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Henry Wiley, Ramaprasad Srinivasan, Marston Linehan, Catherine A Cukras, Tiarnan D L Keenan, Wai T Wong, Emily Y Chew; Ocular findings in a phase 2 trial testing the first-in-class oral HIF-2α inhibitor, PT2385, for renal cell carcinoma in von Hippel-Lindau disease. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2782.
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Von Hippel-Lindau (VHL) disease is caused by mutations in the VHL gene and activation of hypoxia-inducible factors (HIFs), including HIF-2α, leading to development of neoplasms and cysts. We report the eye findings from a phase 2 clinical trial testing the safety and efficacy of a first-in-class oral HIF-2α inhibitor, PT2385 (Peloton Therapeutics, Inc., Dallas, TX), for renal cell carcinoma (RCC) in patients with VHL disease.
In this phase 2, single-arm, open-label trial, adults with VHL disease and at least one RCC (≤ 3 cm) received oral PT2385 (800 mg twice daily). Staging of disease was performed at baseline and every 12 weeks. Baseline eye examination included fundus photography, optical coherence tomography, and ultra-widefield fluorescein angiography (FA), with imaging repeated during follow up at investigator discretion. Retinal hemangioblastomas (RHs) were graded for lesion area, vascularity, and visibility of feeding/draining vessels on fundus photographs. Leakage was evaluated on FA.
Among 4 participants (ages 69, 60, 51, 53) enrolled, 3 manifested one or more RHs. Duration of PT2385 usage for each was 28, 73, 12, and 13 weeks; and duration of follow up was 74, 73, 64, and 46 weeks, respectively. At baseline, 5 RHs (greatest linear dimension [GLD] 330-980 µm) were present in participant 1; 3 RHs (GLD 200-360 µm) in participant 2; and 1 juxtapapillary RH (GLD 700 µm) in participant 4. At 12 weeks, 5/9 RHs showed a decrease in lesion area of >10%, including one lesion in participant 1 that was no longer visible at all, and 6/9 RHs exhibited a decrease in vascularity and/or feeding/draining vessel visibility. Lesions in participant 1 reverted to baseline appearance at 36 weeks, after stopping PT2385 at 28 weeks. Lesion changes in participant 2, who continues to take PT2385, persisted through 73 weeks. Findings in participant 4 remained unchanged through 46 weeks. No new RHs appeared, and visual acuity remained 20/25 or better in all eyes.
PT2385 showed no significant ocular safety concerns and demonstrated a decrease in the size of a subset of small RHs in this phase 2 trial, with effects that appear reversible on stopping treatment. Enrollment in this trial has been halted in anticipation of a phase 2 trial testing a second-generation HIF-2α inhibitor, PT2977, for RCC in patients with VHL disease.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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