Novartis Announces FDA Approval of Beovu for the Treatment of Diabetic Macular Edema

• Approval is based on year one data from the Phase III KESTREL and KITE clinical trials investigating Beovu (brolucizumab-dbll) 6 mg versus aflibercept 2 mg in DME patients^1,2
• In KESTREL and KITE, Beovu was non-inferior to aflibercept in change in best-corrected visual acuity (BCVA) from baseline^1,2
• Patients treated with Beovu in KESTREL and KITE demonstrated a significant reduction from baseline in central subfield thickness (CST) starting at week four and continuing up to week 52^1,2
• KESTREL and KITE were the first pivotal trials to assess an anti-VEGF on six-week dosing intervals in the loading phase, suggesting Beovu may offer fewer injections from the start of treatment through year one^1,2
• Diabetic macular edema (DME) is a leading cause of blindness in adults in developed countries; unmet needs in DME include reducing retinal fluid and addressing the burden of frequent treatment schedules^3,4

East Hanover, N.J., June 1, 2022 — Novartis today announced that the US Food and Drug Administration (FDA) has approved Beovu^® (brolucizumab-dbll) 6 mg for the treatment of diabetic macular edema (DME). Today’s approval represents the second FDA-approved indication for Beovu, which was first approved for the treatment of wet age-related macular degeneration in 2019.

The FDA approval was based on year one data from the Phase III, randomized, double-masked KESTREL and KITE* studies, which met their primary endpoint of non-inferiority in change in best-corrected visual acuity (BCVA) from baseline versus aflibercept at year one^1,2. In aggregate, a numerically lower proportion of patient eyes treated with Beovu had intraretinal fluid, subretinal fluid or both at week 52 versus eyes treated with aflibercept (in KESTREL 60.3% in the Beovu arm versus 73.3% in the aflibercept arm; in KITE 54.2% versus 72.9%, respectively; statistical significance was not tested)².

Through year one, half of Beovu patients (55% in KESTREL and 50% in KITE) remained on a 12-week dosing interval following the loading phase^1,2. During this time (by week 52), patients received a median of seven Beovu injections^1,2. Patients treated with Beovu demonstrated a significant reduction from baseline in central subfield thickness (CST) starting at week four and continuing up to week 52^1,2.

Per the approved Beovu prescribing information, following the loading phase of five doses injected six weeks apart, patients should be treated once every eight to 12 weeks¹. Throughout the KESTREL and KITE trials, aflibercept patients were dosed every eight weeks, as recommended in its FDA-approved label^1,2.

“The FDA approval of Beovu in DME marks a significant milestone for US DME patients, many of whom are of working age and struggle with treatment adherence while juggling multiple doctor’s visits every month,” said Jill Hopkins, SVP and Global Development Unit Head, Ophthalmology, Novartis. “KESTREL and KITE were the first pivotal trials to assess an anti-VEGF on six-week dosing intervals in the loading phase, suggesting Beovu may offer fewer injections from the start of treatment through year one. We look forward to offering a new treatment option to help address the unmet needs of patients with DME. This FDA approval follows the recent European Commission approval and allows more patients around the world to potentially benefit from this important medicine.”

The most common adverse event (≥5%) reported in patients who received Beovu in the DME clinical trials was conjunctival hemorrhage¹. Intraocular inflammation (IOI) rates in KESTREL were 4.7% for brolucizumab 3 mg (including 1.6% retinal vasculitis), 3.7% for Beovu 6 mg (including 0.5% retinal vasculitis), and 0.5% for aflibercept 2 mg². IOI rates in KITE were equivalent (1.7%) between the Beovu 6 mg and aflibercept 2 mg arms with no retinal vasculitis reported². Retinal vascular occlusion was reported in KESTREL for brolucizumab 3 mg (1.1%) and 6 mg (0.5%), and in KITE for brolucizumab and aflibercept (0.6% each)². In KESTREL, the percentage of patients who experienced ≥15 letter loss from baseline at year one was 1.6% for brolucizumab 3 mg, 0% for Beovu 6 mg and 0.5% for aflibercept². In KITE, the percentage of patients who experienced ≥15 letter loss from baseline at year one was 1.1% for Beovu 6 mg and 1.7% for aflibercept². Brolucizumab 6 mg is the commercialized dose of Beovu¹.

Novartis remains committed to bringing Beovu to appropriate patients who may benefit from this important medicine. As of June 2022, Beovu is available as a pre-filled syringe in the US. This will provide eye care professionals an option that offers fewer steps than the vial.

About the KESTREL and KITE clinical trials
KESTREL and KITE are global, randomized, double-masked, Phase III, two-year studies comparing the safety and efficacy of Beovu and aflibercept in the treatment of patients with visual impairment due to DME^6,7. KESTREL and KITE involved 926 total patients in 36 countries^6,7. In the loading phase of both trials, patients in the Beovu arms were treated every six weeks for a total of five doses; patients in the aflibercept arms were treated every four weeks for a total of five doses, in line with its label^6,7. In the first year of the study, following the loading phase, patients in the Beovu arms were subsequently treated every 12 weeks, with those demonstrating disease activity moved to dosing every eight weeks^6,7. After the loading phase, patients in the aflibercept arms were treated every eight weeks^6,7.

About diabetic macular edema (DME)
DME is a common microvascular complication in patients with diabetes that may have a debilitating impact on visual acuity, eventually leading to blindness³. DME is a leading cause of blindness in adults in developed countries, affecting 12% of patients with type 1 diabetes and 28% of those with type 2 diabetes³.

Consistently high blood sugar levels associated with diabetes can damage small blood vessels in the eye, causing them to leak fluid³. This damage leads to an excess of vascular endothelial growth factor (VEGF)^3,8. VEGF is a protein that stimulates the growth of blood vessels^3,8. At elevated levels in DME, VEGF stimulates the growth of abnormal, leaky blood vessels^3,8. The resulting accumulation of fluid (known as edema) in the macula is a key marker of disease activity and can lead to vision loss^3,8. The macula is the area of the retina responsible for sharp, central vision^3.8. Early symptoms of DME include blurry or wavy central vision and distorted color perception, although the disease can also progress without symptoms at early stages^8,9.

About Beovu (brolucizumab) 6 mg
Beovu (brolucizumab, also known as RTH258) 6 mg is approved for the treatment of wet age-related macular degeneration (AMD) in more than 70 countries, including in the US, EU, UK, Japan, Canada and Australia^1,10--13. In March 2022, Beovu was also approved by the European Commission (EC) to treat diabetic macular edema (DME), applying to all 27 European Union member states as well as Iceland, Norway and Liechtenstein¹⁰. Additional trials, which study the effects of brolucizumab in patients with wet AMD, diabetic macular edema (DME), and proliferative diabetic retinopathy (PDR), are currently ongoing.

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-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.

*Kite Pharma, Inc. is neither a sponsor of nor associated with Novartis’ KITE trial.

INDICATION AND IMPORTANT SAFETY INFORMATION

INDICATIONS AND USAGE
Beovu^® (brolucizumab-dbll) injection is indicated for the treatment of Neovascular (Wet) Age-related Macular Degeneration (AMD) and Diabetic Macular Edema (DME).

IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
Beovu is contraindicated in patients with ocular or periocular infections, active intraocular inflammation, or known hypersensitivity to brolucizumab or any of the excipients in Beovu. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, erythema, or severe intraocular inflammation.

WARNINGS AND PRECAUTIONS
Endophthalmitis and Retinal Detachment
Intravitreal injections, including those with Beovu, have been associated with endophthalmitis and retinal detachment. Proper aseptic injection techniques must always be used when administering Beovu. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately.

Retinal Vasculitis and/or Retinal Vascular Occlusion
Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported with the use of Beovu. These immune-mediated adverse events may occur following the first intravitreal injection. Discontinue treatment with Beovu in patients who develop these events. Patients treated with Beovu who experience intraocular inflammation may be at risk of developing retinal vasculitis and/or retinal vascular occlusion and should be closely monitored. Patients should be instructed to report any change in vision without delay.

Increase in Intraocular Pressure
Acute increases in intraocular pressure (IOP) have been seen within 30 minutes of intravitreal injection, including with Beovu. Sustained IOP increases have also been reported. Both IOP and perfusion of the optic nerve head must be monitored and managed appropriately.

Thromboembolic Events
Although there was a low rate of arterial thromboembolic events (ATEs) observed in the Beovu clinical trials, there is a potential risk of ATEs following intravitreal use of VEGF inhibitors. Arterial thromboembolic events are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). The ATE rate in the two controlled 96-week neovascular AMD (nAMD) studies (HAWK and HARRIER) during the first 96-weeks was 4.5% (33 of 730) in the pooled brolucizumab arms compared with 4.7% (34 of 729) in the pooled aflibercept arms.

ADVERSE REACTIONS
Serious adverse reactions, including endophthalmitis, retinal detachment, retinal vasculitis and/or retinal vascular occlusion, increases in intraocular pressure, and arterial thromboembolic events, have occurred following intravitreal injections with Beovu.

The most common adverse events (≥5% of patients) reported in nAMD clinical studies (HAWK and HARRIER) in patients who received Beovu were vision blurred, cataract, conjunctival hemorrhage, vitreous floaters, and eye pain. The most common adverse event (≥5% of patients) reported in DME clinical studies (KITE and KESTREL) in patients who received Beovu was conjunctival hemorrhage.

In a clinical study (MERLIN), patients with nAMD who received Beovu every 4-week maintenance dosing experienced a higher incidence of intraocular inflammation (including retinal vasculitis) and retinal vascular occlusion than patients who received Beovu every 8- or 12-week maintenance dosing in the clinical studies (HAWK and HARRIER). The interval between 2 Beovu doses during maintenance treatment should not be less than 8 weeks.

As with all therapeutic proteins, there is a potential for an immune response in patients treated with Beovu. Anti-brolucizumab antibodies were detected in the pre-treatment sample of 36% to 64% of treatment-naive patients. After initiation of dosing, anti-brolucizumab antibodies were detected in at least one serum sample in 53% to 76% of patients treated with Beovu. Intraocular inflammation was observed in 6% of patients with anti-brolucizumab antibodies detected during dosing with Beovu in clinical trials. Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, are immune-mediated adverse events related to exposure to Beovu. This treatment-emergent antibody response may develop following the first intravitreal injection. Anti-brolucizumab antibodies were not associated with an impact on clinical efficacy.

Please see full Prescribing Information for Beovu.

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
Located in East Hanover, NJ, Novartis Pharmaceuticals Corporation – an affiliate of 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 employs nearly 15,000 people in the United States. For more information, please visit https://www.novartis.us.

References:

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2. Brown DM, Emanuelli A, Bandello F, et al. KESTREL and KITE: 52-Week Results From Two Phase III Pivotal Trials of Brolucizumab for Diabetic Macular Edema. Am J Ophthalmol. 2022;238:157-172.
3. Romero-Aroca P. Managing diabetic macular edema: The leading cause of diabetes blindness. World J Diabetes. 2011;2(6):98-104.
4. Schmidt-Erfurth U, Garcia-Arumi J, Bandello F, et al. Guidelines for the Management of Diabetic Macular Edema by the European Society of Retina Specialists (EURETINA). Ophthalmologica. 2017;237(4):185-222.
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Source: Novartis