F. Hoffmann-La Roche Ltd

Author Of 1 Presentation

Imaging Oral Presentation

FC03.05 - Reduced thalamic atrophy in patients initiating earlier versus delayed ocrelizumab therapy: results from the OLE of OPERA I/II and ORATORIO

Speakers
Presentation Number
FC03.05
Presentation Topic
Imaging
Lecture Time
13:48 - 14:00

Abstract

Background

In multiple sclerosis (MS), thalamic integrity is affected both directly by demyelination, neuronal loss and increasing iron concentration, and indirectly by remote gray and white matter lesions affecting neural projections into and out of the thalamus. Thalamic atrophy may therefore reflect a large fraction of MS-related brain damage and thus represent a useful marker of overall damage and therapeutic efficacy.

Objectives

To assess the efficacy of ocrelizumab (OCR) in patients switching to or maintaining OCR therapy on thalamic atrophy in patients with relapsing MS (RMS) and primary progressive MS (PPMS), participating in the OPERA I/II (NCT01247324/NCT01412333) and ORATORIO (NCT01194570) Phase III trials, respectively.

Methods

At the end of the double-blind controlled treatment period in OPERA I/II, patients entered the open‑label extension (OLE), and either continued to receive OCR (OCR-OCR) or switched from interferon β-1a (IFN β-1a) to OCR (IFN β-1a-OCR). In ORATORIO, patients entered the OLE ~3–9 months after the double-blind period cut-off and either continued OCR (OCR-OCR) or switched from placebo (PBO) to OCR (PBO-OCR). Changes in thalamic volume from the core trial baseline were computed using Jacobian integration and analyzed using a mixed-effect repeated measurement model, adjusted for baseline volume, age, baseline gadolinium-enhancing lesions (presence/absence), baseline T2 lesion volume, region (US vs rest of the world), Expanded Disability Status Scale category (<4, ≥4), week, treatment, treatment and time interaction, and treatment and baseline volume interaction.

Results

In the OLE of OPERA I/II, changes (%) in thalamic volume from baseline at OLE Week 46, 94, 142, 190, and 238, were: –2.88/–2.12 (p<0.001), –3.31/–2.36 (p<0.001), –3.61/–2.78 (p<0.001), –3.68/–3.03 (p<0.001), and –4.07/–3.41 (p<0.001), for IFN β-1a-OCR/OCR-OCR patients, respectively. During the OLE of ORATORIO, changes in thalamic volume at OLE Day 1, Week 48, 96, and 144, were: –3.46/–2.44 (p<0.001), –3.93/–2.61 (p<0.001), –4.30/–3.25 (p<0.001), and –4.86/–3.62 (p<0.001), for PBO-OCR/OCR-OCR patients, respectively.

Conclusions

In the OLE, patients with RMS and PPMS who were initially randomized to ocrelizumab experienced less thalamic volume loss compared with those initiating ocrelizumab later.

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Author Of 2 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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