Novartis International AG: Novartis announces FDA filing acceptance and Priority Review of brolucizumab (RTH258) for patients with wet AMD
Novartis International AG / Novartis announces FDA filing acceptance and
Priority Review of brolucizumab(RTH258) for patients with wet AMD . Processed
and transmitted by West Corporation.The issuer is solely responsible for the
content of this announcement.
* By 2020, over 1.5 million people in the US are likely to have wet AMD, the
leading cause of blindness in industrialized countries
* Filing is based on Phase III data from the HAWK and HARRIER trials for
* Novartis used a priority review voucher to expedite review of brolucizumab
in the US and, if approved by FDA, anticipates launching by the end of 2019
Basel, April 15, 2019 -Novartis announced that the US Food and Drug
Administration (FDA) accepted the companys Biologics License Application
(BLA) for brolucizumab (RTH258) for the treatment of wet age-related macular
degeneration (AMD), also known as neovascular AMD, or nAMD. Seeking to make
brolucizumab available as quickly as possible, Novartis used a priority
review voucher to expedite FDA review. If approved by the FDA, Novartis
anticipates launching brolucizumab by the end of 2019.
Estimates suggest that by 2020, 1.5 to 1.75 million people in the US will be
living with wet AMD, a leading cause of blindness worldwide and a rapidly
growing public health concern. As the disease progresses, patients may
experience loss of central vision, resulting in an inability to complete
daily tasks. Without treatment, vision can rapidly deteriorate and may lead
Reaching this milestone is an important step in our efforts to reimagine the
treatment journey for people with wet AMD and their caregivers, said Fabrice
Chouraqui, President, Novartis Pharmaceuticals Corporation. We are looking
forward to the potential of a new option for patients with wet AMD, who often
have to navigate considerable physical and emotional difficulties caused by
The regulatory application is primarily based on Phase III data from the HAWK
and HARRIER trials - prospective, randomized, double-masked multi-center
studies,. The primary endpoint of these studies was non-inferiority to
aflibercept in mean change in best-corrected visual acuity (BCVA) from
baseline to week 48 (mean change in BCVA of 6.6 letters for brolucizumab 6 mg
versus 6.8 letters for aflibercept in HAWK and 6.9 letters versus 7.6
letters, respectively, in HARRIER). HAWK and HARRIER are the first and only
global head-to-head trials in patients with wet AMD that prospectively
demonstrated efficacy at week 48 starting with a 12-week dosing regimen.
Additionally, at week 48 in the studies, key secondary endpoint assessments
showed significantly fewer brolucizumab patients with disease activity (23.5%
of brolucizumab 6 mg patients versus 33.5% of aflibercept patients in HAWK,
and 21.9% versus 31.4%, respectively, in HARRIER (P=0.0022 for both) as well
as retinal fluid - key markers used by physicians to help guide management of
the disease in clinical practice (31% fewer patients on brolucizumab 6 mg had
intra-retinal fluid (IRF) and/or sub-retinal fluid (SRF) in HAWK, and 26%
fewer in HARRIER, versus aflibercept (P0.0001 for both),.
Wet AMD robs people of their precious sight and takes a major toll on the
lives of millions of people who face not only vision loss, but also the
burden of frequent injections into their eyes, said Dawn Prall George,
executive director, The Support Sight Foundation. We are always excited
about potential new treatment options and hopeful they may help people manage
this devastating disease.
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
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,,. Increased
signaling through the VEGF pathway is associated with pathologic ocular
angiogenesis and retinal edema. 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.
About HAWK and HARRIER study design
With more than 1,800 patients across nearly 400 sites 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 an innovative q12w/q8w regimen, with a majority of
patients on q12w immediately following the loading phase[3-5]. Both studies
are 96-week prospective, randomized, double-masked multi-center studies and
part of the Phase III clinical development of brolucizumab,,.
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,. 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 label at the
time of study initiation[3-6].
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. 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%). 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%).
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 worldwide,. 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 macula,,.
Early symptoms of nAMD include distorted vision or metamorphopsia and
difficulties seeing objects clearly. 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 faces. Without treatment, vision can rapidly deteriorate.
About Novartis in ophthalmology
Novartis Ophthalmology is reimagining the treatment and prevention of visual
impairment and blindness. By pushing the boundaries of medicine and
technology were developing life-changing gene therapies, next-generation
pharmaceuticals, and transformative technologies for diseases and conditions
spanning every area of eye disease, from the front to the back of the eye.
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 American Academy of Ophthalmology. Age-related macular degeneration preferred practice patterns. Available at:https://www.aao.org/preferred-practice-pattern/age-related-macular-degeneration-ppp-2015. Accessed March 2019.
 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.
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 ClinicalTrials.gov. Identifier NCT02434328. Available athttps://clinicaltrials.gov/ct2/show/NCT02434328(link is external). Accessed January 2019.
 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.
 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.
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 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.
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