Benefits of eculizumab in AQP4+ neuromyelitis optica spectrum disorder: Subgroup analyses of the randomized controlled phase 3 PREVENT trial

Palace, Jacqueline; Wingerchuk, Dean M.; Fujihara, Kazuo; Berthele, Achim; Oreja‐Guevara, Celia; Kim, Ho Jin; Nakashima, Ichiro; Lévy, Michaël; Terzı, Murat; Totolyan, Natalia; Shanthi, Vissa; Wang, Kai-Chen; Pace, Amy; Yountz, Marcus; Miller, Larisa; Armstrong, R; Pittock, Sean J.

doi:10.1016/j.msard.2020.102641

Cited by 29 publications

(19 citation statements)

References 27 publications

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“…This interim analysis of the OLE provides data on the long-term safety and efficacy of eculizumab from more than twice the number of PY of eculizumab exposure than in PREVENT (median treatment duration of almost 2.5 years). The combined PREVENT and interim OLE eculizumab safety data reported here are consistent with its known safety profile in patients with AQP4-IgG+ NMOSD 11,15 and with its well-characterized safety profile in its other approved indications, paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and generalized myasthenia gravis, based on clinical trial data and more than 10 years of postmarketing experience. [19][20][21][22][23][24] No new safety signals were observed between the primary analysis of PREVENT and this interim analysis of the OLE.…”

Section: Discussionsupporting

confidence: 81%

“…11,12 This benefit of eculizumab was seen across a wide range of patient subgroups based on concomitant immunosuppressive therapy (IST) and past rituximab use, geographical region, age, race, sex, disease duration, relapse history, and disability status. 15 The safety profile of eculizumab in AQP4-IgG+ NMOSD was consistent with that seen for eculizumab in other approved indications. 11,14 We report an interim analysis (data cutoff date was July 31, 2019) of combined data from PREVENT and its ongoing open-label extension (OLE) on the long-term safety and efficacy of eculizumab in patients with AQP4-IgG+ NMOSD.…”

supporting

confidence: 75%

“…Rates of serious infections were, however, similarly low with eculizumab and placebo, and relapse risks were reduced with eculizumab compared with placebo regardless of prior rituximab use. 15 These results indicate that use of rituximab more than 3 months before study entry did not impact the safety profile or the efficacy of eculizumab during PREVENT.…”

Section: Discussionmentioning

confidence: 70%

“…Because the effect of rituximab on B cells may be sustained for up to 6 to 12 months, peripheral B cells may still have been depleted during PREVENT in some members of both the eculizumab and placebo groups who had received rituximab more than 3 months (equivalent to approximately 5 half‐lives of rituximab) before study screening. Rates of serious infections were, however, similarly low with eculizumab and placebo, and relapse risks were reduced with eculizumab compared with placebo regardless of prior rituximab use 15 . These results indicate that use of rituximab more than 3 months before study entry did not impact the safety profile or the efficacy of eculizumab during PREVENT.…”

Section: Discussionmentioning

confidence: 74%

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

Wingerchuk

Fujihara

Palace

et al. 2021

Annals of Neurology

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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

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Section: Discussionsupporting

confidence: 81%

supporting

confidence: 75%

Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 74%

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

Wingerchuk

Fujihara

Palace

et al. 2021

Annals of Neurology

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“…We are unaware of factors that might explain these differences between populations. Post hoc analysis has demonstrated that the rates of trial agent-related AEs during PREVENT were similar in patients who received eculizumab with and without concomitant ISTs (217.2 AEs/100 PY and 196.1 AEs/100 PY, respectively) (Palace et al, 2021).…”

Section: Discussionmentioning

confidence: 95%

Eculizumab in Asian patients with anti-aquaporin-IgG-positive neuromyelitis optica spectrum disorder: A subgroup analysis from the randomized phase 3 PREVENT trial and its open-label extension

Kim

Nakashima

Shanthi

et al. 2021

Multiple Sclerosis and Related Disorders

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Background Eculizumab, a terminal complement inhibitor, significantly reduced the risk of relapse compared with placebo in patients with anti-aquaporin-4 immunoglobulin G-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) in the PREVENT trial. We report efficacy and safety analyses in Asian patients in PREVENT and its open-label extension (OLE).Methods PREVENT was a double-blind, randomized, phase 3 trial. Patients with AQP4+ NMOSD were randomly assigned (2:1) to receive intravenous eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo.

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Ravulizumab in Aquaporin‐4–Positive Neuromyelitis Optica Spectrum Disorder

Pittock

Barnett

Bennett

et al. 2023

Annals of Neurology

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Objective: CHAMPION-NMOSD (NCT04201262) is a phase 3, open-label, externally controlled interventional study evaluating the efficacy and safety of the terminal complement inhibitor ravulizumab in adult patients with antiaquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). Ravulizumab binds the same complement component 5 epitope as the approved therapeutic eculizumab but has a longer half-life, enabling an extended dosing interval (8 vs 2 weeks). Methods: The availability of eculizumab precluded the use of a concurrent placebo control in CHAMPION-NMOSD; consequently, the placebo group of the eculizumab phase 3 trial PREVENT (n = 47) was used as an external comparator. Patients received weight-based intravenous ravulizumab on day 1 and maintenance doses on day 15, then once every 8 weeks. The primary endpoint was time to first adjudicated on-trial relapse. Results: The primary endpoint was met; no patients taking ravulizumab (n = 58) had an adjudicated relapse (during 84.0 patient-years of treatment) versus 20 patients with adjudicated relapses in the placebo group of PREVENT (during 46.9 patient-years; relapse risk reduction = 98.6%, 95% confidence interval = 89.7%-100.0%, p < 0.0001). Median (range) study period follow-up time was 73.5 (11.0-117.7) weeks for ravulizumab. Most treatment-emergent adverse events were mild/moderate; no deaths were reported. Two patients taking ravulizumab experienced meningococcal infections. Both recovered with no sequelae; one continued ravulizumab treatment. Interpretation: Ravulizumab significantly reduced relapse risk in patients with AQP4+ NMOSD, with a safety profile consistent with those of eculizumab and ravulizumab across all approved indications.

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Benefits of eculizumab in AQP4+ neuromyelitis optica spectrum disorder: Subgroup analyses of the randomized controlled phase 3 PREVENT trial

Abstract: on behalf of the PREVENT Study Group, Benefits of eculizumab in AQP4+ neuromyelitis optica spectrum disorder: subgroup analyses of the randomized controlled phase 3 PREVENT trial, Multiple Sclerosis and Related Disorders (2020), doi:

Cited by 29 publications

References 27 publications

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

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

Eculizumab in Asian patients with anti-aquaporin-IgG-positive neuromyelitis optica spectrum disorder: A subgroup analysis from the randomized phase 3 PREVENT trial and its open-label extension

Ravulizumab in Aquaporin‐4–Positive Neuromyelitis Optica Spectrum Disorder

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