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FDA Grants Orphan Drug Designation to LNS8801 for Metastatic Uveal Melanoma


The FDA has granted an orphan drug designation to the orally bioavailable, highly-specific G protein-coupled estrogen receptor agonist LNS8801 for the treatment of patients with metastatic uveal melanoma.

The FDA has granted an orphan drug designation to the orally bioavailable, highly-specific G protein-coupled estrogen receptor (GPER) agonist LNS8801 for the treatment of patients with metastatic uveal melanoma, according to an announcement from Linnaeus Therapeutics, Inc., the drug developer.1

The agent is currently under exploration in a phase 1/2 adaptive-design clinical trial, where it is being evaluated as both a monotherapy and in combination with pembrolizumab (Keytruda) in patients who previously achieved clinical benefit with immune checkpoint inhibitors and then subsequently experienced disease progression.

In October 2020, the company announced that the first patient in the trial has been dosed;2 this is the first time any company has dosed a patient in a clinical trial that is specifically targeting the GPER in combination with pembrolizumab, according to the announcement.

“We are extremely pleased to have received orphan drug designation for metastatic uveal melanoma from the FDA. This is an important milestone that has emerged from the very promising data we have seen in patients with [this disease] during dose escalation,” Patrick Mooney, MD, chief executive officer of Linnaeus, stated in a press release.

The activity of LNS8801 is dependent on the expression of GPER. Activation of GPER by the agent results in the fast and durable depletion of c-Myc protein levels. Previously, LNS8801 was shown to induce strong antitumor activity in preclinical cancer models, across a range of tumor types; the agent not led to rapid tumor shrinkage, but it was also shown to elicit immune memory.

In the phase 1, dose-escalation portion of the trial, investigators evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of the agent. To be eligible for enrollment, patients had to have histopathologically confirmed locally advanced or metastatic cancer that progressed after at least 1 prior line of therapy, be 18 years of age or older, have an ECOG performance status of 0 or 1, and an estimated life expectancy of 3 months or longer.3

If patients had a thyroid or gall bladder cancer, had any cancer that was estrogen receptor positive, received anticancer treatment within 4 weeks prior to the first dose of the study drug, had unresolved adverse effects from prior anticancer treatment, or had symptomatic primary central nervous system (CNS) tumor, symptomatic CNS metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression, they were excluded.

LNS8801 was given either 3 days/week or once or twice daily during 21-day treatment cycles until either disease progression or intolerable toxicity. Investigators conducted safety analyses at the time of screening, throughout trial participation, and for 30 days after the last dose of the study drug was received.

Through this research, a recommended phase 2 dose (RP2D) of LNS8801 was identified and the phase 2 dose-expansion cohorts have launched. Investigators planned to enroll up to 27 patients who had previously achieved benefit from a PD-1 or PD-L1 therapy and have relapsed on that treatment.

In the second phase of the trial, investigators are evaluating the agent alone and in combination with pembrolizumab. Here, oral LNS8801 will be given for 3 to 7 consecutive days per week for each 21-day cycle until either progressive disease or unacceptable toxicity. Pembrolizumab will be given at a dose of 200 mg every 3 weeks with the first combination arm to receive LNS8801 starting at the RP2D or 1 dose level below determined in the single-agent arm.

“We look forward to further exploring the preliminary results with LNS8801 alone and also in combination with pembrolizumab when we open additional cohorts soon,” Mooney added.

This article originally appeared on our sister publication OncLive.


  1. Linnaeus Therapeutics granted orphan drug designation for LNS8801 for the treatment of patients with metastatic uveal melanoma. News release. Linnaeus Therapeutics, Inc. March 10, 2021. Accessed March 11, 2021. http://bit.ly/3bDk5Z9
  2. Company commences phase 2 study at multiple academic sites in United States. News release. Linnaeus Therapeutics, Inc. October 13, 2020. Accessed March 11, 2021. http://bit.ly/3bEZ8Na
  3. Phase 1 study to determine the MTD, safety, tolerability, PK and preliminary anti-tumor effects of LNS8801 alone and in combination with pembrolizumab. ClinicalTrials.gov. Updated September 25, 2020. Accessed March 11, 2021. https://clinicaltrials.gov/ct2/show/NCT04130516
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