Novartis head-to-head data show superiority of brolucizumab (RTH258) versus aflibercept in secondary endpoint measures of disease activity in nAMD
Nov 16, 2017
Brolucizumab, the first and only anti-VEGF to maintain majority of patients on a 12-week treatment schedule following loading phase, met primary endpoint of non-inferiority vs. aflibercept1
Fewer brolucizumab patients showed signs of disease activity as well as retinal fluid, with superior reductions in retinal thickness due to fluid accumulation shown with brolucizumab1
Reinforces Novartis global leadership in ophthalmology and commitment to provide new treatment options for conditions such as nAMD, the leading cause of blindness in adults2
Frimley, November 13, 2017 – Novartis, a global leader in ophthalmology, announced further positive results from two Phase III head-to-head studies of brolucizumab (RTH258) versus aflibercept. 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 (nAMD). The results of the head-to-head trials, HAWK and HARRIER, were presented at the American Academy of Ophthalmology (AAO) 2017 Annual Meeting1.
nAMD affects more than 600,00 people in the UK and occurs when abnormal blood vessels leak fluid into the eye, causing irreversible damage and ultimately, blindness2. As such, retinal fluid is often a key marker used by physicians to determine injection frequency in clinical practise. Relative to aflibercept, significantly fewer brolucizumab 6 mg patients showed presence of intra-retinal fluid (IRF) and/or sub-retinal fluid (SRF) at Week 16 in both HAWK and HARRIER (35% and 33% fewer, respectively) (P<0.0001). This was continued to Week 48 (31% fewer in HAWK, and 41% fewer in HARRIER1. The reduction in fluid for patients treated with brolucizumab suggests the potential for a long-lasting effect and decreased treatment need.
“Frequent injections into the eye are a standard requirement for nAMD therapies and can be a significant hardship for patients as well as a burden on caregivers. These data clearly demonstrate the potential for brolucizumab to improve visual outcomes while also reducing injection burden,” said Dimitrios, Chief Scientific Officer at Novartis UK. “We have a heritage in developing sight-saving medicines and are very excited to be sharing these latest data which confirm the promise of brolucizumab as the next major advancement in the treatment of nAMD.”
Data also show brolucizumab 6 mg patients demonstrated superior reductions in central subfield thickness (CST)1. In nAMD, an elevated CST— as measured by optical coherence tomography — is a key indicator of abnormal fluid accumulation in the retina3. 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)1.With brolucizumab, significantly fewer patients had active disease at Week 16 in a matched head-to-head comparison. 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)1. Furthermore, brolucizumab safety was comparable to aflibercept with the overall incidence of adverse events balanced across all treatment groups in both studies1.
Brolucizumab is the first and only 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 trials1.
NOTES TO EDITORS
About brolucizumab (RTH258) Brolucizumab (RTH258) is a humanized single-chain antibody fragment (scFv) and the most clinically advanced, humanized 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 characteristics4,5,6.
The proprietary innovative structure results in a small molecule (26 kDa) with potent inhibition of, and high affinity to, all VEGF-A isoforms4,7. In preclinical studies, brolucizumab inhibited activation of VEGF receptors through prevention of the ligand-receptor interaction4,5,6,7. Increased signaling through the VEGF pathway is associated with pathologic ocular angiogenesis and retinal edema8. 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 diseases9.
About HAWK and HARRIER study design With more than 1,800 patients across 400 centers worldwide, HAWK and HARRIER are the first and only global head-to-head trials in patients with nAMD that prospectively demonstrated efficacy at Week 48 using an innovative q12w/q8w regimen, with a majority of patients on q12w immediately following the loading phase1. Both studies are 96-week prospective, randomized, double-masked multi-center studies and part of the Phase III clinical development of brolucizumab10,11.
The studies were designed to compare the efficacy and safety of intravitreal injections of brolucizumab 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 brolucizumab is noninferior to aflibercept in mean change in 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 parameters10,11.
In both trials, patients were randomized 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 label10,11.
Week 16 was an important pre-defined data point, as it represents a timepoint when the treatment assessment for brolucizumab and aflibercept were identical, providing an opportunity to observe how both drugs performed in a matched comparison1.
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 worldwide12,13. 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 damage14,15,16.
Early symptoms of nAMD include distorted vision or metamorphopsia and difficulties seeing objects clearly17. 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 recognize familiar faces14.Without treatment, vision can rapidly deteriorate18.
About Novartis in ophthalmology Novartis is a leading ophthalmology company, with therapies that treat both front and back of the eye disorders, including retina diseases, glaucoma, dry eye and other external eye diseases. In 2016, approximately 200 million patients worldwide were treated with Novartis ophthalmic products.
About Novartis Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2016, the Group achieved net sales of USD 48.5 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 121,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit http://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 2016 Novartis in the UK invested almost £40million in R&D and is the largest commercial sponsor of clinical trials. For more information, please visit www.novartis.co.uk.
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 2017 Annual Meeting on November 10, 2017, New Orleans.
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).
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.