Author’s Name(s): Jennifer Ling, Kirk Stephenson, Olubayo Kolawole, Lica Chui, Cheryl Gregory-Evans, Kevin Gregory-Evans, Maryam Soleimani, Patrick Ma

Author’s Disclosure Block: Jennifer Ling, none; Kirk Stephenson, none; Olubayo Kolawole, none; Lica Chui, none; Cheryl Gregory-Evans, none; Kevin Gregory-Evans, none; Maryam Soleimani, none; Patrick Ma, none

Abstract Body
Purpose: To assess the effect of belzutifan, a first-in-class oral HIF2α inhibitor, on retinal hemangioblastoma (RH) outcomes.Design: Single-centre retrospective controlled cohort study. Methods: Patients with confirmed VHLS and RH. Subjects were taking oral belzutifan for RCC, CNS hemangioblastoma or pancreatic neuroendocrine tumours. Controls also had VHLS and RH but were not taking belzutifan. Patients were compared between oral belzutifan group and control (not taking belzutifan) for ophthalmic structural, functional and therapeutic outcomes regarding pre-existing and new RH.Main Outcome Measures: Demographics, VHL genotype, visual function, behaviour of pre-existing RH, number of new lesions, systemic features and drug-related adverse events (AE). Results: Similar baseline characteristics were identified between belzutifan and control groups for number of patients (16 vs 22), number of eyes (30 vs 33, p=0.9), female proportion (44% vs 45%, p=0.9), mean age (37±9 vs 35±18 years, p=0.62), proportion of type 1 VHLS (94% vs 91%, p=0.75), and large (≥1 exon) VHL deletions (81.3% vs 68.2%, p=0.37). Mean belzutifan duration and dose were 334 ±154 days and 110mg/day, respectively. Comparison of outcomes between belzutifan and control groups showed a statistically significant difference for new lesion development (0/year vs 0.8±1.0/year, p=0.014), non-significant difference in proportion with vision 0.3 LogMAR or better (80% vs 70%, p=0.35) and no difference in final visual acuity (0.4±1.0 vs 0.5±1.0 LogMAR, p=0.98). No severe or ophthalmic drug-related AE occurred. Conclusions: In patients with VHLS, oral belzutifan resulted in stability of pre-existing RH with no new RH developing during the duration of this study. Early use of belzutifan may be a therapeutic avenue to prevent blindness (and mortality) in patients with VHLS when compared with destructive/ablative alternatives, particularly for posterior/juxtapapillary lesions.