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Longer term management of patients with aHUS

Switching to Biosimilar Eculizumab

Biosimilar eculizumab [Bekemv® (made by Amgen) and Epysqli® (made by Samsung Bioepis)] are now available for use in the NHS for the treatment of atypical haemolytic uraemic syndrome.

Patients with an existing diagnosis of aHUS currently on originator eculizumab can be switched to biosimilar eculizumab.

  • Due to the lack of evidence currently available in pregnancy we do not recommend biosimilar use in pregnancy, or patients actively planning pregnancy
  • Bekemv (Amgen) is not licensed for the under 2’s and patients with hereditary fructose intolerance, and should NOT be used in these patients.
  • Epysqli (Samsung) does not have this restriction and can be used in all ages

There has been extensive analytical characterisation, animal studies and PK/PD studies for both biosimilars however it should be noted that neither biosimilar has undergone a clinical trial in aHUS and comparative studies were performed in paroxysmal nocturnal haemoglobinuria due to the relative ease of studies in PNH vs aHUS

Given that the pathogenesis of both PNH and complement mediated aHUS are mediated through the terminal pathway of complement, the successful trials of the biosimilars have established no clinically meaningful differences in safety, purity, and potency in PNH for which the Soliris is licensed; as such efficacy and safety do not need to be re-established in aHUS.

 

Switch to biosimilar eculizumab

We believe biosimilar eculizumab is as efficacious as originator eculizumab.

We have been in communication with Amgen and Samsung Bioepis to ensure

  • drug availability in new/acute cases – this is discussed further here, in relation to patients with a new diagnosis of aHUS
  • logistics regarding switching patients who normally receive their drug in hospital – from originator to biosimilar eculizumab, in the form of a “how to” guide
  • logistics regarding switching patients who normally receive their drug via homecare – from originator to biosimilar eculizumab, in the form of a “how to” guide

 

Further guidance on the process of switching to biosimilar eculizumab are here.

Switching to Ravulizumab

NHS England agreed to fund the use of ravulizumab in aHUS patients from September 2021.

What is Ravulizumab?
Ravulizumab is a new long acting monoclonal antibody targeting C5. Ravulizumab was engineered from Eculizumab and targets the same epitope in C5. A histidine switch was performed in the complementarity-determining regions of eculizumab to preserve binding to C5 in serum but to allow dissociation of C5 from ravulizumab in the acidified endosome. Additionally amino acid alterations to the Fc region of eculizumab resulted in increased efficiency of neonatal Fc receptor- mediated recycling. This resulted in Ravulizumab having an increased half-life of ~52 days compared to ~11 days with Eculizumab. This resulted in up to an 8 week dosing interval with Ravulizumab versus 2 weekly with Eculizumab.

Switch to Ravulizumab
The NRCTC wrote to all patients eligible to switch therapies, inviting them to have an individualised consultation with their named NRCTC consultant, to discuss ravulizumab: how it works; effectiveness; and ultimately whether it was the right option for them to switch therapies.

Further guidance on the process of switching from eculizumab to ravulizumab are here.

Stopping Eculizumab in aHUS

Eculizumab is licenced for long term treatment of complement-mediated aHUS.

1. The decision to stop Eculizumab should be made on an individual patient basis considering factors that will influence the likelihood and consequences of a relapse.

a. The genetic / autoantibody status of the patient

b. The severity of the initial presentation

c. A previous history of relapsing TMA causing organ failure, for example transplant loss

2. Eculizumab should be continued for 6 months before withdrawal is considered. There is no evidence to support a recommendation of 6 months treatment. However it is known that there is a high risk of recurrence in patients treated with a short course of Eculizumab, suggesting that the trigger that precipitated the treated TMA may persist. In addition, after transplantation most recurrences of aHUS (>70%) occur within the first 6 months.

3. Patients should be monitored closely after withdrawal for evidence of relapse. This should be most intensive immediately after withdrawal as it is not known whether disease is controlled or in remission. However, there is no evidence to inform the frequency of testing, therefore the following is a suggested monitoring regime that is based on the monitoring protocol used in the SETS-aHUS study. In some patients, particularly after transplant, there is limited systemic evidence of a recurrent renal thrombotic microangiopathy (ie normal platelet, LDH, blood film and haptoglobins) and the only indication is a deterioration in renal function.

 

Time since last Eculizumab dose Time since last Ravulizumab dose Suggested monitoring
Week 0 Week 0 Baseline – FBC, U&E, LDH and urine P:Cr
Week 2 to 6 Weeks 8 to 12 Weekly – FBC, U&E, LDH and urine P:Cr
Week 6 to 26 Weeks 12 to 32 Fortnightly – FBC, U&E, LDH and urine P:Cr
Week 26 to 104 Weeks 32 to 110 Monthly – FBC, U&E, LDH and urine P:Cr


Monitoring of patients following withdrawal of eculizumab

  • Home monitoring with thrice weekly urinalysis is recommended. The patient is advised to return to hospital for evaluation if microscopic haematuria develops.
  • Patients should be informed about potential symptoms of relapse and advised to seek medical advice if these occur. They should also have the patient alert card (available from the NRCTC) to present to medical staff.
  • Regular blood test monitoring as suggested in the table.
  • Antibiotic prophylaxis should be continued for 4 weeks after the last dose of Eculizumab and 4 months after the last dose of Ravulizumab
  • Eculizumab should be available to treat relapse

 

SETS-aHUS

SETS-aHUS hopes to provide evidence for an alternative strategy for treatment of aHUS based on monitoring and treatment re-introduction rather than continuous Eculizumab treatment. We predict that: 

  •  Possibly over half of patients receiving maintenance Eculizumab treatment could be doing so unnecessarily but there is currently a lack of evidence to support this.
  •  Withdrawal of drug could lead to a reduction in the burden of treatment (intravenous injections every 2 weeks).
  • The potential complications associated with Eculizumab use could be avoided.
  •  A system of surveillance will be needed to detect relapse early for rapid re-initiation of treatment to avoid complications associated with untreated relapse. 

Further details of the SETS-aHUS trial that completed recruitment in 2022 can be found here. 

organ

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Eculizumab and Pregnancy

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Shared Care

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