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15.04.2019 22:04:46

Press Release: 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

brolucizumab

-- 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 company's 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[1]. 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 to blindness[2].

"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 deteriorating vision."

The regulatory application is primarily based on Phase III data from the

HAWK and HARRIER trials - prospective, randomized, double-masked

multi-center studies[3],[4]. 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 (P<0.0001 for both)[5],[6].

"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 characteristics[7-9].

The proprietary innovative structure results in a small molecule (26

kDa) with potent inhibition of, and high affinity to, all VEGF-A

isoforms[7],[10]. In preclinical studies, brolucizumab inhibited

activation of VEGF receptors through prevention of the ligand-receptor

interaction[7],[9],[10]. Increased signaling through the VEGF pathway is

associated with pathologic ocular angiogenesis and retinal edema[11].

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[12].

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[3],[4],[6].

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[3],[4]. In

both trials, patients were randomized to either brolucizumab or

aflibercept[3],[4]. 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[3],[4]. 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[5].

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[5].

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%)[5]. 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%)[6].

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[2],[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 damage to the macula[1],[14],[15].

Early symptoms of nAMD include distorted vision or metamorphopsia and

difficulties seeing objects clearly[16]. 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[14]. Without treatment, vision can

rapidly deteriorate[2].

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 we're 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.

Disclaimer

This press release contains forward-looking statements within the

meaning of the United States Private Securities Litigation Reform Act of

1995. Forward-looking statements can generally be identified by words

such as "potential," "can," "will," "plan," "expect," "anticipate,"

"look forward," "believe," "committed," "investigational," "pipeline,"

"launch," or similar terms, or by express or implied discussions

regarding potential marketing approvals, new indications or labeling for

the investigational or approved products described in this press release,

or regarding potential future revenues from such products. You should

not place undue reliance on these statements. Such forward-looking

statements are based on our current beliefs and expectations regarding

future events, and are subject to significant known and unknown risks

and uncertainties. Should one or more of these risks or uncertainties

materialize, or should underlying assumptions prove incorrect, actual

results may vary materially from those set forth in the forward-looking

statements. There can be no guarantee that the investigational or

approved products described in this press release will be submitted or

approved for sale or for any additional indications or labeling in any

market, or at any particular time. Nor can there be any guarantee that

such products will be commercially successful in the future. In

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April 15, 2019 16:05 ET (20:05 GMT)