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Clinical Trials

Date: 2018-10-29

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the American Academy of Ophthalmology (AAO) 2018 Annual Meeting

Company: Alcon (USA -TX), a Novartis subsidiary (Switzerland)

Product: brolucizumab - RTH258

Action mechanism:

  • protein/antibody. Brolucizumab (RTH258) is a humanized single-chain antibody fragment (scFv). The proprietary innovative structure results in a small molecule (26 kDa) with potent inhibition of, and high affinity to, all VEGF-A isoforms. In preclinical studies, brolucizumab inhibited activation of VEGF receptors through prevention of the ligand-receptor interaction. Inhibition of the VEGF pathway has been shown to inhibit the growth of neovascular lesions, resolve retinal edema and improve vision in patients with chorioretinal vascular diseases.
  • Brolucizumab was initially designed by the Swiss company Esbatech. Alcon, a Novartis subsidiary, acquired Esbatech in  September 2009.

Disease: neovascular wet age-related macular degeneration (AMD)

Therapeutic area: Ophtalmological diseases

Country: USA

Trial details:

  • The study is a two-year, randomized, double-masked, multicenter, three-arm study comparing the efficacy and safety of RTH258 versus aflibercept in subjects with neovascular age-related macular degeneration. The purpose of this study is to compare RTH258 ophthalmic solution for intravitreal (IVT) injection at two dosage levels to aflibercept solution for IVT injection (2 mg) in subjects with untreated active choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) in the study eye. (NCT02307682)
  • HAWK and HARRIER are 96-week prospective, randomized, double-masked multi-center studies and part of the Phase III clinical development of RTH258. The studies were designed to compare the efficacy and safety of intravitreal injections of RTH258 6 mg and 3 mg (HAWK only) versus aflibercept 2 mg in patients with nAMD. The primary efficacy objective of HAWK and HARRIER trials was to confirm that RTH258 is non-inferior to aflibercept in mean change in best-corrected visual acuity (BCVA) from baseline to Week 48. Secondary endpoints include average mean change in BCVA from baseline over the period week 36-48, the proportion of patients on a q12w interval at week 48 and anatomical parameters. In both protocols, patients were randomized to either RTH258 or aflibercept. Immediately following the 3-month loading phase, patients in the RTH258 arms received a q12w dosing interval with an option to adjust to a q8w dosing interval based on masked disease activity assessments at defined visits. Aflibercept was dosed bi-monthly according to its label.

Latest news:

  • • On October 27, 2018, Novartis announced additional brolucizumab Phase III results from year two that reaffirmed its positive year one findings. Brolucizumab met its primary endpoint of non-inferiority versus aflibercept in best corrected visual acuity (BCVA) and exhibited superiority in key retinal outcomes at year one (48 weeks). Secondary endpoints at year two (96 weeks) reaffirmed superiority of brolucizumab 6 mg in reduction of retinal fluid, an important marker of disease activity in patients with neovascular age-related macular degeneration (nAMD)]. Approximately 20 to 25 million people are affected by nAMD, also known as wet AMD, a leading cause of blindness worldwide.
  • The year two HAWK and HARRIER findings demonstrated that fewer patients with nAMD had intra-retinal fluid (IRF) and/or sub-retinal fluid (SRF) - key markers used by physicians to determine injection frequency in clinical practice - with brolucizumab 6 mg versus aflibercept at week 96 [24% for brolucizumab 6 mg vs. 37% for aflibercept in HAWK (P=0.0001); 24% vs. 39%, respectively, in HARRIER (P<0.0001)].
  • Additionally, brolucizumab 6 mg patients continued to demonstrate reductions in central subfield thickness (CST) at week 96. An increase in CST in nAMD is an important measure of abnormal fluid accumulation and edema and may result in reduced vision. Absolute reductions in CST from baseline were -175 µm for brolucizumab 6 mg versus -149 µm for aflibercept in HAWK (P=0.0057) and -198 µm versus -155 µm, respectively, in HARRIER (P<0.0001).
  • Also at week 96, fewer brolucizumab 6 mg patients had sub-retinal pigment epithelium (sub-RPE) fluid (11% for brolucizumab 6 mg vs. 15% for aflibercept in HAWK; 17% vs. 22%, respectively, in HARRIER). Additionally, of the patients on brolucizumab 6 mg who successfully completed year one on a 12-week dosing interval, 82% in HAWK and 75% in HARRIER were maintained on a 12-week dosing interval in year two.
  • As previously announced, HAWK and HARRIER met their primary endpoint of non-inferiority in mean change in BCVA at week 48 with brolucizumab versus aflibercept. Brolucizumab maintained robust visual gains in year two, with mean change in BCVA of 5.9 letters for brolucizumab 6 mg versus 5.3 letters for aflibercept in HAWK, and 6.1 letters versus 6.6 letters, respectively, in HARRIER.
  • No new, previously unreported types of safety events were identified at week 96, and brolucizumab continued to be comparable to aflibercept with the overall incidence of adverse events balanced across all treatment groups in both studies. The most frequent ocular adverse events (>=5% of patients in any treatment arm) were reduced visual acuity, conjunctival hemorrhage, vitreous floaters, eye pain, dry eye, retinal hemorrhage, cataract and vitreous detachment. The most frequent non-ocular adverse events were typical of those reported in a nAMD population; there were no notable differences between arms.
  • These new 96-week data, based on pre-specified secondary endpoints from the HAWK and HARRIER trials, were presented at the American Academy of Ophthalmology (AAO) 2018 Annual Meeting as a follow-up to the year one data presented in November 2017 (see below). (Presentation: Dugel P, et al. Phase 3, randomized, double-masked, multi-center trials of brolucizumab versus aflibercept for neovascular AMD: 96-week results from the HAWK and HARRIER studies. The American Academy of Ophthalmology on October 27, 2018).
  • Brolucizumab met the primary efficacy objective of non-inferiority versus aflibercept in mean change in best-corrected visual acuity (BCVA) from baseline to week 48 with high statistical significance[2]. Additionally, brolucizumab demonstrated superiority in three secondary endpoints considered key parameters of nAMD: central subfield retinal thickness, retinal fluid (intraretinal fluid and/or subretinal fluid) and disease activity.
  • At year two, the most frequent ocular adverse events (>=5% of patients in any treatment arm) for brolucizumab 3 mg, 6 mg and aflibercept, respectively, in HAWK were conjunctival hemorrhage (10.9%, 8.1% and 8.9%), reduced visual acuity (9.5%, 6.1% and 8.1%), vitreous floaters (7.3%, 6.1% and 4.4%), eye pain (7.8%, 5.0% and 5.8%), retinal hemorrhage (3.9%, 5.8% and 5.6%), cataract (5.0%, 5.6% and 3.6%), vitreous detachment (6.7%, 5.3% and 5.3%) and dry eye (5.6%, 5.3% and 7.2%)[1]. The incidences of these events for brolucizumab 6 mg and aflibercept, respectively, in HARRIER were conjunctival hemorrhage (4.6% and 5.1%), reduced visual acuity (8.6% and 7.0%), vitreous floaters (4.1% and 1.4%), eye pain (3.5% and 5.1%), retinal hemorrhage (3.2% and 1.1%), cataract (3.0% and 11.7%), vitreous detachment (2.7% and 2.2%) and dry eye (2.7% and 3.0%)[1]. 
  • On September 22, 2018, Novartis announced a new data analysis showing that retinal fluid was detected less often in patients treated with brolucizumab (RTH258) 6 mg versus aflibercept over four visits between weeks 36 to 48.The data, from pre-specified secondary endpoints of the Phase III HAWK and HARRIER trials, were presented at EURETINA 2018 as a follow-up to data presented in November 2017. The data show that brolucizumab 6 mg had superior fluid resolution versus aflibercept over four visits during weeks 36 to 48. The 36- to 48- week analysis is noteworthy because it provides insight into the effect of maintenance treatment, an important clinical focus for a chronic disease like nAMD. Additionally, the analysis accounts for dosing interval differences between the two medicines. Due to the unique design of the HAWK and HARRIER trials, brolucizumab patients were dosed at various intervals, namely q12w with some adjusted to q8w based on disease activity. Aflibercept patients were dosed at q8w, per the label at the time of trial initiation.

  • In the pre-specified secondary analyses for weeks 36 to 48, patients treated with brolucizumab 6 mg in the HAWK and HARRIER trials had significantly fewer visits in which intraretinal fluid (IRF)/subretinal fluid (SRF) was observed. In HAWK, 47.5% of patients treated with brolucizumab 6 mg q12w or adjusted to q8w had no visits in which IRF/SRF was detected, compared to 42.5% of aflibercept patients (P=0.0012, reflecting distribution across all visits during weeks 36 through 48)[1]. In HARRIER, 53% of patients treated with brolucizumab 6 mg had no visits in which IRF/SRF was detected, compared to 45.5% of aflibercept patients (P=0.0001, reflecting distribution across all visits during weeks 36 through 48)[1]. Importantly, more than half of brolucizumab 6 mg patients were maintained on q12w dosing until week 48. 

  • As previously announced, HAWK and HARRIER achieved their primary endpoints of non-inferiority in mean change in best corrected visual acuity (BCVA) at week 48 with brolucizumab versus aflibercept. The key pre-specified secondary endpoint of non-inferiority in mean change in BCVA between weeks 36 and 48 was also met.

  • • On November 10, 2017,  Novartis announced further  results from two Phase III studies of brolucizumab versus aflibercept were presented at the American Academy of Ophthalmology (AAO) 2017 Annual Meeting. Results showed non-inferiority in primary endpoint, superiority in key retinal health outcomes, and long-lasting effect in patients with neovascular age-related macular degeneration.  In neovascular AMD, abnormal blood vessels leak fluid into the eye, ultimately causing damage and blindness. At week 16, relative to aflibercept, 35% fewer brolucizumab 6 mg patients showed presence of IRF and/or SRF in HAWK, and 33% fewer in HARRIER (P<0.0001 for both). Again at week 48, relative to aflibercept, 31% fewer patients on brolucizumab 6 mg had intra-retinal fluid (IRF) and/or sub-retinal fluid (SRF) in HAWK, and 41% fewer in HARRIER (P<0.0001 for both). The absence of fluid for patients in the brolucizumab arm suggests the potential for a long-lasting effect and decreased treatment need. Additionally, brolucizumab 6 mg patients demonstrated superior reductions in central subfield thickness (CST). In nAMD, an elevated CST-as measured by optical coherence tomography (OCT)-is a key indicator of abnormal fluid accumulation in the retina. Significantly improved CST reductions were evident at week 16 (P=0.0016 in HAWK and P<0.0001 in HARRIER) and at week 48 (P=0.0023 and P<0.0001, respectively).

  • Brolucizumab met the primary efficacy endpoint of noninferiority to aflibercept in mean change in best-corrected visual acuity (BCVA) from baseline to week 48 in both trials. These results were achieved while a majority of brolucizumab patients-57% in HAWK and 52% in HARRIER-were maintained on a q12w dosing interval immediately following the loading phase through week 48
  • Brolucizumab is the first and only anti-vascular endothelial growth factor (anti-VEGF) treatment for nAMD to demonstrate robust visual gains with a majority of patients maintained on a less-frequent 12-week (q12) treatment interval immediately following the loading phase in randomized clinical trials.  Active disease was observed in 23.5% of brolucizumab 6 mg patients versus 33.5% of aflibercept patients in HAWK, and in 21.9% of brolucizumab patients versus 31.4% of aflibercept patients in HARRIER (P=0.0022 for both).
  • Brolucizumab safety was comparable to aflibercept with the overall incidence of adverse events balanced across all treatment groups in both studies. The most frequent ocular adverse events (greater than 5% of patients in any treatment arm) for brolucizumab 3 mg, 6 mg and aflibercept, respectively, in HAWK were reduced visual acuity (8.7%, 6.9% and 8.9%), conjunctival hemorrhage (8.4%, 6.4% and 5.6%), vitreous floaters (6.7%, 5.0% and 3.1%) and eye pain (5.9%, 4.4% and 4.2%). The incidences of these events for brolucizumab 6 mg and aflibercept, respectively, in HARRIER were reduced visual acuity (5.9% and 6.2%), conjunctival hemorrhage (1.9% and 3.3%), vitreous floaters (3.0% and 0.8%) and eye pain (2.7% and 3.3%).
  • The most frequent non-ocular adverse events were typical of those reported in an nAMD population; there were no notable differences between arms. The incidence of arterial thrombotic events (ATE) was 3.9%, 2.5% and 5.5% (brolucizimab 3 mg, brolucizumab 6 mg and aflibercept respectively) in HAWK and 1.6% and 1.1% (brolucizumab 6 mg and aflibercept, respectively) in HARRIER.
  • • On June 20, 2017 , Novartis, reported that RTH258 (brolucizumab) 6 mg met the primary and key secondary endpoints in two Phase III studies, HAWK and HARRIER. RTH258 3 mg, evaluated in HAWK, also met these endpoints. These pivotal studies enrolled more than 1,800 patients with neovascular age-related macular degeneration across 400 centers worldwide. The primary and key secondary efficacy endpoints were non-inferiority of RTH258 to aflibercept in mean change in best-corrected visual acuity (BCVA) from baseline to week 48, and average mean change over the period of week 36-48, respectively.
  • RTH258 demonstrated long-lasting efficacy versus aflibercept dosed every eight weeks. A majority of patients, 57% (HAWK) and 52% (HARRIER), were maintained exclusively on a q12w (every 12 week) interval immediately following the loading phase through week 48.
  • • On February 27, 2015, Alcon announced that, following positive Phase II results, the company has initiated its Phase III clinical study program to evaluate the efficacy and safety of RTH258 versus aflibercept in patients with wet AMD. As part this innovative study program, Alcon expects to enroll approximately 1,700 patients in more than 50 countries worldwide. The primary objective of the first Phase III study is to compare the efficacy of RTH258 3mg and 6mg versus aflibercept 2mg, with the mean change in BCVA, from Baseline to Week 48 as the primary endpoint. The second study within the Phase III trial program will also compare the efficacy of RTH258 versus aflibercept, and is expected to commence in 2015. Patients participating in the Phase III studies will be dosed every three months with RTH258, while a bi-monthly-dosing regimen will be followed for those patients considered unsuitable for a quarterly dosing schedule due to disease activity. Aflibercept will be dosed according to its approved label.

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