MiNA Therapeutics Advances First-in-Class saRNA Therapy MTL-CEBPA into Phase 1 Clinical Trial in Combination with Atezolizumab and Bevacizumab for First-Line Treatment of Advanced Hepatocellular Carcinoma

On December 1, 2021, the National University of Singapore Cancer Institute (NCIS) and MiNA Therapeutics jointly announced that the first patient has been dosed in a Phase 1 clinical trial of MiNA’s small activating RNA therapy, MTL-CEBPA, in combination with the standard treatment atezolizumab and bevacizumab, as a first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Atezolizumab is a PD-L1 inhibitor, and the combination therapy with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab is the first FDA-approved immunotherapy for frontline treatment of liver cancer.

Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Statistics show that more than 750,000 people globally are diagnosed with HCC each year, with the majority of cases occurring in Asia, and nearly half of these cases found in China. The main causes of HCC include chronic hepatitis due to hepatitis B or C virus infections, as well as liver cirrhosis caused by alcohol consumption or non-alcoholic steatohepatitis.

The phenomenon that can specifically upregulate targeting genes is called RNA activation (RNAa), and those small molecule double-stranded RNAs with RNAa function are called small activating RNAs (saRNAs). The chemical structure of saRNA is similar to siRNA, which recruits endogenous transcription complexes to the target gene, leading to increased mRNA expression and upregulated target protein expression.

The press release noted that MTL-CEBPA is the first therapy specifically designed to upregulate CCAAT/Enhancer Binding Protein α (C/EBP-α), a transcription factor and a key regulator in myeloid cell lineage determination and differentiation. Dysregulation of myeloid cells is associated with various diseases. MTL-CEBPA aims to restore C/EBP-α protein to normal levels through an RNA activation mechanism, reducing the immunosuppressive effects of myeloid cells. It consists of double-stranded RNA encapsulated in liposomal nanoparticles. Preclinical studies have demonstrated that MTL-CEBPA can enhance the anti-tumor activity of cancer treatments by targeting dysregulated myeloid cells and diminishing their suppressive effects in the tumor microenvironment.

This open-label Phase 1 trial will enroll approximately 30 patients with unresectable or advanced HCC who have not previously received systemic therapy. The primary objective of the dose-escalation phase is to determine dose-limiting toxicity, while the primary endpoint of the dose-expansion phase is the patients' objective response rate (ORR). Data from the trial are expected to be available in 2023.

References:

[1] National University Cancer Institute, Singapore and MiNA Therapeutics Announce Initiation of a Phase 1 Clinical Study of MTL-CEBPA in Combination With First-line Standard of Care in Advanced Liver Cancer. Retrieved December 1, 2021, from https://www.businesswire.com/news/home/20211130005712/en

(Original text has been abridged)

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