Findings from the EXPAND OCT Substudy.
ECTRIMS 2021.