`
`Jun 11, 2020
`
`Novartis worked with US Food and Drug Administration (FDA) to update Beovu (brolucizumab) prescribing information to guide
`healthcare professionals in their treatment of wet AMD patients1
`
`The update includes characterization of adverse events, retinal vasculitis and retinal vascular occlusion, as part of the spectrum of
`intraocular inflammation observed in the HAWK & HARRIER trials and noted in the original prescribing information1
`
`Novartis has convened a fully dedicated team collaborating with top global external experts, leveraging the collective
`multidisciplinary expertise to examine the root causes, potential risk factors and mitigation of these adverse events2
`
` A
`
` Safety Review Committee established by Novartis noted that the overall rate of vision loss in the study population was similar
`between the Beovu and aflibercept arms in HAWK & HARRIER despite the risk of vision loss associated with the adverse events of
`interest2
`
`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, June 11, 2020 — Novartis announced today that the US Food and Drug Administration (FDA) has approved a label update for
`Beovu® (brolucizumab) to include additional safety information regarding retinal vasculitis and retinal vascular occlusion1. This approval
`follows Novartis’ announcement that it would pursue worldwide label updates after a review and further characterization of rare post-
`marketing safety events reported to Novartis. This is one of many efforts Novartis is taking to help physicians to make informed decisions
`on the use of Beovu, including the establishment of a fully dedicated internal team collaborating with top global experts (a coalition) to
`examine the root causes, risk factors, mitigation and potential treatment protocols2.
`
`The update to the US label includes the addition of a sub-section dedicated to retinal vasculitis and/or retinal vascular occlusion under
`‘Warnings and Precautions’ (section 5)1. It also specifies that these adverse reactions are part of a spectrum of intraocular inflammation
`rates from the Phase III HAWK & HARRIER trials (Table 1)1.
`
`“This label update provides clinicians with important information to guide treatment decisions. We believe Beovu continues to represent
`an important treatment option for patients with wet AMD, with an overall favorable benefit-risk profile,” said Marcia Kayath, Global Head
`of Medical Affairs and Chief Medical Officer, Novartis Pharmaceuticals. “We remain grateful to all doctors who have taken the time to
`share their expertise and treatment experience to contribute to the collective understanding of these safety events. As we proceed to
`examine root causes and potential mitigation strategies, we will continue to communicate findings with transparency and urgency to
`regulatory bodies and healthcare providers.”
`
`Beovu was approved in the US in October 2019 for the treatment of wet age-related macular degeneration (AMD), based on findings
`from the Phase III HAWK and HARRIER clinical trials, in which Beovu demonstrated non-inferiority versus aflibercept in mean change in
`best-corrected visual acuity (BCVA) at year one (week 48)1,3. Beovu demonstrated the ability to maintain a majority of patients on a
`three-month interval immediately after the loading phase1,3.
`
`In early 2020, following receipt by Novartis of rare post-marketing reports of vasculitis, including retinal occlusive vasculitis, Novartis
`initiated its own internal review of these post-marketing safety case reports including the establishment of an external Safety Review
`Committee (SRC) to provide an independent, objective review of these cases and a comparison with select intraocular inflammation
`events seen in the brolucizumab Phase III trials (HAWK & HARRIER)2.
`
`The SRC recently issued a report of its unmasked, independent analysis of HAWK & HARRIER adverse events, finding that cases similar
`to those reported post-marketing were present in the HAWK & HARRIER clinical studies2. The report also noted that the overall rate of
`vision loss in the study population was similar between the brolucizumab and aflibercept arms in HAWK & HARRIER despite the risk of
`vision loss associated with the adverse events of interest2.
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`Regeneron Exhibit 1189.001
`Regeneron v. Novartis
`IPR2021-00816
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`Novartis continues to work with global regulatory authorities to initiate safety information updates to Beovu prescribing information
`worldwide. Beovu has now been approved in more than 30 countries. Beovu also recently received positive Health Technology
`Assessment Reviews (HTA) in countries such as Canada4 and is now fully reimbursed in multiple countries including Japan and
`Switzerland5,6. Novartis remains confident in Beovu as an important treatment option for patients with wet AMD.
`
`Coalition convened as part of ongoing commitment to patient safety
`
`A fully dedicated team of Novartis research, drug development and medical specialists are working with a team of top global experts to
`examine the root causes and potential risk factors associated with the reported adverse events and to determine mitigation and treatment
`recommendations2.
`
`“This broad-based coalition, which includes clinical trialists, epidemiologists, immunologists and uveitis specialists, is exploring innovative
`approaches to analyzing every aspect of available data, with the goal of providing physicians tools and information to safely and
`confidently treat their patients with Beovu,” said Dr. Jeff Heier, Co-President and Medical Director, Director of the Vitreoretinal Service,
`and Director of Retina Research at Ophthalmic Consultants of Boston, Chair of the Safety Review Committee and a member of the
`coalition.
`
`Novartis encourages physicians to continue to report any adverse or suspicious events in accordance with local requirements at
`https://www.report.novartis.com. Novartis remains committed to transparency and will continue to provide updates on
`https://www.brolucizumab.info as information becomes available.
`
`About Beovu (brolucizumab)
`Beovu (brolucizumab, also known as RTH258) is the most clinically advanced humanized single-chain antibody fragment (scFv)3,7.
`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 characteristics7-9.
`
`The proprietary innovative structure results in a small molecule (26 kDa) with potent inhibition of, and high affinity to, all VEGF-A
`isoforms8. Beovu is engineered to deliver a high concentration of drug, thus providing more active binding agents3,7. In preclinical
`studies, Beovu inhibited activation of VEGF receptors through prevention of the ligand-receptor interaction8-10. Increased signaling
`through the VEGF pathway is associated with pathologic ocular angiogenesis and retinal edema11. Inhibition of the VEGF pathway has
`been shown to inhibit the growth of neovascular lesions and suppress endothelial cell proliferation and vascular permeability11.
`
`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 at week 48 using an innovative q12w/q8w
`regimen, with a majority of patients on q12w immediately following the loading phase. Both studies are 96-week prospective, randomized,
`double-masked multi-center studies and part of the Phase III clinical development of Beovu3. 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. The most common adverse events (>=5% of patients) with Beovu were vision blurred, cataract, conjunctival
`hemorrhage, vitreous floaters and eye pain3.
`
`About wet age-related macular degeneration
`Wet AMD 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 million people worldwide12-14. Wet AMD occurs when abnormal blood vessels form underneath the
`macula, the area of the retina responsible for sharp, central vision15-17. These blood vessels are fragile and leak fluid, disrupting the
`normal retinal architecture and ultimately causing damage to the macula15-17.
`
`Early symptoms of wet AMD include distorted vision (or metamorphopsia) and difficulties seeing objects clearly18. Prompt diagnosis and
`intervention are essential17. As the disease progresses, cell damage increases, further reducing vision quality15. This progression can
`lead to a complete loss of central vision, leaving the patient unable to read, drive or recognize familiar faces and potentially depriving
`them of their independence15,19. Without treatment, vision can rapidly deteriorate20.
`
`About Novartis in ophthalmology
`At Novartis, our mission is to discover new ways to improve and extend people's lives. In ophthalmology, we develop and deliver life-
`
`Regeneron Exhibit 1189.002
`Regeneron v. Novartis
`IPR2021-00816
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`changing medicines and therapies for diseases and conditions from front to back of the eye, enabled by data and transformative
`technologies. Our ophthalmic solutions reach more than 150M people per year, from premature infants to the elderly.
`
`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,” “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 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 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 press release as of this date and does not undertake any
`obligation to update any forward-looking statements contained in this press release 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 145
`nationalities work at Novartis around the world. Find out more at
`https://www.novartis.com.
`
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`References
`
`1. Beovu [US prescribing information] East Hanover, NJ. Novartis: 2020.
`2. Data on file. Safety Review Committee Report. Novartis; 2020.
`3. 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.
`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 June
`2020.
`5. 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
`Accessed June 2020.
`6. Swissmedic. Swiss Public Assessment Report. Available at:
`https://www.swissmedic.ch/swissmedic/en/home/humanarzneimittel/authorisations/swisspar.html. Accessed June 2020.
`7. 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.
`8. Escher D, et al. Single-chain antibody fragments in ophthalmology. Oral presentation at EURETINA congress. 2015. Abstract.
`
`Regeneron Exhibit 1189.003
`Regeneron v. Novartis
`IPR2021-00816
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`
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`9. 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 June 2020.
`10. 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.
`11. 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.
`12. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and
`2040: a systematic review and met analysis. Lancet Glob Health. 2014;2:106-16.
`13. Singer M. Advances in the management of macular degeneration. F1000Prime Rep. 2014;6:29.
`14. 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.
`15. National Eye Institute. Facts About Age-Related Macular Degeneration. Available at
`https://nei.nih.gov/health/maculardegen/armd_facts (link is external). Accessed June 2020.
`16. World Health Organization. Priority eye diseases: Age-related macular degeneration. Available at
`http://www.who.int/blindness/causes/priority/en/index7.html (link is external). Accessed June 2020.
`17. NHS Choices. Macular Degeneration. Available at http://www.nhs.uk/Conditions/Macular-degeneration/Pages/Introduction.aspx (link
`is external). Accessed June 2020.
`18. Healthline. What is metamorphopsia? Available at https://www.healthline.com/health/metamorphopsia (link is external). Accessed
`June 2020.
`19. Mitchell J, Bradley C. Quality of life in age-related macular degeneration: a review of the literature. Health Qual Life Outcomes.
`2006;4:97.
`20. 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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`List of links present in page
`
`Regeneron Exhibit 1189.004
`Regeneron v. Novartis
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`https://www.novartis.com/news/media-releases/us-fda-approves-updated-novartis-beovu-label-include-additional-safety-information
`https://www.novartis.com/news/novartis-completes-safety-review-and-initiates-update-beovu-prescribing-information-worldwide
`https://www.report.novartis.com
`https://www.brolucizumab.info
`https://www.novartis.com
`https://twitter.com/novartisnews
`http://www.novartis.com/news/media-library
`mailto:media.relations@novartis.com
`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
`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
`https://www.swissmedic.ch/swissmedic/en/home/humanarzneimittel/authorisations/swisspar.html
`http://iovs.arvojournals.org/article.aspx?articleid=2354604
`https://nei.nih.gov/health/maculardegen/armd_facts
`http://www.who.int/blindness/causes/priority/en/index7.html
`http://www.nhs.uk/Conditions/Macular-degeneration/Pages/Introduction.aspx
`https://www.healthline.com/health/metamorphopsia
`mailto:peter.zuest@novartis.com
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`mailto:amy.wolf@novartis.com
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`Regeneron Exhibit 1189.005
`Regeneron v. Novartis
`IPR2021-00816
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