Two-year head-to-head data for Novartis brolucizumab reaffirm superiority versus aflibercept in reducing retinal fluid in patients with nAMD
Oct 29, 2018
Year two HAWK and HARRIER results consistent with previously announced key secondary endpoint data on retinal fluid (IRF and/or SRF) showing superior reductions versus aflibercept
Superior reductions in central subfield thickness demonstrated at year one were reaffirmed at year two with brolucizumab 6 mg versus aflibercept
Robust visual gains shown in year one with brolucizumab were maintained in year two
Frimley, October 27, 2018– Novartis today announced additional brolucizumab Phase III results from year two (96 weeks) that reaffirmed its positive year one (48 weeks) 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 one1,2, and maintained robust visual gains in year two in patients with neovascular age-related macular degeneration (nAMD)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.
nAMD affects more than 600,000 people in the UK3 and occurs when abnormal blood vessels leak fluid into the eye, causing irreversible damage and ultimately, blindness4,5. As such, retinal fluid is often a key marker used by physicians to determine injection frequency in clinical practice. Relative to aflibercept, fewer brolucizumab 6 mg patients with nAMD had intra-retinal 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[*]. 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 two years, brolucizumab consistently dried retinal fluid better, a key goal for physicians treating patients with nAMD, and maintained robust visual gains, versus aflibercept,” said Dr Mark Toms, Chief Scientific Officer, Novartis Pharmaceuticals UK. “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 sub-retinal 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 studies1. 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 arms1.
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 characteristics6,7,8.
The proprietary innovative structure results in a small molecule (26 kDa) with potent inhibition of, and high affinity to, all VEGF-A isoforms6,9. In preclinical studies, brolucizumab inhibited activation of VEGF receptors through prevention of the ligand-receptor interaction6,8,9. Increased signalling through the VEGF pathway is associated with pathologic ocular angiogenesis and retinal oedema10. 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 diseases11. About HAWK and HARRIER study design With more than 1,800 patients across 400 centres 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 482,12,13. Both studies are 96-week prospective, randomised, double-masked multi-centre studies and part of the Phase III clinical development of brolucizumab12,13.
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 nAMD12,13. 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 initiation2,12,13.
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 significance2. 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 activity2.
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 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. About neovascular age-related macular degeneration (nAMD or wet AMD) nAMD is the leading cause of severe vision loss and legal blindness in people over the age of 65 in North America, Europe, Australia and Asia, impacting an estimated 20 to 25 million people worldwide5,14. nAMD occurs when abnormal blood vessels form underneath the macula, the area of the retina responsible for sharp, central vision. These blood vessels are fragile and leak fluid, disrupting the normal retinal architecture and ultimately causing damage to the macula15,16,17.
Early symptoms of nAMD include distorted vision or metamorphopsia and difficulties seeing objects clearly4,17. Prompt diagnosis and intervention are essential. As the disease progresses, cell damage increases, further reducing vision quality. This progression can lead to a complete loss of central vision, leaving the patient unable to read, drive or recognise familiar faces15. Without treatment, vision can rapidly deteriorate19.
About Novartis in ophthalmology For more than 70 years, patients, caregivers and healthcare providers worldwide have looked to Novartis for state-of-the-art treatments in eye diseases. We continue to invest in science as well as in strategic alliances to help ensure patients have access to screening, diagnosis, and our eye medicines. Our commitment to vision extends globally across ages, from premature infants to seniors, from rare diseases to those affecting millions, from eye drops to gene therapies. Our aspiration: reimagining eye care to help everyone see possibilities.
About Novartis Novartis is reimagining medicine to improve and extend people’s lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the world’s top companies investing in research and development. Novartis products reach nearly 1 billion people globally and we are finding innovative ways to expand access to our latest treatments. About 125 000 people of more than 140 nationalities work at Novartis around the world. Find out more at www.novartis.com. In the UK, Novartis develops, manufactures and markets innovative medicines, devices and diagnostic tests which help improve patient outcomes. Based on four sites across the north and south of England, we employ approximately 1,500 people to serve healthcare needs across the whole of the UK, as well as supporting the global operations of Novartis by manufacturing the active pharmaceutical ingredients used worldwide in many medicines. In 2017 Novartis invested almost £30million in R&D and is a leading sponsor of clinical trials in the UK. For more information, please visit www.novartis.co.uk.
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.
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.