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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

Novartis Pharmaceuticals
Lucentis
10 mg/mL solution for injection (vial and pre-filled syringe)

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

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

Please also refer to the manufacturer’s product literature for recommended storage information at https://www.medicines.org.uk

26 January 2022
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

Information

Ongavia
Biosimilar
Teva
Coherus Biosciences

Development and Regulatory status

Approved (Licensed)
Pre-registration (Filed)
Pre-registration (Filed)
May 22The indication approved by the MHRA is use in adults for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to diabetic macular oedema, proliferative diabetic retinopathy, visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO), and visual impairment due to choroidal neovascularisation. It will be available as a 10 mg/ml solution for injection, and each vial contains 2.3 mg of ranibizumab in 0.23mL solution [19].
May 22MHRA grants MA for FYB201. Teva will market the biosimilar under name Ongavia throughout the UK [19]
Oct 21FDA accepts BLA for review with a target action date of August 2022 [18]
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 plans to re-file its BLA-submission with the FDA in H1 2021. Submission to the EMA is expected to follow [14].
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].
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) and selected other Lucentis indications
Intravitreal

Trial or other data

Oct 21Coherus announce PIII COLUMBUS-AMD study (n=477) demonstrated similarity of CHS-201 and reference product Lucentis in terms of clinical efficacy (mean change at 8 weeks from baseline in best corrected visual acuity=5.1 vs. 5.6 ETDRS letters, respectively), safety, and immunogenicity [17].
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].

Information

Susvimo
New formulation
Roche
Roche

Development and Regulatory status

None
Pre-registration (Filed)
Launched
Jan 22Susvimo is now available for prescribing in the US [17]
Oct 21Approved in US for intravitreal use via ocular implant for the treatment of people with wet, or neovascular, age-related macular degeneration (AMD) who have previously responded to at least two anti-vascular endothelial growth factor (VEGF) injections [16].
Jul 21FDA has granted priority review [15].
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

Further information

Yes

Trial or other data

Feb 22Two-year results of the Archway study showed vision was maintained by Susvimo pts and continued to be non-inferior to monthly ranibizumab injections. In addition, 95% of Susvimo pts were able to go six months without needing additional treatment in the second, third and fourth refill-exchange intervals. It was generally well tolerated and had a favourable safety profile [18]
Jan 22The US Prescribing label for Susvimo has a black box warning for 3-fold higher rate of endophthalmitis with the port delivery system vs monthly ranibizumab injections. In clinical trials, 2% of patients receiving an implant experienced an episode of endophthalmitis [17].
Jul 21First patient enrolled in PIII Velodrome study [15].
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

Information

Byooviz
Biosimilar
Biogen
Biogen

Development and Regulatory status

Licensed but not launched
Licensed but not launched
Launched
Jun 22US launch planned for 1 July. Byooviz is not licensed for diabetic macular oedema or diabetic retinopathy because the dosing formulation is different. List price will be $1,130 per single-use vial, a 40% discount from Roche ’s originator [12].
Sep 21Approved by MHRA with the same indications as in EU [11].
Sep 21Approved in US by FDA for the treatment of neovascular (wet) age-related macular degeneration (AMD), macular edema following retinal vein occlusion (RVO), and myopic choroidal neovascularization (mCNV). [10]
Aug 21Approved in the EU [9].
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).
Wet age-related macular degeneration (AMD) and selected other Lucentis indications
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].

Evidence based evaluations

Information

Ximluci (UK), Xlucane (EU)
Biosimilar
Thornton & Ross (parent company Stada)
Bausch & Lomb

Development and Regulatory status

None
Pre-registration (Filed)
Filing withdrawn
May 22Xbrane withdraws the BLA (Biologics License Application) for its investigational biosimilar candidate after receiving feedback from the FDA that complementary information is required for it to take the decision to accept the BLA and initiate the review. Xbrane will receive more information about the requested complementary information from the FDA in a few weeks, after which a firm timeline for re-submission of the BLA will be communicated. Provided that all requested information is satisfactory added, the BLA would be accepted for initiation of review latest 60 days post re-submission [10].
Feb 22Xbrane expected to file aBLA with FDA Q1 22 [8]
Dec 21Currently pre-registration in the EU [7].
Dec 21Thornton & Ross will be marketing ranibizumab as Ximluci in the UK and intends to apply for a licence for treatment of neovascular (wet) AMD, visual impairment due to diabetic macular oedema (DME), proliferative diabetic retinopathy, visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO), and visual impairment due to choroidal neovascularisation (CNV) [7].
Jun 21On basis of six month interim results from PIII Xplore trial STADA and Xbrane anticipate submitting MAA to EMA and BLA to FDA during second half of 2021 [6]
May 21Xbrane is the originator of Xlucane, and has an agreement with STADA for its development. Xbrane is responsible for development of the product until completion of the marketing authorization applications to EMA and FDA, as well as for supply of the finished pharmaceutical product. STADA will hold the marketing authorisations and will be responsible for sales and marketing of the product across all territories included in the agreement [5].
May 20Under the terms of the agreement with Stada, Bausch and Lomb will be responsible for the sales, marketing and all other commercialization efforts for the biosimilar candidate in the US and Canada following regulatory approval. STADA and Xbrane will be jointly responsible for finalising development of the biosimilar candidate. Xbrane will also provide commercial supply [5].
May 20Bausch + Lomb, a leading global eye health business, has entered into an exclusive licensing agreement with STADA Arzneimittel AG and its development partner, Xbrane Biopharma AB, to commercialise their ranibizumab biosimilar [3].

Category

Intraocular anti-VEGF agent. Will be available as vials (0.23mL, 10mg/mL) and pre-filled syringes (0.165mL, 10mg/mL).
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) and selected other Lucentis indications
Intravitreal

Trial or other data

May 22Xbrane announces that complete top-line data have been published from the Xplore clinical equivalence study for Xlucane. Xlucane met the primary outcome measure and no clinically significant differences were observed regarding secondary efficacy and safety measures [9].
Jun 21STADA and Xbrane announce that their ranibizumab biosimilar met primary endpoint in PIII Xplore trial. It demonstrated equivalent efficacy in Best Corrected Visual Acuity (BCVA) at week 8 and similar pharmacokinetic, safety and immunogenicity profile compared to Lucentis® [6]
Jul 20PIII Xplore trial (NCT03805100) is recruiting in several countries including the US and Europe (not UK). 580 adults aged 50 years and older will be enrolled. Primary outcome is change in Best Corrected Visual Acuity (BCVA) at week 8; collection of these data now due to complete Nov 20 [4].
Dec 18PIII Xplore trial (NCT03805100) is designed to confirm biosimilarity with regards to safety, efficacy and immunogenicity of Xlucane versus Lucentis® in patients with wet form of age-related macular degeneration (wAMD). Primary completion date May 2020 [1].

Evidence based evaluations

SusvimoDiabetic macular oedema - port delivery system

Information

Susvimo
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

SusvimoDiabetic retinopathy without centre-involved diabetic macular oedema - port delivery system

Information

Susvimo
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 - port delivery system
Intravitreal