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Clinical Trial
. 2024 Jul;38(10):1861-1869.
doi: 10.1038/s41433-024-03017-0. Epub 2024 May 28.

ROBIN: a randomised, double-masked, placebo-controlled Phase IIa study of the AOC3 inhibitor BI 1467335 in diabetic retinopathy

Quan Dong Nguyen  1 , Justis P Ehlers  2 , David S Boyer  3 , Xidong Jin  4 , Andrea Giani  5 , Michael S Ehrlich  4   6 ; ROBIN study investigators
Collaborators, Affiliations
Clinical Trial

ROBIN: a randomised, double-masked, placebo-controlled Phase IIa study of the AOC3 inhibitor BI 1467335 in diabetic retinopathy

Quan Dong Nguyen et al. Eye (Lond). 2024 Jul.

Abstract

Objective: To evaluate the safety and efficacy of BI 1467335 in patients with non-proliferative diabetic retinopathy (NPDR).

Methods: ROBIN is a Phase IIa, double-masked, randomised, placebo-controlled study (NCT03238963). Patients with NPDR and without centre-involved diabetic macular oedema were included; all had a best corrected visual acuity letter score of ≥70 Early Treatment Diabetic Retinopathy Study letters in the study eye at screening. Patients received oral BI 1467335 10 mg or placebo once daily for 12 weeks. Post-treatment follow-up was 12 weeks. The primary endpoint was the proportion of patients over the 24 weeks with ocular adverse events (AEs). Secondary endpoints were the proportion of patients with ≥2-step improvement from baseline in DRSS severity level at Week 12 and the proportion of patients with non-ocular AEs at 24 weeks.

Results: Seventy-nine patients entered the study (BI 1467335, n = 40; placebo, n = 39). The proportion of patients with ocular AEs over 24 weeks was greater in the BI 1467335 versus the placebo group (35.0% vs 23.1%, respectively). Treatment-related AEs were reported for similar numbers of patients in the placebo and BI 1467335 group (7.7% vs 7.5%, respectively). At Week 12, 5.7% (n = 2) of patients in the BI 1467335 group had a 2-step improvement in DRSS severity level from baseline, compared with 0% in the placebo group.

Conclusions: BI 1467335 was well tolerated by patients with NPDR. There was a high variability in DRSS levels for individual patients over time, with no clear efficacy signal.

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Conflict of interest statement

QDN declares funding from Boehringer Ingelheim, Genentech, Gilead, Regeneron and Santen, and consulting for Genentech, Novartis, Regeneron and Santen. JPE declares that he is a consultant for Adverum, Aerpio, Alcon, Allergan, Boehringer Ingelheim, Genentech, Leica, Novartis, Regeneron, Roche, Stealth and Zeiss, and receives grant support from Adverum, Alcon, Allergan, Boehringer Ingelheim, Novartis, Roche, Regeneron, Stealth and Zeiss. DSB declares that he is a consultant with Acucela, Alimera Sciences, Allegro, Bayer, EyePoint Pharmaceuticals, ONL Therapeutics, Oxurion and Takeda; is a consultant and researcher with Adverum, Aerpio, Allergan, Apellis, Boehringer Ingelheim, Chengdu Kanghong, Clearside Biomedical, Genentech/Roche, Kodiak, Novartis, Regeneron, REGENXBIO, Roche and Santen; and is a researcher with Aerie Pharmaceuticals, Gemini Therapeutics, Graybug Vision, IONIS Pharmaceuticals, Neurotech, Opthea and Outlook Therapeutics. XJ and AG declare that they are employees of Boehringer Ingelheim. MSE declares that he is an employee of Alexion Pharmaceuticals, but that this work was performed prior to Alexion employment and is not endorsed by Alexion; at the time of project initiation, he was an employee of Boehringer Ingelheim.

Figures

Fig. 1
Fig. 1. Amine oxidase copper-containing 3 (AOC3) mechanism of action and inhibition.
A AOC3 rapidly translocates to the surface of endothelial cells during inflammation. B AOC3 on the retinal endothelium binds to the AOC3 counter-receptor on the leukocyte; aldehydes, ammonia and reactive oxygen species are released, which contribute to inflammation. C AOC3 inhibition reduces leukocyte recruitment, decreasing inflammation. MMP matrix metalloproteinase, RBC red blood cell. Figure adapted from Boyer DS, Rippmann JF, Ehrlich MS, Bakker RA, Chong V, Nguyen QD. Amine oxidase copper-containing 3 (AOC3) inhibition: a potential novel target for the management of diabetic retinopathy. Int J Retina Vitreous. 2021;7:30 [25].
Fig. 2
Fig. 2. Patient disposition.
A CONSORT flow diagram detailing the patient populations of the ROBIN study.
Fig. 3
Fig. 3. Changes in DRSS over time.
A Proportion of patients in the full analysis set with 2-step improvement in DRSS severity level in the study eye over time (%). B Oscillation of DRSS from baseline measurement for individual patients who at any point in time showed 2-step improvement in DRSS severity level. DRSS diabetic retinopathy severity scale, FU follow-up, NA not available.
See this image and copyright information in PMC

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