Oral Hypoxia-Inducible Factor 2a inhibitor Belzutifan in Ocular von Hippel-Lindau Disease
August 2024
Kapil Mishra M.D.
Gavin Herbert Eye Institute
University of California, Irvine
Wiley HE, Srinivasan R, Maranchie JK, et al. Oral hypoxia-inducible factor 2α inhibitor belzutifan in ocular von hippel-lindau disease. Ophthalmology. Published online June 2024:S0161642024003191.
Von Hippel-Lindau (VHL) disease is a hereditary condition characterized by the development of tumors in multiple organs due to mutations in the VHL tumor suppressor gene. Retinal hemangioblastomas (RH) are a common ocular manifestation of VHL disease, occurring in approximately 38% of patients. Ablative therapy is the primary treatment for RH, and in some cases vitrectomy with resection is performed. Juxtapapillary RHs and extensive RHs (involving a large portion of the retina) may not be amenable to ablative or surgical treatments.
The VHL protein (pVHL) regulates cellular responses to oxygen via hypoxia-inducible factors (HIFs). In normal oxygen conditions, pVHL mediates the degradation of HIF-α subunits, including HIF-2α, but in VHL disease, this regulation is disrupted, leading to HIF-2α accumulation. Overexpression of HIF-2α has been linked to various tumors including clear cell renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, pancreatic neuroendocrine tumors (pNETs), and others.
Belzutifan (MK-6482), a small-molecule HIF-2α inhibitor, has been approved in several countries, including the U.S., for treating VHL disease-associated RCC, CNS hemangioblastomas, and pNETs. The approval followed the LITESPARK-004 study, which demonstrated an objective response rate of 64% in RCC patients with belzutifan treatment. More recently, belzutifan was also approved for advanced RCC based on the phase 3 LITESPARK-005 study.
Secondary outcomes of the LITESPARK-004 study included the effect of belzutifan on ocular VHL disease. Prior evaluations indicated a 100% improvement rate in active RHs among participants through an independent reading center (IRC), and the current paper provides a more detailed qualitative analysis of the ocular lesion responses. Participants were treated with oral belzutifan at 120 mg daily until progression, unacceptable toxicity, or other specified events led to discontinuation. Ophthalmic assessments involved BCVA and multimodal imaging of RH measured at baseline and every 12 weeks for at least three years.
The study enrolled 61 participants, and a total of 12 participants (19.7%) had 16 eyes with active RH that were evaluable for response and thus included in the present analysis. The median number of RHs was 2.5 (range, 1-5 RHs) per participant and 2 RHs (range, 1-4 RHs) per eye. All 16 eyes showed an improved response (100%) with the median time to response at 2.7 months (range, 2.5-8.3 months). Visual acuity remained consistent throughout the study. All RHs showed a reduction in area of 10% or more by month 6, 15% or more by month 12, and 30% or more by month 24. Exudation for the peripapillary RHs also decreased.
In conclusion, the LITESPARK-004 study revealed that belzutifan provides durable improvement for RHs in VHL disease, aligning with its efficacy in controlling various VHL-associated tumors. While the study’s limited size and lack of a comparator group are limitations, the observations provide substantial evidence supporting belzutifan use in ocular VHL.
