IL-6 Inhibitor Shows Promise in Diabetic Macular Edema

DENVER — Targeting an inflammatory pathway in diabetic macular edema (DME), in addition to angiogenesis, led to greater improvement in visual acuity and retinal anatomy, a randomized trial showed.

Single-agent ranibizumab (Lucentis) improved best corrected visual acuity (BCVA) by 9.4 letters at 44-48 weeks, which increased to 12.8 letters with the addition of the interleukin (IL)-6 inhibitor vamikibart. Central subfield thickness (CST) declined by an average of 192 µm with ranibizumab alone, increasing to 202 µm when vamikibart was added. More patients treated with the combination had large improvements in BCVA (≥15 letters), normalization of CST (<325 µm), and resolution of macular edema.

The combination was associated with more intraocular inflammation and elevated intraocular pressure (IOP), but cataract events occurred in a similar proportion of patients in the two treatment arms, reported Roger Goldberg, MD, of Bay Area Retina Associates in Walnut Creek, California, at the Association for Research in Vision and Ophthalmology meeting.

A separate trial of vamikibart monotherapy in DME showed the IL-6 inhibitor improved visual acuity and CST, independent of VEGF inhibition, although the improvements were less than those observed with single-agent ranibizumab.

“IL-6 inhibition, in conjunction with an anti-VEGF, really offers an opportunity to help our DME patients, in terms of best corrected visual acuity and in terms of CST,” said Goldberg. “We did see, in the combination arm, issues around intraocular inflammation… . But I think [the two trials] taken together show that IL-6 inhibition offers a distinct benefit that’s isolated from VEGF blockade alone. There’s an ongoing phase I trial investigating a single molecule, a bispecific antibody, targeting both VEGF and IL-6 in patients with DME, with a single injection.”

During a discussion that followed the presentation, an unidentified member of the audience noted that even with the addition of a second drug, a substantial proportion of patients did not meet generally accepted criteria for response.

“I think IL-6 will be an important step forward, but we know that DME is a heterogeneous, complex, multifactorial disease,” said Goldberg. “A single silver bullet, VEGF inhibition, works great but isn’t for all of our patients. I don’t think the IL-6 silver bullet, just targeting that one pathway, is going to be enough for all of the patients because not all of the patients have IL-6-mediated inflammation.”

“What are the biomarkers we can look for to help us better personalize medicine and give patients the exact therapy that they need?” he continued. “I do think we will get there. Having multiple tools in our toolbox is going to be part of the solution to giving patients personalized medicine and treatment that’s going to be best for that patient.”

Baseline BCVA also should be considered when evaluating treatment response, said Arshad Khanani, MD, of Sierra Eye Associates in Reno, Nevada, who presented findings from the monotherapy trial. Patients with higher baseline BCVA have less room for improvement. More questions will arise and have to be addressed as the field moves forward.

“I think this really is a pivotal moment for our field, to have a validated new MOA [mechanism of action] for our patients with diabetic macular edema,” said Khanani. “As the field evolves, is it just two pathways? Is it more than two? What do we need to target?”

Inflammation and DME

Increasingly, the field of ophthalmology has recognized inflammation as a key contributor to DME. Historically, corticosteroids have been used to mitigate the effects of inflammation, but the drugs have well-known safety issues, said Goldberg. VEGF inhibition remains standard of care for DME, but an unmet clinical need exists for well-tolerated treatments that can target inflammation in DME.

IL-6 is elevated in ocular fluids of patients with DME and has a pivotal role in DME pathogenesis, including vascular leakage, leukocyte infiltration, and chronic inflammation.

Vamikibart is a recombinant humanized anti-IL-6 antibody specifically designed for intravitreal delivery, said Goldberg. In a phase I trial vamikibart demonstrated rapid and sustained suppression of IL-6 in the aqueous humor of patients with uveitic macular edema.

Goldberg reported findings from the phase II BARDENAS trial involving patients with type 1 or 2 diabetes and center-involving DME with CST ≥325 µm. The patients were randomized to vamikibart and ranibizumab every 4 weeks or ranibizumab alone. Investigators randomized a total of 187 patients, and the primary endpoint was the change in BCVA during weeks 44-48 in previously untreated patients (n=124).

Baseline characteristics for the untreated subgroup included a mean age of 61-62, majority male (59-67%), mean BCVA 62-64 letters, and mean CST of 482-502 µm.

The primary analysis showing a 3.4-letter improvement in BCVA during weeks 44-48 met prespecified criteria for statistical significance (P=0.0625, prespecified P=0.1). More patients in the combination arm had at least a 15-letter improvement (44.7% vs 28.6%). The difference in CST improvement did not achieve statistical significance, but more patients in the combination arm had CST <325 µm (85.1% vs 71.4%).

Treatment-related ocular AEs occurred more often in the combination arm (10 related to vamikibart, six to ranibizumab) versus ranibizumab monotherapy (four), and more patients stopped one or both drugs in the combination arm (10 vamikibart, eight ranibizumab) than in the monotherapy arm (one).

Intraocular inflammation occurred in nine patients in the combination arm, and two patients developed retinal occlusive vasculitis, versus none treated with single-agent ranibizumab.

Single-Agent Vamikibart

Khanani reported findings from the phase II ALLUVIUM trial evaluating three dosing levels of vamikibart and single-agent ranibizumab. The primary endpoint was change in BCVA in previously untreated patients (n=259) at weeks 44-48. The trial was not designed as a direct comparison of vamikibart and ranibizumab but to evaluate the efficacy of the IL-6 inhibitor.

The primary analysis showed patients randomized to vamikibart had BCVA improvement of about five to seven letters across the three dose levels. The improvement averaged 13 letters in the ranibizumab arm. Across the three vamikibart dosing groups, 15-23% of patients had at least a 15-letter improvement in BCVA (40% in the ranibizumab arm).

An analysis of all patients (N=394), regardless of treatment history, showed BCVA improvement of three to five letters with vamikibart. Across the three doses of vamikibart, 10-18% of patients had at least a 15-letter improvement in BCVA.

Vamikibart treatment led to CST improvement of 50-70 µm in previously untreated patients, 33-40% of whom had resolution of DME, defined as CST <325 µm. Results were similar in the all-comer analysis.