Background

Several lines of evidence indicate essential roles for B cells in the pathogenesis of multiple sclerosis (MS). B cells act as potent antigen-presenting cells and throughout the chronic course of MS, B cell-follicle like structures can be found in the meninges of MS patients. However, whether and how B cells interact with CNS-resident cells, such as microglia and astrocytes to possibly modulate chronic progression of MS remains unclear.

Objectives

In the present study, we aimed at analyzing the interaction of B cells with CNS-resident cells in modulation of chronic CNS inflammation.

Methods

Primary microglia and astrocytes were generated from newborn C57BL/6 mice and were incubated with activated B cells or their supernatants. IL-6 and IL-10 production was abolished by genetic ablation or neutralization of IL-6 or IL-10 using specific antibodies. Thereafter, CNS resident cells were co-cultured with MOG-specific T cells. Further, C57BL/6 mice were depleted of B cells by 3 weekly subcutaneous injections of 0.2 mg murine anti-CD20 prior to immunization with MOG peptide p35-55, a setting in which B cells remain naïve. Microglial and astrocytic activation/modulation was assessed by ELISA, flow cytometry, immunohistochemistry and qRT-PCR.

Results

Incubation of primary microglia or astrocytes with IL-10-neutralized B cell supernatant or co-culture with IL-10-deficient B cells resulted in increased pro-inflammatory cytokine production, an upregulation of co-stimulatory molecules as well as an enhanced capacity to activate T cells as antigen-presenting cells. In vivo, depletion of naïve B cells worsened clinical severity of experimental encephalomyelitis (EAE) and increased the number of CNS infiltrating immune cells. Exacerbation was associated with an enhanced expression of molecules involved in antigen-presentation on microglia cells as well as an upregulation of pro-inflammatory gene products in astrocytes.

Conclusions

These findings highlight that B cells substantially alter the functional status of microglia and astrocytes in chronic CNS inflammation. Specifically, B cell-derived IL-10 is capable of diminishing the inflammatory responses of CNS-resident microglia and astrocytes. Our observation suggests that regulatory B cell function may be important in controlling CNS intrinsic inflammation associated with clinical progression.

Background

Evobrutinib (EVO), a highly selective Bruton’s tyrosine kinase (BTK) inhibitor, has a dual mode of action on B cells and myeloid cells involved in multiple sclerosis (MS) pathogenesis. A Phase II randomized study (NCT02975349) investigated the effect of EVO on immune cells and immunoglobulins (Ig). After a 48-week randomized, double-blind period (DBP), relapsing MS (RMS) patients treated with EVO showed no evidence of B cell depletion or clinically relevant changes in memory or mature-naïve B cell subsets. IgG levels remained stable and slight elevations and reductions, respectively, in IgA and IgM levels were observed.

Objectives

To investigate the long-term effects of EVO on B cells (total, mature-naïve and memory subsets), T cells (total, helper and cytotoxic subsets), NK cells, and Ig levels after 48 additional weeks in the ongoing open-label extension (OLE).

Methods

Adults with RMS were randomized double-blind to EVO 25 mg QD, 75 mg QD, 75 mg BID, or placebo (PBO). PBO patients switched to EVO 25mg QD at Week 24. At Week 48, all patients were OLE-eligible, and received EVO 75 mg QD (median ≈48 weeks), then 75 mg BID. Safety of EVO, including assessment of total B cell counts and Ig levels, was a secondary endpoint; effects on B cell subsets, T cells, and NK cells were exploratory. Immune cell counts were assessed at OLE Week 48 relative to DBP baseline, and Ig levels at OLE Weeks 24 and 48.

Results

Of 213 patients receiving EVO during the DBP, 164 (77%) entered the OLE and 148 (90%) completed ≥60 additional treatment weeks. Investigation of total CD19+ B cells and B cell subsets revealed a decrease in CD19+ B cells and in mature-naïve B cells in all groups originally randomized to EVO. The decrease in mature-naïve B cells was consistent with that observed for CD19+ B cell counts, however no evidence of a change in the memory B cell levels was observed. No relevant changes in IgG levels relative to DBP baseline were observed. Mean IgA and IgM levels remained increased and decreased, respectively, but mean values were within normal ranges. Furthermore, there was no evidence of a change in T or NK cell parameters. Overall, EVO treatment was not associated with an increased risk of infections.

Conclusions

Immune cell numbers and Ig levels seen in patients receiving EVO for 48 weeks of the OLE were consistent with those in the DBP. The results suggest a gradual decline of B cells over time with consistent BTK inhibition, however the clinical meaningfulness of these changes remains to be determined. The observed changes in B cells, IgA and IgM levels were not associated with an enhanced risk of infections. These findings suggest that the continuous pharmacological inhibition of BTK over 96 weeks with EVO does not lead to substantial B cell reductions or changes in Ig levels.

Background

Intrathecal production of immunoglobulin (Ig) and the presence of cerebrospinal fluid (CSF)–specific oligoclonal bands (OCBs) are hallmarks of multiple sclerosis (MS) that persist throughout the disease course and treatment.

Objectives

To describe baseline (BL) correlations of CSF IgM and IgG production with CSF biomarkers and to assess the pharmacodynamic effects of ocrelizumab (OCR) treatment on these parameters in patients with relapsing MS (RMS) from the Ocrelizumab Biomarker Outcome Evaluation (OBOE) study (NCT02688985).

Methods

Seventy-nine of 100 total patients with RMS had available BL CSF samples for assessment of IgG OCBs, IgG and IgM (measured at University Medical Center Göttingen), with demographic, MRI and clinical parameters representative of the total RMS population. CSF samples at either 12 (n=22), 24 (n=24) or 52 (n=17) weeks postdose and from a 12-week reference arm (no OCR; n=16) were assessed for longitudinal changes.

Results

Median (interquartile range [IQR]) CSF levels at BL were as follows: IgG index, 0.79 (0.63–1.28); IgM index, 0.19 (0.11–0.33); CD3⁺ T cell number, 2.52 (0.80–5.61) cells/µL; CXCL13, 9.89 (3.91–31.50) pg/mL; CCL19, 47.95 (31.09–70.86) pg/mL; neurofilament light chain (NfL) 1280.0 (828.1–2968.9) pg/mL. At BL, IgG index and IgM index correlated moderately with levels of B cells (r=0.65, r=0.4 respectively), T cells (r=0.54, r=0.3 respectively) and CXCL13 (r=0.58, r=0.43 respectively), but not CCL19 or NfL. IgG index tended to decrease with OCR treatment and was significantly reduced by 52 weeks (n=17/79; median [IQR] change from BL −9.5% [−20.4% to −0.1%]; p<0.02) compared with stable levels in the reference arm. While IgG OCBs were detected at BL in all patients, IgG OCBs tended to decrease with OCR treatment, with three of 17 patients having no detectable IgG OCBs at 52 weeks. Reductions in IgM index were not observed with OCR treatment.

Conclusions

Baseline CSF levels of B cells, T cells and CXCL13 correlated with IgG index and to a lesser degree IgM index in patients with RMS from the OBOE study. Significant reductions were observed in IgG index with OCR treatment, along with a trend toward reduced OCBs, with three patients showing no detectable OCBs. These data suggest that OCR impacts CSF Ig production, a hallmark of MS not previously thought to be affected by B-cell depletion therapy. These 1-year observations need to be confirmed with longer-term data and correlated with clinical response.

Background

Evobrutinib (EVO) is a highly selective Bruton’s tyrosine kinase inhibitor (BTKI) with a dual mode of action targeting both B cells and myeloid cells, which are known to play a key role in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). Clinical efficacy of EVO in relapsing MS was shown in a Phase II randomized controlled trial (RCT; NCT02975349) with a significant reduction of T1 Gd-enhancing lesions compared to placebo at Week 24 (the primary endpoint of the study) and continued efficacy through Week 48.

Objectives

To report the long-term efficacy of EVO measured as the annualized relapse rate [ARR]), cumulative probability of and time to qualified relapse (QR, change in neurological symptoms or expanded disability status scale score increase attributed to MS lasting ≥24 hours preceded by a stable or improving neurological status ≥30 days).

Methods

In the 48-week double-blind period (DBP), patients received EVO 25mg once daily (QD), 75mg QD, 75mg BID or placebo (PBO) for the first 24 weeks; all arms continued with the original treatment assignment until 48 weeks, except PBO patients who were switched to EVO 25mg QD. At Week 48, all patients could enter the OLE, where treatment was initially EVO 75mg QD (for a median of ≈48 weeks) before switching to 75mg BID. Long-term efficacy of EVO was assessed at up to 60 weeks of OLE.

Results

Of 213 patients randomized to EVO or PBO, 164 (77%) entered the OLE; of these 148 (90%) completed 108 weeks of treatment. For patients initially receiving PBO or EVO 25mg QD, 75mg QD or 75mg BID in the DBP, ARR (95% CI) was 0.37 (0.21, 0.59), 0.52 (0.33, 0.78), 0.25 (0.12, 0.44) and 0.11 (0.04, 0.25), respectively, at Week 48, and 0.31 (0.21, 0.45), 0.37 (0.25, 0.52), 0.18 (0.10, 0.29) and 0.12 (0.06, 0.22) at Week 108. The cumulative probability of QR in these groups was 0.26 (0.14, 0.38), 0.24 (0.12, 0.36), 0.15 (0.05, 0.25) and 0.08 (0.00, 0.16) at Week 48, and 0.39 (0.25, 0.53), 0.34 (0.20, 0.48), 0.25 (0.12, 0.38) and 0.20 (0.08, 0.31) at Week 96, respectively. The estimated time from randomization by which 20% of patients had a qualified relapse was almost three times longer for patients initiated in the DBP with EVO 75mg BID (827 days [327, not evaluable]) than for patients initiated in the DBP with PBO (281 days [99, 407]) and longer than for patients initiated in the DBP with EVO 25mg QD (166 days [61, 606]) and 75mg QD (530 days [244, 838]). EVO was generally well tolerated, with the safety profile maintained during the 60-week OLE.

Conclusions

With EVO 75mg BID, the efficacy (ARR, 0.11) at Week 48 was maintained at 108 weeks. Probability of and time to QR highlighted that, despite switching to EVO 75mg QD/BID in OLE, patients initiated in the DBP on EVO 25mg QD, 75mg QD or PBO did not achieve the same level of efficacy of those initiated in the DBP on 75mg BID. The maximum efficacy observed at the 75mg BID dose correlated with optimal BTK occupancy achieved with BID dosing.

Background

Preventing multiple sclerosis (MS) disease progression is critical in preserving function and quality of life. Fenebrutinib is a potent, highly selective Bruton’s tyrosine kinase (BTK) inhibitor with a dual mechanism of action. Fenebrutinib targets acute and chronic aspects of MS by decreasing B-cell activation and limiting myeloid proinflammatory responses. This profile and studies of fenebrutinib in patients with other inflammatory diseases suggest a potentially favorable benefit-risk ratio, although there are no studies yet in patients with MS.

Objectives

To describe the unique design aspects of the Phase III fenebrutinib clinical trial program as they relate to understanding disease progression across the MS spectrum.

Methods

We developed a Phase III program that will assess disease progression in two identical clinical trials in relapsing MS (RMS) and one trial in primary progressive MS (PPMS).

Results

To understand the effects of fenebrutinib on disease progression, all three trials include 12-week composite Confirmed Disability Progression (cCDP12) as a primary endpoint; the RMS trials also include annualized relapse rate as a co-primary endpoint. The cCDP12 requires at least one of the following: (1) an increase in Expanded Disability Status Score (EDSS) score of ≥1.0 point from a baseline (BL) score of ≤5.5 points, or a ≥0.5 point increase from a BL score of >5.5 points; (2) a 20% increase from BL in time to complete the 9-Hole Peg Test; (3) a 20% increase from BL in the Timed 25-Foot Walk Test. The cCDP12 is a more sensitive assessment of disability than the EDSS, especially at early disease stages, as it provides a quantitative assessment of upper limb function. Comparator arms will include active disease-modifying treatments with known effects on disability progression (PPMS=ocrelizumab; RMS=teriflunomide). Treatment assignments will be 1:1, with estimated enrollment of 734 patients in each of the RMS trials and 946 in the PPMS trial. Study durations will be event driven, with the primary analysis occurring after a prespecified number of cCDP12 events (≥96 or ≥120 weeks in the RMS and PPMS trials, respectively).

Conclusions

Fenebrutinib will be investigated in RMS and PPMS and may offer a unique approach to slowing disease progression in MS. Furthermore, the use of the cCDP12 as a primary endpoint may provide a clearer, more complete picture of disability progression or improvement than the EDSS alone.

Background

Ocrelizumab (OCR) is approved for the treatment of relapsing (RMS) and primary progressive multiple sclerosis (PPMS) at a dose of 600 mg iv twice yearly and showed significant benefit on disability progression (DP). Exposure-response (ER) analyses of the pivotal OCR Phase III studies in patients with RMS or PPMS showed that those with higher exposures (based on individual mean serum concentration [Cmean] exposure quartiles) had a greater benefit on DP vs patients with lower exposure, without an increase in adverse events. While doses of OCR of 1000–2000 mg were studied in a Phase II study, doses >600 mg have not been investigated in Phase III studies in RMS or PPMS patients.

Objectives

To present the OCR higher dose selection rationale and design of two double-blind, parallel-group, randomized Phase IIIb studies (one in RMS and one in PPMS) aiming to explore if a higher dose of OCR will provide even higher benefits vs 600 mg on DP without adversely affecting the established favorable benefit-risk profile.

Methods

The higher dose of OCR in both studies is based on achieving a Cmean of at least that observed in the highest exposure quartile of the Phase III ER analyses while limiting Cmean below that observed with the highest OCR dose of 2000 mg in the Phase II study that had a similar safety profile, except for a slightly higher incidence of infusion-related reactions (pre-medication: methylprednisolone only; no mandatory antihistamine).

Results

Modeling predicts that doses of 1200 mg (patients <75kg) or 1800 mg (patients ≥75kg) twice yearly would fulfill these criteria. Based on data from the pivotal trials, the expected risk reduction vs 600 mg in 12-week composite confirmed DP (cCDP; consisting of time to progression measured by the EDSS, Timed 25-Foot Walk or 9-Hole Peg Test) would be ≥35% in RMS and ≥27% in PPMS. Patients with RMS (EDSS score 0–5.5; N=786) or PPMS (EDSS score ≥3.0–6.5; N=699) will be randomized (2:1) to either the higher dose (above) or OCR 600 mg administered every 24 weeks (first dose divided into 2 infusions separated by 14 days) for ≥120 weeks (minimum 5 doses).

The primary outcome for both trials is risk reduction on cCDP. Immunoglobulin and oligoclonal bands in the CSF will be assessed in a sub-study of up to 288 patients.

Conclusions

These studies will test if higher-dose ocrelizumab provides an even higher benefit on cCDP vs the approved 600 mg dose without adversely affecting the established favorable benefit-risk profile.

Background

In a Phase II randomized study (NCT02975349) in patients with relapsing MS, evobrutinib (EVO) 75 mg twice-daily (BID) reduced total T1 Gd+ lesions (primary endpoint) and annualized relapse rate (ARR) over 24 weeks versus placebo, with efficacy maintained through Week 108. EVO was generally well tolerated.

Objectives

To describe the safety profile of EVO in the long-term treatment of MS by reporting detailed safety data from the study’s open-label extension (OLE) over 60 weeks.

Methods

In the 48-week double-blind period (DBP), patients received EVO 25 mg once-daily (QD) or 75 mg QD, 75 mg BID, or placebo for the first 24 weeks. All arms continued with the original treatment assignment until 48 weeks, except placebo patients who were switched to EVO 25 mg QD. At Week 48, all patients could enter the OLE, where treatment was initially EVO 75 mg QD (for a median of ~48 weeks) before switching to 75 mg BID. Safety was assessed throughout the OLE by the nature, severity, and occurrence of treatment emergent adverse events (TEAEs) by NCI-CTCAE v4.03 criteria, as well as vital signs, ECGs, and clinical laboratory safety parameters.

Results

Of 213 patients who received EVO during the double-blind period, 164 (77%) entered the OLE (safety analysis population) and 148 (90%) completed 60 weeks of treatment. Overall, 107 (65.2%) patients had a treatment emergent adverse event (TEAE), the majority of which were mild (47.6%) or moderate (36.0%), and none led to death. TEAEs were balanced across previous DBP treatment groups; the most frequent TEAEs over the OLE period, including the dose-switch, were nasopharyngitis (7.9%, Grade 2 or less), increased lipase (7.9%, Grade 3 or less), upper respiratory tract infection (6.1%, Grade 2 or less), and urinary tract infection (4.9%, Grade 2 or less); analysis of TEAEs by exposure-adjusted incidence rate showed no evidence of an increase after patients switched to 75 mg BID. Thirteen patients (7.9%) reported a serious TEAE, most frequently related to infections (6 patients, not treatment-related). Five patients (3.0%) had a TEAE during the OLE that led to treatment withdrawal, of which 3 were considered related to treatment (nausea, increased lipase, and increased lipase and amylase). The incidence of overall infections in the OLE was similar to that observed in the DBP. Transient elevated liver aminotransferases reported in the 48-week DBP were not observed in the OLE after prolonged treatment or after the switch to 75 mg BID. No adverse ECG findings were noted across all evobrutinib groups. There was also no apparent effect of EVO dose received in the DBP on safety parameters in the OLE.

Conclusions

In a 60 week OLE period of a Phase II study, the safety of EVO was similar to that seen in the DBP. Overall, long-term EVO treatment was generally well tolerated in patients with relapsing MS.

Background

Background: B cells are key mediators of inflammatory processes in multiple sclerosis, a notion substantiated by the success of B-cell depletion therapies; however, overall depletion does not only target pathogenic B cells but can also affect regulatory B-cell properties. An alternative strategy may be the specific inhibition of Bruton’s tyrosine kinase (BTK), which is centrally involved in B-cell receptor (BCR) signaling and subsequently mediates B-cell activation and differentiation. BTK inhibitors therefore hold the promise to control pathogenic functions such as antigen presentation and cytokine release.

Objectives

Objectives: To evaluate the BTK inhibitor evobrutinib in a mouse model of experimental autoimmune encephalomyelitis (EAE).

Methods

Methods: C57Bl/6 mice received oral evobrutinib or vehicle starting 7 days before immunization with conformational MOG_1-117 protein (a B cell–mediated model of EAE). EAE severity was assessed for 60 days using a standard scale. B-cell maturation and activation markers on B and T cells were analyzed by flow cytometry on day 12 post immunization. T cell proliferation and differentiation were assessed after a 3-day co-culture with BTKi-treated B cells. Intracellular calcium flux was analyzed using calcium-sensitive dyes and BCR or T cell receptor (TCR) stimulation. BTK expression and phosphorylation as well as cytokine production were assessed on healthy human B cells via PhosFlow protocols or ELISA, respectively.

Results

Results: Evobrutinib showed a dose-dependent amelioration of EAE severity throughout the 60-day observation period. Evobrutinib led to an accumulation of follicular type (FO) II B cells and a corresponding reduction in FO I B cells, a BTK-dependent transition. Expression of CD86, CD69, and major histocompatibility complex class II on B cells, and CD25 and CD69 on T cells, was reduced. Evobrutinib inhibited the B cell-mediated proliferation and proinflammatory differentiation of T cells. BCR-mediated mobilization of excitatory calcium was reduced by evobrutinib, while TCR signaling remained unaffected. In human B cells, BTK expression and phosphorylation were depending on the maturation of B cells, while the overall cytokine release was inhibited by evobrutinib.

Conclusions

Conclusion: Evobrutinib efficiently reduces BTK-dependent signaling after BCR stimulation, preventing B-cell activation, proinflammatory differentiation, and function. This translates into reduced CNS inflammation and clinical amelioration in a B cell–mediated EAE model.

Background

The sphingosine-1-phosphate (S1P) modulator siponimod has been approved for the treatment of active secondary progressive multiple sclerosis. While the reduction of relapse frequency represents a well established effect of S1P modulators in the treatment of multiple sclerosis, their impact on progressive disease is still controversial.

Objectives

The objective of this study was to elucidate effects of siponimod treatment on resident CNS cells in the context of glial cell-mediated neurodegenerative pathomechanisms in progressive multiple sclerosis. We focussed on the impact of siponimod treatment on functional microglial phenotypes.

Methods

Experimental autoimmune encephalomyelitis (EAE) was induced in wild type C57BL/6 mice aged 8-12 weeks with MOG_35-55 peptide emulsified in CFA and the additional injection of pertussis toxin. Siponimod treatment was started 20 days post immunization, after mice had reached peak disease and was performed at least for 60 days. Siponimod was administered orally via food pellets containing 3 mg, 10 mg or 30 mg siponimod/kg, respectively. The clinical outcome of mice was measured by the EAE score and their performance in the elevated beam test. After 60 days of treatment, mice were sacrificed for FACS analysis of microglia isolated from brain and spinal cord using the Multi Tissue Dissociation Kit 1.

Results

Siponimod treatment induced a robust reduction of mean clinical scores of mice in all siponimod treatment groups compared to the vehicle group. Dose-dependent clinical differences in disease severity of siponimod-treated mice were observed in the elevated beam test, with mice treated with the highest siponimod dose performing better than mice treated with the low or intermediate siponimod dose. In siponimod-treated animals MHC class II expression of microglial cells was downregulated in a dose-dependent manner.

Conclusions

Therapeutic siponimod treatment started 20 days post immunization and continued over two months leads to a reduction of EAE severity in a dose-dependent manner that is associated with a downregulation of microglial MHC class II expression as a marker of microglial activity. It remains unclear whether the effect of siponimod on microglial activity is directly mediated by modulation of microglial S1P receptors.

Background

Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody associated disease (MOG-AD) are orphan diseases with high impact on quality of life and to date unknown socio-economic burden.

Objectives

The aim of this study was to evaluate costs and health-related quality of life of NMOSD and MOG-AD from the societal perspective.

Methods

In a multicenter cross-sectional study throughout Germany between 04/2017 and 04/2019, the primary data on retrospective consumption of medical and non-medical resources and work ability related to NMOSD and MOG-AD were assessed via standardized and pre-tested paper-based patient questionnaires. Health-related quality of life was captured by the EuroQoL Group EQ-5D-5L questionnaire. Clinical data were retrieved from the Neuromyelitis Optica Study Group (NEMOS) database. Patient recruitment took place at 17 German NEMOS centers. Costs were analyzed in EUR for 2018.

Results

During the recruitment period, 218 of 275 adult patients were screened for eligibility. 212 patients (80.2% women; mean age 49 ± SD 15 years; mean disease duration 9 ± SD 8.5 years; Expanded Disability Status Scale (EDSS) 3.7 ± SD 2.1) were analyzed. The mean total annual per capita cost of illness accounted for EUR 59 576 and the mean index value of the EQ-5D-5L was 0.693. Given an estimated prevalence of NMOSD in Germany of 1.3/100 000, the annual burden from the societal perspective adds to EUR 64.3 Mio for Germany. The most important cost drivers were informal care costs (27.6% of total costs), indirect costs (23.3%; particularly loss of salary) and drugs, especially immunotherapeutics (16.4%). Costs showed a significant positive correlation with disease severity (p<0.0001); in the EDSS 6.5-8.5 subgroup the annual costs were EUR 129 436. Moreover, the health-related quality of life revealed a negative correlation with disease severity (p<0.0001); in the EDSS 6.5-8.5 subgroup the mean index value was 0.195.

Conclusions

These German data from the era without approved standard medications show enormous effects of the disease on costs and quality of life and might be helpful for estimating the impact and cost-effectiveness of new therapeutic approaches.

Background

“Spinal pain”, girdle-like dysesthesia, and painful spasms were noted already in earliest disease descriptions in the 18^th century. Nowadays it has become clear that pain is a frequent and one of the most disabling symptoms in these patients. Due to the rarity of NMOSD most previous studies of pain and depression were relatively small or included a mixed population AQP4-IgG-seropositive and seronegative patients, while recent clinical trials clearly indicate that pathogenetic mechanisms are different in these forms.

Objectives

To evaluate prevalence, clinical characteristics and predictive factors of pain, depression and their impact on the quality of life (QoL) in a large European seropositive neuromyelitis optica spectrum disease (NMOSD) cohort.

Methods

We included 166 patients with aquaporin-4-seropositive NMOSD from 13 tertiary referral centers of Neuromyelitis Optica Study Group (NEMOS). Clinical data, including expanded disability status scale and localization of spinal lesions on MRI, were retrieved from the NEMOS database or local electronic patient records. Data on pain, depression and quality of life were captured by self-reporting questionnaires.

Results

125 (75.3%) patients suffered from chronic NMOSD-associated pain. Of these, 65.9% had neuropathic pain, 68.8% reported spasticity-associated pain and 26.4% painful tonic spasms. Number of previous myelitis attacks (OR 1.27, p=0.018) and involved upper thoracic segments (OR 1.31, p=0.018) were the only predictive factors for chronic pain. Interestingly, the latter was specifically associated with spasticity-associated (OR 1.36, p=0.002), but not with a neuropathic pain. 39.8% suffered from depression (moderate to severe in 51.5%). Pain severity (OR 1.81, p<0.001) and especially neuropathic character (OR 3.44, P<0.001) were strongly associated with depression. 70.6% of patients with moderate or severe depression and 42.5% of those with neuropathic pain had no specific medications. 64.2% of those under symptomatic treatment still reported moderate to severe pain. Retrospectively, 39.5% of pain-sufferers reported improvement of pain after start of immunotherapy: 37.3% under rituximab, 40.0% under azathioprine, 33.3% under mycophenolate mofetil and 66.7% under tocilizumab. However, there was no difference in terms of pain prevalence or intensity in patients with different immunotherapies. Pain intensity, walking impairment and depression could explain 56% of the physical QoL variability, while depression was the only factor, explaining 46% of the mental QoL variability.

Conclusions

Myelitis episodes involving upper thoracic segments are main drivers of pain in NMOSD. Although pain intensity was lower than in previous studies, pain and depression remain undertreated and strongly affect QoL. Interventional studies on targeted treatment strategies for pain are urgently needed in NMOSD.

Background

Until recently, the function of B cell-derived antibodies in central nervous system (CNS) demyelinating disorders has mainly consisted in amplifying ongoing demyelination by complement fixation. With the discovery of antibodies against the water channel aquaporin-4 in the serum of neuromyelitis optica patients, evidence condensed that autoreactive antibodies may also elicit CNS inflammation. However, for another subgroup of patients with CNS demyelinating disorder, which show antibodies against myelin oligodendrocyte glycoprotein (MOG) in the blood, the precise role of these antibodies remains unknown.

Objectives

We hypothesize that in anti-MOG antibody positive patients, MOG-reactive antibodies in the periphery are capable of opsonizing endogenous MOG protein, subsequently triggering CNS inflammation and demyelination. To prove this assumption, we intend to investigate the effect of serum from these patients on the internalization of soluble and membrane-bound MOG protein by generated human antigen-presenting cells.

Methods

For the generation of dendritic cells and macrophages, CD14⁺ myeloid cells were isolated from human peripheral blood mononuclear cells of healthy donors and cultured in the presence of distinct cytokines. Expression of Fcγ receptors as well as antigen uptake by the generated antigen-presenting cells were analyzed by flow cytometry.

Results

Flow cytometry analysis of the generated cells revealed that macrophages highly expressed Fcγ receptors I, II and III. By contrast, dendritic cells only highly expressed Fcγ receptor II. Both dendritic cells and macrophages internalized fluorescently labeled MOG and ovalbumin protein, and the addition of a phagocytosis inhibitor diminished protein uptake. Furthermore, the phagocytosis activity of the generated cells was increased in the presence of rabbit anti-ovalbumin antibodies, indicating that soluble protein can be functionally opsonized by these antibodies.

Conclusions

Generated antigen-presenting cells were capable of internalizing soluble protein and rabbit anti-ovalbumin antibodies mediated opsonization of ovalbumin protein, resulting in an enhanced antigen uptake. In ongoing experiments, we investigate the effect of whole immunoglobulin G from anti-MOG antibody positive patients on the internalization of soluble and membrane-bound MOG protein by human antigen-presenting cells.

Background

Multiple sclerosis (MS) is a chronic inflammatory neurological disease that requires life-long treatment, and new therapies must be safe and effective over a long treatment duration. Ocrelizumab is a humanized antibody that selectively targets CD20⁺ B cells and has been shown to be efficacious for the treatment of both relapsing MS (RMS) and primary progressive MS (PPMS). Effectiveness data in large, real-world populations are needed for better informed clinical treatment.

Objectives

CONFIDENCE (ML39632, EUPAS22951) evaluates the safety and effectiveness of ocrelizumab in patients with RMS & PPMS in a real-world setting. Here, we present the first analysis of one-year effectiveness data from patients newly treated with ocrelizumab.

Methods

CONFIDENCE is a non-interventional study in patients with RMS or PPMS newly treated (up to 30 days prior or 60 days after enrolment) with ocrelizumab or other selected disease modifying therapies (DMTs) during the course of their disease. Data will be collected for 3000 ocrelizumab-treated patients and 1500 patients treated with other DMTs according to label at ~250 centers in Germany for up to 10 years. Here, we analyze effectiveness outcomes for patients treated with ocrelizumab for the first year, including treatment success (the proportion of patients with no relapse, progression or treatment discontinuation due to an adverse event) and change in Expanded Disability Status Scale (EDSS) from baseline. In addition, we will present patient-reported outcomes. Safety assessments are presented separately.

Results

As of 30 June 2020, 2,129 patients have been recruited for ocrelizumab treatment. The interim analysis is expected to include data from approximately 559 patients newly treated with ocrelizumab that had one year of follow up. Of these patients, ~82% had RMS and ~18% had PPMS. Mean (standard deviation [SD]) baseline EDSS was 3.3 (1.9) for patients with RMS and 4.5 (1.7) for patients with PPMS. Preliminary data show that 64% of patients were female (66% female RMS; 55% female PPMS). Over an observational period of one year, 83.6% of RMS and 93.2% of PPMS patients experienced treatment success. About 85.3% of patients with RMS experienced no relapses. The mean (SD) change in EDSS from baseline after one year of treatment was 0.0 [0.6] for patients with RMS and 0.1 [0.6] for patients with PPMS.

Conclusions

This analysis of one-year interim data in the CONFIDENCE study shows the effectiveness of ocrelizumab in a real-world setting.

Background

Hallmarks of secondary progressive multiple sclerosis (SPMS) are amongst others progressive motoric dysfunction and cognitive decline. Siponimod (Mayzent®), a selective sphingosine-1-phosphate receptor modulator, has been approved by the EMA for the treatment of active SPMS, evidenced by relapses or imaging features of inflammatory activity. AMASIA (ImpAct of Mayzent® (Siponimod) on secondAry progressive multiple Sclerosis patients in a long-term non-Iinterventional study in GermAny) is the first prospective non-interventional study to assess long-term effectiveness and safety of siponimod in clinical routine and the impact on quality of life and socioeconomic conditions.

Objectives

Characterization of the siponimod patient profile and SPMS diagnostic criteria based on clinical routine in Germany.

Methods

In AMASIA treatment effects of siponimod will be analyzed in 1,500 SPMS patients over 3 years. Disability progression and cognitive changes are evaluated every 6 months by the expanded disability status scale (EDSS) and the symbol digit modalities test (SDMT). Additional measures including MS activity by magnetic resonance imaging (MRI), assessments of functional domains, and questionnaires from patient’s, physician’s, and relatives’ perspectives of disability progression, cognitive worsening, and quality of life as well as socioeconomic aspects are analyzed.

Results

Results of the first interim analysis will be presented and will show patient characteristics of the first approx. 200 patients in Germany treated with siponimod in clinical routine. These data will include demography, but also all relevant clinical information including disease and therapy history, allowing for a comparison with data from phase II and III clinical studies with siponimod.

Conclusions

The combination of clinical parameters and patient reported outcomes including quality of life and socioeconomics allows a more detailed insight in the siponimod treated SPMS patient population in clinical routine in Germany. This will contribute to a better understanding of SPMS management in the medical community.

Background

As of April 2020, >160,000 patients with relapsing forms of multiple sclerosis (RMS) or primary progressive MS (PPMS) worldwide had started treatment with ocrelizumab (OCR), a humanized monoclonal antibody selectively targeting CD20⁺ B-cells.

Pivotal studies established the risk-benefit profile of OCR under controlled trial conditions.

Objectives

Real-world data are needed to further characterise the safety of OCR in clinical practice. Here we present 1-year, real-world safety data for patients receiving OCR.

Methods

CONFIDENCE (ML39632, EUPAS22951), a non-interventional, post-authorization safety study, aims to enrol 3,000 patients with RMS or PPMS newly treated (up to 30 days prior or 60 days after enrolment) with OCR and 1,500 patients newly treated with other selected DMTs according to label at ~250 German neurological practices. Each patient is followed for 7.5–10 years. Study visits, documented circa every 6 months, follow routine clinical practice. The primary outcome is the incidence and type of uncommon adverse events (AEs) (incidence of 0.1% to 1% [1 to 10 out of 1000 patients] or less). Statistical analyses are mainly descriptive and exploratory. Assessments of effectiveness (secondary objectives) are presented separately.

Results

As of 30 June 2020, 2,129 patients treated with OCR had been recruited. The interim analysis is expected to include approximately 559 OCR-treated patients, ~82% with RMS and ~18% with PPMS, with 1-year follow-up data (mean baseline age [SD], 45.5 [11.4] years; 64.4% female; mean baseline EDSS [SD] RMS 3.3 [1.9], PPMS 4.5 [1.7]). Preliminary data showed that ~63.0% of patients had ≥1 AE during OCR treatment; ~26.8% had treatment-related AEs (TRAEs). The most common AEs were infections and infestations (~31.5%), nervous system disorders (~14.7%), and general disorders and administration site conditions (~12.3%). The incidence of serious AEs was ~14.0%, most frequently infections and infestations (~3.6%; RMS, ~3.9% [n=18]; PPMS, ~1.9% [n=2]), nervous system disorders (~3.2%), and injury, poisoning and procedural complications (~2.1). The most frequent serious infections were urinary tract infections (~1.3% [n=7]) and pneumonia (~0.5% [n=3]). Seven patients overall (1.3%) had treatment-related serious infections.

Conclusions

The safety profile of OCR in this first interim analysis of the CONFIDENCE study, representing a real-world population currently treated with OCR in Germany, was consistent with controlled clinical trials.

Background

B cell depleting anti-CD20 antibodies (ab) are highly effective in multiple sclerosis (MS). Besides B cells, a population of proinflammatory T cells express CD20. The origin of these CD20 positive T cells and whether their depletion contributes to the clinical effect of anti-CD20 is unclear.

Objectives

This study is focused on characterizing CD20+ T cells both in naive and experimental autoimmune encepahalomyelitis (EAE) mice and in humans.

Methods

CD20+ T cells were analyzed for their phenotype, cytokine expression and developmental state using flow cytometry, FACS, ELISA, RT pcr and microscopy. Spleens, inguinal lymph nodes, blood and spinal cord from wild type, 2D2, µMT and CD20KO mice as well as PBMCs from MS patients were examined. Splenoculture and B cell-T cell coculture with 2D2 T cells and various B cells (wt, CD20KO, membrane stained) were used to analyze CD20 content and transfer. EAE was induced by immunization of the mice with CFA and MOG peptide.

Results

When compared to CD20- T cells, CD20+ T cells show enhanced features of pathogenicity both in mice as well as in patients with MS. In wild-type mice, CD20+ T cells expand during EAE, while B cell-deficient mice do not exhibit CD20+ T cells. T cells themselves are not able to generate CD20 and in splenocyte cultures, de novo development of CD20+ T cells is strictly dependent on the presence of B cells expressing CD20. In direct B cell-T cell cocultures, CD20 is transferred from B cells to T cells via trogocytosis. Along the same lines, transfer of CD20 expressing B cells into B cell-deficient mice results in the development of CD20+ T cells.

Conclusions

CD20 on T cells relies on its transfer from B cells via trogocytosis. Thus, T cell CD20 is a marker for their recent activating interaction with a B cell, explaining the pronounced pro-inflammatory phenotype of these T cells. These data suggest that depletion of CD20+ T cells may substantially support the effectiveness of anti-CD20 ab therapy in MS, and their reappearance in the blood may serve as a marker for reemerging pathogenic B cell – T cell interaction.

Background

Ocrelizumab (OCR) is a humanised anti-CD20+ monoclonal antibody approved for the treatment of relapsing and primary progressive forms of multiple sclerosis (RMS and PPMS). Real-world evidence on adherence and persistence with OCR is limited.

Objectives

To examine the persistence and adherence to OCR in a real-world setting.

Methods

CONFIDENCE (ML39632, EUPAS22951) is an ongoing non-interventional, post-authorization safety study, aiming to enroll 3,000 patients newly treated with OCR and 1,500 patients newly treated with other DMTs at ~250 centers in Germany. Follow up regardless of discontinuation of treatment will be for up to 10 years. In this ad-hoc analysis of CONFIDENCE, persistence and adherence were measured exclusively for patients treated with OCR with at least one post-initiation (i.e., first two 300mg doses IVs') assessment visit. Persistence was examined as a survival function of event-free time from discontinuation. Patients were considered at-risk until the last assessment visit recorded prior to data cut-off (31 March 2020) or censored at time of OCR discontinuation, whichever occurred first. Adherence was assessed using median time intervals between infusions.

Results

Overall, 1614 patients treated with OCR were included in this analysis; 1296 patients with RMS and 318 with PPMS. Median [IQR] age at OCR initiation was 42 [44, 57] years and 52 [33, 51] years in patients with RMS and PPMS, respectively. Most RMS patients were females (66.7%) while gender distribution in PPMS patients was approximately equal (51.6% females). Median [IQR] disease duration from diagnosis up to OCR initiation was longer in RMS (7.9 [3.0, 14.7] years) than in PPMS patients (3.4 [0.8, 9.7] years). Median [IQR] EDSS at OCR start was 3.0 [2.0, 4.5] and 4.5 [3.5, 6.0] in the RMS and PPMS population, respectively. At data cut-off, the median [IQR] OCR exposure duration was 7.85 [5.5, 13.1] months for RMS and 6.87 [0.5, 12.5] months for PPMS patients. Overall, the median time between infusions ranged from 5.9 and 6.0 months and did not differ between RMS and PPMS cohorts. Treatment persistence at 18 months was 96.6% (95% CI: 95.3-97.8%) and very consistent between RMS and PPMS patients.

Conclusions

Adherence to disease-modifying therapy (DMT) is critical for achieving therapeutic goals in MS. This analysis shows high treatment persistence for OCR patients at 18 months and strong adherence to recommendations to administer OCR infusions every 24 weeks.

Background

Intrathecal production of immunoglobulin (Ig) and the presence of cerebrospinal fluid (CSF)–specific oligoclonal bands (OCBs) are hallmarks of multiple sclerosis (MS) that persist throughout the disease course and treatment.

Objectives

To describe baseline (BL) correlations of CSF IgM and IgG production with CSF biomarkers and to assess the pharmacodynamic effects of ocrelizumab (OCR) treatment on these parameters in patients with relapsing MS (RMS) from the Ocrelizumab Biomarker Outcome Evaluation (OBOE) study (NCT02688985).

Methods

Seventy-nine of 100 total patients with RMS had available BL CSF samples for assessment of IgG OCBs, IgG and IgM (measured at University Medical Center Göttingen), with demographic, MRI and clinical parameters representative of the total RMS population. CSF samples at either 12 (n=22), 24 (n=24) or 52 (n=17) weeks postdose and from a 12-week reference arm (no OCR; n=16) were assessed for longitudinal changes.

Results

Median (interquartile range [IQR]) CSF levels at BL were as follows: IgG index, 0.79 (0.63–1.28); IgM index, 0.19 (0.11–0.33); CD3⁺ T cell number, 2.52 (0.80–5.61) cells/µL; CXCL13, 9.89 (3.91–31.50) pg/mL; CCL19, 47.95 (31.09–70.86) pg/mL; neurofilament light chain (NfL) 1280.0 (828.1–2968.9) pg/mL. At BL, IgG index and IgM index correlated moderately with levels of B cells (r=0.65, r=0.4 respectively), T cells (r=0.54, r=0.3 respectively) and CXCL13 (r=0.58, r=0.43 respectively), but not CCL19 or NfL. IgG index tended to decrease with OCR treatment and was significantly reduced by 52 weeks (n=17/79; median [IQR] change from BL −9.5% [−20.4% to −0.1%]; p<0.02) compared with stable levels in the reference arm. While IgG OCBs were detected at BL in all patients, IgG OCBs tended to decrease with OCR treatment, with three of 17 patients having no detectable IgG OCBs at 52 weeks. Reductions in IgM index were not observed with OCR treatment.

Conclusions

Baseline CSF levels of B cells, T cells and CXCL13 correlated with IgG index and to a lesser degree IgM index in patients with RMS from the OBOE study. Significant reductions were observed in IgG index with OCR treatment, along with a trend toward reduced OCBs, with three patients showing no detectable OCBs. These data suggest that OCR impacts CSF Ig production, a hallmark of MS not previously thought to be affected by B-cell depletion therapy. These 1-year observations need to be confirmed with longer-term data and correlated with clinical response.

Background

Hallmarks of secondary progressive multiple sclerosis (SPMS) are amongst others progressive motoric dysfunction and cognitive decline. Siponimod (Mayzent®), a selective sphingosine-1-phosphate receptor modulator, has been approved by the EMA for the treatment of active SPMS, evidenced by relapses or imaging features of inflammatory activity. AMASIA (ImpAct of Mayzent® (Siponimod) on secondAry progressive multiple Sclerosis patients in a long-term non-Iinterventional study in GermAny) is the first prospective non-interventional study to assess long-term effectiveness and safety of siponimod in clinical routine and the impact on quality of life and socioeconomic conditions.

Objectives

Characterization of the siponimod patient profile and SPMS diagnostic criteria based on clinical routine in Germany.

Methods

In AMASIA treatment effects of siponimod will be analyzed in 1,500 SPMS patients over 3 years. Disability progression and cognitive changes are evaluated every 6 months by the expanded disability status scale (EDSS) and the symbol digit modalities test (SDMT). Additional measures including MS activity by magnetic resonance imaging (MRI), assessments of functional domains, and questionnaires from patient’s, physician’s, and relatives’ perspectives of disability progression, cognitive worsening, and quality of life as well as socioeconomic aspects are analyzed.

Results

Results of the first interim analysis will be presented and will show patient characteristics of the first approx. 200 patients in Germany treated with siponimod in clinical routine. These data will include demography, but also all relevant clinical information including disease and therapy history, allowing for a comparison with data from phase II and III clinical studies with siponimod.

Conclusions

The combination of clinical parameters and patient reported outcomes including quality of life and socioeconomics allows a more detailed insight in the siponimod treated SPMS patient population in clinical routine in Germany. This will contribute to a better understanding of SPMS management in the medical community.