Background

Alemtuzumab is an anti-CD52 monoclonal antibody therapy approved for treating RRMS. Although alemtuzumab is associated with non–MS-related secondary autoimmune events, the role pre-existing non-MS autoimmunity plays in secondary autoimmunity is unclear.

Objectives

To assess the impact of 1) pre-existing non-MS autoimmunity and 2) post-alemtuzumab thyroid autoimmunity on subsequent onset of new autoimmunity up to 9 years after initiating alemtuzumab.

Methods

In clinical trials (NCT00050778, NCT00530348, NCT00548405, NCT00930553, NCT02255656), patients were monitored for autoimmune adverse events (AEs). All patient- and investigator-reported AEs were recorded. An autoimmune event was pre-existing if it occurred prior to initiating alemtuzumab or was in the medical history database.

Results

A total of 1216 patients from the alemtuzumab clinical development program who received alemtuzumab 12 mg were included in the analysis. Ninety-six had pre-existing non-MS autoimmunity. Up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) pre-existing autoimmunity; similar percentages of patients with versus without pre-existing autoimmunity had ≥2 new autoimmune events (5.2% vs 8.2%, respectively). Most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab. Treatment-emergent thyroid autoimmunity after alemtuzumab Course 1 was not associated with subsequent nonthyroid autoimmunity after Course 2 (0% of patients with vs 3.0% of patients without thyroid autoimmunity after Course 1). Similarly, thyroid autoimmunity after Course 2 did not predict nonthyroid autoimmunity after Course 3 (1.8% vs 2.0%, respectively). Among 25,292 patients treated with alemtuzumab in the postmarketing setting as of 31 March 2019, additional events (occurring 18–36 months post treatment) included autoimmune hepatitis (10.7 in 10,000) and hemophagocytic lymphohistiocytosis (2.7 in 10,000).

Conclusions

Over 9 years after alemtuzumab initiation, pre-existing non-MS autoimmunity was not associated with subsequent new autoimmune disease. Emergence of thyroid autoimmunity after Courses 1 and 2 does not appear to predict subsequent serious autoimmune disease.

STUDY SUPPORT: Sanofi and Bayer HealthCare Pharmaceuticals.

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which leads to the formation of focal confluent lesions of primary demyelination in the white and gray matter and to diffuse damage and neurodegeneration in the entire brain. MS is the leading cause of non-traumatic neurological disability in young adults. In the majority of patients multiple sclerosis starts with a relapsing remitting course

(RRMS), which may at later times transform into secondary progressive disease (SPMS).

In about 10% of patients the relapsing remitting disease is skipped and the patients

show progression from the onset, the so called primary progressive MS (PPMS). Despite these distinctions, all clinical forms of MS appear to reflect the same underlying disease process. And although inflammation is typically associated with relapses, and neurodegeneration with progression, it is now recognized that both pathologies are present in essentially all patients across the entire disease continuum.

Siponimod is a selective S1P modulator that is approved for relapsing forms of MS including

active SPMS. Ocrelizumab, cladribine, and ozanimod can also be used for patients with active SPMS. Ocrelizumab is the only approved disease-modifying therapy for the treatment of PPMS.

An increase number of trials and diversity of therapeutic approaches for progressive MS provides hope for future effective therapy.

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which leads to the formation of focal confluent lesions of primary demyelination in the white and gray matter and to diffuse damage and neurodegeneration in the entire brain. MS is the leading cause of non-traumatic neurological disability in young adults. In the majority of patients multiple sclerosis starts with a relapsing remitting course

(RRMS), which may at later times transform into secondary progressive disease (SPMS).

In about 10% of patients the relapsing remitting disease is skipped and the patients

show progression from the onset, the so called primary progressive MS (PPMS). Despite these distinctions, all clinical forms of MS appear to reflect the same underlying disease process. And although inflammation is typically associated with relapses, and neurodegeneration with progression, it is now recognized that both pathologies are present in essentially all patients across the entire disease continuum.

Siponimod is a selective S1P modulator that is approved for relapsing forms of MS including

active SPMS. Ocrelizumab, cladribine, and ozanimod can also be used for patients with active SPMS. Ocrelizumab is the only approved disease-modifying therapy for the treatment of PPMS.

An increase number of trials and diversity of therapeutic approaches for progressive MS provides hope for future effective therapy.

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which leads to the formation of focal confluent lesions of primary demyelination in the white and gray matter and to diffuse damage and neurodegeneration in the entire brain. MS is the leading cause of non-traumatic neurological disability in young adults. In the majority of patients multiple sclerosis starts with a relapsing remitting course

(RRMS), which may at later times transform into secondary progressive disease (SPMS).

In about 10% of patients the relapsing remitting disease is skipped and the patients

show progression from the onset, the so called primary progressive MS (PPMS). Despite these distinctions, all clinical forms of MS appear to reflect the same underlying disease process. And although inflammation is typically associated with relapses, and neurodegeneration with progression, it is now recognized that both pathologies are present in essentially all patients across the entire disease continuum.

Siponimod is a selective S1P modulator that is approved for relapsing forms of MS including

active SPMS. Ocrelizumab, cladribine, and ozanimod can also be used for patients with active SPMS. Ocrelizumab is the only approved disease-modifying therapy for the treatment of PPMS.

An increase number of trials and diversity of therapeutic approaches for progressive MS provides hope for future effective therapy.

Background

Several studies showed prognostic value of serum neurofilament light chain (sNfL) in relapsing multiple sclerosis (RMS). For the first time, we explored the association of sNfL and subclinical disease activity using data from the APLIOS trial.

Objectives

To evaluate the potential of sNfL as a patient-level biomarker for monitoring subclinical disease activity in RMS patients.

Methods

In the APLIOS open-label study of ofatumumab 20 mg s.c in RMS (n=284), frequent (14 time points over 12 weeks) sNfL measurements were performed (Siemens sNfL RUO assay on ADVIA Centaur®). MRI scans were done every 4 weeks. The potential monitoring value of sNfL was examined in 3 ways: 1) Age-adjusted geometric mean sNfL over time was estimated in 3 subgroups: patients who had on-study clinical relapses (r⁺), patients with presence of gadolinium-enhancing T1 (GdT1) lesions at or post-baseline but no clinical relapses (GdT1⁺r⁻) and patients with neither lesions nor clinical relapses (GdT1⁻r⁻); 2) As high-frequency sampling permitted an estimation of daily sNfL levels, every report of GdT1 lesion was linked to the estimated sNfL level at the time of the scan (using a recurrent-events analysis); and 3) Patient-level predictions of GdT1 lesion were done using the last sNfL value before the corresponding scan and compared with MRI-based predictions (in terms of across-scan average area under the receiver operating characteristics curve [AUC]).

Results

Over the study course, the age-adjusted geometric mean sNfL levels in the GdT1⁻r⁻group (n=153) were low compared to other two subgroups, with 95% CIs below those of the r⁺ (n=15) and GdT1⁺r^– (n=116) groups. After adjusting for baseline age and MRI covariates, a between-patient difference of 50% higher sNfL at the time of GdT1 scan was associated with a 29% higher risk of persistent GdT1 lesion (p<0.0001). At the individual patient level, the predictive power of the last sNfL value (AUC=0.76) before scan for presence of GdT1 lesion was similar to that of baseline GdT1-count (AUC=0.77).

Conclusions

This study suggests sNfL may have utility for monitoring of subclinical disease activity in RMS patients as shown by its predictive value of GdT1 lesion activity. Assessments of sNfL could complement regular MRIs, and may provide an alternative in cases where standard MRI monitoring is infeasible.

Background

Ofatumumab, a fully human anti-CD20 monoclonal antibody with a monthly 20 mg s.c. dosing regimen, demonstrated superior efficacy vs teriflunomide and a favorable safety profile in the Phase 3 ASCLEPIOS I/II relapsing multiple sclerosis (RMS) trials.

Objectives

To evaluate the benefit-risk profile of ofatumumab treatment in patients with early RMS in the Phase 3 ASCLEPIOS I/II trials.

Methods

Key efficacy and safety outcomes were assessed in the subgroup of 615 newly diagnosed (within 3 years before screening), treatment-naïve (no prior disease-modifying therapy [DMT] use) patients who received ofatumumab or teriflunomide as a first-line therapy in ASCLEPIOS I/II trials (32.7% of the total 1882 patients).

Results

Baseline characteristics of the newly diagnosed, treatment-naïve subgroup were typical of early MS patients (median age and MS duration since diagnosis (years) were 36 and 0.35, respectively). Compared to patients on teriflunomide, ofatumumab reduced ARR by 50.3% (0.09 vs 0.18; p<0.001), 3mCDW risk by 38% (10.1% vs 12.8%; p=0.065), 6mCDW risk by 46% (5.9% vs 10.4%; p=0.044), gadolinium-enhancing T1 lesions/scan by 95.4% (0.02 vs 0.39: p<0.001), and new/enlarging T2 lesions/year by 82.0% (0.86 vs 4.78, p<0.001). Treatment-emergent adverse events (AEs) occurred in 84.7% ofatumumab vs 86.0% teriflunomide-treated patients; serious AEs were reported in 7.0% and 5.3%, respectively. No cases of malignancies were reported in this newly diagnosed subgroup, randomized to either drug. Infection rates were comparable between ofatumumab (56.1%) and teriflunomide (56.5%); serious infections rates were 1.9% and 0.7%, respectively, and no opportunistic infections were reported. Systemic injection reactions were only imbalanced between ofatumumab and teriflunomide (with placebo injections) at the first injection given at the study site, and 99.8% of injection reactions were mild-to-moderate in this subgroup; after the 4^th injection, >70% RMS patients self-injected at home. Compliance of all patients with ofatumumab was high (98.8%).

Conclusions

Ofatumumab is the first high efficacy DMT that can be self-administered at home, as demonstrated in Phase 3 ASCLEPIOS I/II trials. Ofatumumab showed superior efficacy vs teriflunomide in newly diagnosed, treatment-naïve patients with low absolute relapse rates, very low MRI lesion activity and prolonged time to disability worsening, consistent with the overall study population.

Background

Ponesimod (PON) is a sphingosine-1-phosphate receptor 1 modulator. Activation of these receptors on cardiomyocytes during treatment initiation cause transient effects on heart rate (HR) and antrioventicular (AV) conduction. The OPTIMUM phase 3 study assessed efficacy, safety, and tolerability of PON and teriflunomide (TER) in relapsing multiple sclerosis.

Objectives

We report on the cardiac safety profile of ponesimod versus teriflunomide in the phase 3 OPTIMUM study (NCT02425644).

Methods

Patients (18-55 years) were randomized 1:1 to PON (20 mg) or TER (14 mg) for 108 weeks. For PON, a gradual 14-day up-titration starting with 2 mg was implemented to address 1^st-dose cardiac effects. Cardiac safety was assessed by blood pressure (BP) and 12-lead ECG measurements. Cardiac treatment-emergent adverse events (TEAEs), major adverse cardiovascular (CV) events (MACE; defined as CV death, non-fatal myocardial infarction [MI], and non-fatal stroke), and TEAEs of special interest (AESIs) are reported.

Results

Of 1131 patients who received treatment (PON: n=565, TER: n=566), baseline mean HR was 70.6 bpm (PON), 70.3 bpm (TER), range 45-126 bmp. Cardiac TEAEs leading to treatment discontinuation occurred in 1 (0.2%) patient on PON (cardiomyopathy) and 2 (0.4%) patients on TER (1 atrial fibrillation, 1 coronary artery insufficiency). No MACE were reported on PON; 3 MACE occurred on TER. HR and rhythm AESIs were reported in 29 (5.1%) PON patients vs. 24 (4.2%) TER patients. Incidence of HR and rhythm AESIs on Day 1 in the PON group (2 mg) was 2.1%, and included bradycardia (HR<50bpm) in 0.7% and 1^st degree AV block in 0.5%; vs. 0.4% in TER. Max mean reduction in HR from pre- to post-dose on Day 1 was observed at 2h post-dose for PON at -8.7bpm compared with -1.7bpm for TER. On Day 1, 3 patients on PON had post-dose asymptomatic HR≤40bpm, all had pre-treatment HR<55bpm. On Day 1, new ECG findings of sinus bradycardia was 20.0% in patients at risk for symptomatic bradyarrhythmia, compared to 3.0% (all asymptomatic) in patients who were not at-risk. The up-titration was not associated with clinically significant bradyarrhythmia events; none were serious or leading to discontinuation of treatment, no 2^nd degree or higher AV blocks were reported.

Conclusions

In the 2-year OPTIMUM study, PON treatment was not associated with an increased risk for major CV events such as MI, stroke, or CV death compared to TER. The up-titration regimen successfully mitigates 1^st-dose effects and supports removing the requirement for 1^st-dose cardiac monitoring in patients without risk factors of symptomatic bradycardia.

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

The MAGNIFY-MS study (NCT03364036) aims to determine the onset of action of cladribine tablets 3.5 mg/kg over 2 years (CT3.5) in patients with relapsing multiple sclerosis (RMS). Efficacy data from the pivotal trial CLARITY showed that outcomes in CT3.5-treated patients were superior to placebo with regard to number and relative reduction of standardized combined unique active (CUA) lesions over the 96-week trial. Carrying out early and frequent magnetic resonance imaging (MRI) will provide valuable insights into the onset of action of CT3.5.

Objectives

To report on the onset of action of CT3.5 by observing changes in counts of CUA MRI lesions during the first 6 months of the MAGNIFY-MS study.

Methods

MRI scans were performed at screening, baseline, and at months 1, 2, 3 and 6 following CT3.5 treatment on patients with highly active RMS. Differences in CUA lesions between post-baseline periods (period 1, months 1–6, period 2, months 2–6, and period 3, months 3–6) were compared to the baseline period. CUA lesion count was standardized to period length and number of MRIs in a period. A mixed effects linear model was used to account for within pooled centre correlation and adjusted for CUA lesion count during the baseline period, age, and baseline expanded disability status scale (EDSS; >3, ≤3). Type-I-error inflation due to multiple testing was controlled by a gatekeeping procedure.

Results

The full analysis set considered for primary analysis included 270 patients. Reductions in mean CUA count were observed from month 1 onwards compared to baseline; by -1.193 in period 1, -1.500 in period 2 and -1.692 in period 3 (all p<0.0001). In particular, the mean T1 Gd+ lesion counts were decreased from month 2 onwards compared to baseline; by -0.857 at month 2, -1.355 at month 3 and -1.449 at month 6 (all p<0.0001). Sensitivity analysis using negative binomial distribution showed that the treatment effect increased with time measured as lack of CUA in subsequent periods; by 61% in period 1, 77% in period 2, and 87% in period 3 (all p<0.0001). The proportion of patients without any CUA lesions increased in the first 6 months; by 52% in period 1 (p=0.0241), 66% in period 2 (p<0.001), and 81% in period 3 (p<0.001).

Conclusions

MRI was used to assess disease activity in a group of highly active RMS on CT3.5 treatment from one month onwards. Data show an early onset of action on CUA lesions that was significant from month 1 versus baseline, with a treatment effect that increased over the first 6 months.

Background

Ongoing safety reporting is crucial to understanding the long-term benefit–risk profile of ocrelizumab in patients with multiple sclerosis (MS). Safety/efficacy of ocrelizumab have been characterized in Phase II (NCT00676715) and Phase III (NCT01247324; NCT01412333; NCT01194570) trials in patients with relapsing-remitting MS, relapsing MS (RMS) and primary progressive MS (PPMS).

Objectives

To report longer-term safety evaluations from ocrelizumab clinical trials and open-label extension (OLE) periods up to January 2020 and selected post-marketing data.

Methods

Safety outcomes are reported for the ocrelizumab all-exposure population in Phase II/III trials and associated OLEs plus ongoing Phase IIIb trials in MS (VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, LIBERTO and CONSONANCE). The number of post-marketing ocrelizumab-treated patients is based on estimated number of vials sold and US claims data. To account for different exposure lengths, rates per 100 patient years (PY) are presented.

Results

In clinical trials, 5,680 patients with MS received ocrelizumab (18,218 PY of exposure) as of January 2020. Reported rates per 100 PY (95% confidence interval) were: adverse events (AEs), 248 (246–251); infections, 76.2 (74.9–77.4); serious AEs, 7.34 (6.96–7.75); serious infections, 2.01 (1.81–2.23); malignancies, 0.46 (0.37–0.57); and AEs leading to discontinuation, 1.06 (0.92–1.22). As of April 2020, over 158,000 patients with MS have initiated ocrelizumab globally in the post-marketing setting. Data remain generally consistent with those observed in clinical trials.

Conclusions

Reported rates of AEs in the ocrelizumab all-exposure clinical trial population and post-marketing settings remain generally consistent with the controlled treatment period in RMS/PPMS populations. Rates of serious infections and malignancies remain within the range reported for patients with MS in real-world registries. In patients with RMS and PPMS, ocrelizumab demonstrates a consistent and favorable safety profile, and these longer-term data are in accordance with the safety outcomes initially observed during the controlled treatment periods. Regular reporting of longer-term safety data will continue.

Background

Multiple sclerosis (MS), a chronic disabling disease requiring long-term treatment and regular monitoring, is associated with negative effects on health-related quality of life (HRQoL). CLARIFY-MS (NCT03369665) aims to assess the impact of cladribine tablets (CT) 10 mg (3.5 mg/kg cumulative dose over 2 years; CT3.5) on HRQoL and treatment satisfaction in patients with highly-active relapsing MS (RMS).

Objectives

To present an interim analysis of CLARIFY-MS at 6 months after initiating treatment with CT, assessing treatment satisfaction through the Treatment Satisfaction Questionnaire for Medication (TSQM) v1.4 and safety through the collection of safety assessments in highly-active RMS patients.

Methods

CLARIFY-MS is an ongoing phase IV, open label, single arm, multicenter, 2-year study. Patients with RMS received CT3.5, with 2 weeks of active treatment per course (week 1 and 5 of each year). TSQM v1.4 was used to assess patient-reported treatment satisfaction (a score of 100 is the best possible rating). The TSQM measures 14 items across four domains: effectiveness (three items), side effects (five items), convenience (three items), and global satisfaction (three items).Treatment-emergent adverse events (TEAEs), serious adverse events (AEs), and lymphocyte counts were recorded.

Results

Treatment satisfaction: Of 554 patients screened, 482 received CT. The age and Expanded Disability Status Scale adjusted global treatment satisfaction score (95% confidence interval) at Month 6 was 70.0 (66.6–73.5). Treatment-experienced patients (prior treatment with disease-modifying drugs [DMDs]) reported similar treatment satisfaction scores to DMD-naïve patients (70.2 vs 68.7). At Month 6, >75% of patients rated the TSQM side effects score with 100. The mean side effects score was 91.9, mean convenience 86.6. Safety: 275 patients (57.1%) experienced ≥1 TEAE after drug initiation, most commonly headache and lymphopenia. Most post-baseline lymphopenias were of grade 1-2; 33 patients (6.8%) experienced grade 3 lymphopenia and no grade 4 lymphopenia was observed.

Conclusions

This interim analysis of CLARIFY-MS found that at 6 months, patients were generally satisfied with CT treatment. The convenience of CT treatment and side effect profile were especially important to patients. Safety results at 6 months post-treatment are consistent with the known safety profile, with no new emerging safety signal; most lymphopenias were grade 1-2.