Accent Therapeutics Inc. will receive $55 million up front and as much as $1.1 billion in milestones as part of a substantial new three-molecule deal with Astrazeneca plc, which committed to exploring what Astrazeneca’s oncology chief, José Baselga, called the "compelling" field of targeting RNA-modifying proteins (RMPs) for the treatment of cancer.

Beyond the financial aspects, the deal presented a number of features that made it a good fit, Accent CEO Shakti Narayan told BioWorld. First, with hundreds of potential RMPs available to target, Astrazeneca's oncology expertise "amplifies and accelerates our ability to go after many more programs than we'd be able to go after on our own," he said. The deal will also help the startup build out its preclinical and clinical abilities while retaining important commercial product rights and the ability to do additional deals in the future.

Astrazeneca said its team believes that "advances in epigenomic capabilities and inhibitors targeting key processes, including chromatin remodeling and RNA modification, will advance the next wave of innovation in cancer treatment," the company said.

Under the terms of the collaboration agreement, Accent will be responsible for R&D for a nominated preclinical program, carrying it through to the end of phase I trials. Afterward, Astrazeneca will lead development and commercialization activities, with Accent having the option to jointly develop and commercialize the chosen candidate with Astrazeneca in the U.S. In the event it does so, the partners would split profits and losses in the U.S.

Accent stands to receive tiered royalties on any net sales of products from the collaboration ranging from mid-single digits to low-double digits. In addition, Astrazeneca retained an exclusive option to license worldwide rights to two further preclinical discovery programs, for which Accent would run certain preclinical activities, it said.

Shakti Narayan, CEO, Accent

Accent, formally launched in May 2018 with a $40 million series A, has developed a platform built around epitranscriptomics – the field referring to RMPs that control many aspects of RNA biology – to pursue precision cancer therapies. Backers at the time included the Column Group and Atlas Venture, which worked together to form the company in 2017, along with Ecor1 Capital.

The small molecule-focused company completed a $63 million series B financing in April, led by Ecor1 Capital and an expanded syndicate, with proceeds intended to advance development of the company's lead programs, METTL3 and ADAR1. METTL3 is an RNA methyltransferase implicated in acute myeloid leukemia, specific solid tumors and immuno-oncology, the company said. ADAR1 is an RNA editor with compelling validation for solid tumors with elevated intrinsic type I interferon-stimulated gene signaling and has also been suggested to play a key role in immuno-oncology, it said.

RNA plays central role in cellular function, so it's no surprise that a host of proteins and enzymes work on it, modifying it chemically, thereby altering its function. RMPs gone awry can have a host of implications, including in a variety of cancers, Narayan explained.

As an example, an estimated 15% to 30% of solid tumors have intrinsically high innate immune activity, something that can be measured by looking at interferon-stimulating genes (ISGs). Certain ISGs are overexpressed almost as a signature of that activity, Narayan explained. Inhibiting or knocking out ADAR1, an enzyme that edits RNA, selectively kills those tumor cells with high ISG expression.

"By focusing on the signature and the biology associated with it, we're able to go after a target that selectively kills specific types of tumors," such as certain head and neck cancers, he said. "Equally important, by having that signature, we're able to use it to identify and stratify patients who would be most likely to respond to an ADAR inhibitor.”

Though Accent will remain focused this year on advancing its work with Astrazeneca, the year ahead also holds potential for additional dealmaking and advancement of the RMP field. Other companies working on RMP programs include Kymera Therapeutics Inc., Storm Therapeutics Ltd., Gotham Therapeutics Inc., Ribometrix Inc. and Skyhawk Therapeutics Inc., which has established a multitude of partnerships.

Narayan doesn't sound concerned. "Frankly, from my perspective, the space is so new and there are so many interesting targets, I think it only helps the overall space by having more people working on this, increasing our chances as an industry of being able to get drugs to patients," he said.

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