The licence and supporting evidence for ranibizumab biosimilars

Licensed indications

Byooviz, Ongavia, Rimmyrah and Ximluci are licensed in adults for the treatment of:

• neovascular (wet) age-related macular degeneration (AMD)
• visual impairment due to diabetic macular oedema (DMO)
• proliferative diabetic retinopathy (PDR)
• visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO)
• visual impairment due to choroidal neovascularisation (CNV)

These are the same licensed indications, in adults, as the originator product Lucentis.

Presentation

Not all biosimilar products will be in the same presentations as the originator product Lucentis.

Byooviz is available as:

• a vial-only pack
• a vial, filter needle and injection needle pack

Ongavia is available as:

• a vial-only pack

Rimmyrah and Ximluci are available as:

• a vial-only pack
• a vial and filter needle pack

Lucentis reference product is available as:

• a vial-only pack
• a vial and filter needle pack
• a pre-filled syringe

No ranibizumab biosimilars are currently available as a pre-filled syringe. Please refer to the individual SPCs for any additional requirements for administration.

Evidence supporting safety and efficacy

Byooviz

A randomised trial in 705 patients with untreated neovascular age-related macular degeneration, showed that the ranibizumab biosimilar (Byooviz) was clinically equivalent to the reference product when 0.5mg was given via intravitreal injection every 4 weeks for 48 weeks.

The first primary outcome was the change from baseline BCVA at 8 weeks. Equivalence was defined as a margin of 3 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. The second primary outcome was the change from baseline in central subfield thickness (CST) at 4 weeks. Equivalence was defined as a margin of 36 micrometres.

Ranibizumab biosimilar (Byooviz) and reference ranibizumab (Lucentis) showed mean improvements of +6.2 and +7.0 ETDRS letters respectively – an adjusted treatment difference of -0.8 letters with a 90% confidence interval ranging between -1.8 to +0.2 letters. For CST, the ranibizumab biosimilar (Byooviz) and reference ranibizumab (Lucentis) showed mean changes from baseline of -108 micrometres and -100 micrometres respectively. This was an adjusted treatment difference of -8 micrometres, with a 95% confidence interval ranging between -19 micrometres to +3 micrometres. These findings support the equivalent efficacy of the ranibizumab biosimilar (Byooviz) to the reference product.

The safety profile and immunogenicity of ranibizumab biosimilar (Byooviz) and the reference product were similar.

Ongavia

A randomised trial in 477 patients with newly diagnosed, treatment-naïve neovascular age-related macular degeneration, showed that the ranibizumab biosimilar (Ongavia) was clinically equivalent to the reference product when 0.5mg was given by intravitreal injection every 4 weeks for 48 weeks.

The primary outcome was change from baseline BCVA at 8 weeks before the third injection was given. Equivalence was defined as a margin of 3 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. The assessment of BCVA at 8 weeks has been endorsed by the regulatory authorities as being appropriate.

In the European relevant population of 429 patients, ranibizumab biosimilar (Ongavia) and reference ranibizumab (Lucentis) showed mean improvements of +5.2 and +6.0 ETDRS letters respectively – an adjusted difference of -0.7 letters with a 95% confidence interval ranging between -2.3 to +0.9 . These results support ranibizumab biosimilar (Ongavia) equivalence to the reference product.

The frequency and type of ocular adverse effects and immunogenicity were similar.

Rimmyrah

A randomised trial in 616 patients with newly diagnosed, treatment-naïve neovascular age-related macular degeneration, showed that the ranibizumab biosimilar (Rimmyrah) was clinically equivalent to the reference product when 0.5mg was given by intravitreal injection every 4 weeks for 48 weeks.

The primary outcome was the change at 8 weeks from baseline BCVA using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Equivalence was defined as a margin of 3.49 letters.

The ranibizumab biosimilar (Rimmyrah) and reference ranibizumab (Lucentis) showed mean improvements of +6.3 (± 9.13) and +7.3 (±8.82) ETDRS letters respectively. The 90% confidence interval (-2.23 to 0.13) of the difference between the 2 treatment groups (P = 0.1434) was within the predefined equivalence range. These results support ranibizumab biosimilar (Rimmyrah) equivalence to the reference product.

The safety profile and immunogenicity of ranibizumab biosimilar (Rimmyrah) and the reference product were similar.

Ximluci

A randomised trial in 582 patients with untreated neovascular age-related macular degeneration, showed that the ranibizumab biosimilar (Ximluci) was clinically equivalent to the reference product when 0.5mg was given via intravitreal injection every 4 weeks for 52 weeks.

The primary outcome was the change from baseline BCVA at 8 weeks using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Equivalence was defined as a margin of 3.5 letters.

The ranibizumab biosimilar (Ximluci) and reference ranibizumab (Lucentis) showed mean improvements of +4.6 and +6.4 ETDRS letters respectively – a difference of -1.8 letters. The 90% confidence interval for least-squares mean difference in change from baseline was within the predefined equivalence margin. These results support ranibizumab biosimilar (Ximluci) equivalence to the reference product.

The safety profile and immunogenicity of ranibizumab biosimilar (Ximluci) and the reference product were similar.

Differences between brands

Comparisons of administration, excipients and shelf life between ranibizumab biosimilars and the originator product Lucentis.

Administration

The ranibizumab biosimilar SmPCs all state that administration must be by a qualified ophthalmologist experienced in intravitreal injections. However, professional guidance covers administration by non-medical healthcare professionals, providing they have been fully trained in the technique of injection by an ophthalmic specialist doctor.

These requirements are the same as those for Lucentis.

Dilution

All ranibizumab products are administered via intravitreal injection. They do not require dilution prior to administration.

Excipients

All biosimilar products and the originator product Lucentis contain the same excipients.

Sodium content

All ranibizumab products can be considered sodium free. They do not list sodium as an excipient.

Other excipients of interest

Polysorbate 20

All ranibizumab products contain polysorbate 20.

Latex

All ranibizumab products are latex free.

Storage and stability

All ranibizumab products should be stored in a refrigerator (2°C to 8°C) and kept in the outer carton to protect from light.

Prior to use, the following unopened product may be stored within their expiry date at temperatures not exceeding 30°C, for a single period of up to 2 months:

• Byooviz vial for injection

Prior to use, the following unopened product may be stored within their expiry date at room temperature (25°C), for up to 48 hours:

• Ximluci vial for injection

Prior to use, the following unopened products may be stored within their expiry date at room temperature (25°C), for up to 24 hours:

• Lucentis, Ongavia and Rimmyrah vials for injection
• Lucentis pre-filled syringe

NICE recommendations

NICE recommends ranibizumab as a treatment option for most of the biosimilar licensed indications but does not differentiate between the different licensed anti-VEGF treatments available.

NICE guidance on treatment of age-related macular degeneration published in 2018 states that no clinically significant differences in effectiveness and safety of aflibercept, bevacizumab and ranibizumab were seen in the trials considered, so comparable regimes will be more cost effective if the agent has lower net acquisition, administration and monitoring costs.

For treatment of diabetic macular oedema, visual impairment caused by macular oedema secondary to retinal vein occlusion and choroidal neovascularisation associated with pathological myopia, NICE recommends ranibizumab as a treatment option.

NICE guidance on the management and monitoring of diabetic retinopathy recommends that anti-VEGF treatment can be offered to patients whose proliferative diabetic retinopathy remains active after complete panretinal photocoagulation. Currently, ranibizumab is the only anti-VEGF treatment licensed for proliferative diabetic retinopathy.

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

Update history