Background

Intrathecal production of immunoglobulin (Ig) and the presence of cerebrospinal fluid (CSF)–specific oligoclonal bands (OCBs) are hallmarks of multiple sclerosis (MS) that persist throughout the disease course and treatment.

Objectives

To describe baseline (BL) correlations of CSF IgM and IgG production with CSF biomarkers and to assess the pharmacodynamic effects of ocrelizumab (OCR) treatment on these parameters in patients with relapsing MS (RMS) from the Ocrelizumab Biomarker Outcome Evaluation (OBOE) study (NCT02688985).

Methods

Seventy-nine of 100 total patients with RMS had available BL CSF samples for assessment of IgG OCBs, IgG and IgM (measured at University Medical Center Göttingen), with demographic, MRI and clinical parameters representative of the total RMS population. CSF samples at either 12 (n=22), 24 (n=24) or 52 (n=17) weeks postdose and from a 12-week reference arm (no OCR; n=16) were assessed for longitudinal changes.

Results

Median (interquartile range [IQR]) CSF levels at BL were as follows: IgG index, 0.79 (0.63–1.28); IgM index, 0.19 (0.11–0.33); CD3⁺ T cell number, 2.52 (0.80–5.61) cells/µL; CXCL13, 9.89 (3.91–31.50) pg/mL; CCL19, 47.95 (31.09–70.86) pg/mL; neurofilament light chain (NfL) 1280.0 (828.1–2968.9) pg/mL. At BL, IgG index and IgM index correlated moderately with levels of B cells (r=0.65, r=0.4 respectively), T cells (r=0.54, r=0.3 respectively) and CXCL13 (r=0.58, r=0.43 respectively), but not CCL19 or NfL. IgG index tended to decrease with OCR treatment and was significantly reduced by 52 weeks (n=17/79; median [IQR] change from BL −9.5% [−20.4% to −0.1%]; p<0.02) compared with stable levels in the reference arm. While IgG OCBs were detected at BL in all patients, IgG OCBs tended to decrease with OCR treatment, with three of 17 patients having no detectable IgG OCBs at 52 weeks. Reductions in IgM index were not observed with OCR treatment.

Conclusions

Baseline CSF levels of B cells, T cells and CXCL13 correlated with IgG index and to a lesser degree IgM index in patients with RMS from the OBOE study. Significant reductions were observed in IgG index with OCR treatment, along with a trend toward reduced OCBs, with three patients showing no detectable OCBs. These data suggest that OCR impacts CSF Ig production, a hallmark of MS not previously thought to be affected by B-cell depletion therapy. These 1-year observations need to be confirmed with longer-term data and correlated with clinical response.

Background

In the pivotal trials of ocrelizumab (OCR) in patients with relapsing-remitting multiple sclerosis (RRMS; OPERA I, OPERA II), ≈75% of participants had no previous disease-modifying therapy (DMT).

Objectives

To report 2-year findings from the Phase IIIb CHORDS study (NCT02637856) investigating OCR in patients with RRMS who had a suboptimal response with previous DMT.

Methods

CHORDS enrolled patients who had a suboptimal response (≥1 relapse, ≥1 T1 gadolinium [Gd]-enhancing lesion or ≥2 new/enlarging T2 lesions) after ≥6 months of treatment with 1 to 3 previous DMTs. All participants received OCR 600 mg every 24 weeks for 96 weeks and were included in the intention-to-treat (ITT) population. Annualized relapse rate (ARR), changes in Expanded Disability Status Scale (EDSS) and safety were assessed in the ITT population. The primary endpoint was the proportion of patients free of any protocol-defined event (i.e. relapse, T1 Gd-enhancing lesion, new/enlarging T2 lesion, 24-week confirmed disability progression [CDP] on the EDSS) and was evaluated using a modified ITT (mITT) population, which imputed as having an event those patients who terminated early for lack of efficacy or death and excluded patients who discontinued for reasons other than an event.

Results

The ITT population included 608 patients with a mean (SD) time since diagnosis of 4.2 (3.03) years. The most frequently used DMTs prior to enrollment included glatiramer acetate (49.3%), dimethyl fumarate (35.4%) and fingolimod (20.1%). In the mITT population (576 [94.7%]), 48.1% of patients were free of all protocol-defined events, and most experienced freedom from individual events (relapse, 89.6%; T1 Gd-enhancing lesions, 95.5%; new/enlarging T2 lesions, 59.5%; 24-week CDP, 89.6%) over 96 weeks. Similar results were observed for the primary endpoint in those who received 1 vs >1 prior DMT (50.9% vs 44.5%) as well as for individual events (relapse, 90.0% vs 89.2%; T1 Gd-enhancing lesion, 95.8% vs 95.1%; new/enlarging T2 lesion, 61.4% vs 57.1%; 24-week CDP, 90.9% vs 87.9%). The adjusted ARR over 96 weeks was 0.046. Most patients had stable (<1-point change; 61.5%) or improved (≥1-point decrease; 22.7%) EDSS scores. There were no deaths or new safety signals.

Conclusions

This analysis demonstrates the potential benefits of ocrelizumab treatment over 2 years in patients with RRMS who are relatively early in the disease course and have experienced suboptimal response on prior DMTs.

Background

Minority patients with multiple sclerosis (MS), including those of African ancestry (AA) and Hispanic and Latino ethnicity (HA), have greater disease severity and faster progression than Whites. Minorities are vastly underrepresented in clinical trials, owing to poor access and cultural, economic and other participation barriers. Ocrelizumab (OCR), an anti-CD20 therapy targeting B cells, reduced the rates of disease activity and progression in patients with relapsing MS (RMS) and primary progressive MS in pivotal studies; however, minority participation was <10%.

Objectives

To investigate the efficacy and safety of OCR in AA and HA patients with RMS (2017 McDonald criteria) who meet the US prescribing information criteria in a single-arm Phase IV clinical study designed exclusively to meet the needs of these specific demographic groups.

Methods

An industry-sponsored collaborative approach rooted in minority needs and known knowledge gaps was used.

Results

Key differences between CHIMES (NCT04377555) and other MS trials are as follows:

1. CHIMES was developed in collaboration with patients with MS, patient advocacy groups and investigators.

2. Inclusion criteria allow for ≈150–200 participants with specific, well-controlled, pre-existing comorbidities and baseline creatinine levels within race-specific limits; these factors may disproportionately limit minority patient qualification in other trials.

3. OCR was chosen because of the indications that AA patients with MS may have greater B-cell–mediated pathology, such as a higher CSF IgG index.

4. Written materials will be available in English and Spanish and will be reviewed by a minority patient panel to ensure that they are easy to understand.

5. To enable early results, the primary endpoint is disease activity, defined by the proportion of patients free of protocol-defined events (clinical relapses, CDP or MRI activity) at the end of year 1.

6. All patients may participate in the second-year extension to study disease progression and various biomarker endpoints.

7. One-third of patients will participate in a substudy to assess CSF-specific biomarkers at two time points.

Conclusions

Findings from CHIMES are expected to improve current understanding of MS disease biology, treatment response and clinical trial participation among AA and HA patients with MS, with the ultimate goals of increasing high-quality standard of care to traditionally underserved populations and enhancing equality through clinical research.