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Safety in Lactation: Subfoveal choroidal neovascularisation

21 September 2020VEGF inhibitors are used for age-related macular degeneration, administered by intravitreal injection. They are also large molecules with a high molecular weight. These factors will…
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Refrigerated Storage

LucentisNovartis Pharmaceuticals UK Ltd

Novartis Pharmaceuticals UK Ltd
Lucentis
Solution for injection and solution for injection in pre-filled syringe and vial, 10mg/ml

In the event of an inadvertent temperature excursion the following data may be used:

Prior to use, the unopened tray may be kept at room temperature (25°C) for up to 24 hours.

Contact Novartis Medical Information in all cases where a deviation from the recommended storage conditions has occurred. Details of the temperature excursion and the product batch number will be requested. Refer to the current BNF for company contact details.
Please also refer to the manufacturer’s product literature for recommended storage information at https://www.medicines.org.uk

Do not freeze.

Store in the original package in order to protect from light.

14 May 2020
London MI Service

Lactation Safety Information

Yes
Very limited published evidence of safety
Negligible levels anticipated in milk due to the drug’s properties
16 September 2020

New Medicines

LucentisRetinopathy of prematurity (ROP)

Information

Lucentis
Licence extension / variation
Novartis
Novartis

Development and Regulatory status

Launched
Launched
Phase III Clinical Trials
September 2019
Sep 19Licence change approved in EU [9].
Jul 19Recommended for EU approval by CHMP - the additional indication is "treatment of retinopathy of prematurity (ROP) with zone I (stage 1+, 2+, 3 or 3+), zone II (stage 3+) or AP-ROP (aggressive posterior ROP) disease." [7].
Dec 18Pre-registration in EU [6].
Mar 17Filings planned for 2018 [2].

Category

Vascular endothelial growth factor inhibitor
ROP develops in 16% of all premature births, the figure rising to around 60% of infants weighing less than 1500 g at birth and 65% for infants less than 1250 g; however, severe ROP is uncommon. A review in the USA in 2008 looked at 4.67 million live births. The total incidence of ROP was 0.12% overall and 7.35% for premature infants with hospital stay greater than 14 days [1].
Retinopathy of prematurity (ROP)
Intravitreal

Trial or other data

Sep 19PIII RAINBOW (n=225) study is published; it reports higher rate of treatment success (survival with no active retinopathy) with ranibizumab 0.2 mg vs. laser therapy, but this was of borderline statistical significance (80% vs. 66%; OR 2.19, 95% Cl 0.99–4.82, p=0.051) [8].
Sep 18Novartis announced that treatment with ranibizumab did not meet the primary endpoint in the global randomised, parallel-assignment, open-label, PIII RAINBOW trial (n=300), and marginally missed statistical significance for demonstrating superiority to laser surgery. However, since 80% of patients achieved treatment success with ranibizumab vs 66% with laser, the company still plans to file outside of the US for this indication [5].
Dec 17PIII RAINBOW trial (NCT02375971) completed [4].
Jun 16Novartis initiates the extension study RAINBOWExt in patients who were treated for ROP in the core RAINBOW study (CRFB002H2301E1; NCT02640664). The study intends to enrol approximately 300 patients in Belgium, Estonia, Hungary, Slovakia, Italy, Lithuania, Czech Republic and Austria [3].
Dec 15Novartis initiates the PIII RAINBOW trial to evaluate efficacy and safety of intravitreal ranibizumab compared with laser therapy for the treatment of infants born prematurely with retinopathy of prematurity (CRFB002H2301; NCT02375971). The randomised, parallel-assignment, open-label, controlled trial intends to enrol 300 patients in Austria, Belgium, Croatia, Czech Republic, Estonia, France, Slovakia, Denmark, Finland, Poland, Greece, Germany, Hungary, India, Italy, Japan, Lithuania, Turkey and the UK [3].

Evidence based evaluations

25 July 2019EPAR

LucentisModerately-severe to severe non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR)

Information

Lucentis
Licence extension / variation
Novartis
Novartis

Development and Regulatory status

Launched
Launched
Launched
November 2019
Nov 19Approved in EU for treatment of proliferative diabetic retinopathy (PDR) in adults [13].
Sep 19Recommended for EU approval by CHMP - the additional indication is treatment of proliferative diabetic retinopathy (PDR) in adults [12].
Dec 18Pre-registration in EU [11].
Mar 18FDA approves Lucentis 0.3 mg prefilled syringe (PFS) for treatment of all forms of diabetic retinopathy. The FDA granted priority review for treatment of diabetic retinopathy without diabetic macular oedema based on results from the PIII Protocol S trial [7,8].
Feb 15Approved in the US to treat diabetic retinopathy in patients with diabetic macular oedema. Approval is based on two PIII studies involving 759 participants who were treated and followed for three years. Patients injected with Lucentis showed significant improvement in the severity of their DR at two years compared to patients who did not receive an injection [5].
Dec 14FDA assigns ranibizumab breakthrough therapy status as a treatment for diabetic retinopathy [4].
Oct 14US FDA has accepted the supplemental Biologics License Application (sBLA) and granted Priority Review of ranibizumab for the treatment of diabetic retinopathy. The FDA confirmed action date is February 6, 2015.
Aug 14Genentech submits a supplemental Biologics License Application for ranibizumab to the US FDA for treatment of diabetic retinopathy. The submission is based on results of the RISE and RIDE sham treatment-controlled Phase III trials [1].

Category

Vascular endothelial growth factor inhibitor
In pts with type 1 diabetes, proliferative retinopathy affects about 40% after 20 years. Maculopathy affects 10-20% of pts. In type 2 diabetes, these changes may be found at diagnosis because subclinical hyperglycaemia may have been present for a prolonged preceding period. Over 25 years, there is a significant cumulative rate of progression to diabetic retinopathy (83%), to diabetic macular oedema (29%) and clinically significant macular oedema (17%) [2].
Moderately-severe to severe non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR)
Intravitreal

Further information

Yes
Suspended

Trial or other data

Nov 18Other trials being used in support of the EU licence application will be the completed PIII REVEAL and RESTORE trials. The PIII REVEAL trial assessed ranibizumab 0.5mg as adjunctive therapy to laser photocoagulation and/or monotherapy in 390 Asian patients with visual impairment due to DMO, from China, Hong Kong, Japan, South Korea, Singapore and Taiwan (NCT00989989). The PIII RESTORE trial of ranibizumab in 345 patients with visual impairment due to DMO (NCT00687804) was conducted in Australia, Belgium, Canada, France, Germany, Greece, Hungary, Italy, Netherlands, Spain, Switzerland, Turkey and the UK. The study was designed to confirm the efficacy and safety of intravitreal injections of ranibizumab 0.5mg as adjunctive therapy to laser photocoagulation and/or monotherapy. The primary endpoint was the mean change in BCVA from baseline to the average level from months 1-12. One-year results were presented in May 2010. The study met its primary endpoint (both ranibizumab arms p < 0.0001 vs laser alone). An open-label 2-year extension of the RESTORE trial evaluating individualised ranibizumab treatment in 240 patients was completed in April 2012; favourable results have been reported (NCT00906464) [6,7].
Nov 18Lucentis is currently licensed in the EU for treatment of visual impairment due to diabetic macular oedema [10].
Feb 18PIII Protocol S trial to compare ranibizumab treatment with panretinal laser treatment in 305 patients with proliferative diabetic retinopathy, with and without diabetic macular oedema, completes in the US (NCT01489189) [9].
Oct 14RISE and RIDE were two identical phase 3 studies (n=759). Pts randomised to receive monthly treatment with 0.3 mg or 0.5 mg ranibizumab or sham injection. The primary objective was to evaluate the safety, tolerability and efficacy of ranibizumab in DME patients as measured by the primary efficacy endpoint of percentage of subjects gaining = 15 letters in best corrected visual acuity (BCVA) score compared with baseline at 24 months. At Month 24, an exploratory analysis demonstrated a higher proportion of patients treated with ranibizumab had observed a three-step or more improvement of their disease compared to sham, as determined by color fundus photography.The benefits of ranibizumab treatment achieved at Month 24 were maintained through Month 36 [3].
Oct 14The US FDA submission is based on results of the RISE and RIDE Phase III trials in which meaningful improvements in the disease were observed in a clinically significant proportion of diabetic retinopathy patients treated with ranibizumab at two years compared to patients treated with sham injections (control group). Benefits of ranibizumab treatment were maintained during year three of treatment. The safety in the RISE and RIDE Phase III trials was consistent with previous studies [3].

Evidence based evaluations

Information

New formulation
Roche
Roche

Development and Regulatory status

None
Pre-registration (Filed)
Pre-registration (Filed)
Jun 21US FDA accept NDA; a decision is expected by 23/10/21 [14].
Apr 21Filed in EU. Rolling submission to FDA almost complete [13].
Feb 21EU filing now expected 2021 [12].
Feb 21Rolling submission to the US was initiated in 2020 [12].
Jul 20Roche announces results from the Archway study will be submitted to health authorities around the world, including the U.S. FDA and the EMA for consideration of regulatory approval for the treatment of nAMD [11].
Apr 20Roche pipeline lists planned filing for AMD in 2020 [7]
Oct 19EU & US filings now expected earlier in 2020 [6].
Jul 18Filings planned for 2021 or later [4].

Category

First-ever eye implant to achieve sustained delivery of ranibizumab, a vascular endothelial growth factor inhibitor.
About 1 in 100 people aged 65-75, and about 1 in 8 people aged over 85 have ARMD severe enough to cause serious visual loss. About twice as many women over the age of 75 have ARMD compared with men of the same age [1]. The wet (neovascular) form is less common but results in more serious loss of vision. the incidence of wet AMD in England is around 4.8% of those aged over 65 [2].
Wet age-related macular degeneration (AMD) - port delivery system
Implantation

Trial or other data

Dec 20PIIIb VELODROME trial (NCT04657289; Study WR42221) is planned to start recruiting May 2021 (n=442). This global, multicentre, randomised, visual assessor-masked study is designed to assess the efficacy, safety, and pharmacokinetics of the Port Delivery System with ranibizumab (PDS) 100 mg/mL delivered every 36 weeks (Q36W) compared with every 24 weeks (Q24W) in patients with neovascular age-related macular degeneration (nAMD). The study is expected to complete in Sep 2023 [10].
May 20Positive topline results from the randomised, multicentre, open-label PIII Archway study reported the primary endpoint was met among pts with the PDS who received refills every 6 months. The PDS was also generally well-tolerated with a favorable benefit-risk profile. The primary endpoint of the trial was the change in BCVA from a baseline at the average of Week 36 and Week 40.[8]
Jun 19Recruitment completes in PIII Archway study [6].
Apr 19PII LADDER study published in Ophthalmology 2019. pii: S0161-6420(18)33328-1 [6].
Sep 18Positive primary data from LADDER study presented at ASRS 2018 [5].
Sep 18First patient enrolled in PII/III Portal extension study (NCT03683251). 500 patients from LADDER or Archway will receive refills of 100mg/ml ranibizumab every 24 weeks; patients without the PDS will receive the PDS and subsequent refills. Primary outcome is safety [5].
Sep 18First patient enrolled in PIII Archway study (NCT03677934). 360 patients will be randomised to the ranibizumab PDS every 24 weeks or intravitreal ranibizumab every 4 weeks. Primary outcome is change in BCVA from baseline at the average of week 36 and week 40 [5].
May 18PII LADDER trial completes collection of primary outcome data [4].
Sep 17Recruitment complete in PII LADDER study [3].
Sep 15PII LADDER trial starts (NCT02510794). This is a 4-arm study in which 200 patients will be randomised to one of three ranibizumab formulations delivered via implant or Lucentis monthly intravitreal control injections. Primary outcome is time to first refill [3].

Evidence based evaluations

ByoovizNeovascular (wet) AMD; diabetic macular oedema; proliferative diabetic retinopathy; macular oedema secondary to RVO; choroidal neovascularisation

Information

Byooviz
Biosimilar
Biogen
Biogen

Development and Regulatory status

Phase III Clinical Trials
Recommended for approval (Positive opinion)
Pre-registration (Filed)
Jun 21Recommended for EU approval by CHMP – the full indication is “Byooviz is indicated in adults for: treatment of neovascular (wet) age-related macular degeneration (AMD); treatment of visual impairment due to diabetic macular oedema (DME); treatment of proliferative diabetic retinopathy (PDR); treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO); treatment of visual impairment due to choroidal neovascularisation (CNV). Byooviz will be available as a 10 mg/ml solution for injection [8].
Nov 20The FDA has accepted for review the Biologics License Application for SB11 [7].
Oct 20Samsung Bioepis have announced that the EMA has accepted for review the Marketing Authorisation Application for SB11, a proposed biosimilar referencing Lucentis [6].

Category

Biosimilar of ranibizumab, an anti-angiogenic antibody fragment targeted against the vascular endothelial growth factor-A (VEGF-A).
Neovascular (wet) AMD; diabetic macular oedema; proliferative diabetic retinopathy; macular oedema secondary to RVO; choroidal neovascularisation
Intravitreal

Trial or other data

May 20Primary endpoints met in a randomised, double-blinded, PIII trial comparing efficacy, safety and immunogenicity of SB11 vs. Lucentis® in pts with nAMD, demonstrated equivalent efficacy in terms of change in BCVA at wk 8 and CST at wk 4. The mean change in BCVA was 6.2 letters for SB11 vs. 7.0 letters for Lucentis. The mean change in CST was −108.4 μm for SB11 vs −100.1 μm for Lucentis. The incidence of side effects was similar (66%) with both. [5]
Dec 19Samsung Bioepis and Biogen enter into an agreement to commercialise ranibizumab biosimilar in USA, Canada and Europe [4].
Feb 19PIII trial NCT03150589 has completed recruitment [3].
Mar 18PIII trial to evaluate the efficacy, safety, pharmacokinetics and immunogenicity of SB11 compared to Lucentis® in subjects with neovascular age-related macular degeneration starts (SB11G31AMD; NCT03150589). Evaluation of the change from baseline in Best Corrected Visual Acuity (BCVA) and Central Subfield Thickness (CST) are the defined primary endpoints of the trial. The trial intends to enrol approximately 704 patients in the US, Czech Republic, Germany, Hungary, India, South Korea, Poland, Russia, the UK. Collection of primary outcome data is due to complete Dec 19 [1,2].

Information

Xlucane
Biosimilar
Thornton & Ross (parent company Stada)
Bausch & Lomb

Development and Regulatory status

None
Phase III Clinical Trials
Phase III Clinical Trials

Category

Intraocular anti-VEGF agent
The estimated prevalence of AMD in the UK is 4.8% of those over 65 years of age and 12.2% of those aged 80 years or more. There are around 70,000 new diagnoses in the UK each year. About 10% of all cases have wet (neovascular) AMD. Wet AMD accounts for about 60% of advanced AMD [1].
Wet age-related macular degeneration (AMD)
Intraocular

Evidence based evaluations

Information

ranibizumab biosimilar (FYB201)
Biosimilar
Teva
Coherus Biosciences

Development and Regulatory status

None
Pre-registration (Filed)
Phase III Clinical Trials
Jun 21Bioeq has positive pre-BLA filing meeting with US FDA [16].
Jun 21Formycon and Bioeq announce that marketing authorization application (MAA) for FYB201 has been submitted to the European Medicines Agency [15].
Mar 21Formycon and Bioeq announce their intention to obtain regulatory approval for ranibizumab biosimilar in Canada, Australia, the UK and Switzerland [12].
Mar 21Coherus Bioseciences has conducted a pre-BLA meeting with the US FDA for the planned submission of a BLA. It plans to launch in the US in 2023 if approved [12].
Mar 21Bioeq holds the exclusive global marketing rights for the product, and is actively seeking partners to out-license the drug. In Nov 19, Bioeq entered into an agreement with Coherus for the marketing and distribution of ranibizumab biosimilar in the US [12].
Mar 21Formycon plans to re-file its BLA-submission with the FDA in H1 2021. Submission to the EMA is expected to follow [14].
Sep 20In its latest half-year report, Formycon reports that its development activities in the second half of 2020 will focus on preparations for submission to the EMA and re-submission to the FDA [11].
Feb 20FDA requests additional data as the contract manufacturer of the active ingredient of FYB201 had moved part of the process equipment to another part of its site after batches of FYB201 for process qualification had already been produced. FDA has asked for additional data from the new production environment. As Formycon estimates this will take at least 4 months they have withdrawn the licence application and will resubmit after incorporating the new data [11].
Dec 19Filed in the US by licence partner Bioeq AG [10].
Dec 19Bioeq aims to file a license application with the Food and Drug Administration (FDA) before the end of 2019 and Coherus plans to launch the product on the US market in 2021 [9].
Dec 19Development going ahead in US in collaboration with Bioeq, who will distribute and market FYB201 [8].

Category

Intraocular anti-VEGF agent
About 1 in 100 people aged 65-75, and about 1 in 8 people aged over 85 have ARMD severe enough to cause serious visual loss. About twice as many women over the age of 75 have ARMD compared with men of the same age [3]. The wet (neovascular) form is less common but results in more serious loss of vision. the incidence of wet AMD in England is around 4.8% of those aged over 65 [4].
Wet age-related macular degeneration (AMD)
Intravitreal

Trial or other data

Jun 18PIII COLUMBUS-AMD trial completes [13].
May 18Interim top-line data from PIII COLUMBUS-AMD trial announced showing comparable efficacy between ranibizumab biosimilar (FYB 201) and Lucentis. The primary endpoint of the change in the best corrected visual acuity after eight weeks was achieved, and the confidence interval lies within the pre-defined equivalence limits [12].
Jan 17PIII trial comparing FYB201 with Lucentis (NCT02611778, COLUMBUS-AMD) started in August 2016, estimated final collection date for primary outcome data is March 2020 [6].
Nov 15Trial planned to start in Oct (see above) initiated. This PIII trial (EudraCT 2015-001961-20; COLUMBUS-AMD) plans to recruit 650 patients with sites across the EU (inc. UK) and US. The primary outcome is The primary efficacy endpoint is the change from baseline FCP retinal thickness evaluated by SD-OCT at one month [5].
Oct 15PIII trial initiated comparing FYB201 and Lucentis for efficacy and safety in neovascular age related macular degeneration [2].

Diabetic macular oedema - port delivery system

Information

Licence extension / variation
Roche
Roche

Development and Regulatory status

None
None
Phase III Clinical Trials

Category

First-ever eye implant to achieve sustained delivery of ranibizumab, a vascular endothelial growth factor inhibitor.
Diabetic macular oedema (DMO) the most common cause of visual impairment in diabetes mellitus. More than 3.3 million people have been diagnosed with diabetes in England and Wales (2017), and approximately 7% of people with diabetes may have DMO [1].
Diabetic macular oedema - port delivery system
Implantation

Trial or other data

Jun 18PIII COLUMBUS-AMD trial completes [13].
May 18Interim top-line data from PIII COLUMBUS-AMD trial announced showing comparable efficacy between ranibizumab biosimilar (FYB 201) and Lucentis. The primary endpoint of the change in the best corrected visual acuity after eight weeks was achieved, and the confidence interval lies within the pre-defined equivalence limits [12].
Jan 17PIII trial comparing FYB201 with Lucentis (NCT02611778, COLUMBUS-AMD) started in August 2016, estimated final collection date for primary outcome data is March 2020 [6].
Nov 15Trial planned to start in Oct (see above) initiated. This PIII trial (EudraCT 2015-001961-20; COLUMBUS-AMD) plans to recruit 650 patients with sites across the EU (inc. UK) and US. The primary outcome is The primary efficacy endpoint is the change from baseline FCP retinal thickness evaluated by SD-OCT at one month [5].
Oct 15PIII trial initiated comparing FYB201 and Lucentis for efficacy and safety in neovascular age related macular degeneration [2].

Diabetic retinopathy without centre-involved diabetic macular oedema

Information

Licence extension / variation
Roche
Roche

Development and Regulatory status

None
None
Phase III Clinical Trials

Category

First-ever eye implant to achieve sustsianed delivery of ranibizumab, a vascular endothelial growth factor inhibitor
In type 1 diabetes, microaneurysms start to appear after five years in 25% of cases, affect half of cases at 10 years and nearly all patients after 20 years. Proliferative retinopathy, as defined by a formation of new vessels, appears after 10 years and affects about 40% after 20 years. In type 2 diabetes, these changes may be found at diagnosis. Over 25 years, there is a significant cumulative rate of progression to DR (83%) [1].
Diabetic retinopathy without centre-involved diabetic macular oedema
Intravitreal