Novartis announced additional brolucizumab phase 3 results from year 2 (96 weeks) that reaffirmed its positive year 1 (48 weeks) findings. Brolucizumab met its primary endpoint of noninferiority versus aflibercept in best corrected visual acuity (BCVA) and exhibited superiority in key retinal outcomes at year one,1,2 and maintained robust visual gains in year 2 in patients with neovascular age-related macular degeneration (AMD).1 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.
Relative to aflibercept, fewer brolucizumab 6 mg patients with wet AMD had intraretinal fluid (IRF) and/or sub-retinal fluid (SRF) 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)]1[i]. 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 two1.
“Over 2 years, brolucizumab consistently dried retinal fluid better, a key goal for physicians treating patients with nAMD, and maintained robust visual gains, versus aflibercept,” Dr. Mark Toms, Chief Scientific Officer, Novartis Pharmaceuticals UK, said in a company news release. “These results further reinforce our confidence in brolucizumab as an important scientific advancement and support our goal of reimagining care for people living with nAMD, the leading cause of sight loss of adults in the UK.”
Additionally, brolucizumab 6 mg patients continued to demonstrate reductions in two further measures of fluid – central subfield thickness (CST) and subretinal pigment epithelium (sub-RPE) – at week 961:
- 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)1*.
- Fewer brolucizumab 6 mg patients had sub-RPE fluid: 11% for brolucizumab 6 mg vs. 15% for aflibercept in HAWK (P=0.1213), 17% vs. 22% (P=0.0371), respectively, in HARRIER1.
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.1 The most frequent ocular adverse events (≥5% of patients in any treatment arm) were reduced visual acuity, conjunctival haemorrhage, vitreous floaters, eye pain, dry eye, retinal haemorrhage, cataract and vitreous detachment1. The most frequent non-ocular adverse events were typical of those reported in a nAMD population; there were no notable differences between arms.1
About brolucizumab (RTH258)
Brolucizumab (RTH258) is a humanised single-chain antibody fragment (scFv) and the most clinically advanced, humanised single-chain antibody fragment to reach this stage of development. Single-chain antibody fragments are highly sought after in drug development due to their small size, enhanced tissue penetration, rapid clearance from systemic circulation and drug delivery characteristics.6,7,8
The proprietary innovative structure results in a small molecule (26 kDa) with potent inhibition of, and high affinity to, all VEGF-A isoforms.6,9 In preclinical studies, brolucizumab inhibited activation of VEGF receptors through prevention of the ligand-receptor interaction.6,8,9 Increased signalling through the VEGF pathway is associated with pathologic ocular angiogenesis and retinal oedema.10 Inhibition of the VEGF pathway has been shown to inhibit the growth of neovascular lesions, resolve retinal oedema and improve vision in patients with chorioretinal vascular diseases.11
About HAWK and HARRIER study design
With more than 1,800 patients across 400 centers worldwide, HAWK (NCT02307682) and HARRIER (NCT02434328) are the first and only global head-to-head trials in patients with nAMD that prospectively demonstrated efficacy at week 48 using a q12w/q8w regimen, with a majority of patients on q12w immediately following the loading phase through to Week 48.2,12,13 Both studies are 96-week prospective, randomised, double-masked multi-centre studies and part of the Phase III clinical development of brolucizumab.12,13
The studies were designed to compare the efficacy and safety of intravitreal injections of brolucizumab 6 mg (HAWK and HARRIER) and 3 mg (HAWK only) versus aflibercept 2 mg in patients with nAMD.12,13 In both trials, patients were randomised to either brolucizumab or aflibercept. Immediately following the 3-month loading phase, patients in the brolucizumab 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 at the time of study initiation.2,12,13
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, presence of retinal fluid (intraretinal fluid and/or subretinal fluid) and disease activity.2
At year 2, 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 haemorrhage (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 haemorrhage (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 haemorrhage (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
- 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. Presented at: The American Academy of Ophthalmology on October 27, 2018, Chicago.
- Dugel P, et al. HAWK & HARRIER: 48-week results of 2 multi-centered, randomized, double-masked trials of brolucizumab versus aflibercept for neovascular AMD. Presented at: The American Academy of Ophthalmology on November 10, 2017, New Orleans.
- Minassian DC, et al. Modelling the prevalence of age-related macular degeneration (2010-2020) in the UK: expected impact of anti-vascular endothelial growth factor (VEGF) therapy. Br J Ophthalmol. 2011 Oct;95(10):1433-6.
- Macualr Society. Wet AMD. Available at https://www.macularsociety.org/wet-amd. Accessed October 2018.
- Schmidt-Erfurth U, et al. Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA). Br J Ophthalmol. 2014;98:1144-1167.
- Escher D, et al. Single-chain antibody fragments in ophthalmology. Oral presentation at EURETINA congress. 2015. Abstract.
- Nimz EL, et al. Intraocular and systemic pharmacokinetics of brolucizumab (RTH258) in nonhuman primates. The Association for Research in Vision and Ophthalmology (ARVO) annual meeting. 2016. Abstract 4996.
- Gaudreault J, et al. Preclinical pharmacology and safety of ESBA1008, a single-chain antibody fragment, investigated as potential treatment for age related macular degeneration. ARVO Annual Meeting abstract. Invest Ophthalmol Vis Sci 2012;53:3025. http://iovs.arvojournals.org/article.aspx?articleid=2354604 (link is external). Accessed October 2018.
- Tietz J, et al. Affinity and Potency of RTH258 (ESBA1008), a Novel Inhibitor of Vascular Endothelial Growth Factor A for the Treatment of Retinal Disorders. IOVS. 2015; 56(7):1501.
- Qazi Y, et al. Mediators of ocular angiogenesis. J. Genet. 2009;88(4):495-515.
- Kim R. Introduction, mechanism of action and rationale for anti-vascular endothelial growth factor drugs in age-related macular degeneration. Indian J Ophthalmol. 2007;55(6):413-415.
- ClinicalTrials.gov. Identifier NCT02307682. Available at https://clinicaltrials.gov/ct2/show/NCT02307682 (link is external). Accessed October 2018.
- ClinicalTrials.gov. Identifier NCT02434328. Available at https://clinicaltrials.gov/ct2/show/NCT02434328 (link is external). Accessed October 2018.
- Chopdar A, et al. Age related macular degeneration. BMJ. 2003;26(7387):485-488.
- World Health Organization. Priority eye diseases: Age-related macular degeneration. Available athttp://www.who.int/blindness/causes/priority/en/index7.html (link is external). Accessed October 2018.
- NHS Choices. Macular Degeneration. Available at http://www.nhs.uk/Conditions/Macular-degeneration/Pages/Introduction.aspx (link is external). Accessed October 2018.
- National Eye Institute. Facts About Age-Related Macular Degeneration. Available athttps://nei.nih.gov/health/maculardegen/armd_facts (link is external). Accessed October 2018.
- NHS Choices. Macular degeneration – Symptoms. Available at http://www.nhs.uk/Conditions/Macular-degeneration/Pages/Symptoms.aspx (link is external). Accessed October 2018.
- van Lookeren Campagne M, et al. Mechanisms of age-related macular degeneration and therapeutic opportunities. J Pathol. 2014; 232(2):151-64. doi: 10.1002/path.4266.