Blood neurofilament light levels predict non-relapsing progression following anti-CD20 therapy in relapsing and primary progressive multiple sclerosis: findings from the ocrelizumab randomised, double-blind phase 3 clinical trials

Abstract

Background: Neurofilament light chain (NfL), a neuronal cytoskeletal protein that is released upon neuroaxonal injury, is associated with multiple sclerosis (MS) relapsing activity and has demonstrated some prognostic ability for future relapse-related disease progression, yet its value in assessing non-relapsing disease progression remains unclear.

Methods: We examined baseline and longitudinal blood NfL levels in 1421 persons with relapsing MS (RMS) and 596 persons with primary progressive MS (PPMS) from the pivotal ocrelizumab MS trials. NfL treatment-response and risk for disease worsening (including disability progression into the open-label extension period and slowly expanding lesions [SELs] on brain MRI) at baseline and following treatment with ocrelizumab were evaluated using time-to-event analysis and linear regression models.

Findings: In persons from the RMS control arms without acute disease activity and in the entire PPMS control arm, higher baseline NfL was prognostic for greater whole brain and thalamic atrophy, greater volume expansion of SELs, and clinical progression. Ocrelizumab reduced NfL levels vs. controls in persons with RMS and those with PPMS, and abrogated the prognostic value of baseline NfL on disability progression. Following effective suppression of relapse activity by ocrelizumab, NfL levels at weeks 24 and 48 were significantly associated with long-term risk for disability progression, including up to 9 years of observation in RMS and PPMS.

Interpretation: Highly elevated NfL from acute MS disease activity may mask a more subtle NfL abnormality that reflects underlying non-relapsing progressive biology. Ocrelizumab significantly reduced NfL levels, consistent with its effects on acute disease activity and disability progression. Persistently elevated NfL levels, observed in a subgroup of persons under ocrelizumab treatment, demonstrate potential clinical utility as a predictive biomarker of increased risk for clinical progression. Suppression of relapsing biology with high-efficacy immunotherapy provides a window into the relationship between NfL levels and future non-relapsing progression.

Funding: F. Hoffmann-La Roche Ltd.

Keywords: Biomarker; Disease progression; Multiple sclerosis; NfL; Ocrelizumab.

Fig. 1

Comparison of baseline serum NfL distributions in (a) persons with RMS in OPERA I (n = 701) and II (n = 720); (b) persons with RMS pooled from OPERA I/II (n = 1421), persons with PPMS from ORATORIO (n = 596), and HDs (n = 118); (c) persons with RMS (n = 560) or PPMS (n = 141) with acute disease activity grouped by study; and (d) persons with RMS (n = 688) or PPMS (n = 464) without acute disease activity grouped by study. Statistical comparisons were conducted with the Kolmogorov–Smirnov test. HD = healthy donor; Gd = gadolinium; NfL = neurofilament light; ns = not significant; PPMS = primary progressive multiple sclerosis; RMS = relapsing multiple sclerosis. ∗∗∗P < 0.0001.

Fig. 2

Relationship between baseline serum NfL and thalamic volume reduction during the controlled treatment period in each treatment arm of OPERA I and II and ORATORIO.∗ The mean and 95% CI of percentage volume reduction at each brain MRI time point compared with baseline are shown. In both studies, a greater reduction in THV was observed at the end of the controlled treatment period in persons with high baseline NfL (above median, solid lines) compared with low baseline NfL (below median, dotted lines). Moreover, greater THV reduction was observed in persons randomised to comparator treatment (IFNβ-1a in OPERA, purple; PBO in ORATORIO, grey) vs. ocrelizumab (blue). IFN = interferon; NfL = neurofilament light; MRI = magnetic resonance imaging; OCR = ocrelizumab; PBO = placebo; THV = thalamic volume. ∗Study individuals included persons with RMS with MRI data at weeks 24 and 96 (OPERA I and II) and persons with PPMS with MRI data at weeks 24 and 120 (ORATORIO).

Fig. 3

Relationship between baseline NfL and baseline SEL burden and SEL volume expansion during the controlled treatment period in the ocrelizumab treatment arms of OPERA I and II and ORATORIO. High or low NfL was determined by levels above or below the baseline median. In both studies, NfL elevation at baseline was associated with greater baseline SEL count (a and e), greater baseline SEL-T2LV (b and f), greater SEL-T1LV expansion (c and g), and greater T1 signal intensity reduction within SELs (d and h). The mean and 95% CI of each SEL measure is shown. SEL = slowly expanding lesion; NfL = neurofilament light; OCR = ocrelizumab; T1LV = T1 lesion volume; T2LV = T2 lesion volume; H = high; L = low.

Fig. 4

Relationship between baseline NfL and disability progression during the controlled treatment period in each treatment arm of OPERA I and II (a) and ORATORIO (e). High or low NfL was determined by levels above or below the baseline median. NfL elevation at baseline was prognostic for CDP24 only in persons with RMS without acute disease activity receiving IFNβ-1a (c) and in persons with PPMS receiving placebo therapy (e). Baseline NfL was not predictive of CDP24 in persons receiving ocrelizumab treatment (b, d, and f). P values are shown for log-rank tests comparing high vs. low NfL groups. IFN = interferon; NfL = neurofilament light; OCR = ocrelizumab; PBO = placebo; CDP24 = 24-week confirmed disability progression; PPMS = primary progressive multiple sclerosis; RMS = relapsing multiple sclerosis; BL = baseline; H = high; L = low.

Fig. 5

Blood NfL levels (GM and 95% CI, top)∗ and relative change from baseline (% reduction in GM and 95% CI, bottom) during the controlled treatment in OPERA I and II (left) and ORATORIO (right). NfL levels were significantly reduced following ocrelizumab treatment in persons with RMS and persons with PPMS, both vs. comparator treatment and vs. baseline levels. GM = geometric mean; HD = healthy donor; IFN = interferon; NfL = neurofilament light; OCR = ocrelizumab; PBO = placebo; pNfL = plasma neurofilament light; sNfL = serum neurofilament light. ∗NfL levels from the HD cohort were adjusted to median ages in OPERA (38 years) and ORATORIO (47 years) to determine median, 10th percentile, and 90th percentile levels. ^†Significant reduction in NfL following ocrelizumab treatment vs. comparator arms; plots show GMs of NfL and 95% CIs.

Fig. 6

Relationship between week 48 (unadjusted) blood NfL and risk for subsequent 24-week CDP in persons with RMS and those with PPMS receiving ocrelizumab treatment. High or low NfL was determined using sNfL above or below 10.6 pg/mL in OPERA I and II, and pNfL above or below 7.5 pg/mL in ORATORIO. The comparison EDSS was the baseline value when no CDP event occurred prior to NfL measurement or a re-baselined EDSS value when a CDP event occurred prior to NfL measurement. Differences between high vs. low NfL groups on risk for CDP was assessed using a log-rank test. IFN = interferon; NfL = neurofilament light; OCR = ocrelizumab; PBO = placebo; pNfL = plasma neurofilament light; sNfL = serum neurofilament light; DB = double-blind period; OLE = open-label extension period; H = high; L = low; CDP = confirmed disability progression.