FDA Places Partial Clinical Hold on Nuvation's Cancer Therapeutic

FDA Places Partial Clinical Hold on Nuvation's Cancer Drug

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On Monday morning, Nuvation Bio announced that the U.S. Food and Drug Administration placed a partial clinical hold on its Phase I dose-escalation study of NUV-422.

NUV-422 is intended for the treatment of solid tumors including those as a result of high-grade glioma, HR+/HER2- advanced breast cancer and metastatic castration-resistant prostate cancer.

Nuvation’s clinical trial began enrolling patients in December 2020 which aimed to investigate the maximum tolerated dose of NUV-422. Recently, the company was investigating higher doses of the drug when patients already enrolled in the trial began experiencing uveitis, or inflammation that occurs inside of the eye. Symptoms of uveitis include redness, pain, light sensitivity, blurred vision and dark floating spots in the field of vision.

After several patients experienced uveitis, Nuvation paused enrollment of new patients and began to assess the adverse events with investigators and uveitis experts. After reaching out to the FDA for guidance, a partial clinical hold was placed on the trial which means no new patients will be enrolled in the program but patients already participating may continue to receive treatment.

"We are committed to patient safety across all of our studies and to working collaboratively with the FDA to develop, as efficiently as possible, new medicines where existing therapies are inadequate,” David Hung, M.D., founder, president and CEO of Nuvation Bio, said in a press release. “Based upon the recent development of uveitis as a potential safety signal, we will conduct an overall risk/benefit analysis of the NUV-422 program.”

NUV-422 is a selective small molecule that inhibits cyclin-dependent kinases (CDKs) 2, 4 and 6. Previous research has shown that CDK 4 and 6 are key regulators of the cell cycle, and dysregulation of the pathways results in increased cell proliferation, which is observed in many types of cancer. Although CDK 4 and 6 inhibitors have been used clinically to treat cancer, malignant cells are able to evade the treatments by increasing signaling through CDK 2. By inhibiting CDK 2, 4 and 6, NUV-422 can inhibit a tumor’s escape route and effectively eliminate cancerous cells.

Nuvation intends to provide updates on the direction of the NUV-422 program after receiving feedback from the FDA and completing its internal risk-benefit analysis. It is unclear why uveitis has occurred in these patients, although the condition can sometimes be caused by immune system abnormalities. Other causes include infection or injury, although the condition can occur seemingly with no cause in about half of all cases, according to the Mayo Clinic.

Ocular adverse reactions can be common in oral chemotherapeutic agents, although researchers report they are underestimated and underreported. Ocular manifestations can vary widely and include retinal detachment, dry eye, photosensitivity and visual disturbances. While it is unclear exactly why these adverse events occur, it is important for patients taking biological agents to be examined for ocular complaints, as many ocular manifestations can result in permanent damage.

The FDA granted NUV-422 Orphan Drug Designation for the treatment of patients with malignant gliomas and Fast Track Designation for the treatment of high-grade gliomas. The drug is also being investigated in a Phase Ib/IIa study in conjunction with fulvestrant for the treatment of patients with HR+/HER2- breast cancer and in a Phase Ib/II study in conjunction with enzalutamide in patients with metastatic castration-resistant prostate cancer.

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