OTX-2002 is a therapeutic agent designed to influence gene expression without altering the underlying DNA sequence. It operates as an epigenomic controller, targeting the regulatory mechanisms governing gene activity. Its development aims to treat various diseases, particularly those driven by problematic gene expression.
Understanding OTX-2002
OTX-2002 is a bicistronic messenger RNA (mRNA)-encoded epigenomic controller. It delivers genetic instructions to cells, prompting them to produce proteins that modify gene expression. The compound is encased within liver-targeting lipid nanoparticles (LNPs), tiny fat-like bubbles that deliver the mRNA to target cells.
The primary biological target for OTX-2002 is the MYC gene. MYC is a proto-oncogene that, when overactive, contributes to cancer development by regulating cell proliferation, differentiation, and programmed cell death. OTX-2002 regulates the activity of this gene.
How OTX-2002 Works
OTX-2002 works by initiating a cascade of events within cells. Once liver-targeting lipid nanoparticles deliver the bicistronic mRNA into tumor cells, cellular machinery translates it into two distinct epigenomic controllers. These controllers consist of a DNA binding domain and an epigenetic effector protein.
The two epigenomic controllers bind to regulatory regions within the MYC gene’s insulated genomic domain. This domain is a DNA loop. By binding to these sites, OTX-2002 induces epigenetic modifications at two locations within the MYC gene. These modifications lead to a pre-transcriptional downregulation of MYC gene expression, meaning the gene is less active before it can be copied into mRNA. This reduction in MYC levels inhibits cell proliferation in tumor cells.
Diseases OTX-2002 Targets
OTX-2002 is being developed to treat specific types of cancer where the MYC gene is overactive. Its primary target is hepatocellular carcinoma (HCC), which is the most common form of primary liver cancer. The observation that MYC overexpression is linked to aggressive disease in up to 70% of HCC cases provides the rationale for targeting HCC.
Beyond HCC, OTX-2002 is also being investigated for other solid tumor types where the MYC oncogene is overexpressed. The broad involvement of MYC in more than 50% of all human cancers makes it a significant target for various cancer treatments. By downregulating MYC expression, OTX-2002 aims to inhibit tumor growth and viability across a range of MYC-associated malignancies. Preclinical studies have shown that OTX-2002 can decrease the viability of multiple HCC cell lines and reduce tumor size and growth rate in animal models.
Current Research and Development
OTX-2002 is currently in clinical development, being evaluated in the Phase 1/2 MYCHELANGELO™ I trial. This trial includes adult patients with relapsed or refractory hepatocellular carcinoma and other solid tumors associated with MYC oncogene overexpression. Preclinical data for OTX-2002 have been published in Nature Communications, highlighting its potential to regulate the MYC gene, which was previously considered difficult to target.
The preclinical findings demonstrated that treatment with OTX-2002 led to a rapid reduction in both MYC mRNA and protein levels, decreased viability in HCC cell lines, and showed a dose-dependent reduction in tumor size and growth rate in animal models. These studies also indicated synergistic antitumor activity when OTX-2002 was combined with standard-of-care agents like tyrosine kinase inhibitors or immune checkpoint inhibitors. Early clinical data from the MYCHELANGELO™ I trial have been consistent with these preclinical findings, showing on-target increases in cell-free DNA MYC methylation signals and reductions in MYC mRNA levels in patients.
Safety Profile and Considerations
In early clinical studies, OTX-2002 has generally been well tolerated by patients. No dose-limiting toxicities have been observed, and the maximum tolerated dose has not yet been reached. Most adverse events reported were mild to moderate, specifically Grade 1 or 2, accounting for approximately 87% of these events.
The most common treatment-related adverse events were infusion-related reactions, which occurred in about 26% of patients. This finding is generally consistent with the known safety profiles of other therapeutics delivered using lipid nanoparticles. One serious adverse event of elevated aspartate aminotransferase was reported after the dose-limiting toxicity period, but it resolved within four days with minimal intervention. Pharmacokinetic analyses indicate that OTX-2002 is quickly cleared from the body and does not accumulate with repeated doses, and there have been low levels of immune response observed, which did not impact its pharmacokinetics.