Table 2.

Evaluation of new/enlarging T2 lesions, brain volume change, and blood NfL at week 48 as potential surrogate markers for CDP24 during controlled treatment period (week 96 in OPERA, week 144 in ORATORIO).

Study	Sample size (biomarker- available population)	Candidate surrogate marker	Unadjusted CoxPH model CDP24 ∼ treatment arm		Adjusted CoxPH model CDP24 ∼ treatment arm + surrogate marker					Treatment effect explained by surrogate
			HR for OCR vs. comparator arm (95% CI)	P value	HR for OCR vs. comparator arm (95% CI)	OCR arm P value	1 SD in surrogate marker	HR per 1 SD in surrogate marker (95% CI)	Candidate surrogate P value
OPERA I and II	1656	None (ITT population)	0.60 (0.43–0.84)	0.003	–	–	–	–	–	–
	1404	New/enlarging T2 lesions from BL to W48	0.62 (0.44–0.88)	0.008	0.67 (0.47–0.95)	0.026	5.6	1.15 (1.04–1.27)	0.0065	13%
	1261	% Brain volume change from BL to W48	0.63 (0.44–0.91)	0.013	0.68 (0.47–0.98)	0.039	0.75	0.77 (0.66–0.91)	0.0014	12%
	1270	log10 (W48 sNfL)	0.65 (0.44–0.94)	0.023	0.72 (0.49–1.1)	0.098	0.21	1.39 (1.17–1.64)	0.00012	22%
ORATORIO (n = 463)	732	None (ITT population)	0.75 (0.58–0.98)	0.04	–	–	–	–	–	–
	662	New/enlarging T2 lesions from BL to W48	0.76 (0.57–1.00)	0.049	0.84 (0.63–1.12)	0.23	7.0	1.17 (1.05–1.3)	0.004	33%
	612	% Brain volume change from BL to W48	0.68 (0.51–0.91)	0.009	0.67 (0.5–0.89)	0.006	0.74	0.81 (0.71–0.91)	0.0007	−4.3%
	463	CDP24 ∼ arm + log10 (W48 pNfL)	0.71 (0.51–0.99)	0.045	0.73 (0.52–1.02)	0.064	0.20	1.23 (1.04–1.45)	0.013	6.4%

In persons with RMS, week 48 NfL shows elements of a surrogate biomarker, as addition of NfL to a Cox PH model that evaluates the impact of ocrelizumab treatment on CDP24 during the controlled treatment period reduces the treatment effect size compared with a model without NfL. Analysis is limited to the ITT study population with available week 48 data for candidate surrogate markers.

HR = hazard ratio; OCR = ocrelizumab; CDP24 = 24-week confirmed disability progression; NfL = neurofilament light; ITT = intention to treat.