Science Pool

RNA Epitranscriptomics as a Novel Therapeutic Target – Evotec and STORM Therapeutics Developing a METTL3 Inhibitor

In many diseases, genes are not altered, but their regulation is disturbed, and only recently have approaches emerged to target gene regulation as a therapeutic tool.

How are genes and their expression regulated? While the central dogma of the 1960s DNA->RNA->protein still holds true, recent advances in molecular biology have provided much insight into how cells regulate which genes are transcribed into mRNA and how translation of RNA into proteins is regulated. It is now known that mRNA can undergo many chemical modifications, induced by a variety of enzymes. These modifications affect mRNA maturation, stability, and lifespan, as well as the rate and duration of translation and mRNA degradation. Likewise, some small modifications can either prematurely terminate protein synthesis, reduce peptide yield, or alter the amino acid sequence of the translated protein.

While the existence of post-transcriptional RNA modifications has been known for more than 30 years, their mechanisms, functional consequences and connection with human diseases including cancers have only recently been elucidated, making RNA epitranscriptomics an unexplored and exciting field for drug discovery. Meanwhile, more than 150 RNA modifications have been reported and approximately 300 RNA-modifying enzymes have a potential as novel therapeutic targets.

Evotec’s partner Storm Therapeutics is amongst the first companies to pursue RNA-modifying enzymes as drug targets. The company identified RNA methyltransferases, a class of approximately 75 enzymes, as the most promising target class. Some have been identified as important regulators of cancer development and progression and thus represent promising novel antitumoral targets. Storm focused on METTL3, an enzyme involved in the co-transcriptional methylation of internal adenosine residues in eukaryotic mRNAs. This enzyme regulates fundamental aspects of mRNA life cycle, such as splicing, transport to the cytoplasm, stability, and translation into protein. It was known that in AML cell lines, knocking out METTL3 leads to a pronounced antiproliferative effect associated with a reduction of the BCL2 (anti-apoptotic factor). In other models, a marked upregulation of genes associated with innate immunity, such as those in the interferon (IFN) signaling pathway was demonstrated following METTL3 depletion.

However, tackling new classes of enzymes such as RNA methyltransferases requires breaking new ground in assay development, screening, and downstream hits to guide progression. To address these challenges, Storm and Evotec began collaborating in 2016, which later evolved into an integrated drug discovery and development alliance focused on novel small molecule RNA epigenetic drugs for oncology and other diseases. Using Evotec’s fully integrated small molecule drug discovery and development platform, including biomarker support (development of a m6A-mRNA level evaluation technic), STC-15 was identified. STC-15 is a potent, selective small molecule inhibitor of the mRNA modifying enzyme, METTL3. STC-15 was developed from high throughput screening to candidate nomination in less than three years.

In preclinical cancer models, treatment with STC-15 significantly inhibits tumor growth. In addition, a profound cell-intrinsic interferon response was observed, following an accumulation of double-stranded RNA. In mouse models, the induction of innate immunity mechanisms, such as the interferon pathway, enhanced T-cell mediated cancer cells killing. This work has been recently published in Cancer Discovery, a leading cancer journal (Guirguis, Ofir-Rosenfeld et al., 2023). Notably, it activated innate immune pathways and inhibited tumor growth as effectively as anti-PD1 therapy in some models. In addition, the data showed that the combination of the two agents resulted in significantly greater activity, leading to tumor regression and durable anti-cancer immunity. Detailed investigation of the mechanism of action of the two treatments revealed that they act independently, providing a strong rationale for their combination. This added significantly to previous studies where STC-15 demonstrated efficacy in leukemia models through mechanisms such as inhibition of leukemia stem cell function (Yankova et al., Nature, 2021). Furthermore, additional combination studies revealed a high degree of synergy between STC-15 and Venetoclax, a BLC2 inhibitor and standard of care therapy for acute myeloid leukemia (AML) patients.

This data provided the rationale for the development of STC-15 both as a monotherapy and as a combination partner for immune checkpoint inhibitors or with BCL2 inhibitors for the treatment of solid tumors and leukemias, respectively. Following the selection of STC-15 as a first-in-class development candidate in 2020, the seamless integration from project initiation to IND using Evotec’s INDiGO platform led to the entry of STC-15 into Phase I clinical trials in 2022. The orally bioavailable, highly selective METTL3 inhibitor is being developed for the treatment of solid tumors and may also have potential in AML.

A phase 1, multi-center, open-label, first-in-human study is evaluating multiple ascending daily oral doses of STC-15 in a 3+3 cohort design. The study is designed to systematically evaluate the safety and tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of STC-15 in adult patients with advanced malignancies. Dose levels for further evaluation in expansion cohorts will be selected based on all available PK, PD, target engagement (including m6A-mRNA level evaluation), efficacy, safety, and tolerability data, including long-term safety data beyond dose-limiting toxicities (DLTs).

Patient enrolment started in November 2022, and the company anticipates top-line results in 2024.

The development demonstrates the benefits of Evotec’s integrated, accelerated IND-enabling platform to support the exploration of novel and exciting biology to maximize innovation, to execute efficiently with rapid and seamless integration from target to IND.

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