F. Hoffmann-La Roche Ltd

Author Of 3 Presentations

Biomarkers and Bioinformatics Poster Presentation

P0123 - Ocrelizumab reduces thalamic volume loss and clinical progression in PPMS and RMS independent of baseline NfL and other measures of disease severity (ID 1621)

Speakers
Presentation Number
P0123
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Neurofilament light chain (NfL) is a biomarker of neuroaxonal injury in multiple sclerosis (MS). Thalamic atrophy occurs early and may be a sensitive marker of overall brain damage. Ocrelizumab (OCR) reduced brain atrophy and NfL in patients with relapsing MS (RMS) and those with primary progressive MS (PPMS).

Objectives

To examine the independent impact of OCR and baseline (BL) NfL on thalamic volume (TV) and clinical progression in patients with PPMS and RMS, including those with RMS without acute BL activity (i.e. no gadolinium–enhancing [Gd+] lesions or relapse in the last 3 months).

Methods

Patients were from OPERA I/II (RMS, n=1,421) and ORATORIO (PPMS, n=596). Thalamic atrophy was calculated as annualized percentage TV change (PTVC) from Wk 24 to the end of controlled treatment (ORATORIO, Wk 120; OPERA I/II, Wk 96). OCR treatment (vs IFNβ-1a [RMS] or placebo [PPMS]) and log-transformed BL NfL were examined for associations with PTVC (linear regression) and 24-week confirmed disability progression (Cox regression) adjusting for BL demographic and disease characteristics.

Results

In patients with PPMS and RMS, OCR treatment (PTVC: +0.47% and +0.33%, respectively) and lower BL NfL (+0.20% and +0.33% per 2-fold lower NfL) independently associated with a smaller TV reduction (all p<0.005). Adjusting for BL NfL level, Gd+ lesion count, T2 lesion volume and BL disability, OCR still reduced disability progression on Expanded Disability Status Scale (EDSS) (PPMS, hazard ratio [HR]=0.73; RMS, HR=0.65; both p<0.05]), 9-Hole Peg Test (9HPT) (PPMS, HR=0.53, p=0.002; RMS, HR=0.52, p=0.059), Timed 25-Foot Walk (T25FW) (PPMS, HR=0.79, p=0.063), Symbol Digit Modalities Test (RMS, HR=0.54, p=0.002) and time to EDSS 6 (RMS, HR=0.42, p=0.009). In patients with PPMS, higher BL NfL was associated with worsening on 9HPT (HR=1.34 per 2-fold higher NfL), T25FW (HR=1.19) and time to EDSS 7 (HR=1.78) (all p<0.05). In patients with RMS without acute BL activity, higher BL NfL was associated with EDSS worsening (HR=1.49), progression independent of relapse activity (PIRA) (HR=1.61), 9HPT (HR=2.1) and time to EDSS 6 (HR=2.24) (all p<0.05).

Conclusions

Ocrelizumab treatment remained associated with reduced thalamic atrophy and clinical progression after adjusting for baseline NfL and other factors. Higher BL NfL was associated with increased rates of thalamic atrophy and clinical progression in patients with PPMS and those with RMS without acute disease activity.

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Biomarkers and Bioinformatics Poster Presentation

P0125 - Ocrelizumab treatment induces a sustained blood NfL reduction in patients with PPMS and RMS (ID 1865)

Speakers
Presentation Number
P0125
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Blood neurofilament light chain (NfL) is a biomarker of neuroaxonal injury associated with acute disease activity and may be prognostic for disability progression in patients with multiple sclerosis (MS). Ocrelizumab (OCR) is an anti-CD20 monoclonal antibody indicated for relapsing MS (RMS) and primary progressive MS (PPMS).

Objectives

To assess the impact of OCR on blood NfL distribution in patients with RMS from the OPERA I and II trials and those with PPMS from ORATORIO.

Methods

Pretreatment and posttreatment NfL levels (measured using the SiMOA assay) with OCR vs interferon β-1a (OPERA I and II; n=1,421) or placebo (ORATORIO; n=596) were compared using geometric mean (GM) and GM ratios (GMR). Patients were stratified by presence/absence of acute disease activity at baseline (BL) (T1 gadolinium [Gd]-enhancing lesions and/or relapse in prior 3 months for RMS; T1 Gd-enhancing lesions for PPMS). Age-adjusted NfL distributions (using a linear model for log-NfL and age derived from a healthy donor [HD] cohort) at BL and after OCR were compared with HD using the Kolmogorov-Smirnov test.

Results

Significant reductions in NfL were observed 3 months after OCR initiation (RMS, GMR=0.80; PPMS, GMR=0.89) and sustained through the end of controlled treatment (RMS [96 weeks], GMR=0.56; PPMS [120 weeks], GMR=0.81; all p<0.0001). Age-adjusted BL serum NfL was elevated in patients with RMS disease activity (GM [95% CI]=12.7 [11.9–13.6] pg/mL) vs those without (5.5 [5.3–5.7] pg/mL) and HD (4.1 [3.9–4.4] pg/mL; all p<0.0001). In OCR-treated patients with RMS, GM [95% CI] serum NfL levels after 96 weeks (with activity at BL, 4.4 [4.2–4.6] pg/mL; without activity at BL, 4.1 [4.0–4.3] pg/mL) were comparable to HD (4.1 [3.9–4.4] pg/mL; all p>0.1). Age-adjusted BL plasma NfL was also elevated in PPMS patients with disease activity (GM [95% CI]=8.7 [7.5–10.1] pg/mL) vs those without (4.9 [4.6–5.2] pg/mL) and HD (3.1 [2.9–3.3] pg/mL; all p<0.0001). In OCR-treated patients with PPMS, GM [95% CI] plasma NfL levels after 120 weeks (with activity at BL, 4.6 [4.1–5.1] pg/mL; without activity at BL, 4.2 [4.0–4.4] pg/mL) were reduced from BL (all p<0.005) but remained elevated vs HD (all p<0.001).

Conclusions

NfL is highly elevated in patients with acute MS disease activity, and more subtle elevations are observed in RMS and PPMS patients without detectable disease activity. Ocrelizumab significantly reduces NfL in RMS and PPMS patients with and without detectable disease activity.

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Clinical Trials Poster Presentation

P0230 - Rationale and design of two Phase IIIb studies of ocrelizumab at higher than the approved dose in patients with RMS and PPMS (ID 971)

Abstract

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.

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