Long-Term Safety and Efficacy of Eculizumab in Aquaporin-4 IgG-Positive NMOSD

Abstract

Objective: During PREVENT (NCT01892345), eculizumab significantly reduced relapse risk versus placebo in patients with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD). We report an interim analysis of PREVENT's ongoing open-label extension (OLE; NCT02003144) evaluating eculizumab's long-term safety and efficacy.

Methods: Patients who completed PREVENT could enroll in the OLE to receive eculizumab (maintenance dose = 1,200 mg/2 weeks, after a blinded induction phase). Safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis.

Results: Across PREVENT and the OLE, 137 patients received eculizumab and were monitored for a median (range) of 133.3 weeks (5.1-276.9 weeks), for a combined total of 362.3 patient-years (PY). Treatment-related adverse event (AE) and serious adverse event (SAE) rates were 183.5 in 100 PY and 8.6 in 100 PY, respectively. Serious infection rates were 10.2 in 100 PY in eculizumab-treated patients versus 15.1 in 100 PY in the PREVENT placebo group. No patient developed a meningococcal infection. At 192 weeks (3.7 years), 94.4% (95% confidence interval [CI], 88.6-97.3) of patients remained adjudicated relapse-free. The adjudicated annualized relapse rate was 0.025 (95% CI = 0.013-0.048) in all eculizumab-treated patients versus 0.350 (95% CI = 0.199-0.616) in the PREVENT placebo group. During the OLE, 37% of patients (44 of 119 patients) stopped or decreased background immunosuppressive therapy use.

Interpretation: This analysis demonstrates that eculizumab's long-term safety profile in NMOSD is consistent with its established profile across other indications. This analysis also demonstrated the sustained ability of long-term eculizumab treatment to reduce relapse risk in patients with AQP4-IgG+ NMOSD. ANN NEUROL 2021;89:1088-1098.

FIGURE 1

Patient disposition through July 31, 2019. ^aFifteen patients reached the end of PREVENT relapse‐free, and 26 patients entered the OLE following a relapse as determined by the treating physician. ^bSixty‐four patients reached the end of PREVENT relapse‐free, and 14 patients entered the OLE following a relapse as determined by the treating physician. ^cThe 13 patients who withdrew consent (patient decision) during PREVENT included 1 patient in the placebo group who did not wish to continue taking an investigational product, and 12 patients in the eculizumab group who withdrew for the following reasons: a change in life situation or moving to a different area (7 patients); unknown reasons (3 patients); ongoing AEs not related to study drug and difficult venous access (1 patient); and clinical trial fatigue (1 patient). ^dThe 7 patients who withdrew consent (patient decision) during the OLE included 4 in the placebo/eculizumab group for the following reasons: a change in life situation or moving to a different area (2 patients); to receive treatment with traditional Chinese medicine (1 patient); and unwillingness to continue study visits following an SAE at enrollment and 1 month on study (1 patient). Three patients in the eculizumab/eculizumab group withdrew for the following reasons: study dosing schedule and an AE described as urticaria (1 patient); inability to travel to the study site owing to back pain (1 patient); and a change in life situation (1 patient). AE = adverse event; OLE = open‐label extension; SAE = serious adverse event.

FIGURE 2

Clinical profiles of patients receiving eculizumab during PREVENT and the OLE who experienced adjudicated relapses. ARR = annualized relapse rate; EDSS = Expanded Disability Status Scale; IST = immunosuppressive therapy; NMOSD = neuromyelitis optics spectrum disorder; OLE = open‐label extension.

FIGURE 3

Time to first adjudicated relapse during eculizumab treatment during the PREVENT OLE by treatment arm (OLE participants, N = 119). Patients who did not experience an adjudicated on‐trial relapse were censored at the OLE interim cutoff date. The tick marks indicate censoring of data. Proportions of patients who were relapse‐free at OLE weeks 48, 96, and 144 were estimated using the Kaplan–Meier product limit method. Ecu, eculizumab; OLE = open‐label extension.

FIGURE 4

Change from eculizumab baseline in EDSS score over time through 1 year in the combined PREVENT and OLE eculizumab group. *, **, and *** represent the 2‐sided nominal p value of 0.05, 0.01, and 0.001, respectively, testing whether the LS mean change from baseline equals 0. The LS mean, 95% CI, and p value are from a restricted maximum likelihood based repeated‐measures analysis of change from eculizumab baseline. The repeated‐measures model included terms of visit and baseline score. OLE visits at weeks 26, 40, and 52 are shown as weeks 24, 36, and 48, respectively. CI = confidence interval; EDSS = Expanded Disability Status Scale; LS = least‐squares; OLE = open‐label extension.

FIGURE 5

Change from eculizumab baseline in (A) HAI score, (B) mRS score, (C) EQ‐5D‐3L VAS and (D) EQ‐5D‐3L index score over time through 1 year in the combined PREVENT and OLE eculizumab group. *, **, and *** represent the 2‐sided nominal p value of 0.05, 0.01, and 0.001, respectively, testing whether the LS mean change from baseline equals 0. The LS mean, 95% CI, and p value are from a restricted maximum likelihood based repeated‐measures analysis of change from eculizumab baseline. The repeated‐measures model included terms of visit and baseline score. OLE visits at weeks 26, 40, and 52 are shown as weeks 24, 36, and 48, respectively. CI = confidence interval; EQ‐5D‐3L = 3‐level 5‐dimension EuroQol questionnaire; HAI = Hauser Ambulation Index; LS = least‐squares; mRS = modified Rankin Scale; OLE = open‐label extension; VAS = visual analog scale.