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The licence and supporting evidence for eculizumab biosimilar

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Topics: BiosimilarsEculizumab

Two licensed eculizumab biosimilars are available: Bekemv and Epysqli. Learn about the licensed indications, supporting evidence and key differences.

Contents
  1. Licensed indications
    1. Soliris licence
    2. Bekemv licence
    3. Epysqli licence
    4. Unlicensed use
  2. Evidence for biosimilarity
    1. Bekemv
    2. Epysqli
  3. Differences between brands
    1. Diluent
    2. Sodium content
    3. Sorbitol
    4. pH of concentrate
    5. Stability
  4. NICE recommendations

Licensed indications

There are differences between the licensed indications for the reference product, Soliris, and biosimilar brands.

Eculizumab is designated as an orphan medicine. Patents for the orphan indications of paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS) have expired allowing biosimilar approvals for these indications. Patents for generalised myasthenia gravis (gMG) and neuromyelitis optica spectrum disorder (NMOSD) are still in force.

Soliris licence

Soliris is licensed for the following indications:

  • PNH in adults and children
  • aHUS in adults and children
  • Refractory gMG in patients aged 6 years and above who are anti-acetylcholine receptor (AChR) antibody-positive
  • NMOSD in adults who are anti-aquaporin-4 antibody-positive with a relapsing course of the disease

Bekemv licence

Bekemv is licensed for use in adults and children aged 2 and over for the following indication:

  • PNH
  • aHUS

Use in babies and young children below 2 years of age is contraindicated due to the presence of sorbitol as an excipient.

Epysqli licence

Epysqli is licensed for adults and children for:

  • PNH

A request for a licence extension for aHUS has been submitted to the MHRA. The manufacturer anticipates a decision in April 2024.

Unlicensed use

Use of an eculizumab biosimilar for a Soliris (reference product) indication still under patent, gMG or NMOSD, or use of Epysqli for aHUS would be considered unlicensed use.

If Soliris is currently being used for an unlicensed or off-label indication, then it will also be unlicensed or off-label if Bekemv or Epysqli are used instead.

Preparing to use eculizumab biosimilar provides links to commissioning statements for unlicensed uses of eculizumab.

Evidence for biosimilarity

The clinical efficacy, safety profile and immunogenicity of eculizumab biosimilars (Bekemv and Epysqli) and the reference product are similar. See the associated Public Assessment Reports for full details.

Bekemv

Two comparative studies were submitted to support the biosimilar licence application for Bekemv.

A published randomised, double-blind, parallel crossover efficacy and safety study in 42 adult patients with PNH demonstrated similarity in clinical efficacy between Bekemv and eculizumab reference product (900mg every 14 days). In all comparisons as determined by haemolysis measured by lactate dehydrogenase levels. Serum total and unbound eculizumab concentrations were also similar between treatment groups

A published randomised, double‐blind, single‐dose pharmacokinetic (PK)/ pharmacodynamic (PD) study of 300mg Bekemv, Soliris (US) or Soliris (EU) approved products in 219 healthy male adults demonstrated primary outcomes of PK and PD parameters were within pre-specified equivalence margins. Safety and immunogenicity profiles were also similar; no subjects developed neutralising antibodies.

The formulation used for the PK/PD study was the same formulation as Soliris; satisfactory analytical comparability assessments have been conducted to support formulation changes. The formulation used in the clinical study was comparable to the final commercial formulation.

Epysqli

Two comparative studies were submitted to support the biosimilar licence application for Epysqli.

A published randomised, double-blind, crossover study in patients with PNH compared eculizumab biosimilar to Soliris. At week 26, the mean difference in lactate dehydrogenase levels between Epysqli and Soliris were within pre-defined equivalence margins. Treatment groups were  comparable in terms of number of transfused red blood cell units, PK and PD parameters and adverse effects.

A published randomised, double‐blind, single 300mg dose, three arm study in 240 healthy subjects compared Epysqli with either EU or US Soliris products. Primary outcome results demonstrated bioequivalence as 90% confidence intervals for area under the concentration-time curve were within the pre-defined equivalence margins of 80% to 125% respectively. Secondary outcomes showed comparable PD, safety, immunogenicity between Epysqli and the reference product eculizumab.

Differences between brands

Comparisons of excipients and shelf life between eculizumab biosimilars and the reference product (Soliris):

Diluent

Soliris, Bekemv and Epysqli can be diluted with:

  • Sodium chloride 0.45% or 0.9%
  • Glucose 5%

Sodium content

Consider the sodium burden of the undiluted vials of eculizumab (see below) along with any burden related to chosen diluent.

Considering sodium content of medicines provides further information on sodium in medicines

Soliris (undiluted vials)

Each 300mg vial contains 500mmol of sodium

Bekemv (undiluted vials)

This product is essentially sodium free, in other words there is less than 1mmol of sodium (23mg) per 300mg dose.

Epysqli (undiluted vials)

This product is essentially sodium free prior to dilution, in other words there is less than 1mmol of sodium (23mg) per 300mg dose.

Each 300mg vial contains ~0.57mmol of sodium.

Sorbitol

Bekemv contains sorbitol (50mg/mL).

Take a detailed history with regard to hereditary fructose intolerance (HFI) prior to giving Bekemv; do not use in patients with HFI unless strictly necessary.

Use in babies and young children (below 2 years of age) is contraindicated, as they may not yet be diagnosed with HFI. Medicines containing sorbitol or fructose given intravenously may be life-threatening in this population.

Soliris and Epysqli do not contain sorbitol; therefore, there are no age restrictions to use in children.

pH of concentrate

Soliris and Epysqli are pH 7.0

Bekemv is pH 5.2

Stability

Comparisons of storage and in use stability between eculizumab biosimilars and the reference product (Soliris):

Undiluted vials

Store in a refrigerator (2°C to 8°C). The following brand specific excursions at room temperature are permitted providing the vials are stored in the original package.

Soliris

One single excursion of up to 3 days is permissible; after which the product can be put back in the refrigerator.

Bekemv

One single excursion up to 7 days is permissible; after which the product can be put back in the refrigerator.

Epysqli

One single excursion up to 2 months is permissible; after which the product can be put back in the refrigerator.

Following dilution

Following dilution, eculizumab biosimilars and reference products should be used immediately. Additional stability data is available for the eculizumab biosimilars if prepared in controlled and validated aseptic conditions.

Bekemv

Bekemv can be stored for 96 hours at 2°C to 8°C or up to 48 hours at room temperature.

Epysqli

Epysqli diluted in sodium chloride 0.45% or 0.9% can be stored for 3 months at 2°C to 8°C, followed by up to 72 hours at room temperature (up to 30°C) after removal from refrigeration.

Epysqli diluted in glucose 5% can be stored for 24 hours at 2°C to 8°C, followed by up to 24 hours at room temperature (up to 30°C) after removal from refrigeration.

NICE recommendations

Where NICE has already recommended the reference biological medicine, the same guidance will apply to the biosimilar. Biosimilars do not require a separate or additional Technology Appraisal (TA).

Eculizumab is recommended by NICE (HST1) for treating atypical haemolytic uraemic syndrome if coordinated through an expert centre.