FDA Grants Breakthrough Therapy Designation, Orphan Drug Designation to MK-6482

The FDA granted breakthrough therapy designation to MK-6482 for the treatment of patients with von Hippel-Lindau disease-associated renal cell carcinoma and orphan drug designation to MK-6482 for von Hippel-Lindau disease.

The FDA has granted breakthrough therapy designation to the hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor MK-6482 for the treatment of patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) with nonmetastatic RCC tumors less than 3 centimeters in size, unless immediate surgery is required, according to Merck, the developer of the agent.1

In addition, the FDA also granted orphan drug designation to MK-6482 for VHL. Both designations are based on data from an open-label phase 2 trial evaluating the HIF-2α inhibitor in patients with VHL-associated clear cell RCC. Results from this trial were presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Meeting.

“Merck’s diverse and expansive oncology pipeline is focused on bringing forward innovative new treatments to patients in need and continues to show important progress,” Scot Ebbinghaus, MD, vice president of clinical research at Merck Research Laboratories, said in a press release. “These designations for MK-6482 support the potential of targeting HIF-2α in certain patients with von Hippel-Lindau disease, who currently have limited treatment options and face an increased risk for benign tumors as well as several types of cancer, including renal cell carcinoma.”

As of December 6, 2019, 61 patients were enrolled in the phase 2 trial.2 The median duration of treatment was 9.9 months (range, 1.9-18.2) and 95.1% of patients remained on therapy; however, 3 patients discontinued treatment due to an adverse event (n = 1), death (fentanyl toxicity, n = 1), or patient decision (n = 1).

Overall, there were 17 confirmed responses (ORR, 27.9%; 95% CI, 17.1-40.8%) and 8 (13.1%) unconfirmed responses, which were documented at 1 timepoint and to be confirmed at subsequent timepoint. All confirmed responses were partial responses. Among the total cohort, 53 (86.9%) saw a decrease in the size of their target lesions.

Of the 17 patients with a confirmed response, median duration of response was not reached (range, 2.1-9.0 months) and median time to response was 5.5 months (range, 2.7-14.0). Responses were also observed in central nervous system, retinal, and pancreatic lesions. Notably, the median progression-free survival (PFS) was not reached; however, the 12-month PFS rate was 98.3%.

With regard to safety, treatment-related AEs (TRAEs) occurred in 96.7% of patients, and were mostly grade 1 (44.3%) or grade 2 (42.6%). The most common (≥20%) TRAEs were anemia (83.6%), fatigue (49.2%), and dizziness (21.3%). Moreover, grade 3 TRAEs occurred in 9.8% of patients, and consisted primarily of fatigue (4.9%) and anemia (3.3%). There were no grade 4 or 5 TRAEs. One patient discontinued because of a TRAE (dizziness).

Currently, MK-648 is being evaluated in a phase 3 trial in advanced RCC (NCT04195750), a phase 2 trial in VHL-associated RCC (NCT03401788), and a phase 1/2 dose-escalation and dose-expansion trial in advanced solid tumors, including advanced RCC (NCT02974738).


1. FDA Grants Breakthrough Therapy Designation to Merck’s Novel HIF-2α Inhibitor MK-6482 for Treatment of Certain Patients With Von Hippel-Lindau Disease- Associated Renal Cell Carcinoma [news release]. Kenilworth, NJ. Published July 29, 2020. mrknewsroom.com/newsroom/news-releases/news-details/2020/FDA-Grants-Breakthrough-Therapy-Designation-to-Mercks-Novel-HIF-2-Inhibitor-MK-6482-for-Treatment-of-Certain-Patients-With-Von-Hippel-Lindau-Disease--Associated-Renal-Cell-Carcinoma/default.aspx. Accessed July 29, 2020.

2. Jonasch E, Donskov F, Iliopoulos O, et al. Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau disease–associated renal cell carcinoma. Presented at: 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Meeting. Abstract #: 5003.