Very limited published evidence of safety

Negligible levels anticipated in milk due to the drug’s properties

Sep 19 · Licence change approved in EU [9].

Jul 19 · Recommended 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 18 · Pre-registration in EU [6].

Mar 17 · Filings planned for 2018 [2].

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].

Sep 19 · PIII 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 18 · Novartis 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 17 · PIII RAINBOW trial (NCT02375971) completed [4].

Jun 16 · Novartis 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 15 · Novartis 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].

25 July 2019 · EPAR

NIHR

Nov 19 · Approved in EU for treatment of proliferative diabetic retinopathy (PDR) in adults [13].

Sep 19 · Recommended for EU approval by CHMP - the additional indication is treatment of proliferative diabetic retinopathy (PDR) in adults [12].

Dec 18 · Pre-registration in EU [11].

Mar 18 · FDA 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 15 · Approved 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 14 · FDA assigns ranibizumab breakthrough therapy status as a treatment for diabetic retinopathy [4].

Oct 14 · US 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 14 · Genentech 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].

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].

Nov 18 · Other 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 18 · Lucentis is currently licensed in the EU for treatment of visual impairment due to diabetic macular oedema [10].

Feb 18 · PIII 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 14 · RISE 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 14 · The 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].

EPAR

NIHR

SMC

Nov 20 · The FDA has accepted for review the Biologics License Application for SB11 [7].

Oct 20 · Samsung Bioepis have announced that the EMA has accepted for review the Marketing Authorisation Application for SB11, a proposed biosimilar referencing Lucentis [6].

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].

May 20 · Primary 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 19 · Samsung Bioepis and Biogen enter into an agreement to commercialise ranibizumab biosimilar in USA, Canada and Europe [4].

Feb 19 · PIII trial NCT03150589 has completed recruitment [3].

Mar 18 · PIII 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].

NIHR

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].

NIHR

Feb 21 · EU filing now expected 2021 [12].

Feb 21 · Rolling submission to the US was initiated in 2020 [12].

Jul 20 · Roche 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 20 · Roche pipeline lists planned filing for AMD in 2020 [7]

Oct 19 · EU & US filings now expected earlier in 2020 [6].

Jul 18 · Filings planned for 2021 or later [4].

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].

Dec 20 · PIIIb VELODROME trial (NCT03677934; 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 20 · Positive 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 19 · Recruitment completes in PIII Archway study [6].

Apr 19 · PII LADDER study published in Ophthalmology 2019. pii: S0161-6420(18)33328-1 [6].

Sep 18 · Positive primary data from LADDER study presented at ASRS 2018 [5].

Sep 18 · First 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 18 · First 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 18 · PII LADDER trial completes collection of primary outcome data [4].

Sep 17 · Recruitment complete in PII LADDER study [3].

Sep 15 · PII 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].

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].

Mar 21 · Coherus 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 21 · Bioeq 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 20 · In 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 20 · FDA 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 19 · Filed in the US by licence partner Bioeq AG [10].

Dec 19 · Bioeq 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 19 · Development going ahead in US in collaboration with Bioeq, who will distribute and market FYB201 [8].

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].

Jan 19 · PIII trial recruitment completed for NCT 2611778 (COLUMBUS-AMD) [7].

Jan 17 · PIII 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 15 · Trial 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 15 · PIII trial initiated comparing FYB201 and Lucentis for efficacy and safety in neovascular age related macular degeneration [2].