[Edaily Reporter NA EUN-KYUNG ] The global competition for new RNA-editing drugs is now fully entering the clinical trial phase. However, major companies’ development efforts remain focused on rare and genetic diseases. This is why #Rznomics Inc.’s RZ-001—which directly replaces specific RNA in cancer cells with therapeutic RNA—is garnering attention, having secured positive patient responses and even received Regenerative Medicine Advanced Therapy (RMAT) designation from the U.S. Food and Drug Administration (FDA).

Global RNA Editing Competition Centered on Rare Diseases

According to the pharmaceutical and biotech industry on the 21st

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ProQR announced on the 9th (local time) that it had begun the first dosing for its next-generation RNA editing candidate, AX-0811

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marking the start of full-scale clinical trials. This trial is designed to evaluate safety, pharmacokinetics, and pharmacodynamic parameters in healthy adults.

RZ-001, which recognizes specific RNA in cancer cells, replaces it with therapeutic RNA, and has demonstrated actual patient response, is effectively a frontrunner in this field.

While both AX-0811 and RZ-001 are RNA-editing therapies targeting the liver, their indications differ. AX-0811 is a candidate for the treatment of cholestatic liver diseases, including biliary atresia, whereas RZ-001 is being developed as a treatment for hepatocellular carcinoma. AX-0811 is an oligonucleotide that utilizes the body’s adenosine deaminase-like RNA (ADAR) to modify specific nucleotides. RZ-001 works by having an RNA-replacement enzyme locate and cleave the human telomerase reverse transcriptase (hTERT) RNA in cancer cells, then replace it with therapeutic RNA.

The global competition in RNA editing technology is currently centered on treatments for rare and genetic diseases, with companies such as Acidian Therapeutics, Airner, and ProQual leading the way. Acidian, whose technology is most similar to RZ-001, is also prioritizing the development of treatments for rare diseases rather than anticancer drugs. An exon is the part of a gene that contains the information for making proteins. Acidian is applying its technology—which replaces mutated RNA exons with normal ones—to ACDN-01 and is currently conducting a Phase 1/2 clinical trial for Stargardt disease, a rare eye disorder. The RNA editing agreements Acidian has signed with Roche and Eli Lilly also target neurological disorders and hereditary kidney diseases.

Remix Therapeutics and Argent Therapeutics are also developing anticancer drugs that block the growth of cancer cells at the RNA level. However, the candidates from these two companies are oral small-molecule compounds that induce the mis-synthesis of mRNA containing the blueprint for the MYB protein—which promotes cancer cell growth—and then cause the cells to degrade it. This differs in both mechanism of action and drug form from RZ-001, which directly replaces a portion of the cancer cell’s RNA with RNA containing therapeutic genes. In other words, while the candidates from these two companies are drugs that cause the body to discard the instructions for cancer growth, RZ-001 is a therapeutic agent that replaces those instructions with therapeutic ones.

Three Bypass Strategies That Overcome Tumor Heterogeneity and Delivery Barriers

RNA editing companies prioritize rare diseases because it is easier to target a single genetic cause, and it is relatively easier to deliver therapeutics to specific tissues such as the retina or liver. In contrast, tumors consist of a mix of cancer cell populations with varying target expression levels, even within the same patient’s tumor. Since some cancer cells that the therapeutic fails to reach may survive and proliferate again, high tumor penetration and cancer selectivity are required.

RZ-001 adopted three strategies to circumvent the challenges of anti-cancer RNA editing. First, it uses hTERT RNA—which is highly expressed in many cancer cells—as a marker to identify cancer cells. Second, it reduces the burden of systemic administration by delivering the RNA exonuclease via an adenovirus vector injected directly into the tumor. Finally, instead of repairing hTERT RNA into normal RNA, it is replaced with herpes simplex virus thymidine kinase (HSV-tk) RNA. When valacyclovir is subsequently administered, HSV-tk converts valacyclovir into a cytotoxic substance, inducing cancer cell death.

In April, Rznomics Inc. presented interim results from a combination clinical trial involving 13 liver cancer patients at the American Association for Cancer Research (AACR) meeting. The trial added RZ-001 to the standard treatment for advanced liver cancer—atezolizumab and bevacizumab. Based on tumor size, 5 of the 13 patients (38.5%) showed a treatment response, while 8 patients (61.5%) showed a response according to the liver cancer evaluation criteria, which also reflect a reduction in viable tumor tissue. There were no serious adverse events related to RZ-001, nor were there any cases of treatment discontinuation due to such events. Based on these findings, the FDA designated RZ-001 as a RMAT in May. Moving forward, the company must demonstrate that adding RZ-001 results in greater tumor reduction and longer-lasting effects compared to the existing standard of care.

The Commercialization Potential Demonstrated by Telomericin and Adstiladrin

Although they are not RNA-replacement therapies like RZ-001, recently emerged virus-based anticancer drugs demonstrate the commercial potential of the individual technological components that make them up. Telomelisin, developed by Oncolys BioPharma and launched last month in Japan as a treatment for esophageal cancer, is an adenovirus that proliferates selectively in cancer cells using the hTERT promoter. This is an example of hTERT-based cancer selectivity that has actually reached the approval and commercialization stage.

Adstiladrin, a bladder cancer treatment approved in the U.S. by Ferring Pharmaceuticals, uses a non-replicating adenovirus type 5 (Ad5) to deliver the interferon alpha-2b gene to the bladder. This is a precedent for the commercialization of a strategy that uses a viral vector to deliver therapeutic genes to the tumor site. However, since neither product is an RNA editor, they do not serve as direct comparators to demonstrate the success potential of the RZ-001 platform itself.

Products designated for RMAT may be eligible for accelerated approval based on surrogate endpoints or intermediate clinical endpoints that reasonably predict clinical benefit, provided they meet future requirements. The key challenge is to replicate the initial results—based on only 13 patients—in a larger patient population and to distinguish the effects of atezolizumab and bevacizumab from the additional contribution of RZ-001. It is also necessary to determine whether RECIST or mRECIST should be adopted as the primary endpoint for approval, whether the duration of response (DOR) is sufficient, and whether efficacy is observed in tumors that were not directly injected.

Other challenges include standardizing the intratumoral administration procedure across medical institutions and demonstrating the consistency, titer, purity, potency, and immunogenicity of the adenovirus across production batches at a commercial production level.

Rznomics Inc. official stated, “While we cannot say at this stage that RZ-001 has a high likelihood of receiving accelerated approval, the RMAT designation has created an environment in which we can finalize our clinical, CMC, and regulatory strategies with the FDA.” The official added, “As data accumulates, we plan to comprehensively discuss the target patient population, key evaluation metrics, criteria for assessing clinical efficacy, safety, and commercial manufacturing plans.”