F. Hoffmann-La Roche Ltd

Author Of 6 Presentations

Biomarkers and Bioinformatics Poster Presentation

P0037 - Change in serum neurofilament light chain levels: ENSEMBLE 1-year interim results (ID 945)

Speakers
Presentation Number
P0037
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Early treatment of multiple sclerosis (MS) provides significant long-term benefits. The aim of the Phase IIIb ENSEMBLE study (NCT03085810) is to evaluate the effectiveness and safety of ocrelizumab (OCR) in patients with early-stage relapsing-remitting MS (RRMS). Neurofilament light chain (NfL) is a marker of neuroaxonal injury. OCR reduced elevated NfL levels in patients with relapsing MS and primary progressive MS to those of healthy donors in the OPERA and ORATORIO studies over 96 weeks. NfL levels are assessed yearly in ENSEMBLE.

Objectives

To report 1-year NfL analyses from ENSEMBLE.

Methods

Treatment-naive patients with a diagnosis of early-stage RRMS (age, 18–55 years inclusive; Expanded Disability Status Scale [EDSS] score ≤3.5) per 2010 revised McDonald criteria and a disease duration from the first documented clinical attack consistent with MS disease of ≤3 years and ≥1 clinically reported relapse or ≥1 sign of MRI activity within 12 months of enrollment were included. Patients will receive OCR 600 mg every 24 weeks (first dose, 2×300 mg separated by 14 days) for the 192-week treatment period (maximum 8 doses). Serum NfL levels are measured via the Simoa Quanterix Advantage kit.

Results

A total of 582 patients were included in the NfL evaluation (female, 64.3%; mean [SD]: age, 32.4 [9.2] years; baseline EDSS, 1.70 [0.96]; time since MS symptom onset, 1.08 [0.84] years) with characteristics comparable with the overall population (N=678). The median serum NfL level at baseline was 13.20 pg/mL; 81.8% of patients had levels greater than healthy donors (HDs; 7.1 pg/mL). Median NfL levels at baseline in patients stratified by age, gender and EDSS score were consistent with those of the overall population. The highest median NfL levels at baseline were observed in patients with T1-weighted contrast-enhancing lesions (CELs) at screening (18.71 pg/mL; n=260) and relapses within 3 months of enrollment (14.91 pg/mL; n=217). At Week 48 the median serum NfL level was reduced to 6.35 pg/mL; 60.8% of patients had levels comparable to or lower than the HD level. Decreases in median serum NfL levels were observed, independent of the baseline demographics and disease characteristics of age, gender, EDSS score, CELs, relapses and reason for enrollment.

Conclusions

NfL levels at baseline and patterns of change over 48 weeks were in line with previous evaluations and decreased considerably after 1 year of treatment with ocrelizumab.

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Clinical Trials Poster Presentation

P0219 - Ocrelizumab Phase IIIb efficacy from CASTING: 2-year NEDA (MRI re-baselined) subgroup rates in RRMS patients with a suboptimal response to prior DMTs (ID 974)

Speakers
Presentation Number
P0219
Presentation Topic
Clinical Trials

Abstract

Background

Patients with relapsing-remitting multiple sclerosis (RRMS) often experience disease activity despite receiving a disease-modifying therapy (DMT). The Phase IIIb CASTING study (NCT02861014) of ocrelizumab evaluated the efficacy/safety in patients with RRMS who had a prior suboptimal response to one or two DMTs (primary endpoint: 2-year no evidence of disease activity [NEDA] rate).

Objectives

To evaluate CASTING 2-year NEDA outcomes by inclusion criteria, baseline characteristics and prior DMT.

Methods

Patients (Expanded Disability Status Scale [EDSS] score ≤4.0; discontinued prior DMT of ≥6 months’ duration due to suboptimal disease control) received intravenous ocrelizumab 600 mg every 24 weeks for 96 weeks. The primary endpoint of NEDA (with prespecified MRI re-baselining at Week 8) was defined as absence of: protocol-defined relapses, 24-week confirmed disability progression, T1‑weighted contrast-enhancing and new/enlarging T2-weighted lesions over 2 years.

Results

A total of 680 patients were evaluated (female, 64%; mean [SD] baseline EDSS score, 2.1 [1.1]; pretreated with one or two DMTs, including orals and injectables, n=411 [60.4%]/n=269 [39.6%]; enrolled due to activity of: MRI only, n=167 [24.6%]; relapse only, n=238 [35.0%]; MRI and relapse, n=275 [40.4%]). After 2 years, 74.8% (n/N=492/658) of patients had NEDA (with MRI re-baselined at Week 8). The NEDA rate was highest among patients enrolled due to MRI activity alone (80.6%) versus enrollment for relapse (75.1%) or relapse with MRI (70.5%). NEDA rates across disease-related subgroups were highest in the subgroups of baseline EDSS score <2.5 (77.2%), ≤1 relapse prior to enrollment (78.2%) and the event leading to enrollment occurring ≥6 months prior to study entry (75.8%) versus the counterpart subgroups of EDSS score ≥2.5 (70.8%), >1 relapse prior to enrollment (66.3%) and the event leading to enrollment occurring <6 months prior to entry (71.0%). The NEDA rate did not vary by baseline age (≤40 years, 74.7%; >40 years, 75.0%). NEDA rates were higher in patients receiving one prior DMT (77.6%) versus two prior DMTs (70.3%) and remained generally high when stratified by the last prior DMT received before enrollment: interferons, 81.1%; glatiramer acetate, 73.9%; dimethyl fumarate, 73.8%; teriflunomide 69.8%; fingolimod, 68.9%.

Conclusions

The NEDA rate was high overall and across a wide range of disease-related and demographic subgroups, regardless of prior treatment background.

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Clinical Trials Poster Presentation

P0220 - Ocrelizumab Phase IIIb efficacy: 1-year NEDA rates (with MRI re-baselining) from the ENSEMBLE study in early-stage relapsing-remitting MS patients (ID 849)

Abstract

Background

Early treatment of multiple sclerosis (MS) has been shown to provide significant long-term benefits in terms of Expanded Disability Status Scale (EDSS) score versus delayed treatment (patients switching from placebo to active treatment). ENSEMBLE (NCT03085810) is a Phase IIIb study evaluating the effectiveness and safety of ocrelizumab (OCR) in patients with early-stage relapsing-remitting multiple sclerosis (RRMS). Assessments of effectiveness in ENSEMBLE include composite endpoint measures, e.g. the proportion of patients with no evidence of disease activity (NEDA).

Objectives

To report ENSEMBLE 1-year interim NEDA rates.

Methods

Treatment-naive patients with a diagnosis of early-stage RRMS (age, 18–55 years inclusive; EDSS score ≤3.5) per 2010 revised McDonald criteria and a disease duration from the first documented clinical attack consistent with MS disease of ≤3 years and ≥1 clinically reported relapse or ≥1 sign of MRI activity within 12 months of enrollment were included. Patients received OCR 600 mg every 24 weeks (first dose 2×300 mg separated by 14 days) throughout the 192-week (4-year) treatment period (max 8 doses). Clinical assessments will be conducted every 24 weeks. NEDA is defined as absence of: protocol-defined relapses (PDRs), 24-week confirmed disability progression (24W-CDP), T1-weighted contrast-enhancing (CEL) and new/enlarging T2-weighted (T2w) lesions. The effects of OCR are not immediate. MRI measures were re-baselined at Week 8 (prespecified) so that the calculation of NEDA would reflect a more accurate treatment effect.

Results

A total of 678 patients (female, 64.6%) were enrolled (74.6% of patients based on the presence of reasons of both MS relapse and MRI activity) and analyzed. Baseline demographics and disease characteristics reflected a population with early-stage disease (mean [SD]: age, 32.4 [9.1] years; baseline EDSS, 1.71 [0.95]; time since RRMS diagnosis, 0.36 [0.40] years; time since MS symptom onset, 1.10 [0.84] years). At Week 48 most patients (84.8% [n/N=545/643]) reached NEDA. Most patients were free of PDR (98.1%), 24W-CDP (94.1%), CEL (94.2%; re-baselined) and new/enlarging T2w (95.2%; re-baselined) lesions. NEDA calculated without MRI re-baselining was achieved by 62.1% of patients (n/N=404/651). Safety results were consistent with prior studies.

Conclusions

In ENSEMBLE, the Year 1 NEDA rate with MRI re-baselining was high (84.8%) in patients with early-stage disease. No new safety signals were observed.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0392 - Shorter infusion time of ocrelizumab: results from the ENSEMBLE PLUS study in patients with relapsing-remitting multiple sclerosis (ID 900)

Speakers
Presentation Number
P0392
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR) is an intravenously administered anti-CD20 antibody approved for relapsing and primary progressive multiple sclerosis (MS). Shortening the infusion duration to 2hrs reduces the total site stay (including mandatory pre-medication/infusion/observation) from 5.5–6hrs, to 4hrs, which may reduce patient and site staff burden.

Objectives

ENSEMBLE PLUS aims to investigate the safety and tolerability of OCR when administered over a shorter infusion time.

Methods

ENSEMBLE PLUS is a randomized, double-blind substudy to the ENSEMBLE study (NCT03085810). In ENSEMBLE, treatment-naïve patients with active, early-stage relapsing-remitting MS (18–55 years; disease duration ≤3 years; EDSS score 0–3.5) receive OCR 600mg infusions every 24 weeks for 192 weeks. In ENSEMBLE PLUS, OCR (600mg) administered over the approved infusion time (3.5hrs; conventional duration), was compared with a 2hr infusion (shorter duration); the infusion duration of the initial 2×300mg dose was unaffected. The frequency and severity of infusion-related reactions (IRRs) were assessed during and 24hrs post-infusion. The ENSEMBLE PLUS primary endpoint was the proportion of patients with IRRs at the first Randomized Dose.

Results

In total, 373 and 372 patients were randomized to the conventional and shorter infusion groups, respectively. At the first Randomized Dose, 99 patients (26.5%) in the conventional and 107 (28.8%) in the shorter infusion group had IRRs (difference in proportions, stratified estimates [95% CI]: 2.4% [-3.8, 8.7]); most common symptoms during the infusion were throat irritation, dysphagia and ear pruritus, whilst 24hrs post-infusion were fatigue, headache and nausea. IRRs led to infusion slowing/temporary interruption in 22 patients (5.9%) in the conventional and 39 (10.5%) in the shorter infusion group. The majority of IRRs were mild or moderate. Across all Randomized Doses, four severe (Grade 3) IRRs occurred in total, one in the conventional and three in the shorter infusion group. Overall, >99% of IRRs resolved without sequelae in both groups. No IRRs were serious, life-threatening or fatal; no IRR-related discontinuations occurred. Adverse events (AEs) and serious AEs were consistent with the known OCR safety profile.

Conclusions

Frequency and severity of IRRs were similar between conventional and shorter infusions. No new safety signals were detected. Shorter ocrelizumab infusions reduce the infusion site stay, thus may reduce patient and staff burden.

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Patient-Reported Outcomes and Quality of Life Poster Presentation

P1039 - Improvements in patient-reported SymptoMScreen scores among ocrelizumab-treated patients with RRMS: 2-year results from the CASTING clinical trial (ID 977)

Speakers
Presentation Number
P1039
Presentation Topic
Patient-Reported Outcomes and Quality of Life

Abstract

Background

SymptoMScreen is a patient-reported outcome tool designed to rapidly assess symptom limitations across 12 symptoms commonly affected in people with multiple sclerosis (MS). Each domain is scored on a 7-point Likert scale (0 [not affected] to 6 [total limitation]) and domain scores are summed to calculate a total score ranging from 0 to 72. SymptoMScreen is used in the ongoing, open-label, single-arm, Phase IIIb CASTING clinical trial (NCT02861014).

Objectives

To report 2-year changes in SymptoMScreen scores among patients with relapsing-remitting MS (RRMS) from CASTING.

Methods

In CASTING, patients with RRMS (Expanded Disability Status Scale [EDSS] score ≤4.0 at screening; disease duration ≤10 years) and a prior suboptimal response to ≥6 months of treatment with one or two disease-modifying therapies (DMTs; including orals and injectables) received intravenous ocrelizumab 600 mg every 24 weeks for 96 weeks. SymptoMScreen was performed at baseline, Week 48 (1-year interim data) and Week 96 (2-year final data).

Results

A total of 680 patients (female, 64%; mean [SD] baseline EDSS score, 2.1 [1.1]) who were previously treated with one (n=414 [60.4%]) or two (n=269 [39.6%]) DMTs were enrolled (most frequently for MRI with relapse activity [40.4%]) and evaluated in the intent-to-treat population; 644 patients completed treatment. Total SymptoMScreen mean (SD) score reflected mild symptom burden at baseline (15.19 [12.67]) and improved significantly through Year 2 (13.62 [12.51]; p<0.001 [p values were not adjusted for multiplicity]). Statistically significant improvements after 2 years were observed for sensory symptoms (Δ-0.28; p<0.001), fatigue (Δ-0.23; p<0.001), vision (Δ-0.21; p<0.001), depression (Δ-0.15; p<0.01) and dizziness (Δ-0.14; p<0.01) domains. Non-significant improvements in symptom burden after 2 years (p>0.05) were observed in walking (Δ-0.1), cognition (Δ-0.10), anxiety (Δ-0.07), bodily pain (Δ-0.05), hand function (Δ-0.03) and bladder control (Δ-0.01), while a non-significant worsening was observed in the spasticity domain (Δ+0.04). The proportion of patients with at least one symptom causing at least moderate limitation (domain score ≥4) decreased from 31.6% at baseline to 26.3% at Year 2.

Conclusions

Patients with RRMS and a suboptimal response to therapy who switched to ocrelizumab experienced an improvement in symptom burden in the majority of SymptoMScreen domains after 2 years, which was most pronounced in sensory, fatigue and vision.

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Reproductive Aspects and Pregnancy Poster Presentation

P1132 - Pregnancy outcomes in patients treated with ocrelizumab (ID 957)

Speakers
Presentation Number
P1132
Presentation Topic
Reproductive Aspects and Pregnancy

Abstract

Background

Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody approved for the treatment of relapsing and primary progressive multiple sclerosis (MS). As many MS patients are women of reproductive age, pregnancy outcomes in OCR-exposed patients are of relevance.

Objectives

To report an update on pregnancy outcomes in women with MS receiving OCR in clinical trials and post-marketing.

Methods

Analysis includes pregnancies in women receiving OCR in clinical trials/post-marketing (global safety database). Women of childbearing potential should use contraception while on treatment and for 6 or 12 months after the last OCR infusion, depending on local regulations. Based on the average terminal half-life of 26 days and the lack of relevant placental transfer in the 1st trimester, a fetus was considered to have fetal OCR exposure if the last infusion occurred within 3 months of conception, during pregnancy, or if the date was unknown.

Results

As of March 27, 2020, 726 total pregnancies exposed to OCR in women with MS (n=608) or unknown indication (n=118) were reported. Of the 608 MS pregnancies, 234 were considered to have fetal OCR exposure, 102 were not, and 272 had unknown exposure. Preliminary outcomes of total MS pregnancies (n/%) were: 156/64.2% live births, 37/15.2% elective/therapeutic abortions, 42/17.3% spontaneous abortions, 3/1.2% stillbirths, 5/2.1% ectopic pregnancies; 134 pregnancies were ongoing, 80 lost to follow-up (FU) and 151 had unknown/not reported (NR) outcomes. Of the 156 total live births, 6 congenital malformations were reported. Preliminary outcomes of MS pregnancies with fetal OCR exposure (n/%) were: 62/59.6% live births, 24/23.1% elective/therapeutic abortions, 15/14.4% spontaneous abortions, 2/1.9% stillbirths, 1/1.0% ectopic pregnancies; 55 pregnancies were ongoing, 37 lost to FU and 38 had unknown/NR outcomes. Infant health questionnaires were received from 13 live births with up to 1-year FU and will continue to be collected, including data on vaccinations and infections: 9 infants had no infections and 1 had a resolved infection.

Conclusions

Cases reviewed to date do not suggest an increased risk of adverse pregnancy outcomes (including spontaneous abortions or malformations) with OCR use, whether or not fetal exposure occurred or was unknown. The updated outcomes remain in line with prior reports and within the expected epidemiologic range. Data continue to be collected and assessed as per post-authorization commitments.

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