Phase 3 GLOW2 trial shows tarcocimab improves diabetic retinopathy severity with extended dosing

Positive topline results from the phase 3 GLOW2 trial suggest that tarcocimab tedromer (Zenkuda), an investigational anti–vascular endothelial growth factor (VEGF) biologic, may offer durable disease control in patients with diabetic retinopathy (DR), including those with more advanced disease. The findings, announced by Kodiak Sciences, indicate significant improvements in diabetic retinopathy severity and reduced progression to sight-threatening complications compared with sham treatment.

Trial overview

GLOW2 is a randomized, phase 3 superiority study evaluating intravitreal tarcocimab tedromer in patients with moderately severe to severe nonproliferative DR, as well as proliferative DR (PDR) and mild diabetic macular edema (DME). The study builds on the earlier GLOW1 trial and expands inclusion criteria to reflect a broader, higher-risk population.

Patients were randomized to receive either sham injections or tarcocimab tedromer, administered at baseline, weeks 4 and 8, followed by extended dosing intervals reaching every 6 months by week 44. The primary endpoint was the proportion of patients achieving a ≥2-step improvement in the Diabetic Retinopathy Severity Scale (DRSS) at week 48.

According to the company, 62.5% of patients treated with tarcocimab achieved a ≥2-step DRSS improvement compared with 3.3% in the sham group (P < .0001). Secondary endpoints also favored treatment, including an 85% relative risk reduction in prespecified sight-threatening complications—defined as progression to PDR or development of center-involving DME—through week 48.

Additionally, 13.7% of treated patients achieved a ≥3-step DRSS improvement versus none in the control group. Safety findings were described as favorable, with no reported cases of intraocular inflammation, retinal vasculitis, or occlusive vasculitis, and low rates of cataract comparable to sham.

These findings remain preliminary and have not yet been published in a peer-reviewed journal.

Clinical context

Diabetic retinopathy remains a leading cause of vision loss globally, particularly among working-age adults. The progression from nonproliferative DR to proliferative disease or DME is associated with significant morbidity. Anti-VEGF therapies, including aflibercept and ranibizumab, have demonstrated efficacy in improving DR severity and preventing progression; however, their use in earlier-stage DR has been limited by the need for frequent injections.¹²

Clinical trials such as PANORAMA (aflibercept) and RISE/RIDE (ranibizumab) have shown that anti-VEGF therapy can induce regression in DR severity and reduce complications, but treatment burden remains a key limitation to widespread preventive use.¹³

The potential for extended dosing intervals, as suggested in GLOW2, may address this barrier if efficacy and safety are confirmed.

Drug background

Tarcocimab tedromer is an anti-VEGF antibody biopolymer conjugate designed to increase intraocular durability. The molecule is based on Kodiak’s proprietary antibody biopolymer conjugate platform, which aims to extend drug residence time in the vitreous.

Earlier studies have evaluated tarcocimab in neovascular age-related macular degeneration (nAMD) and DME, with mixed results. The phase 3 DAVIO 2 trial in nAMD did not meet its primary endpoint for noninferiority to aflibercept, raising questions about the platform’s consistency across indications.⁴

The GLOW program represents a separate development pathway focused specifically on DR, where endpoints such as DRSS improvement differ from visual acuity–based outcomes used in nAMD and DME trials.

Interpretation and expert perspective

The magnitude of DRSS improvement reported in GLOW2 appears consistent with prior anti-VEGF studies in DR. However, the inclusion of patients with PDR and mild DME distinguishes this trial from earlier DR prevention studies, which often excluded more advanced disease.

The reported durability—transitioning to 6-month dosing intervals after a loading phase—could represent a meaningful advance if replicated in clinical practice. However, experts may note that real-world durability often differs from controlled trial settings, and adherence patterns, retreatment criteria, and long-term outcomes remain critical considerations.

Additionally, the absence of intraocular inflammation is notable given historical safety concerns with some long-acting intraocular biologics, although full safety data and longer follow-up are needed.

Limitations and next steps

Several limitations should be considered. The results are based on a company press release and have not yet undergone peer review or regulatory evaluation. Detailed subgroup analyses, durability beyond 48 weeks, and visual acuity outcomes have not been fully disclosed.

Moreover, comparisons to active anti-VEGF comparators were not included, limiting conclusions about relative efficacy versus current standard treatments.

Kodiak Sciences has indicated plans to submit a biologics license application (BLA) to the US Food and Drug Administration. Regulatory review will determine whether the GLOW1 and GLOW2 data are sufficient to support approval.

Further data presentation at scientific meetings and publication in peer-reviewed journals will be essential to contextualize these findings within the broader DR treatment landscape.

References

1. Wykoff CC, et al. Effect of intravitreal aflibercept on diabetic retinopathy severity: PANORAMA trial. JAMA Ophthalmol. 2019.
   https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2739059

2. Nguyen QD, et al. Ranibizumab for diabetic retinopathy: RISE and RIDE trials. Ophthalmology. 2012.
   https://www.aaojournal.org/article/S0161-6420(12)00538-6/fulltext

3. Brown DM, et al. Intravitreal aflibercept for diabetic retinopathy without DME. Ophthalmology. 2019.
   https://www.aaojournal.org/article/S0161-6420(19)30277-0/fulltext

4. Kodiak Sciences. DAVIO 2 trial results (tarcocimab in nAMD).
   https://clinicaltrials.gov/study/NCT03790852

5. ClinicalTrials.gov. GLOW2 study of tarcocimab tedromer in diabetic retinopathy.
   https://clinicaltrials.gov/study/NCT04471766

6. Kodiak Sciences. Press release: GLOW2 topline results.
   https://ir.kodiak.com/news-releases/news-release-details/kodiak-sciences-announces-positive-topline-results-glow2-second