Primary outcomes of the VIDI study: phase 2, double-masked, randomized, active-controlled study of ASP8232 for diabetic macular edema

Abstract

Background: ASP8232 is a potent and specific small molecule vascular adhesion protein-1 (VAP-1) inhibitor. This study evaluated the effect of ASP8232 on excess retinal thickness when given alone or in combination with ranibizumab in patients with center-involved diabetic macular edema (CI-DME).

Methods: This was a phase 2a, placebo and sham-injection controlled, double-masked, randomized, parallel-group clinical trial. Participants were patients with CI-DME and central subfield thickness (CST) ≥ 375 µm in the study eye as assessed by spectral domain optical coherence tomography. Eligible patients were randomized to (1) daily oral ASP8232 40 mg monotherapy; (2) combination therapy of daily oral ASP8232 40 mg and monthly intravitreal ranibizumab 0.3 mg; or (3) monthly intravitreal ranibizumab 0.3 mg monotherapy. The treatment period was 12 weeks. CST and best corrected visual acuity (BCVA) were assessed at baseline and at Weeks 2, 4, 8, 12, 16 and 24. The primary outcome was the mean percent change from baseline in excess CST at Week 12. Secondary outcomes were BCVA, safety and tolerability, and pharmacokinetic and pharmacodynamic characteristics of ASP8232.

Results: After 12 weeks, the mean (95% confidence interval) percent change in excess CST was 11.4% (- 15.0%, 37.8%) in the ASP8232 group, - 61.7% (- 86.1%, - 37.2%) in the ASP8232/ranibizumab group, and - 75.3% (- 94.8%, - 55.8%) in the ranibizumab group. The change from baseline in the two ranibizumab arms was statistically significant (P < 0.001) as was the difference between the ranibizumab groups and the ASP8232 group (P < 0.001). Mean (SD) increase in BCVA score from baseline was 3.1 (7.3) in the ASP8232 group, 5.2 (7.1) in the ASP8232/ranibizumab group, and 8.2 (9.5) in the ranibizumab group. The increase from baseline in BCVA score was statistically and clinically significant in the ranibizumab group compared with the ASP8232 group (P = 0.015). ASP8232 resulted in near complete inhibition of plasma VAP-1 activity whilst ranibizumab had no effect.

Conclusions: Near complete inhibition of plasma VAP-1 activity with ASP8232 had no effect on CST in patients with CI-DME. Furthermore, combination therapy did not provide additional benefit to treatment with ranibizumab alone, which significantly reduced CST and improved BCVA.Trial registration clinicaltrials.gov; NCT02302079. Registered on November 26, 2014.

Keywords: ASP8232; Center-involved diabetic macular edema; Central subfield thickness; Clinical trial; Ranibizumab; VAP-1 inhibitor.

Conflict of interest statement

QDN: chaired the Steering Committee for the RISE and RIDE studies of ranibizumab for diabetic macular edema; Grants from Astellas, Genentech, and Regeneron; scientific advisory boards for Astellas, Genentech, and Regeneron. YJS: Research Support from Astellas, Genentech, Optovue; Personal Fees from Genentech/Roche and Optos. BB: Research Support from Genentech, Regeneron, Allegro. DB: Grants from Astellas and Genentech/Roche, Regeneron, Bayer, Adverum, Allergan, Regenxbio, Clearside Biomedical, OHR, Heidelberg, Novartis, Thrombogenics, Ophthotech, NEI, Kanghong Biotech, Samsung, Ophthea, Apellis; Personal Fees from Genentech/Roche, Adverum, Allergan, Regenxbio, Clearside Biomedical, OHR, Bayer, Heidelberg, Novartis, Optos, Zeiss, Thrombogenics, Santen, Senju, Kanghong Biotech, Samsung, Apellis. DVD: Grants from Genentech, Regeneron, Santen. AGH: Personal Fees from Astellas; Employee of Astellas. SP: Grants from Genentech, Novartis, Ophthotech, Allergan, Opthea, Clearside, Samsung, Aerpio, Regeneron, Graybug and Taiwan Liposome Company. FMR: Nothing to disclose. YS: advisory board and research support from Castle Biosciences. RWR: Employee of Astellas.

Figures

Fig. 1

Percent change (95% CI) from baseline in excess CST at EoT visit (FAS). CI, confidence interval; CST, central subfield thickness; EoT, end of treatment; FAS, full analysis set

Fig. 2

Mean (95% CI) change from baseline in absolute CST values in the study eye (FAS). CI, confidence interval; CST, central subfield thickness; FAS, full analysis set; LDD, last dose date; LOCF, last observation carried forward

Fig. 3

Mean (95% CI) change from baseline in absolute CST values in the fellow eye (FAS). CI, confidence interval; CST, central subfield thickness; FAS, full analysis set; LDD, last dose date; LOCF, last observation carried forward

Fig. 4

Mean (95% CI) change from baseline in ETDRS calculated BCVA score (FAS). FAS, full analysis set; LDD, last dose date; LOCF, last observation carried forward

Fig. 5

Mean plasma concentration of ASP8232 (pharmacokinetic analysis set). LDD, last dose date

Fig. 6

Mean (SD) VAP-1 activity in plasma (pharmacodynamic analysis set). LDD, last dose date