AAN 2023: Updates on role of ravulizumab in NMOSD and gMG

Dysregulation in the complement system is central to the pathogenesis of several diseases, including neuromyelitis optica spectrum disorder (NMOSD) and myasthenia gravis (MG). This article summarizes select presentations from the 2023 American Academy of Neurology (AAN) Annual Meeting covering the latest efficacy and safety data of ravulizumab, the long-acting complement component 5 (C5) inhibitor used to treat NMOSD and MG.

CHAMPION-NMOSD: Ravulizumab significantly reduced relapses in NMOSD
“Anti–aquaporin-4 antibody [AQP4 Ab]–positive NMOSD is a rare and severely disabling autoimmune inflammatory disease of the central nervous system [CNS],” said Dr Sean Pittock of the Center for Multiple Sclerosis and Autoimmune Neurology of the Mayo Clinic in Rochester, Minnesota, US. “It is characterized by unpredictable relapses that may result in irreversible neurological disability and death.” [Lancet Neurol 2007;6:805-815; Brain 2012;135:1834-1849; Neurology 2015;85:177-189; Front Neurol 2018;9:888; Nat Rev Dis Primers 2020;6:85; N Engl J Med 2022;387:631-639]

The phase III PREVENT trial previously demonstrated that Q2W intravenous (IV) administration of the short-acting C5 inhibitor and humanized monoclonal antibody, eculizumab, significantly lowered the risk of relapse in patients with AQP4-immunoglobulin G (IgG)–positive NMOSD by 94 percent vs placebo. [N Engl J Med 2019;381:614-625]

Ravulizumab is structurally related to eculizumab but has a longer elimination half-life, allowing a more prolonged dosing interval (Q8W). [PLoS One 2018;13:e0195909; Mult Scler Relat Disord 2020;46:102538] Its efficacy and safety in adult patients with AQP4 Ab–positive NMOSD is currently being investigated in the ongoing pivotal, open-label phase III CHAMPIONNMOSD trial. [Pittock S, et al, AAN 2023, abstract S5-002; Ann Neurol 2023;doi:10.1002/ana.26626]

Study design
CHAMPION-NMOSD included patients ≥18 years of age with confirmed AQP4 Ab–positive NMOSD, with at least one relapse in the last 12 months before screening and an Expanded Disability Status Scale (EDSS) score of ≤7, who were vaccinated against Neisseria meningitidis within 3 years of starting ravulizumab therapy (n=58). They received a weight-based IV loading dose (2,400–3,000 mg) of ravulizumab on day 1, followed by a weight-based maintenance dose (3,000–3,600 mg) on day 15 and Q8W thereafter.

Since eculizumab was already approved for NMOSD treatment when CHAMPION-NMOSD started, a placebo could not be used as a control in the trial. Instead, the placebo group (n=47) from eculizimab’s earlier PREVENT trial was used as an external comparator.

The primary efficacy endpoint was time to first adjudicated on-trial relapse and associated relapse risk reduction in the ravulizumab group vs the PREVENT placebo group. Secondary endpoints included adjudicated on-trial annualized relapse rate (ARR), and clinically important changes from baseline in Hauser Ambulation Index (HAI) score.

Zero relapses with ravulizumab
“At the end of the primary treatment period [ie, when all patients in the ravulizumab group had completed a minimum of 50 weeks of treatment or discontinued before that time point], the study met its primary endpoint, with no patients having adjudicated relapses with ravulizumab vs 20 patients in the placebo group having relapses [relapse risk reduction, 98.6 percent; p<0.0001; median follow-up period, 73.5 weeks for ravulizumab vs 36.0 weeks for placebo],” highlighted Pittock. (Figure) [Pittock S, et al, AAN 2023, abstract S5-002]

The ARR for ravulizumab was 0.00 (upper 95 percent confidence interval [CI], 0.04), which was significantly lower than the predefined comparator ARR (0.25; p<0.0001). Meanwhile, significantly fewer patients experienced clinically important HAI score worsening with ravulizumab (n=2/58; 3.4 percent) vs placebo (n=11/47; 23.4 percent; p=0.023; odds ratio, 0.16; 95 percent CI, 0.03–0.77). [Pittock S, et al, AAN 2023, abstract S5-002; Ann Neurol 2023;doi:10.1002/ana.26626]

No unexpected safety signals
“There were no new or unexpected safety signals reported in the trial,” Pittock continued. Any treatment-emergent adverse events (AEs) were reported in 91.4 percent of patients in the ravulizumab group, although these were mostly mild to moderate in severity. Two vaccinated patients experienced meningococcal infections but recovered with no sequelae after prompt management. No deaths were reported. [Ann Neurol 2023;doi:10.1002/ana.26626]

Conclusions
“CHAMPION-NMOSD showed that ravulizumab was associated with significantly lowered risk of relapse and HAI score worsening vs placebo, with no new safety signals identified,” said Pittock. “Ravulizumab represents a new potential therapy for adults with AQP4 Ab–positive NMOSD that combines strong efficacy, a favourable safety profile, and an 8-week dosing interval.”

CHAMPION MG: Ravulizumab in gMG
Aberrant complement activation is also involved in the pathogenesis of anti-acetylcholine receptor antibody (AChR Ab)–positive generalized MG (gMG). [Ann N Y Acad Sci 2018;1412:113-128; Immunotargets Ther 2020;9:317-331; Biochim Biophys Acta 2015;1852:651-657; F1000Res 2016;5:1513]

Current treatment options for gMG (ie, immunosuppressive therapies) are limited by their slow onset of action and associated long-term serious AEs. [Front Neurol 2020;11:981; Front Neurol 2020;11:538; Autoimmun Rev 2021;20:102712; Ther Adv Neurol Disord 2019;12:1756286419832242] Meanwhile, the phase III, randomized, double-blind, placebo-controlled CHAMPION MG trial previously demonstrated that weight-based dosing of ravulizumab for 26 weeks resulted in rapid and sustained improvements in both patient- and clinician-reported outcomes (ie, Myasthenia Gravis–Activities of Daily Living [MG-ADL] scale and Quantitative Myasthenia Gravis [QMG] total scores, respectively) in patients ≥18 years of age with AChR Ab–positive gMG. Ravulizumab’s safety profile also did not limit patients’ treatment. [NEJM Evid 2022;doi:10.1056/EVIDoa2100066]

Ravulizumab efficacy in gMG consistent regardless of previous IVIg treatment
“We conducted a subgroup analysis of CHAMPION MG to determine the differences in response to ravulizumab according to previous IV immunoglobulin [IVIg] treatment,” said Dr Glen Frick of Alexion, AstraZeneca Rare Disease in Boston, Massachusetts, US. Patients were divided into the following subgroups: no prior IVIg use, any (acute or chronic) IVIg use, or chronic IVIg use. [Bril V, et al, AAN 2023, poster P1.5-013]

A total of 96 patients received prior IVIg treatment (placebo, n=51; ravulizumab, n=45), with 46 having received prior chronic IVIg therapy (placebo, n=22; ravulizumab, n=24). The least squares (LS) mean changes in MG-ADL total score from baseline for ravulizumab vs placebo at week 26 were -2.1 (95 percent CI, -3.6 to -0.5), -1.3 (95 percent CI, -2.6 to 0.0), and -1.1 (95 percent CI, -2.8 to 0.6) in patients with history of no, any or chronic IVIg use, respectively. LS mean changes in QMG total scores from baseline vs placebo at week 26 were -2.4 (95 percent CI, -4.2 to -0.7), -1.6 (95 percent CI, -3.2 to -0.0), and -2.3 (95 percent CI, -4.6 to 0.1), respectively.

These results show that ravulizumab-treated patients with AChR Ab–positive gMG had improved muscle strength and daily function irrespective of any previous IVIg treatment.

First response achieved as early as week 2 after ravulizumab initiation
“We also conducted a post hoc subgroup analysis on the primary data of CHAMPION MG to determine the treatment responses of patients with AChR Ab–positive gMG in CHAMPION MG at earlier timepoints,” said Dr Ali Habib of the University of California in Irvine, California, US. [Habib A, et al, AAN 2023, poster P1.5-004]

Response was defined as improvement from baseline in either MG-ADL total score by ≥3 points or QMG total score by ≥5 points. Data were included from patients with MG-ADL total score of ≥6 at ravulizumab initiation who received ravulizumab in the randomized controlled or open-label extension period.

“Our analysis included 139 patients who were treated with ravulizumab for up to 60 weeks,” he noted. “Results showed that cumulative proportions of patients achieving MG-ADL response by weeks 2, 4, 12, 26, and 60 were 45.3 percent, 55.4 percent, 66.2 percent, 75.5 percent, and 82.0 percent, respectively. Median time to first MG-ADL response was 29.0 days [95 percent CI, 16.0–70.0].”

“Notably, first response to ravulizumab was achieved by almost half of patients with AChR Ab–positive gMG as early as week 2 after initiating treatment [ie, one ravulizumab infusion], and by twothirds of patients by week 12 after treatment initiation,” summarized Habib.

PK/PD analyses support Q8W ravulizumab dosing in NMOSD and gMG
“To help regulators understand the rationale behind ravulizumab’s prolonged dosing interval [ie, Q8W], we retrospectively analyzed the pharmacokinetics [PK] and pharmacodynamics [PD] of ravulizumab using data from CHAMPION-NMOSD,” explained Stephan Ortiz of Alexion, AstraZeneca Rare Disease in Boston, Massachusetts, US. “The PK study’s endpoint was maintenance of ravulizumab’s serum concentration above the predefined therapeutic threshold [175 μg/mL], while the PD endpoint was serum concentration of free C5 – both during the primary treatment period.” [Ortiz S, et al, AAN 2023, abstract S5-004]

A similar retrospective analysis was also performed using data from the randomized, placebo-controlled period of CHAMPION MG. [J Neurol 2023;doi:10.1007/s00415-023-11617-1]

In both analyses, target serum ravulizumab concentrations were achieved immediately after the loading dose (within 60 minutes in CHAMPION-NMOSD and within 30 minutes in CHAMPION MG). This was maintained throughout the treatment periods (ie, 50 weeks and 26 weeks, respectively), irrespective of age, body weight and body mass index. Inhibition of serum-free C5 in both trials was complete and sustained throughout the treatment periods. No treatment-emergent anti-drug antibodies were observed. [Ortiz S, et al, AAN 2023, abstract S5-004; J Neurol 2023;doi:10.1007/s00415-023-11617-1]

These PK/PD results support the use of ravulizumab Q8W for immediate, complete and sustained inhibition of terminal complement C5 in patients with APQ4 Ab–positive NMOSD and AChR Ab–positive gMG.

Summary
Results from CHAMPION-NMOSD and CHAMPION MG confirm the critical role of complement inhibition in patients with APQ4 Ab–positive NMOSD and AChR Ab–positive gMG. With its long elimination half-life, IV ravulizumab dosed Q8W represents a valid treatment option for these patients by providing early and sustained efficacy with acceptable tolerability.