Novel Protein Inhibitor Shows Antitumor Activity in Patients with NHL

Published in Clinical Cancer Research, preliminary results (part one) of a two-part, first-in-human, open-label, multicenter study show that monotherapy with JNJ-64619178­—a novel, selective inhibitor of protein arginine methyltransferase 5 (PRMT5)—demonstrated manageable dose-dependent toxicity and achieved preliminary antitumor activity in patients with advanced malignant solid tumors or B cell non-Hodgkin lymphomas (NHL) who previously received or were ineligible for standard treatment options.

“The protein arginine methyltransferase 5 is overexpressed in several human cancers and has been shown to have oncogenic properties via epigenetic mechanisms. PRMT5 promotes the proliferation, invasion, and migration of cancer cells, and, therefore, represents a promising target in cancer drug discovery,” observes Irene Braña, MD, principal investigator of the Vall d’Hebron Institute of Oncology’s (VHIO) Head and Neck Cancer Group, CORE Phase 1 investigator of VHIO’s Research Unit for Molecular Therapy of Cancer (UITM)–Caixa Research, and lead investigator of the present study in Spain.

Recent studies have shown that inhibition of PRMT5 has antitumor activity in subsets of cancer cell lines and animal models across various tumor types. This study—directed by first author Manish R. Patel, MD, director of Drug Development, Florida Cancer Specialists/Sarah Cannon Research Institute (USA)—was designed to identify the maximum tolerated dose and a recommended Phase 2 dose for monotherapy with JNJ-64619178­. It would also evaluate the safety and preliminary efficacy of this potential new second-generation epigenetic therapy in adult patients with similar cancer profiles. 

“Based on our reported safety data and preliminary antitumor activity, especially in patients with ACC [adenoid cystic carcinoma], we have identified the maximum tolerated dose and recommended Phase 2 trial dose. To our knowledge, this is the first full report of a Phase 1 study of a PRMT5 inhibitor, a target that has attracted extensive and ongoing clinical development,” says Maria Vieito, MD, clinical investigator of Braña’s group and corresponding author of the paper. 

A potential second-generation epigenetic therapy

Conducted at sites including UITM–Caixa Research headed by Elena Garralda, MD, the study enrolled 90 patients with different advanced solid tumors who had received a median of three prior lines of systemic therapy and were treated with JNJ-64619178 monotherapy. Developed by Janssen Research and Development, JNJ-64619178­ is a potent, selective inhibitor of PRMT5, an enzyme that plays an important role in protein methylation and the development of various cancers. 

The most common treatment-emergent adverse events reported were hematologic and gastrointestinal which were more frequent and acute with dosage increase. Overall, JNJ-64619178 was well-tolerated with generally less toxicity compared to other cancer therapies targeting epigenetic mechanisms.

“While preliminary results are encouraging, further development of this class of PRMT5 inhibitors as monotherapy for solid tumors will require the identification of robust biomarkers to select those patients who would most likely benefit from this type of epigenetic-based therapy. Additional preclinical studies may also identify promising combination strategies targeting PRMT5,” concludes Braña.

- This press release was originally published on the Vall d'Hebron Institute of Oncology website