Two-year data support brolucizumab for diabetic macular oedema

The 100-week results of the phase III KESTREL and KITE studies reflect the long-term efficacy and durability of brolucizumab in improving visual and anatomical outcomes in patients with diabetic macular oedema (DMO).

“The noninferior visual acuity (VA) gains achieved with brolucizumab 6 mg (BRO6) at week 52 were maintained over 100 weeks and were comparable to those of aflibercept in both studies,” said the researchers.

The least-squares mean (LSM) changes in best-corrected VA (BCVA) achieved with BRO6 vs aflibercept 2 mg (AFL) at week 52 were sustained through week 100 in both KESTREL (+8.8 vs +10.6 letters) and KITE (+10.9 vs +8.4 letters). [Am J Ophthalmol 2024:260:70-83]

Similarly, the LSM changes in central subfield thickness (CSFT) achieved with brolucizumab 3 mg (BRO3), BRO6, and AFL at week 52 in KESTREL were sustained through week 100 (-172, -173, and -170 μm). Estimated CSFT differences were -1 μm (BRO3 vs AFL) and -3 μm (BRO6 vs AFL). In KITE, CSFT reductions were larger (LSM change from baseline, -202 μm [BRO6] vs -173 μm [AFL]), with an estimated difference of -29 μm in favour of BRO6.

Safety profile

In KESTREL, the rates of ocular adverse events (AEs) with BRO3, BRO6, and AFL that were deemed treatment-related were 6.3, 4.2, and 1.6 percent, respectively. Most events were mild-to-moderate in severity.

There were few participants who had at least 1 severe ocular AE in both KESTREL (4.2, 2.6, and 3.7 percent for BRO3, BRO6, and AFL, respectively) and KITE (3.4 percent [BRO6] and 2.2 percent [AFL]).

The incidences of treatment discontinuation owing to an ocular AE were 3.7, 1.6, and 1.1 percent for the respective BRO3, BRO6, and AFL arms in KESTREL, and 2.8 percent (BRO6) and 2.2 percent (AFL) in KITE.

AEs of special interest

The rates of intraocular inflammation (IOI) up to week 100 were 5.3, 4.2, and 1.1 percent in the respective BRO3, BRO6, and AFL arms in KESTREL, and 2.2 percent (BRO6) and 1.7 percent (AFL) in KITE. Overall, there were a total of 40 IOI events tied to brolucizumab during the 100-week study period, half of which occurring within the first 6 months.

There were few cases of retinal vasculitis in KESTREL in year 1, but there were no new reports by year 2. In KITE, no cases were reported throughout the entire study.

Year 2 only saw five cases of retinal vascular occlusion (RVO) in KESTREL and none in KITE.

“Because of the confirmed safety signal of retinal vasculitis and/or RVOs, typically occurring in the presence of IOI, there is greater potential for severe, permanent vision loss during treatment with brolucizumab vs aflibercept,” the researchers said. “[T]herefore, continued vigilance and monitoring for any signs of IOI-related events with prompt and intensive management is recommended.” [Ophthalmology 2021;128:1050-1059; Ophthalmol Retina 2021;5:519-527]

Suboptimal VA gains in clinical practice

DMO can lead to visual impairment and blindness in patients with diabetes, the researchers pointed out. “Despite advances in treatment options, there continues to be a significant unmet need for effective and safe therapies with extended durability.”

Intravitreal anti-vascular endothelial growth factors are the first-line of treatment for DMO. [PLoS One 2020;15:e0233595; Acta Ophthalmol 2018;96:e942-e949; Diabetes Ther 2018;9:2271-2289] “[However,] suboptimal VA gains are common in routine clinical practice, an observation at least partially attributable to undertreatment,” they said.

In KESTREL, 566 participants were randomized 1:1:1 to BRO3, BRO6, or AFL. In KITE, 360 patients were randomized 1:1 to BRO6 or AFL. Brolucizumab recipients received five loading doses at Q6W intervals followed by Q12W dosing, with the option to adjust to Q8W if disease activity was identified during any of the disease activity evaluations. Aflibercept recipients across both studies received five loading doses Q4W, followed by a fixed Q8W dose until end of study.

“It is important to highlight that KESTREL and KITE used a Q6W loading regimen for BRO [as opposed to the] standard Q4W dosing interval,” they said. “[This] was based on the results of the phase I/II study which demonstrated that the peak effect of BRO6 on BCVA gains and CSFT reduction was at week 6.”

The 52-week data from KESTREL and KITE have led to the approval of brolucizumab in over 40 countries for the treatment of visual impairment owing to DMO. [https://www.ema.europa.eu/en/documents/product-information/beovu-epar-product-information_en.pdf; https://www.novartis.com/us-en/sites/novartis_us/files/beovu.pdf, accessed May 7, 2024]