Novartis Announces Positive Phase III Results for Beovu® in Diabetic Macular Edema with Dosing Intervals Up to 16 Weeks

Novartis recently announced positive results from two Phase 3 clinical trials evaluating the next-generation ophthalmic drug Beovu (brolucizumab, 6 mg) versus Eylea (aflibercept, 2 mg) for the treatment of diabetic macular edema (DME). The Year 2 results of the pivotal Phase 3 KITE trial evaluated Beovu with dosing intervals of up to 16 weeks, while the one-year KINGFISHER study evaluated Beovu administered every 4 weeks. Both trials confirmed the generally well-tolerated safety profile of Beovu. Currently, Beovu is approved for the treatment of wet age-related macular degeneration (wet-AMD) at a dose of 6 mg. Based on results from the pivotal KESTREL and KITE trials, Novartis has submitted applications to the U.S. FDA and the European EMA for a new indication of Beovu for DME, and the company plans to submit applications to other markets in due course.

Results from Year 2 (Week 100) of the KITE trial indicate that the majority of patients who successfully completed the initial 12-week dosing cycle following the loading phase maintained a dosing interval of either 12 or 16 weeks through the end of the study. As previously reported, the KITE trial met its primary endpoint at Year 1 (Week 52), demonstrating that the change from baseline in best-corrected visual acuity (BCVA) was non-inferior to Eylea. During Year 1, Beovu demonstrated greater reductions compared to Eylea in central subfield thickness (CSFT) and in the number of study eyes with intraretinal fluid and/or subretinal fluid (IRF/SRF), which served as secondary endpoints related to retinal fluid. Year 2 results were consistent with Year 1 findings, including maintenance of BCVA, greater reductions in CSFT, and a reduction in the number of eyes with IRF/SRF in both the Beovu and Eylea treatment arms. CSFT is a key indicator of intraretinal fluid, and the presence of fluid is a critical marker of disease activity. Year 2 results from KESTREL, another Phase 3 trial evaluating Beovu for the treatment of DME, will be announced in the fourth quarter of this year.

Another Phase 3 trial, the KINGFISHER trial, met its primary endpoint: at Year 1 (Week 52), Beovu administered every 4 weeks was non-inferior to Eylea in terms of change from baseline in BCVA. Additionally, Beovu demonstrated superiority over Eylea on key fluid-related secondary endpoints at Year 1, including a reduction in CSFT and the number of eyes with IRF/SRF.

In the KITE trial, the most common overall adverse events (≥5%) were cataracts and dry eye. In the KITE trial, the incidence of intraocular inflammation (IOI) was 2.2% in the Beovu group and 1.7% in the Eylea group, with no retinal vasculitis (RV) reported in either group. The incidence of retinal vascular occlusion (RO) was 0.6% in the Beovu group and 0.6% in the Eylea group. In the KITE trial, most IOI events were manageable and occurred without clinical complications. No RO events were associated with inflammation or vasculitis.

In the KINGFISHER trial, the most common (≥5%) overall adverse events were COVID-19 and hypertension. The incidence of IOI was 4.0% in the Beovu group (including 0.9% RV) and 2.9% in the Eylea group (including 0.6% RV). The incidence of RO in the Beovu and Eylea groups was 0.3% and 0.6%, respectively. Most IOI events were manageable and resolved without any clinical complications. No RO events were associated with inflammation or vasculitis.

Further details regarding the KITE and KINGFISHER trials will be presented at the upcoming medical conference.

Wet AMD (wet-AMD, image source: retinaboston.com)

DME is a leading cause of blindness in patients with diabetes, affecting 21 million people globally, with a prevalence of 12% among those with type 1 diabetes and 28% among those with type 2 diabetes. Persistent hyperglycemia associated with diabetes damages the small blood vessels in the eye, causing them to leak fluid. Fluid accumulation in the macula (known as edema) leads to vision loss. The macula is the region of the retina responsible for sharp, central vision. Early symptoms of DME include blurred or wavy central vision and distorted color vision; however, the disease may also progress asymptomatically in its early stages.

Beovu is a next-generation anti-vascular endothelial growth factor (VEGF) agent approved in the United States in October 2019 and in the European Union in February 2020 for the treatment of wet age-related macular degeneration (wet-AMD). To date, Beovu has been approved for marketing in over 40 countries worldwide. In June 2020, the US label for Beovu was updated to include additional safety information regarding retinal vasculitis (RV) and retinal vascular occlusion (RO).

Wet age-related macular degeneration (wet-AMD, nAMD) is a leading cause of blindness, affecting over 20 million people worldwide. Frequent intravitreal injections are a common reason for treatment discontinuation among patients with wet-AMD.

Notably, Beovu is the first anti-VEGF drug with efficacy comparable to Eylea (aflibercept) that maintains efficacy without compromise when maintenance therapy is administered at 3-month dosing intervals following a 3-month loading phase in eligible patients with wet-AMD. By reducing the frequency of injections, it improves patient treatment adherence, thereby effectively maintaining patients' vision.

The active pharmaceutical ingredient of Beovu is brolucizumab (RTH258), a humanized single-chain antibody fragment (scFv) that targets all isoforms of vascular endothelial growth factor-A (VEGF-A). Single-chain antibody fragments have garnered significant attention in drug development due to their small size, enhanced tissue penetration, rapid clearance from systemic circulation, and favorable drug delivery characteristics. The innovative structure of brolucizumab results in a molecular weight of only 26 kDa, conferring potent inhibitory activity against all VEGF-A isoforms with high affinity. In preclinical studies, brolucizumab inhibits VEGF receptor activation by blocking ligand-receptor interactions. Increased VEGF pathway signaling is associated with pathological ocular angiogenesis and retinal edema. In patients with chorioretinal vascular diseases, inhibition of the VEGF pathway suppresses the growth of neovascular lesions, alleviates retinal edema, and improves vision.

In China, Beovu has entered Phase III clinical trials for indications such as wet AMD and diabetic retinopathy.

Note: The original text has been abridged.

Source: Novartis announces positive results from Phase III trials of Beovu® in diabetic macular edema, including dosing intervals up to 16 weeks

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