Eculizumab in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome: 10‐year pharmacovigilance analysis

Socié, Gèrard; Caby‐Tosi, Marie‐Pierre; Marantz, Jing L.; Cole, Alexander J.; Bedrosian, Camille L.; Gasteyger, Christoph; Mujeebuddin, Arshad; Hillmen, Peter; Walle, Johan Vande; Haller, Hermann

doi:10.1111/bjh.15790

Cited by 175 publications

(136 citation statements)

References 67 publications

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“…The long-term tolerability of eculizumab was consistent with its known adverse event profile from established indications [21][22][23][24][25], and no new safety signals were observed since the interim analysis of the open-label extension study [14].…”

Section: Discussionsupporting

confidence: 59%

‘Minimal symptom expression’ in patients with acetylcholine receptor antibody-positive refractory generalized myasthenia gravis treated with eculizumab

et al. 2020

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Background The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, doubleblind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension. Methods Attainment of 'minimal symptom expression' was evaluated using patient-reported outcome measures of gMG symptoms [MG activities of daily living scale (MG-ADL), 15-item MG quality of life questionnaire (MG-QOL15)] at the completion of REGAIN and during the open-label extension. 'Minimal symptom expression' was defined as MG-ADL total score of 0-1 or MG-QOL15 total score of 0-3. Results At REGAIN week 26, more eculizumab-treated patients achieved 'minimal symptom expression' versus placebo [MG-ADL: 21.4% vs 1.7%; difference 19.8%; 95% confidence interval (CI) 8.5, 31.0; p = 0.0007; MG-QOL15: 16.1% vs 1.7%; difference 14.4%; 95% CI 4.3, 24.6; p = 0.0069]. During the open-label extension, the proportion of patients in the placebo/eculizumab group who achieved 'minimal symptom expression' increased after initiating eculizumab treatment and was sustained through 130 weeks of open-label eculizumab (MG-ADL: 1.7 to 27.8%; MG-QOL15: 1.7 to 19.4%). At extension study week 130, similar proportions of patients in the eculizumab/eculizumab and placebo/eculizumab groups achieved 'minimal symptom expression' (MG-ADL: 22.9% and 27.8%, respectively, p = 0.7861; MG-QOL15: 14.3% and 19.4%, respectively, p = 0.7531). The long-term tolerability of eculizumab was consistent with previous reports. Conclusions Patients with AChR+ refractory gMG who receive eculizumab can achieve sustained 'minimal symptom expression' based on patient-reported outcomes. 'Minimal symptom expression' may be a useful tool in measuring therapy effectiveness in gMG. Trial registration ClinicalTrials.gov NCT01997229, NCT02301624.

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Section: Discussionsupporting

confidence: 59%

‘Minimal symptom expression’ in patients with acetylcholine receptor antibody-positive refractory generalized myasthenia gravis treated with eculizumab

et al. 2020

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“…5,22 A long-term study of eculizumab for the treatment of PNH showed an overall rate of 0.25 meningococcal infections per 100 patient-years, with almost all patients having previously received meningococcal vaccination. 23 In this study, patients were required to be vaccinated against meningococcal infection within 3 years before, or at the time of, initiating study treatment. No cases of meningococcal disease were reported by the time of data cut-off.…”

Section: Discussionmentioning

confidence: 99%

One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria naïve to complement inhibitor therapy: open-label extension of a randomized study

Schrezenmeier

Kulasekararaj

Mitchell

et al. 2020

Therapeutic Advances in Hematology

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Background: Ravulizumab, the only long-acting complement C5 inhibitor for adults with paroxysmal nocturnal hemoglobinuria (PNH), demonstrated non-inferiority to eculizumab after 26 weeks of treatment in complement inhibitor-naïve patients during a phase III randomized controlled trial. We present open-label extension results with up to 52 weeks of treatment. Methods: Patients assigned to ravulizumab every 8 weeks (q8w) or eculizumab every 2 weeks during the randomized primary evaluation period received ravulizumab q8w during the 26-week extension. Efficacy endpoints were lactate dehydrogenase (LDH) normalization, transfusion avoidance, breakthrough hemolysis (BTH), LDH levels, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and stabilized hemoglobin. Serum free C5 levels and safety were assessed. Outcomes as of the data cut-off (4 September 2018) were summarized using descriptive statistics. Results: Overall, 124 patients continued ravulizumab, and 119 switched from eculizumab to ravulizumab. During the extension, 43.5% and 40.3% of patients in the ravulizumab–ravulizumab and eculizumab–ravulizumab arms, respectively, achieved LDH normalization; 76.6% and 67.2% avoided transfusion. BTH decreased in the eculizumab–ravulizumab arm; no events were associated with free C5 ⩾0.5 μg/mL while receiving ravulizumab. Overall, 73.4% and 65.5% of patients in the ravulizumab–ravulizumab and eculizumab–ravulizumab arms, respectively, achieved stabilized hemoglobin. Similar proportions of patients achieved ⩾3-point improvement in FACIT-Fatigue at week 52 (ravulizumab–ravulizumab, 64.5%; eculizumab–ravulizumab, 57.1%). All patients maintained free C5 <0.5 μg/mL during the ravulizumab extension, including those who experienced C5 excursions ⩾0.5 μg/mL while receiving eculizumab during the primary evaluation period. Adverse events were comparable between groups and decreased over time. Conclusion: In adult, complement inhibitor–naïve patients with PNH, ravulizumab q8w for up to 52 weeks demonstrated durable efficacy and was well tolerated, with complete and sustained free C5 inhibition and a decreased incidence of BTH with no events associated with loss of free C5 control. Trial registration: ClinicalTrials.gov identifier, NCT02946463

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“…1). Eculizumab is approved by the FDA for the treatment of PNH, atypical haemolytic uraemic syndrome and, most recently, for refractory myasthenia gravis and NMOSD [164][165][166][167][168][169][170][171][172] .…”

Section: Targeting C5mentioning

confidence: 99%

Complement in neurological disorders and emerging complement-targeted therapeutics

2020

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The human complement system is an effector of innate and adaptive humoral immunity. The system comprises soluble membrane-bound proteins (opsonins) that act collectively to recognize pathogens and non-self material and subsequently initiate opsonization and phagocytosis or lysis of pathogens. The proteolytic fragments that derive from complement activation can be targeted by white blood cells and endothelial cells, leading to extravasation and migration of immune cells at the sites of inflammation. Other physiological functions of complement include timely removal of altered and senescent self, tissue remodelling, cell lysis, chemotaxis, opsonization, inflammation and immune cell stimulation 1-4. Complement activation products link the innate and adaptive immune systems by acting directly on receptors on T cells and B cells or by modulating dendritic cell functions 5-8. Disruption of the delicate coordination required for complement activation and control is fundamental in the pathogenic mechanism of several autoimmune neurological disorders, and is even emerging as a contributor in some neurodegenerative diseases. As a result, interest is increasing in targeting complement as a therapeutic approach to prevent ongoing tissue destruction in several difficult-to-treat neurological diseases. In this Review, we provide an overview of the main components of the initial complement activation pathways, the lytic pathway and the factors associated with inappropriate complement activation or control in disease initiation and progression. We consider the role of complement in the tissue destruction that is responsible for the genesis of the most common autoimmune neurological diseases, including complement-mediated myopathies, myasthenia gravis, neuropathies and CNS disorders. We also discuss the role of complement in some neurodegenerative disorders, including Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), Huntington disease, traumatic brain injury and even schizophrenia. Finally, we discuss emerging complement-targeted therapies, such as monoclonal antibodies, fusion proteins and cyclic peptides, that inhibit the functions of individual complement proteins, especially therapies that disrupt the lytic pathway. Some of these therapeutic agents have been approved or are being tested in phase I-III clinical trials and promise to change the therapeutic armamentarium for treatment of neurological conditions that respond poorly to existing immunotherapies.

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Eculizumab in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome: 10‐year pharmacovigilance analysis

Cited by 175 publications

References 67 publications

‘Minimal symptom expression’ in patients with acetylcholine receptor antibody-positive refractory generalized myasthenia gravis treated with eculizumab

‘Minimal symptom expression’ in patients with acetylcholine receptor antibody-positive refractory generalized myasthenia gravis treated with eculizumab

One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria naïve to complement inhibitor therapy: open-label extension of a randomized study

Complement in neurological disorders and emerging complement-targeted therapeutics

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