1. amsrp 2019 krieger 9-30.ppt · s.l. hauser [336]. presented at ectrims 2019. stockholm, se....

MS

Update from European Congress: Impact of Emerging Data & Paradigm Shifts

on Therapeutic Landscape

Stephen C. Krieger, MD Associate Professor of Neurology

Icahn School of Medicine Corinne Goldsmith Dickinson Center for MS

Mount Sinai Medical CenterNew York, NY

Krieger - Emerging Data Updates

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Disclosures

• Consultant – Biogen, EMD Serono, Genentech, Genzyme, Mallinckrodt, MedDay, Novartis,

Teva, and TG Therapeutics

• Non-promotional lectures: Biogen, EMD Serono, and Novartis

• Will be discussing off-label products, emerging therapies or strategies

Learning Objectives

• Review advances in MS recently presented data at ECTRIMS 2019

• Discuss emerging concepts being introduced into clinical practice

• Describe seminal studies with potential impact on clinical management of MS

• Identify areas of research focus that may impact clinical practice in coming years


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Sorting Through the Studies/Data

Scientific Sessions

Educational Sessions

Hot Topics Young InvestigatorsPosters/

AbstractsTOTAL

100 70 30 15 1669 1714

ECTRIMS 2019 Scientific Programme Online. Available at:http://www.professionalabstracts.com/ectrims2019/iplanner/#/grid/1568160000

Overview

• Clinical trials– Late breaking

– Updates from registration studies

• Long-term safety and determinants of response

• Molecular biomarkers and predictive tools

• Emerging research and future treatment (i.e., Big Data and Deep Learning, Stem cell, Epigenetics)


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Clinical Study Updates• ASCLEPIOS• OPTIMUM• EXPAND • ORATORIO• Natalizumab Extended Interval Dosing

Efficacy and Safety of Ofatumumab Versus Teriflunomide In Relapsing Multiple Sclerosis: Results of the Phase 3 ASCLEPIOS I and II Trials

• Background: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is under development with amonthly 20 mg subcutaneous (sc) dosing regimen for the treatment of RMS.

• Objective: To investigate the efficacy and safety of ofatumumab versus teriflunomide in RMS patients.

• Method: ASCLEPIOS I and II are double-blind, double-dummy, active comparator-controlled, parallel-group,innovative, adaptive design, multicenter trials.

• Patients were randomized (1:1) to receive either ofatumumab 20 mg sc injections every 4 weeks (after an initialloading regimen of 20 mg sc doses on Days 1, 7 and 14) or teriflunomide 14 mg orally once daily, for up to 30months. The studies have flexible durations, with termination occurring in the blinded core treatment epoch accordingto pre-specified criteria.

• Patients aged 18-55 years with an EDSS score of 0-5.5 at screening who experienced ≥1 relapse in the past year or≥2 relapses in the past 2 years or a Gd+ MRI scan during the year before randomization were included.

• The primary endpoint is the annualized relapse rate (ARR). Key secondary endpoints include 3- and 6-monthconfirmed disability worsening (CDW), 6-month confirmed disability improvement (CDI), MRI-related outcomes andserum neurofilament light chain levels; safety and tolerability are also being assessed.

S.L. Hauser [336]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session 17“Late Breaking News”


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Efficacy and Safety of Ofatumumab Versus Teriflunomide in Relapsing Multiple Sclerosis

Efficacy and Safety of Ponesimod Compared to Teriflunomide in Patients With Relapsing Multiple Sclerosis: Results of the Randomized, Active-controlled, Double-blind, Parallel-group Phase 3 OPTIMUM Study

• Objective: The OPTIMUM phase 3 study (NCT02425644) evaluates efficacy and safety of oral ponesimod vs. teriflunomide in adult patients with RMS– Primary endpoint: annualized relapse rate over 108 weeks– Secondary endpoints: fatigue-related symptoms assessed with Fatigue Symptom and Impact Questionnaire-

Relapsing Multiple Sclerosis (FSIQ-RMS), cumulative unique active lesions (CUALs) on MRI to Week 108, and time to 12- and 24-week disability accumulation to end-of-study. Safety and tolerability are assessed.

• Methods: Multicenter, randomized, double-blind, parallel-group, active-controlled superiority study enrolled patients with established diagnosis of MS, as per 2010 McDonald criteria, with a relapsing course from onset and EDSS score of 0-5.5 inclusive and recent clinical or MRI disease activity.

• Patients were randomized (1:1) to receive either ponesimod 20 mg or teriflunomide 14 mg once-daily and the respective placebo for 108 weeks.

• The 14-day gradual up-titration regimen starting with 2 mg once-daily was implemented to mitigate potential effects on heart rate associated with S1P-receptor modulators.

L.Kappos [93]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session 3 “DMT inRRMS”.


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Efficacy and Safety of Ponesimod Compared to Teriflunomide in Patients With Relapsing Multiple Sclerosis: Results of the Randomized, Active-controlled, Double-blind, Parallel-group Phase 3 OPTIMUM Study (Results I)

• Results: In total, 1133 patients were randomized at 162 sites in 28 countries. Randomization was stratified by prior-disease modifying treatment in last 2years (yes: 39.4%; no: 60.6%) and EDSS score at baseline (≤3.5: 83.4%; >3.5 16.6%).

• The mean age was 36.7 years and the majority (65%) were female. Most patients were recruited in Europe with 51% from EU countries.

• Mean baseline EDSS score was 2.6 and mean disease duration 7.6 years. Mean pre-study 12-month relapse rate was 1.3, and 483 (42.7%) patients had ≥1 gadolinium-enhancing T1 lesions on baseline MRI.

L.Kappos [93]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session 3 “DMT inRRMS”.

Efficacy and Safety of Ponesimod Compared to Teriflunomide in Patients With Relapsing Multiple Sclerosis: Results of the Randomized, Active-controlled, Double-blind, Parallel-group Phase 3 OPTIMUM Study (Results II)

• Primary endpoint: Ponesimod significantly reduced annualized relapse rate (ARR) compared to teriflunomide by 30.5% (ARR = 0.202 for ponesimod 20 mg vs. 0.290 for teriflunomide 14 mg, p=0.0003).

• Secondary endpoints– Ponesimod had a significant effect on fatigue symptoms compared to teriflunomide (mean difference: -3.57, p=0.0019) as

measured by the Fatigue Symptoms and Impacts Questionnaire - Relapsing Multiple Sclerosis (FSIQ-RMS) – A 56% reduction (p<0.0001) in the number of combined unique active lesions (CUALs) was observed with ponesimod

compared to teriflunomide. – The 12-week confirmed disability accumulation (CDA) was observed in 10.1% and 12.4% of patients in the ponesimod and

teriflunomide arms, respectively; however, the result was not statistically significant.

• Safety: The safety profile observed for ponesimod in the OPTIMUM study was consistent with previous studies of ponesimod and the known safety profile for other S1P receptor modulators. The most commonly observed adverse events included nasopharyngitis, headache, upper respiratory tract infections and an increase in alanine amino transferase.

• Conclusion: The results of this first large randomized controlled phase 3 study comparing two oral disease-modifying treatments across important clinical and MRI outcomes will help to determine the role of ponesimod, a selective S1P1 functional antagonist, as a potential treatment option in relapsing MS.

L.Kappos [93]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session 3 “DMT inRRMS”. Press Release: https://markets.businessinsider.com/news/stocks/new-head-to-head-phase-3-study-data-show-ponesimod-superiority-versus-aubagio-teriflunomide-14-mg-in-

adults-with-relapsing-multiple-sclerosis-ms-1028516683


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Siponimod Delays the Time to Wheelchair in Patients With SPMS: Results From the EXPAND Study

• Background: SPMS is associated with insidious worsening of walking disability, which eventually results in increased dependence on a wheelchair. Siponimod was recently shown to be efficacious in slowing down disability progression and cognitive decline in a typical SPMS population (EXPAND study). Here, we report the effect of siponimod in delaying time to wheelchair dependence.

• Objective: To evaluate the effect of siponimod compared to placebo in delaying disability progression to Expanded Disability Status Scale (EDSS) ≥7 (i.e. needing a wheelchair), sustained until the end of the EXPAND study, in patients with SPMS.

• Methods: In the EXPAND study, time to reach EDSS ≥7 was assessed post hoc using 2 different models: a survival analysis and a multistate model. – The survival analysis was performed on the subset of patients with a baseline EDSS score of 6.5 who were at

high risk of reaching wheelchair during EXPAND study (siponimod, N=293; placebo, N=119). – The multistate model was performed on the overall EXPAND population (siponimod, N=1099; placebo, N=546);

three disease states were defined based on EDSS values of ≤5, 5.5-6, and 6.5. The transitions from one state to the next and the sojourn times in each state were calculated. The model also predicted time to EDSS ≥7 from any disease state by using all transitions through all intermediate states. Assuming that treatment effect is preserved, results were extrapolated from estimated parameters to calculate median time to progression to EDSS ≥7 for the overall population.

P. Vermersch [158]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session 5“DMT in progressive MS.”

Siponimod Delays the Time to Wheelchair in Patients With SPMS: Results From the EXPAND Study (Results)

Vermersch [158]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session 5“DMT in progressive MS.”


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Siponimod Delays the Time to Wheelchair in Patients With SPMS

Vermersch [158]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session 5“DMT in progressive MS.”

Sustained Reduction in Confirmed Disability Progression in Patients With Primary Progressive MS Treated With Ocrelizumab : Open-label Extension Period of Phase III ORATORIO Trial (6.5-Study Year Follow-up Data)

• Background: The efficacy and safety of OCR in PPMS were demonstrated vs PBO in the Phase III ORATORIO study (NCT01194570)

• Objective: To assess the effect of switching to or earlier initiation of OCR therapy on confirmed disability progression for at least 24 weeks, in the open-label extension of ORATORIO

• Methods: In the ORATORIO double-blind period, patients (N=732) were randomized (2:1) to OCR or PBO and followed for ≥120 weeks until a prespecified number of CDP events occurred. At the end of the double-blind period, patients remained on blinded treatment until the trial outcome was ascertained (extended controlled period). At the start of the OLE, patients continued (OCR-OCR) or switched from PBO to OCR (PBO-OCR). By Week 240 the last patient had entered the OLE.

– Time to onset of 12- and 24-week-CDP (increase from baseline [CDP-EDSS score of ≥1 point if baseline EDSS ≤5.5 or ≥0.5 points if baseline EDSS >5.5)

– Time to 24-week CDP on the 9-Hole Peg Test (CDP-9HPT; ≥20% increase from baseline in the timed 9HPT) were analyzed up to Week 312 (all patients had ~3 study years of OLE follow-up).

• Results: 72% of patients entered the OLE

J.S. Wolinsky [159]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session 5“DMT in progressive MS.”

CDP = confirmed disability progression; EDSS = expanded disability status scale; OCR = ocrelizumab; OLE = open-label extension; PBO = placebo; PPMS = primary progressive multiple sclerosis.

24-week CDP 24-week CDP-9HPT

Double-Blind Period, OCR Reduced Risk: 25% (p=0.037) 45% (p<0.001)


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Sustained Reduction in Confirmed Disability Progression in Patients With Primary Progressive MS Treated With Ocrelizumab : Open-label Extension Period of Phase III ORATORIO Trial (6.5-Study Year Follow-up Data) - Results

• The safety profile observed in the OLE was generally consistent with that seen during the DBP.• Conclusions: After 6.5 study years (312 weeks) of follow-up, the proportion of patients with CDP-EDSS and CDP-9HPT was lower

in patients who initiated OCR treatment earlier compared with patients initially receiving PBO; patients initiating OCR 3-5 study years (144-240 weeks) earlier accrued less disability progression compared with patients switching from PBO.

Time 24-week CDP–EDSS (%) 24-week CDP-9HPT (%)

Week PBO-OCR OCR-OCR Δ (p-value) PBO-OCR OCR-OCR Δ (p-value)

168* 44.7 33.3 11.4 (p=0.005) 29.7 17.9 11.8 (p=0.001)

192 49.3 37.8 11.5 (p=0.006) 32.5 21.6 10.9 (p=0.005)

264 58.7 48.0 10.7 (p=0.011) 39.4 26.9 12.5 (p=0.003)

312 64.8 51.7 13.1 (p=0.002) 43.1 30.6 12.5 (=0.004)

J.S. Wolinsky [159]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session 5 “DMT in progressive MS.”

*(12 weeks after the first patients entered the OLE)

Radiographic Disease Activity in Patients on Natalizumab Extended Interval Dosing

• Background: Natalizumab (NTZ) is a highly efficacious therapy for relapsing forms of multiple sclerosis (MS), but is associated with risk of progressive multifocal leukoencephalopathy (PML). A previous study demonstrated that extending NTZ dosing to every 35-43 days (EID) was associated with lower PML risk than the standard (every 28 days) dosing (SID). This finding raises the important question of whether NTZ should be administered as EID.

• Methods: MS patients receiving NTZ prior to May 31, 2018 at NYU (New York, NY) or Rocky Mountain (Salt Lake City, UT) MS centers were retrospectively identified. EID cohorts were defined similarly to definitions used for the previous PML risk study.

• For definition 1 (DEF 1), the last 18 months of treatment was considered (≤15 infusions in the last 18 months) while definition 3 (DEF 3) considered the entire infusion history (mean of ≤10 infusions/year).

• Eligible patients were required to have ≥24 months of treatment; ≥1 MRI available for review; no gaps > 3 months on treatment; no infusions ≤ 21 days apart; and had no PML.

• Disease activity was identified by review of MRI radiology reports evaluating for presence of gadolinium (Gd) and new T2 lesions. Generalized Estimating Equation (GEE) logistic models and SAS 3.4 were used in the data analyses.

L. Zhovtis Ryerson [Poster Session 3. P1621]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019.


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Radiographic Disease Activity in Patients on Natalizumab Extended Interval Dosing (Results)

• Results: 690 patients met the criteria

• For DEF 1, no difference was observed between EID and SID in the odds of presence of Gd lesions (n=500) (OR/month increase 1.1; 95% CI 0.93, 1.31; p=0.27) or new T2 lesions (n=450) (OR/month increase 1.11; 95%CI 0.99, 1.24; p=0.07)

• Similarly, for DEF 3 no difference was observed between EID and SID in the odds of presence of Gd lesions (n =401) (OR/month increase1.00; 95%CI0.983, 1.025; p=0.75)

• There is a small increase in the odds of presence of new T2 lesions in EID group (n =437) (OR/month increase1.05; 95% CI 1.01, 1.10; p=0.02)

• GEE models included adjustments for the frequencies of MRIs for Gd lesions

• Conclusions: The study helps address a currently unmet need for evaluating EID NTZ efficacy

• These findings suggest that EID of NTZ does not result in significant increased radiological MS disease activity compared to SID, providing further evidence that NTZ efficacy is comparable with EID

L. Zhovtis Ryerson [Poster Session 3. P1621]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019.

No Significant Difference in Relapse Outcomes in Patients Switching to Natalizumab Extended Interval Dosing or Remaining on Standard Interval Dosing: Propensity Score Comparative Effectiveness Analysis of Patients in the TYSABRI Observational Program

• Introduction: The approved dosing of natalizumab (300-mg infusion every 4 weeks [standard interval dosing, SID]) is associated with risk of progressive multifocal leukoencephalopathy (PML). A retrospective safety analysis has shown that PML risk is reduced with extended interval dosing (EID) compared with SID. The data collected by the real-world, long-term TYSABRI Observational Program (TOP) include exact infusion dates (since 2014), physician-intended dosing frequency, and dates of deliberate dosing frequency changes, and are well-suited to assess relative efficacy of EID vs SID.

• Objectives: To compare relapse outcomes in TOP patients who switched to natalizumab every-6 weeks EID after 1 year of SID with patients who remained on SID

• Methods: Eligible TOP patients had ≥1 year of natalizumab SID. Patients with dosing intervals ≥12 weeks or ≤3 weeks were excluded. EID patients had a single physician-intended change in dosing frequency from SID to EID; SID patients received all dosing as SID.

• Treatment duration-matched EID and SID patients (199 pairs) were compared by propensity score matching (PSM) with age, sex, Expanded Disability Status Scale score, time from MS onset, natalizumab exposure duration, and relapse activity (both pre-natalizumab and on SID before switching) as covariates.

• Negative binomial model-estimated annualized relapse rate (ARR) and Kaplan-Meier-estimated risk of relapse were compared for PSM-matched EID patients during the post-switch follow-up period and SID patients during the exposure-matched follow-up period.

H. Butzkueven [Poster Session 2. P1033]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019.


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No Significant Difference in Relapse Outcomes in Patients Switching to Natalizumab Extended Interval Dosing or Remaining on Standard Interval Dosing: Propensity Score Comparative Effectiveness Analysis of Patients in the TYSABRI Observational Program (Results)

• Results: After PSM, 135 pairs of EID and SID patients were included. Demographic and disease characteristics were well balanced between groups (standard differences ≤0.033). Mean treatment duration was 4.4 years in both groups.

• There was no difference in ARR (EID: 0.231 [95% confidence interval (CI), 0.145-0.367]; SID: 0.254 [0.160-0.402]; P=0.774) or risk of relapse (hazard ratio [95% CI], 1.021 [0.583-1.789]; P=0.940) between patient groups.

• Conclusions: This PSM analysis of real-world TOP data demonstrates no significant difference in relapse outcomes between patients who switched to natalizumab EID after ≥1 year on SID and patients who remained on SID.

• These results are consistent with prior unmatched analyses that concluded that efficacy is maintained after switching to EID. Anongoing randomized prospective trial of EID vs SID will provide a more complete understanding of the effectiveness of natalizumab EID.

H. Butzkueven [Poster Session 2. P1033]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019.

EID = extended interval dosing; SID = standard interval dosing; TOP = TYSABRI Observational Program.

Long-term Outcomes: Safety

• Serum Immunoglobulin Levels And Risk Of Serious Infections In The Pivotal Phase III Trials Of Ocrelizumab In Multiple Sclerosis And Their Open-label Extensions


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Serum Immunoglobulin Levels and Risk of Serious Infections in the Pivotal Phase III Trials of Ocrelizumab in Multiple Sclerosis and Their Open-label Extensions

• Background: Exposure-dependent decreased serum levels of immunoglobulin (Ig)G, IgM and/or IgA can occur in patients treated with B-cell-depleting therapies. An increased risk of serious infections (SIs) has been observed, mainly with reduced serum IgG levels.

• Objectives: To assess serum Ig levels over 5.5 years and evaluate a potential association between a decrease in IgG, IgM or IgA levels and SIs, in the Phase III OPERA I/OPERA II (NCT01247324; NCT01412333) and ORATORIO (NCT01194570) trials/open-label extensions of ocrelizumab (OCR) in MS

• Methods: Serum IgG, IgM and IgA levels were measured at least every 24 weeks. Lower limit of normal (LLN) for IgG, IgA and IgM was defined as 5.65g/L, 0.70g/L and 0.40g/L, respectively. SI rates during episodes of < LLN were compared with SI rates during episodes of ≥ LLN. Episodes of < LLN were defined as from the day the laboratory value reached < LLN, until normalization. Analyses are presented using a July 2018 data-cut.

T. Derfus [65]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session 2 “Safety assessment in post-approval phase”.

Serum Immunoglobulin Levels and Risk of Serious Infections in the Pivotal Phase III Trials of Ocrelizumab in Multiple Sclerosis and Their Open-label Extensions (Results)

Over 5.5 years of OCR treatment, a reduction in serum Ig levels was observed, with an apparent association with increased rates of SIs. The association was strongest for IgG and less so for IgM or IgA.

T. Derfus [65]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session 2 “Safety assessment in post-approval phase”.

Over 5.5 years of OCR treatment, the relative reduction (%) in serum levels were

AEs / 100 PY%

Proportion of Pts <LLN at Week 264 (%)

IgG: 5.7% IgA: 5.4% IgM: 29.2%


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Long-term Outcomes: Determinants of Response

• Radiologically Isolated Syndrome: A 10-year Follow-up Study To Identify Factors Predicting A Clinical Event

• Long Term Outcomes. Changes In MS Prognosis Through The CIS Barcelona Cohort: A 25-year Tale• Detection Of Subtle Gait Disturbance And Future Fall Risk In Early Multiple Sclerosis

Radiologically Isolated Syndrome: A 10-year Follow-up Study to Identify Factors Predicting A Clinical Event

• Objectives: To investigate risk factors for the development of a seminal clinical event in RIS using a 10-year, multi-national, retrospectively-identified subject dataset.

• Background: Our original observation published in 2014 identified male sex, age ≤37, and presence of spinal cord lesion involvement as factors increasing the 5-year risk of evolution from RIS to MS.

• Methods: Retrospectively identified RIS subjects according to the RISConsortium criteria (Okuda, 2009) from a worldwide cohort included 22 databases from 5 countries. Subjects were prospectively followed up and underwent serial clinical and MRI studies. Sex, age, presence of at least one spinal cord lesion, presence of gadolinium enhanced (Gd+) lesions, dissemination in time on follow up MRI, positive CSF, on the risk of the first clinical event were analyzed. Time to first clinical event was compared across different groups by univariate and multivariate analyses using Cox regression models.

• Results: Data were available in 451 RIS subjects (F: 358 (78.2%)). Mean age from RIS diagnosis was 37.1 years (y) (median: 37.0 y, range: 11-74 y) with mean clinical follow-up time of 5.9 y (median: 4.6 y, range: 0.01-22 y). Twelve subjects were under 18 years.

C. LeBrun-Frenay [97]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session 4.“What determines the long-term outcome of MS?”


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Radiologically Isolated Syndrome: A 10-year Follow-up Study to Identify Factors Predicting A Clinical Event – 10-year Risk of Clinical Conversion


Radiologically Isolated Syndrome: A 10-year Follow-up Study to Identify Factors Predicting A Clinical Event - Risk Factors



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Radiologically Isolated Syndrome: A 10-year Follow-up Study to Identify Factors Predicting A Clinical Event – Risk Stratification


Long Term Outcomes. Changes in MS Prognosis Through the CIS Barcelona Cohort: A 25-year Tale

• Background: The natural history of MS may have changed in the era of MS treatments• Objectives: To assess how changes in diagnostic criteria and time to DMT initiation have modified MS course over the

last 25 years• Methods: From 1994 to 2017, 1160 patients with CIS were prospectively included in the CIS Barcelona cohort• Different epochs, according to the different sets of diagnostic criteria used in each period, were established:

– 1994-2000– 2001-2005– 2006-2009– 2010-2016– 2017

• Newer diagnostic criteria were applied to non-diagnosed patients from previous epochs. In these cases, the year of the new criteria publication was considered the time of diagnosis.

• We evaluated the time elapsed from the CIS to diagnosis and from CIS to DMT across the different periods. These times were confirmed in a sensitivity analysis considering the first 3 years after a CIS. The impact of the Will Rogers phenomenon was measured. We studied Kaplan-Meier estimates and proportional Hazards (PH) Cox models to estimate the age of reaching confirmed EDSS 3.0 and 6.0 in the different periods under the delayed entry frame. PH models were adjusted for demographics, topography, baseline T2 lesions, oligoclonal bands and DMT before second attack.

M. Tintoré [98]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session 4 “Whatdetermines long-term outcome of MS?”


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Long Term Outcomes. Changes in MS Prognosis Through the CIS Barcelona Cohort: A 25-year Tale - Results

• Results: 1139 patients followed for a mean of 8.6 years. Patients with CIS:

• The Will Rogers phenomenon showed that patients diagnosed with McDonald 2017 had a protective hazard ratio (HR) (95% confidence interval) of reaching EDSS 3.0 of HR = 0.66 (0.46-0.99) compared to patients diagnosed using Poser.

• Analyzing age at EDSS 3.0 and considering patients diagnosed in 1994-2000 as the reference:

• Conclusions: The time from CIS to MS diagnosis and to first treatment has been profoundly shortened. MS prognosis has deeply changed due to the Will Rogers phenomenon (false improvement) and early treatment initiation.

M. Tintoré [98]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session 4 “Whatdetermines long-term outcome of MS?”

1994-2000 2010-2016 P-value

Mean time to diagnosis (yrs) 2.9 0.9 (p< 0.0001)

Mean time to DMT initiation (yrs) 4.8 0.79 (p< 0.0001)

Year of Diagnosis 2001-2005 2006-2010 2010-2016

Adjusted hazard ratio (aHR) 0.60 (0.38-0.93) 0.31 (0.16-0.59) 0.32 (0.15-0.69)

Detection of Subtle Gait Disturbance and Future Fall Risk in Early Multiple Sclerosis

• Background: Patients with early MS often report gait and balance dysfunction that is often not captured by traditional objective metrics, i.e., EDSS, Timed 25 Foot Walk (T25FW). Falls and fall-related injuries are recognized as critical health concerns in persons with MS, but little is known about risk for falls very early in the disease course.

• Objective: To investigate the sensitivity of traditional versus higher challenge tasks of gait and balance for detection of subtle patient-reported gait dysfunction and future fall risk in early MS.

• Methods: Persons with early MS (RADIEMS cohort: n=185; ≤5.0 yrs diagnosed [median=2.0]; 165 RRMS, 20 CIS) reported gait dysfunction (MS Walking Scale, MSWS) and underwent traditional disability metrics (EDSS, T25FW).

• Patients and matched healthy controls (n=50) completed clinically-feasible challenge tasks of gait endurance (Two-Minute-Walk, 2MWT), standing balance (NIH Toolbox), and dynamic balance (Balance Boards; tandem walk on two 3-meter boards of different widths, 11.4cm, 3.8cm).

• MRIs assessed global and regional brain volumes, total T2 lesion volume (T2LV), infratentorial T2LVs and counts, and c-spine lesion counts. Falls, near-falls and fall-related injuries were assessed after one year in all patients. We examined links between all performance tasks and patient-reported gait, MRI markers, and risk for future falls.

R. Brandstadter [177]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session“RIMS 1: How can rehabilitation influence the progression of MS?”


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Detection of Subtle Gait Disturbance and Future Fall Risk in Early Multiple Sclerosis (Results)

• Results: Patients had low disability on the EDSS (median=1.0) and T25FW was normal (4.1±0.6 seconds)• However, 31.5% of patients reported at least mild gait disturbance (MSWS)• Patients performed worse on higher challenge balance tasks, but not gait tasks, compared with healthy controls.• Only dynamic balance reliably discriminated between patients reporting no vs mild gait difficulty. • Balance tasks were more correlated with all MRI metrics than were walking tasks (T25FW, 2MWT) and EDSS. • Thirty percent of patients reported either a fall or near-fall after one year, and 8 patients reported moderate to severe

fall-related injuries, including long bone fractures. Poor dynamic balance was the only performance task independently predicting falls.

• Conclusions: Balance plays a leading role in gait dysfunction early in early MS. • Clinically-feasible higher-challenge balance tasks were most sensitive to patient-reported gait, MRI disease markers,

and risk of future falls (vs gait tasks, which were much less sensitive)

R. Brandstadter [177]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session“RIMS 1: How can rehabilitation influence the progression of MS?”

Biomarkers: The NfL Story Continues


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Serum Neurofilament Light Chain is Associated with MS Outcomes and Comorbidity in a Large Population of People With Multiple Sclerosis

• Introduction: Serum neurofilament light chain (sNfL) is a promising biomarker for measuring disease activity and severity in multiple sclerosis (MS). Evaluation of sNfL in large, heterogeneous MS populations with more diverse demographics and comorbid conditions is sparse.

• Objectives: To assess the association between sNfL and MS demographic and disease characteristics as well as the impact of comorbidities on sNfL levels in a large heterogeneous cohort of MS patients.

• Methods: The MS Partners Advancing Technology and Health Solutions (MS PATHS) program is a network of MS Centers in the US (7) and Europe (3).

• Standardized collection of clinical information and biosamples are acquired during routine clinic visits. sNfL levels were measured in serum samples from 1969 MS PATHS MS patients, and in 130 local healthy controls (HC) via Single Molecule Array (SIMOA, NF-light® Advantage, Quanterix).

• Age-specific cut-points of sNfL levels were derived from HC data; patients with sNfL levels ≥ or < the age-specific 97.5th percentile in HCs were classified as having elevated sNfL (sNfL-E) or normal sNfL (sNfL-N), respectively.

• MS patients with sNfL-E vs. sNfL-N were compared with respect to walking speed, manual dexterity, and processing speed using linear models (GLMs) adjusting for age, sex, disease subtype/duration and MS therapy

• We assessed whether sNfL differed by race or by comorbidity status using multivariable GLMs that also adjusted for disability.

K. Fitzgerald [23]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Young Investigators Session 1 “Biomarkers”.

Serum Neurofilament Light Chain is Associated with MS Outcomes and Comorbidity in a Large Population of People With Multiple Sclerosis (Results)

• Results: Of the 1969 MS patients (74% female; mean age 48y [SD: 12.0y]; 18% non-white), 483 (25%) participants were classified as sNfL-E. – Relative to sNfL-N, MS patients with sNfL-E had slower walking and manual dexterity speeds (mean %

difference [95% CI]: • walking speed: 10% slower [6%, 14%]; p< 0.001• manual dexterity: 7% slower [5%, 10%]; p< 0.001) • lower processing speed scores (mean difference -3.78 [-4.84, -2.70]; p< 0.001).

– Diabetics were more likely to have sNfL-E (OR: 2.24; 95%CI: 1.41, 3.58; p=0.0007). – The cross-sectional association between obesity and sNfL was complex and may vary by disability. sNfL levels

did not differ by race or in patients with hyperlipidemia, hypertension or renal insufficiency (all p>0.05).• Conclusions: In this large, real-world cross-sectional study of people with MS, elevated sNfL was associated with

poorer neurologic function and with diabetes. Follow-up studies are needed to assess if comorbidities modify longitudinal associations between sNfL and MS outcomes.

K. Fitzgerald [23]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Young Investigators Session 1 “Biomarkers”.


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Big Data & Deep Learning

• Machine Learning In MRI Research In MS• To Design, Implement And Sustain Big Data

Collection In MS

To Design, Implement and Sustain Big Data Collection in MS

• There are only a few large, multicenter, prospective, structured observational cohort studies recording outcomes in Multiple Sclerosis (MS) in the world.

• Most of these are nationally based cohort studies, notably in Sweden, Denmark, Italy, France, the Czech Republic and several German registries, including the NTD network, the German MS Society Registry and the MSDS3D collaboration. Some are essentially population-based registries, e.g., the Swedish, Danish and Czech Registries.

• The multinational MSBase Registry comprises around 130 largely academic specialist centers from over 30 countries sharing a minimum dataset. Resources to maintain and improve registries are scarce. All successful models require strong and independent governance.

• Collaboration with industry, which typically involves the conduct of commissioned data analyses rather than data sharing, is a necessity that drives investment in infrastructure and data quality. Increasingly professional and sophisticated analyses of “real-world” outcomes data have been conducted in the last decade. The registry-based statistical analysis teams are in close contact with each other and industry statisticians to constantly benchmark, improve and standardize techniques.

• There have been great analysis successes which sustain and increase the popularity and utility of the large MS registries. Head-to-head treatment comparison studies based on observational datasets are increasingly accepted. Registry-derived data has been used to support numerous administrative submissions for registration, reimbursement and label change purposes. We are now entering the era where registry-based serious adverse event analysis from large MS cohorts will become the standard method of post-approval safety studies (PASS) for new drugs in Europe. In order to conduct PASS and other mega-studies, several large registries are successfully combining their individual datasets in the BigMS Group. The future will see registriesplacing much greater effort on individual outcome prediction, including integration of patient self-monitoring tools and quantitative MRI outcomes such as brain volume and lesion number change

H. Butzkueven [167]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session 7“How to achieve a structured assessment and quality assurance in MS care.”


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Patient Monitoring by Wearable Devices Integrated in MS Care

• Capture patient function, symptoms in free-living (in between office visits)

• More sensitive measures of patient function

• Improved measures of disability

• Predictive ability– Predictor of attack

– Predictor of falls

T. Chitnis [166]. Presented at ECTRIMS 2019. Stockholm, SE. September 11-13, 2019. Scientific Session 7“How to achieve a structured assessment and quality assurance in MS care.”


• Abstract missing



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• Abstract missing


Biosensor monitoring challenges•Evaluation and optimization of appropriate devices•Advanced data extraction and analysis•Fit, aesthetics, and technology challenges•Consideration of privacy/security•Medical-legal considerations•Ethics approval•Cost

Concluding Thoughts: The State of MS Research

• Next-Gen versions of S1Ps, B cell depleters, fumarates, and others

• Early diagnosis and treatment is indeed changing the disease

• NfL is about to become part of practice with many unanswered questions about its use

• RIS studies and pre-clinical prodrome suggests need for earlier, more detailed assessment

• Measures of real-world function, PROs, and big data acquisition are a meaningful supplement to standard assessments and trials


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1. amsrp 2019 krieger 9-30.ppt · s.l. hauser [336]. presented at ectrims 2019. stockholm, se....

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