NEW YORK – Accent Therapeutics is advancing the first of its pipeline drugs targeting RNA-modifying proteins into investigational new drug (IND)-enabling studies in a range of cancers including tumors with microsatellite instability (MSI-high).
Accent's lead small molecule therapeutic program inhibits DHX9, an RNA helicase that binds and unwinds double-stranded RNA and DNA. It stabilizes the genome through regulation of cellular processes such as DNA replication, transcription, translation, and RNA processing and transport. Loss of DHX9 interferes with DNA replication and increases genome instability.
Accent Founder and CSO Robert Copeland explained that DHX9's role in stabilizing the genome is what could make DHX9 inhibitors effective against MSI-high cancers, which comprise a subset of colorectal, uterine, gastric, and other malignancies. The Lexington, Massachusetts-based company is expecting to submit an investigational new drug application for the anti-DHX9 drug in the second half of 2024 and begin clinical trials in late 2024 or early 2025.
"To the best of our knowledge, we're the only company that has small molecule inhibitors of [DHX9] and is pursuing that as a precision cancer therapeutic," Copeland said.
Accent launched in 2018 with $40 million in Series A financing and secured another $63 million in a Series B round in April 2020. The company's mission is to discover and develop therapeutics targeting modifications in post-transcriptional RNA — a new field analogous to epigenetics known as epitranscriptomics. These modifications affect gene expression through regulation of RNA stability, localization, and functional efficiency. In cancer, disruption of the epitranscriptome has been implicated as a driver of tumor growth and drug resistance.
Copeland founded Accent with Howard Chang, a professor of cancer genomics at Stanford University, and Chuan He, a professor of biochemistry at the University of Chicago. Before Accent, Copeland was a founder and CSO at Epizyme, where Copeland guided the development of Tazverik (tazemetostat), an inhibitor of the histone-modifying protein EZH2 approved in the US for non-Hodgkin lymphoma and epithelial sarcoma, and numerous other clinical programs involving proteins that modify DNA.
"In 2017, I was approached by the Column Group about starting a new company that would be focused not on chromatin and histone modifications but instead RNA modifications," Copeland said. However, Copeland added, "it's very difficult to have potent selective small molecules that will bind directly to RNA."
Instead, Accent's approach is to target the proteins involved in modifying RNA. "It's a novel area of medicine in targeting RNA pathobiology, [but] we're doing it through a very well-established mechanism of small molecules that inhibit enzyme targets," Copeland said.
Accent is particularly focused on cancer, he noted, because that's the area with the most extensive literature on the effects of RNA modification. Early in the company's history, Accent researchers studied the human genome and identified hundreds of genes involved in RNA modification. They began systematically assessing the effects of knocking out those genes in cancer cells, looking for a promising anti-cancer result.
Those efforts produced about 1,500 candidate RNA-binding proteins, and from that the researchers picked out about a dozen that were attractive as precision oncology targets, Copeland said. A subset of those became discovery targets for small molecule inhibitors including the preclinical-stage ADAR1 program in head and neck cancer, non-small cell lung cancer, and tumors refractory to checkpoint inhibitors; a discovery-stage program targeting the RNA exonuclease XRN1 in the same set of cancers; and an undisclosed preclinical program in ovarian, triple-negative breast, small cell lung, and colorectal cancers. Accent also licensed a program targeting METTL3 to Ipsen in 2021 for R&D, manufacturing, and commercialization in acute myeloid leukemia.
However, DHX9, as Accent's most advanced in-house program, made an attractive target, Copeland said, because it is "absolutely essential" for survival of cancers characterized by deficiencies such as DNA damage repair. At the same time, in normal cells, Accent has found that DHX9 is dispensable.
"We can define which cancers are likely to respond to DHX9 knockdown or inhibition with a small molecule, and in that way, identify patients that are most likely to benefit," Copeland said. Accent has selected a lead drug candidate and begun investigational new drug application-enabling studies with the intention of submitting an application in the second half of 2024, which if cleared by the FDA will allow it to take the agent into clinical trials.
In preclinical studies, targeting DHX9 was lethal to cancer cells, and in mice, reduction of DHX9 expression did not have any adverse effects on body weight, blood biochemistry, and histology of various tissues compared to control mice. In data presented at the American Association of Cancer Researchers annual meeting earlier this year, Accent showed that inhibitors of DHX9 had anti-proliferative activity in MSI colorectal cancer cells with defective mismatch repair and that oral dosing of mice with the DHX9 inhibitor ATX968 resulted in robust and durable tumor regression correlating with intra-tumoral expression of the mRNA circBRIP1, a potential biomarker for clinical studies.
Copeland said it is likely that Accent's initial clinical studies for DHX9 will focus on MSI-high colorectal cancer, an indication well-supported by preclinical data. However, in the course of IND-enabling studies, Accent researchers will seek to understand the full spectrum of cancers that may be treatable with a DHX9 inhibitor before committing to a plan for clinical trials.
"We're going to make our decision on the specifics of the clinical trial design probably in the first half of 2024," Copeland said. In considering how to position such a drug on the market, Copeland added that the company would most likely establish activity of the drug in a relapsed or refractory patient population then attempt to build a case for its use in earlier lines of therapy. But, ultimately, those expectations could change depending on data collected from clinical studies. Biomarkers for patient stratification will also be an integral part of clinical trials for a DHX9 inhibitor, Copeland noted.
In addition to its internally run drug development efforts, Accent has also been active in pursuing partnerships for its pipeline programs. In June 2020, Accent inked a deal with AstraZeneca to discover, develop, and commercialize cancer therapies targeting RNA-modifying proteins. Accent received an upfront payment of $55 million from AstraZeneca in that deal and is eligible to receive up to $1.1 billion in milestone payments, option fees, and tiered royalties based on net sales.
Thus far, Accent has not actively pursued a partnership for the DHX9 program. However, following the data presentation at AACR, Copeland said, "That talk really created a lot of interest on the part of large pharma to engage with Accent. We've had many different conversations, and we are open to further conversations."