Cyteir Therapeutics Inc., a Lexington, Mass.-based company exploiting synthetic lethality to fight cancer, is extending its series B financing with $40.2 million to support a recently launched phase I/II study of its lead candidate, CYT-0851, an oral small-molecule inhibitor of the protein RAD51. Novo Holdings led the round, joined by existing investors Venrock, Droia Oncology Ventures, Osage University Partners, Lightstone Ventures and Celgene Corp. Venrock led an initial $29 million series B investment in the company in March. Prior to that, the company raised a $5.5 million series A round in November 2015.

As part of the series B closing, Karen Hong of Novo Ventures, which provides consulting services to Novo Holdings, will join Cyteir's board.

Mutating cancer to death

Spun out of the Bar Harbor, Maine-based Jackson Laboratory in 2012, the company has an exclusive license to key technologies and patents based on the work of company founder and Chief Scientific Officer Kevin Mills, formerly an associate professor of genetics at the lab and associate director for translational partnerships in its cancer center.

Mills' work underpins a platform that leverages the relationship between DNA-damaging enzymes known as cytidine deaminases and RAD51, a protein that is essential for the repair of DNA breaks in cancer cells, but plays very little role in healthy cells. Cyteir's CYT-0851 is a small-molecule inhibitor of RAD51 designed to reduce the ability of cancer cells to self-repair through homologous recombination.

"The idea is really that we're getting cancers to mutate themselves to death," Cyteir's president and CEO, Markus Renschler, told BioWorld.

Preclinical data the company presented at the 2019 American Association for Cancer Research Annual Meeting demonstrated that the compound reduces activity of RAD51, reduces levels of DNA repair and increases levels of DNA damage leading to the death of cancer cells.

While damaged cancer cells typically seek to self-repair, "we picked RAD51 because it is the only step where there is no redundancy in the system," Renschler said. "RAD51 is absolutely required to fix that damage."

Though, according to Cortellis, the University of Chicago has reported doing some work to advance its own RAD51 inhibitors, Cyteir is the only organization with a disclosed clinical program leveraging the approach.

A combination study

The company's trial, which will enroll up to 200 patients with B-cell malignancies and solid tumors, is expected to generate phase I results within one to 1.5 years, while initial proof of concept could take another year. In the phase I portion, in addition to the usual dose-finding, safety and pharmacokinetics evaluations, the company will also be looking at cytidine deaminase overexpression as a biomarker, a focus that will support its efforts to develop a companion diagnostic for identifying patients whose tumors are more susceptible to RAD51 inhibition.

The phase II part of the trial, which will employ a Simon two-stage design and include six disease-specific cohorts, will seek to evaluate overall response rates.

Should the monotherapy trial succeed, the company may also move on to further investigate preclinical findings that have suggested CYT-0851 has synergy with PARP inhibitors.

In addition to funding efforts to evaluate CYT-0851, the new financing will also support Cyteir's work to identify other new targets of its approach. The idea is to "find another critical factor that, together with some tumor characteristic – in our case a gain-of-function, a gain in damage – to come up with a new target." So far, the company's team has identified a half-dozen such targets currently in validation, Renschler said.

As the venture moves ahead, Renschler said that "our hope is really to grow this into a full-integrated biotech company" with commercial capability, and to retain the rights to the products, at least in the U.S. "The investors are in for the long haul here," he said. "They've all committed to not only this round, but also the next round."

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