Brolucizumab for DME

Pivotal trial data show robust efficacy with reduced injection burden and favourable safety. Cheryl Guttman Krader reports from AAO 2021 in New Orleans, USA

Brolucizumab-dbll 6 mg (Beovu®, Novartis) may prove useful in diabetic macular oedema (DME) treatment, according to study data presented by Dilsher Dhoot MD during the Retina Subspecialty Day.

Presenting the 52-week results from the KESTREL and KITE studies, Dr Dhoot reported brolucizumab 6 mg was non-inferior to aflibercept in the primary endpoint analysis of mean change in BCVA from baseline at week 52. Patients in the brolucizumab arms received fewer injections compared to the aflibercepttreated patients.

“In both KESTREL and KITE, more than half of patients treated with brolucizumab 6 mg were maintained on a quarterly dosing schedule through week 52 after completing the loading phase. During the first year, brolucizumab-treated patients received a median of seven injections versus nine injections for the aflibercept groups,” Dr Dhoot said.

Treatment with brolucizumab 6 mg was associated with early and durable robust improvements in central subfield thickness (CST) from baseline. Compared to aflibercept, higher proportions of patients treated with brolucizumab 6 mg achieved overall fluid resolution (intraretinal and/or subretinal) and intraretinal fluid resolution.

Importantly, the adverse event data from the two studies showed no evidence that underlying diabetes had a negative impact on a brolucizumab-related incidence of intraocular inflammation.

“The sample size [in KESTREL and KITE] is too small to conclude diabetes is somehow protective against intraocular inflammation. However, we can potentially conclude diabetes is not deleterious as we compare the DME patients to the population in the nAMD trials,” said Dr Dhoot, commenting on the safety profile of brolucizumab in the DME studies relative to that observed in the neovascular age-related macular degeneration clinical trials.

STUDY DESIGN KESTREL and KITE have a planned follow-up of 100 weeks. Enrolling a total of 926 patients across 36 countries, the studies are comparing brolucizumab with aflibercept administered according to its labelled directions (five monthly injections, then every eight weeks). KITE investigated only the 6 mg dose of brolucizumab. KESTREL included 3 mg and 6 mg brolucizumab arms—but the 3 mg dose did not meet the non-inferiority margin in the primary endpoint analysis of mean change in BCVA from baseline at week 52.

All brolucizumab groups received five loading doses given at six-week intervals and then entered a maintenance phase with injections given every 12 weeks. Based on findings at prespecified disease activity assessment visits (weeks 32, 36, and 48 in the first year), the brolucizumab injection frequency could decrease to every eight weeks per the masked investigator’s discretion.

ANATOMIC DATA DETAILS Dr Dhoot noted data from the week 32 and week 52 visits give a unique opportunity to evaluate brolucizumab and aflibercept in a head-to-head fashion concerning anatomic timepoints.

“At week 32, patients are eight weeks out after receiving their last doses in all treatment arms, and at 52 weeks, the aflibercept patients and half of the brolucizumab patients are four weeks postdosing while the remaining brolucizumab patients on the q12w interval are eight weeks postdosing. Therefore, the week 52 assessments actually favour aflibercept.”

Against that background, Dr Dhoot reported that in KITE, the mean change in CST from baseline averaged from visits at weeks 40 to 52 was significantly greater in the brolucizumab 6 mg group compared to aflibercept (-187.1 vs -157.7 microns). In addition, the proportion of eyes reaching a CST ≤280 microns were significantly greater with brolucizumab 6 mg at week 32 and week 52 versus aflibercept.

Furthermore, smaller proportions of patients in the brolucizumab 6 mg groups had intraretinal and/or subretinal fluid present at weeks 32 and 52 compared to the aflibercept groups. Looking only at intraretinal fluid showed it was present in fewer patients in the brolucizumab 6 mg groups than the aflibercept groups at weeks 4, 16, 32, and 52.

Brolucizumab was also associated with clinically relevant improvements in diabetic retinopathy. In both KESTREL and KITE, 29% of patients treated with brolucizumab achieved a ≥2-step improvement in DRSS score from baseline at week 52. For this endpoint, pooled results from the two studies showed non-inferiority of brolucizumab 6 mg to aflibercept.

ADVERSE EVENTS Overall rates of ocular and nonocular adverse events were similar among treatment groups in each study. Across all five study arms, there were five cases of endophthalmitis, including one with brolucizumab 6 mg and two with aflibercept. Three cases of endophthalmitis were culture positive.

Brolucizumab was associated with higher intraocular inflammation rates than aflibercept only in KESTREL, and the rate was higher with brolucizumab 3 mg versus 6 mg (4.7% vs 3.7%). The seven cases recorded in the 6 mg arm included one case of retinal vasculitis in a patient who also had a retinal vascular occlusion.

“Both the retinal vasculitis and retinal vascular occlusion resolved without treatment, and the patient had a 14-letter gain from baseline BCVA at week 52,” Dr Dhoot reported.

In KITE, the intraocular inflammation rate was 1.7% in both the brolucizumab 6 mg and aflibercept arms. There was a single case of retinal vascular occlusion in each arm that was not related to intraocular inflammation.

Dilsher Dhoot MD practices at California Retina Consultants, Santa Barbara, California, USA. ddhoot@yahoo.com