Arrakis Therapeutics Inc. has completed a $75 million series B financing to continue its work on small-molecule medicines that directly target RNA to treat disease, primarily cancers.

Arrakis is chasing the creation of a new class of medicines using RNA-targeted small molecules (rSMs). Its platform allows Arrakis to predict and validate RNA target structure, find druggable pockets and identify drug-like hits. The new funding will be used to build a pipeline of rSMs the company hopes will lead to the clinic. That means going after the undruggable targets, ones in which current therapeutic approaches don't work.

Arrakis' Michael Gilman also goes from part-time to full-time CEO as he steps away from the CEO chair at Obsidian Therapeutics Inc. He remains Arrakis' chairman.

The company name comes from the series of Dune books by Frank Herbert. Arrakis is the desert planet where the fictional drug called spice is harvested, and "we view our company's pursuit of RNA-targeted small molecules as a new cosmos for drug discovery," Gilman told BioWorld.

One of the undruggable targets Arrakis is studying is the Myc cellular oncogene, a transcription factor found in most cancers and one that often drives tumor growth. Aptose Biosciences Inc. has gone after Myc and been frustrated with the results. (See BioWorld Today, Jan. 24, 2017.)

However, Aptose is still on the case with APTO-253, which has demonstrated down-regulation of Myc. The company presented its preclinical evidence at the American Association for Cancer Research's annual meeting two weeks ago.

An inhibitory protein that has been used for proof of principle of Myc inhibition through transgenic delivery was also able to inhibit Myc after intravenous delivery in animal models. The protein, called Omomyc, was first developed by Laura Soucek, who is a principal investigator at the Vall d'Hebron Institute of Oncology's mouse models of cancer therapies group, more than 20 years ago. Myc is hyperactive, either through overexpression of Myc protein itself or through deregulation of upstream oncogenes such as KRAS, in multiple solid tumors. And like KRAS itself, Myc has long been considered a poster child of undruggability. First, the protein is what's called "intrinsically disordered," that is, it does not have one defined shape that can be targeted in the same way that, for example, ATP binding pockets in enzymes can. Its localization in the nucleus makes it more challenging to drug than surface receptors, or even cytoplasmic molecules. Finally, Myc also plays a critical role in normal cell proliferation, which has long led to fears that inhibiting Myc would cause "catastrophic" side effects in normal tissues, Soucek said. (See BioWorld, March 21, 2019.)

Waltham, Mass.-based Arrakis plans to refine and expand its rSM drug discovery platform to find RNA-targeted small molecules and take those candidates to the clinic.

Gilman said Arrakis quests after compounds that are as drug-like as possible by "screening libraries of highly drug-like compounds through a technically complex but biophysically straightforward method. And we've had great success so far. We're getting hits to every target we screen. These hits are remarkably bland to look at, which is a good thing. They are delightfully druglike. They have affinities typical of protein screens, low µM or better, and, importantly, are selective for the RNA we've screened.

"Along the way, we're learning the dos and don'ts of RNA screens and are using those lessons to build a highly curated internal compound library, rich in RNA-friendly scaffolds and rigorously purged of troublemakers, of which there are plenty in most libraries," he added.

Gilman is on the board of the Novartis Venture Fund and Scholar Rock and on the scientific advisory board of Futurx. He was founder and CEO of Padlock Therapeutics Inc., a venture-funded company focused on autoimmune disease, acquired by Bristol-Myers Squibb Co. in 2016. Arrakis' founding CEO and current chief scientific officer is Jennifer Petter, who has been vice president of drug discovery at Avila Therapeutics Inc. When Avila was acquired by Celgene Corp. in 2012, she became the company's vice president of chemistry, which she held until she founded Arrakis in 2015.

The series B financing was co-led by Venbio Partners and Nextech Invest, with participation by new investors Omega Funds, HBM Healthcare Investments, GV (formerly Google Ventures), Wuxi Apptec Venture Fund and Alexandria Venture Investments, as well as all existing investors Canaan Partners, Advent Life Sciences, Pfizer Ventures, Celgene, Osage University Partners and the estate of Henri Termeer.

Arrakis' series A financing for $38 million was completed in February 2017. The funding was led by Canaan Partners with participation by Advent Life Sciences, Pfizer Inc., Celgene, Osage University Partners and Henri Termeer. (See BioWorld Today, Feb. 28, 2017.)

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