Interventions for atypical haemolytic uraemic syndrome

Pugh, Dan; O’Sullivan, Eoin D.; Duthie, Fiona; Masson, Philip; Kavanagh, David

doi:10.1002/14651858.cd012862.pub2

Cited by 11 publications

(6 citation statements)

References 88 publications

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“…Studies investigating the treatment of CM-HUS with eculizumab, to be discussed later, typically enrolled about 100 patients and most have been nonrandomized. 23 In addition, there is difficulty in obtaining head-to-head comparisons between eculizumab and ravulizumab in the treatment of CM-HUS, again owed to the low prevalence and heterogeneity of the disease. For example, the 301 study, which demonstrated noninferiority of ravulizumab to eculizumab for PNH, consisted of 246 patients.…”

Section: Comparisons Between Pnh and Cm-husmentioning

confidence: 99%

“…Substantial improvements were observed in estimated glomerular filtration rate and QOL in patients in eculizumab and ravulizumab studies. 23 Another global phase III clinical trial, known as ALXN1210-aHUS-311, investigated outcomes of 58 patients with CM-HUS treated with ravulizumab over a 26-week period. The primary endpoint of complete thrombotic microangiopathy response (defined as normalization of platelet count and lactate dehydrogenase and 25% or more improvement in serum creatinine), was met in 53.6% of patients.…”

Section: Therapeutic Advancesmentioning

confidence: 99%

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Complement Inhibitors in the Management of Complement-Mediated Hemolytic Uremic Syndrome and Paroxysmal Nocturnal Hemoglobinuria

Begum¹,

Khan²,

Boisclair

et al. 2023

American Journal of Therapeutics

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Background:Complement-mediated HUS (CM-HUS) and paroxysmal nocturnal hemoglobinuria (PNH) are rare hematologic disorders that cause dysregulation and hyperactivation of the complement system. Historically, treatment of CM-HUS involved plasma exchange (PLEX), often with limited benefit and variable tolerance. Conversely, PNH was treated with supportive care or hemopoietic stem cell transplant. Within the last decade, monoclonal antibody therapies that block terminal complement pathway activation, have emerged as less invasive and more efficacious options for management of both disorders. This manuscript seeks to discuss a relevant clinical case of CM-HUS and the evolving landscape of complement inhibitor therapies for CM-HUS and PNH.Areas of Uncertainty:Eculizumab, the first humanized anti-C5 monoclonal antibody, has been the standard of care in treating CM-HUS and PNH for over a decade. Although eculizumab has remained an effective agent, the variability in ease and frequency of administration has remained an obstacle for patients. The development of novel complement inhibitor therapies with longer half-lives, has allowed for changes in frequency and route of administration, thus improving patient QOL. However, there are limited prospective clinical trial data given disease rarity, and limited information on variable infusion frequency and length of treatment.Therapeutic Advances:Recently, there has been a push to formulate complement inhibitors that improve QOL while maintaining efficacy. Ravulizumab, a derivative of eculizumab, was developed to allow for less frequent administration, while remaining efficacious. In addition, the novel oral and subcutaneous therapies, danicopan and crovalimab, respectively, along with pegcetacoplan are currently undergoing active clinical trials, and poised to further reduce treatment burden.Conclusion:Complement inhibitor therapies have changed the treatment landscape for CM-HUS and PNH. With a significant emphasis on patient QOL, novel therapies continue to emerge and require an in-depth review of their appropriate use and efficacy in these rare disorders.Clinical Case:A 47-year-old woman with hypertension and hyperlipidemia presented with shortness of breath and was found to have hypertensive emergency in the setting of acute renal failure. Her serum creatinine was 13.9 mg/dL; elevated from 1.43 mg/dL 2 years before. The differential diagnosis for her acute kidney injury (AKI) included infectious, autoimmune, and hematologic processes. Infectious work-up was negative. ADAMTS13 activity level was not low at 72.9%, ruling out thrombotic thrombocytopenic purpura (TTP). Patient underwent a renal biopsy, which revealed acute on chronic thrombotic microangiopathy (TMA). A trial of eculizumab was initiated with concurrent hemodialysis. The diagnosis of CM-HUS was later confirmed by a heterozygous mutation in complement factor I (CFI), resulting in increased membrane attack complex (MAC) cascade activation. The patient was maintained on biweekly eculizumab and was eventually transitio...

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Section: Comparisons Between Pnh and Cm-husmentioning

confidence: 99%

Section: Therapeutic Advancesmentioning

confidence: 99%

Complement Inhibitors in the Management of Complement-Mediated Hemolytic Uremic Syndrome and Paroxysmal Nocturnal Hemoglobinuria

Begum¹,

Khan²,

Boisclair

et al. 2023

American Journal of Therapeutics

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“…2 Over the last decade, eculizumab has become the standard of care in the treatment of aHUS, greatly improving patient outcomes as evidenced in published reports of clinical trials and real-world efficacy and safety data. [5][6][7][8][9][10][11][12][13] Eculizumab is a humanized monoclonal antibody that targets and inhibits complement component 5 (C5) and ablates terminal complement activation, which is a key component of the pathophysiology of aHUS. 5,[14][15][16][17][18] Ravulizumab, a next-generation complement C5 inhibitor, was developed by modifying the molecular structure of eculizumab and is also approved for the treatment of aHUS and paroxysmal nocturnal haemoglobinuria (PNH).…”

Section: What Is K Nown and Objec Tivementioning

confidence: 99%

Ravulizumab 100 mg/mL formulation reduces infusion time and frequency, improving the patient and caregiver experience in the treatment of atypical haemolytic uraemic syndrome

Dixon

Sabus

2022

Clinical Pharmacy Therapeu

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What is known and objective:The C5 inhibitor eculizumab is the standard of care for treatment of atypical haemolytic uraemic syndrome (aHUS). Ravulizumab, a nextgeneration C5 inhibitor, was engineered to have a longer terminal half-life than eculizumab. We describe practical benefits of the advanced ravulizumab 100 mg/mL formulation.Comment: Use of ravulizumab results in fewer maintenance infusions per year (25%-50%) compared with eculizumab. Maintenance infusion time of ravulizumab 100 mg/ mL is 2-4 times shorter than ravulizumab 10 mg/mL in all weight cohorts and approximately half that of eculizumab for patients weighing <40 kg. Ravulizumab 100 mg/mL requires fewer vials annually than eculizumab in most weight cohorts. What is new and conclusion:With ravulizumab 100 mg/mL, patients and caregivers experience fewer infusions per year and decreased annual infusion times, improving infusion experience. Infusion centres can expect corresponding decreases in resource utilization.

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“…aHUS has an incidence of 0.23 to 0.42 cases/million/year with a mortality rate of up to 25% during the acute phase. Around 50% of the patients that survive the acute phase require acute renal replacement therapy (RRT) which in most cases results in a chronic need for RRT [4].…”

Section: Introductionmentioning

confidence: 99%

Eculizumab Versus Ravulizumab for the Treatment of Atypical Hemolytic Uremic Syndrome: A Systematic Review

Shahid,

Qayyum

2023

Cureus

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Atypical hemolytic uremic syndrome (aHUS) is a type of thrombotic microangiopathy and is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney failure. The complement cascade plays an integral role in aHUS. Mutations in the complement cascade, especially in the alternative pathway (AP) lead to an unregulated and continuous activation of the cascade. Eculizumab and ravulizumab are humanized monoclonal antibodies that inhibit the complement cascade. This systematic analysis reviews the evidence for both antibodies to compare them in terms of safety and efficacy. This review will also assess the evidence for biomarker associations with interventions, the role of genetic mutations in the prognosis of disease, and the financial burden of both treatment options. An in-depth search was conducted across PubMed, Science Direct, and Cochrane Library following the PRISMA 2020 guidelines. Both eculizumab and ravulizumab were comparable in safety and efficacy but ravulizumab was preferred by patients and their caregivers as it posed a lower financial burden and had less frequent dosing. Soluble complement 5b-9 (sC5b), especially in urine, has the potential to be used as a biomarker to assess response to treatment. Genetic mutations, especially mutations in complement factor I (CFI), membrane cofactor protein (MCP), and complement factor H (CFH), were associated with a higher risk of recurrence, and therefore care should be taken when attempting to discontinue treatment in this subset of patients. Treatment with a monoclonal antibody should be initiated as soon as a genetic mutation is identified. Blinded, double-arm, clinical trials preferably with larger sample sizes are needed to effectively compare both the monoclonal antibodies.

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Interventions for atypical haemolytic uraemic syndrome

Cited by 11 publications

References 88 publications

Complement Inhibitors in the Management of Complement-Mediated Hemolytic Uremic Syndrome and Paroxysmal Nocturnal Hemoglobinuria

Complement Inhibitors in the Management of Complement-Mediated Hemolytic Uremic Syndrome and Paroxysmal Nocturnal Hemoglobinuria

Ravulizumab 100 mg/mL formulation reduces infusion time and frequency, improving the patient and caregiver experience in the treatment of atypical haemolytic uraemic syndrome

Eculizumab Versus Ravulizumab for the Treatment of Atypical Hemolytic Uremic Syndrome: A Systematic Review

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