Hepatocellular Carcinoma RNA-Editing Therapy Gets FDA IND Clearance


RZ-001 previously received IND clearance from the South Korean Ministry of Food and Drug Safety in June.

Rznomics’s RZ-001, an investigational ribozyme-based RNA reprogramming therapy, has received clearance of its investigational new drug (IND) application from the FDA, which will allow for initiation of a phase 1/2a clinical trial for patients with hepatocellular carcinoma (HCC).1

RZ-001 is based on trans-splicing ribozyme technology and is intended to treat HCC by both selectively suppressing expression of human telomerase reverse transcriptase (hTERT) in cancer cells and editing hTERT mRNA to encode for and express herpes simplex virus thymidine kinase (HSVtk) sequence in order to produce cytotoxic effects in the cancer cells. Preclinical research in animal models also indicated that this approach encourages immune cell entry into HCC tumors. Additional potential advantages of the technology include the ability to proportionally regulate gene expression to target endogenous cellular RNA levels, ability to edit large stretches of target RNA upstream of all mutation sites, elimination of the need for potentially antigenic proteins or cofactors, and avoidance of the concerns regarding genomic toxicity and permanent genome change that come with DNA editing.

“The translation of the first trans-splicing-based RNA editing approach into an FDA-approved phase 1/2a clinical trial is an exciting achievement and a critical milestone for the RNA editing field,” Bruce Sullenger, PhD, Joseph and Dorothy Beard professor of surgery, Duke University, and scientific advisory board member, Rznomics, said in a statement regarding the news.1 “I am very excited about Rznomics' preclinical progress on ribozyme design and gene delivery optimization. The advances have allowed them to create and now translate a promising therapy, RZ-001, into the clinic. I and the entire editing field are eager to learn if RZ-001 and mRNA reprogramming is safe and able to combat HCC in patients. Rznomics is clearly a leader at bringing novel editing strategies to cancer patients that desperately need innovative, breakthrough therapies.”

The planned international dose escalation and expansion clinical trial will recruit patients with HCC with no extrahepatic metastasis. Rznomics previously received IND clearance for RZ-001 from the South Korean Ministry of Food and Drug Safety in June of this year, and a phase 1/2a clinical trial (NCT05595473) is already underway in South Korea. The multicenter, open-label trial in South Korea is recruiting patients aged 18 years or older with a diagnosis of HCC that is stage B or C according to Barcelona Clinic Liver Cancer staging classification. Participants are required to have hTERT positive expression, an Eastern Cooperative Oncology Group score of 0 or 1, a Child-Pugh score of A to B7, and a life expectancy of at least 3 months. Patients with moderate or severe ascites, carcinomas other than HCC, or a history of hepatic encephalopathy or HIV positivity are excluded from the study. 

In the dose escalation part of the study, participants will be assigned to 1 of 4 dose levels and receive the associated dose of RZ-001 via intratumoral injection along with valganciclovir. The dose expansion part will treat patients with a fixed dose selected based on the dose escalation phase. The study’s primary end points include the number of participants with dose-limiting toxicities in the dose escalation part of the study and the number participants who experience adverse events in both the dose escalation and expansion parts. Additional end points include changes in overall response rate, duration of response, progression free survival, and overall survival in both the dose expansion and dose escalation parts. Locations for the trial include Samsung Medical Center, Seoul National University Hospital, Severance Hospital, Seoul St. Mary's Hospital, and Kyungpook National University Hospital, and the trial is estimated to be completed in May 2029.2

"It's a monumental achievement of Rznomics that RZ-001, the first trans-splicing ribozyme therapy at the front of our therapeutic pipeline, has successfully received the IND approval in both Korea and the United States,” Seong-Wook Lee, chief executive officer and founder, Rznomics, added to the statement.1 “I am really grateful that RZ-001 earned the opportunity to potentially fulfill the unmet needs of HCC patients. Through the advanced development phase, I hope Rznomics can provide more new therapeutic options to patients suffering from intractable diseases. Rznomics will further expand our pipeline by targeting indications with highly unmet medical needs for which the unique characteristics of our platform technology may be the most competitively applied."

In addition to HCC, Rznomics will also seek to test RZ-001 for the treatment of glioblastoma multiforme. The company intends to submit an IND for that indication before the end of 2022. The company’s pipeline also includes other ribozyme-based RNA editing treatments: RZ-003, which is intended to treat Alzheimer disease, and RZ-004, which is intended to treat retinitis pigmentosa.

1. RZNOMICS Inc. received FDA approval to initiate clinical development of trans-splicing ribozyme-based RNA editing technology in liver cancer patients. News release. Rznomics Inc. October 25, 2022. http://www.rznomics.com/bbs/?so_table=promote_en&mode=VIEW&num=59&category=&findType=&findWord=&sort1=&sort2=&page=1 
2. Goal of FDA approval for simultaneous clinical trials in multiple countries within this year. News release. Rznomics Inc. June 21, 2022. http://www.rznomics.com/bbs/?so_table=promote_en&mode=VIEW&num=52&category=&findType=all&findWord=RZ-001&sort1=&sort2=&page=1 
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