European Medicines Agency (EMA) approves safety label update for Novartis Beovu®

• Novartis worked with the EMA to update the Beovu® (brolucizumab) label to guide physicians in their treatment of wet AMD  
   
• The update includes the additional characterization of retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation¹
   
• Novartis has established a multidisciplinary panel of internal experts collaborating with external advisors to examine the root cause, potential risk factors and mitigation of these adverse events
   
• Novartis is confident that Beovu continues to represent an important treatment option for patients with wet AMD, with an overall favorable benefit/risk profile 

Basel, September 14, 2020 — Novartis announced today that the Committee for Medicinal Products for Human Use (CHMP), has approved an update to the Beovu® (brolucizumab) Summary of Product Characteristics (SmPC) to include additional information regarding retinal vasculitis and retinal vascular occlusion¹. Typically, these events occurred in the presence of intraocular inflammation. This approval follows Novartis’ announcement that it would pursue worldwide label updates after a review and further characterization of post-marketing safety events reported to Novartis.

The update to the EU label includes the addition of retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation under “Special warnings and precautions for use” (section 4.4) and “Undesirable effect” (section 4.8). The label notes that patients developing these events should discontinue treatment and the events should be promptly managed¹.

“This label update is one of the many efforts Novartis is taking to help physicians make informed decisions,” said Marcia Kayath, Global Head of Medical Affairs and Chief Medical Officer, Novartis Pharmaceuticals. “Novartis is committed to fully understanding and transparently communicating the safety profile of Beovu. To this purpose, we have established a coalition, which is a fully dedicated internal team collaborating with top global experts to examine the root cause, risk factors, mitigation and potential treatment recommendations.”

The label update is applicable to all 27 European Union member states as well as the UK, Iceland, Norway and Liechtenstein¹. Beovu is now approved for the treatment of wet AMD in more than 40 countries, including in the US², EU¹, UK¹, Japan³, Canada⁴ and Australia⁵.

About Beovu (brolucizumab)
Beovu (brolucizumab, also known as RTH258) is the most clinically advanced humanized single-chain antibody fragment (scFv)^6-8. 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^8-10.

The proprietary innovative structure results in a small molecule (26 kDa) with potent inhibition of, and high affinity to, all VEGF-A isoforms⁹. Beovu is engineered to deliver a high concentration of drug, thus providing more active binding agents^6-8. In preclinical studies, Beovu inhibited activation of VEGF receptors through prevention of the ligand-receptor interaction^9-11. Increased signaling through the VEGF pathway is associated with pathologic ocular angiogenesis and retinal edema¹². Inhibition of the VEGF pathway has been shown to inhibit the growth of neovascular lesions and suppress endothelial cell proliferation and vascular permeability¹².

Beovu is approved in more than 40 countries, including in the US², EU¹, UK¹, Japan³, Canada⁴ and Australia⁵, based on the results of the HAWK and HARRIER clinical trials.

About the HAWK and HARRIER studies
With more than 1,800 patients across nearly 400 centers worldwide, HAWK (NCT02307682) and HARRIER (NCT02434328) are the first global head-to-head trials in patients with wet AMD that prospectively demonstrated efficacy of Beovu at week 48 using an innovative q12w/q8w regimen, with a majority of patients on q12w immediately following the loading phase^6,7. Both studies are 96-week prospective, randomized, double-masked multi-center studies and part of the Phase III clinical development of Beovu^6,7. 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 wet AMD^6,7. The most common adverse events (>=5% of patients) with Beovu were vision blurred, cataract, conjunctival hemorrhage, vitreous floaters and eye pain^6,7.

Disclaimer
This media update 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,” “may,” “could,” “would,” “expect,” “anticipate,” “seek,” “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 media update, 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 media update 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 particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this media update as of this date and does not undertake any obligation to update any forward-looking statements contained in this media update as a result of new information, future events or otherwise.

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 800 million people globally and we are finding innovative ways to expand access to our latest treatments. About 109,000 people of more than 140 nationalities work at Novartis around the world. Find out more at
https://www.novartis.com.

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References
1.    Beovu [summary of product characteristics] Basel, Switzerland. Novartis: 2020.
2.    Beovu [US prescribing information] East Hanover, NJ. Novartis: 2019
3.    Pharma Japan. National Health Insurance Pricing. Available at: https://pj.jiho.jp/sites/default/files/pj/document/2020/05/New%20Drugs%20to%20Be%20Added%20to%20NHI%20Price%20List%20on%20May%2020_1.pdf. Accessed September 2020.
4.    Canadian Agency for Drugs and Technologies in Health. CADTH Canadian Drug Expert Committee Recommendation. Available at: https://cadth.ca/sites/default/files/cdr/complete/SR0632%20Beovu%20-%20CDEC%20Final%20Recommendation%20%E2%80%93%20May%2025%2C%202020_for%20posting.pdf. Accessed September 2020.
5.    Beovu [prescription medicine decision summary] Australia. Novartis: 2020.
6.    Dugel P, Koh A, Ogura Y, et al; HAWK and HARRIER Study Investigators. HAWK and HARRIER: Phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology. 2020;127(1):72-84
7.    Dugel PU, Singh RP, Koh A, et al. HAWK and HARRIER: 96-Week outcomes from the phase 3 trials of brolucizumab for neovascular age-related macular degeneration [published online ahead of print]. Ophthalmology. 2020. https://doi.org/10.1016/j.ophtha.2020.06.028.
8.    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
9.    Escher D, et al. Single-chain antibody fragments in ophthalmology. Oral presentation at EURETINA congress. 2015. Abstract.
10.  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 February 2020
11.  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.
12.  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.

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