Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study

Lee, Jong Wook; Fontbrune, Flore Sicre de; Lee, Lily Wong Lee; Pessôa, Viviani; Gualandro, Sandra Fátima Menosi; Füreder, Wolfgang; Птушкин, В. В.; Rottinghaus, Scott T.; Volles, Lori; Shafner, Lori; Aguzzi, Rasha; Pradhan, Rajendra; Schrezenmeier, Hubert; Hill, Anita

doi:10.1182/blood-2018-09-876136

Cited by 274 publications

(425 citation statements)

References 27 publications

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“…Moreover, crovalimab treatment resulted in clinically meaningful improvements in fatigue, physical functioning, and global health status/QoL, on average, and reflected the sustained and effective suppression of complement activation, comparing favorably with results reported for other C5 inhibitors in treatment-naive patients. 1,3,13 An excess of C5 binding sites has been reported to correlate with low incidence of BTH. 19 Using SMART, the accumulation of tC5 was limited, and eculizumab-pretreated patients experienced a major drop in tC5 (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

“…This compares to BTH event rates of 0 to 0.14 (ravulizumab) and 0.06 to 0.46 (eculizumab), as reported in recent phase 3 studies. 2,3 Given that these were conducted in well-controlled, label-dose, and moderate weight patient populations, crovalimab seems to have a favorable activity with regard to BTH event rate. It must be noted that BTH analysis was introduced post hoc, possibly limiting the comparability with pivotal trials of ravulizumab.…”

Section: Discussionmentioning

confidence: 99%

“…It must be noted that BTH analysis was introduced post hoc, possibly limiting the comparability with pivotal trials of ravulizumab. 2,3 A limitation of the study is the lack of a randomized design and a formal comparison arm. Our study uses a design in part 3 to allow for a switchover comparison on an individual patient level.…”

Section: Discussionmentioning

confidence: 99%

“…Paroxysmal nocturnal hemoglobinuria (PNH) is a life-threatening syndrome with sudden onset of hematuria, anemia, and thrombosis. Eculizumab 1 and ravulizumab 2,3 (recently approved in the United States, European Union, and Japan) are used to treat PNH; they reduce intravascular hemolysis and improve quality of life (QoL) and, likely, survival. 4,5 However, a prospective cohort study reported that IV eculizumab, at the label dose of 900 mg every 2 weeks, was not effective in all patients, delivering detectable hemolytic activity (CH50 .…”

Section: Introductionmentioning

confidence: 99%

“…6 In addition, no published data exist on patients treated with 1200 mg of eculizumab every 2 weeks switching to ravulizumab, because these patients were excluded from the pivotal trials. 2,3 For these patients, only IV treatment options are available at this time. 2 Furthermore, a single missense C5 heterozygous mutation (c.2654G→A, single nucleotide polymorphism [SNP]) in ;3% of the Japanese population is associated with a lack of response to eculizumab 7 and, likely, to ravulizumab as well, because both bind to the same epitope.…”

Section: Introductionmentioning

confidence: 99%

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The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria

Röth

Nishimura

Nagy

et al. 2020

Blood

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Complement C5 inhibition is the standard of care (SoC) for patients with paroxysmal nocturnal hemoglobinuria (PNH) with significant clinical symptoms. Constant and complete suppression of the terminal complement pathway and the high serum concentration of C5 pose challenges to drug development that result in IV-only treatment options. Crovalimab, a sequential monoclonal antibody recycling technology antibody was engineered for extended self-administered subcutaneous dosing of small volumes in diseases amenable for C5 inhibition. A 3-part open-label adaptive phase 1/2 trial was conducted to assess safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy in healthy volunteers (part 1), as well as in complement blockade–naive (part 2) and C5 inhibitor–treated (part 3) PNH patients. Twenty-nine patients were included in part 2 (n = 10) and part 3 (n = 19). Crovalimab concentrations exceeded the prespecified 100-µg/mL level and resulted in complete and sustained terminal complement pathway inhibition in treatment-naive and C5 inhibitor–pretreated PNH patients. Hemolytic activity and free C5 levels were suppressed below clinically relevant thresholds (liposome assay <10 U/mL and <50 ng/mL, respectively). Safety was consistent with the known profile of C5 inhibition. As expected, formation of drug-target-drug complexes was observed in all 19 patients switching to crovalimab, manifesting as transient mild or moderate vasculitic skin reactions in 2 of 19 participants. Both events resolved under continued treatment with crovalimab. Subcutaneous crovalimab (680 mg; 4 mL), administered once every 4 weeks, provides complete and sustained terminal complement pathway inhibition in patients with PNH, warranting further clinical development (ClinicalTrials.gov identifier, NCT03157635).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria

Röth

Nishimura

Nagy

et al. 2020

Blood

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Efficacy and Safety of Ravulizumab, a Complement C5 Inhibitor, in Adults With Amyotrophic Lateral Sclerosis

Genge,

van den Berg,

Frick

et al. 2023

JAMA Neurol

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ImportanceAdditional therapies for amyotrophic lateral sclerosis (ALS) are urgently needed. Immune-mediated complement activation may be involved in ALS pathogenesis as evidenced by the upregulation of terminal components; thus, complement inhibition could potentially slow progression.ObjectiveTo evaluate the safety and efficacy of the terminal complement C5 inhibitor ravulizumab in adults with ALS.Design, Setting, and ParticipantsThis double-blind, placebo-controlled, parallel-group, multinational, randomized, phase 3 clinical trial was conducted from March 30, 2020, to October 17, 2021, in 81 ALS specialty centers across 17 countries. A preplanned, unmasked, nonbinding interim futility analysis was conducted when 33% of participants had completed week 26, wherein a conditional power of less than 10% would halt the trial. A total of 478 individuals were screened, and 96 were excluded. Inclusion criteria were weight of 40 kg or more, fulfillment of the El Escorial diagnostic criteria, and a minimal prestudy Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) progression score of –0.3 points per month.InterventionsStudy treatment consisted of placebo or a weight-based dose of intravenous ravulizumab every 8 weeks until week 42. Participants could continue standard-of-care treatment.Main Outcomes and MeasuresThe primary end point was change from baseline in ALSFRS-R score at week 50 based on the Combined Assessment of Function and Survival (CAFS).ResultsA total of 382 participants were randomly assigned 2:1 to receive ravulizumab (n = 255; mean [SD] age, 58.6 [10.6] years; 94 female [36.9%] and 161 male [63.1%]) or placebo (n = 127; mean [SD] age, 58.0 [11.0] years; 58 female [45.7%] and 69 male [54.3%]). The interim analysis showed that the observed mean change from baseline in ALSFRS-R at week 50 was −14.67 points (SE, 0.89 points; 95% CI, −16.42 to −12.91 points) for ravulizumab and −13.33 points (SE, 1.22 points; 95% CI, −15.72 to −10.93 points) for placebo, with no significant difference between the groups (mean [SE] difference, −1.34 [1.46] points; 95% CI, −4.21 to 1.53 points). Based on these data, the trial was terminated for futility. The primary analysis at week 50 showed no significant difference in CAFS between groups (mean [SE], 5.5 [10.8] points; 95% CI, −15.7 to 26.6 points; P = .61). Overall incidence rates for treatment-emergent adverse events were similar for ravulizumab (204 participants [80.0%]) and placebo (108 participants [85.0%]).Conclusions and RelevanceThis trial rapidly showed that terminal complement C5 inhibition with ravulizumab did not slow functional decline in participants with ALS and that the safety profiles of ravulizumab and placebo were similar. Highly effective, novel treatments are critically needed to slow functional decline and extend survival in patients with ALS.Trial RegistrationClinicalTrials.gov Identifier: NCT04248465

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