Syndax Pharmaceuticals Inc. closed a $40 million Series A financing to pursue combination therapies for cancer, with an initial focus on how histone deacetylase (HDAC) inhibitors may enhance the effectiveness of nuclear receptor ligands.

Domain Associates and MPM Capital co-led the round, which also included Avalon Ventures, Forward Ventures and Pappas Ventures.

Syndax was founded in late 2005 by Eckard Weber, partner at Domain Associates, and Ronald Evans of the Salk Institute for Biological Studies. The company is focused on making combination drug development in oncology "a little more rational," according to President and CEO Joanna Horobin.

While many cancer drugs are first developed as single-agents in late-stage patients, they often eventually get used in combinations. Syntax will consider combinations from the get-go and will "think mechanistically about why you would put this drug with that," Horobin said. She added that the company will not combine two drugs into a single pill, but will rather develop novel molecules and seek approval in a combination setting.

At the moment, Syndax's primary asset is intellectual property licensed from the Salk Institute concerning the combination of HDAC inhibitors and nuclear receptor ligands. The rationale is that the HDAC inhibitors will allow expression of silenced genes associated with cell growth, which the nuclear receptor ligands otherwise would be unable to target.

Horobin gave the example of tamoxifen, a nuclear receptor ligand that can become ineffective over time, forcing patients to move on to chemotherapy. The addition of an HDAC inhibitor potentially could reactivate the drug's target, restoring its effectiveness.

With intellectual property rights in hand, Syndax is well on its way to building a pipeline. Horobin said the company plans to announce "in the next week or two" a deal to in-license a clinical-stage product and is "actively evaluating" other, complementary products. She added that Syndax plans to initiate clinical studies this year and that the Series A should provide sufficient capital to complete Phase II clinical trials in two cancer indications.

Although Horobin declined to provide details regarding the drug to be in-licensed, it likely will be an HDAC inhibitor or a nuclear receptor ligand. HDAC inhibitors in particular have generated significant interest of late, with Merck & Co. Inc.'s Zolinza (suberoylanilide hydroxamic acid) approved last fall for cutaneous T-cell lymphoma.

Syndax's name reflects its interest in finding synergy between two classes of drugs, one of which is HDAC inhibitors.

Biotechs working in the space include CuraGen Corp., of Branford, Conn., and partner TopoTarget A/S, of Copenhagen, Denmark, which are conducting several Phase I and Phase II cancer trials with the HDAC inhibitor Belinostat (PXD101); MethylGene Inc., of Montreal, and partner Pharmion Corp., of Boulder, Colo., which have the HDAC inhibitor MGCD0103 in multiple Phase II cancer trials; and Gloucester Pharmaceuticals Inc., of Cambridge, Mass., which is conducting pivotal cancer trials with the HDAC inhibitor romidepsin (depsipeptide).

Another potential licensor is EntreMed Inc., of Rockville, Md., which has a preclinical HDAC inhibitor program. Horobin once served as EntreMed's executive vice president of commercial development. She also currently serves on the board of Nascent Pharmaceuticals Inc., which is seeking a partner for its HDAC inhibitor, Araflor (NP50501). One of Syndax's co-founders, Peter Ordentlich, previously worked on HDAC inhibitors at X-Ceptor Therapeutics Inc., now owned by Exelixis Inc.

S*BIO Pte. Ltd. of Singapore also has a preclinical HDAC program, and some companies, including Tikvah Therapeutics Inc., are studying HDAC inhibitors in non-oncology indications.

Beyond the HDAC inhibitor and nuclear receptor ligand combination, Horobin said Syndax may evaluate its pipeline of cancer drugs in other combination settings.

Like many new venture-backed companies today, Syndax will employ only a limited number of drug development experts, relying on contract research organizations for much of the heavy lifting. Weber called the company a "semi-virtual drug development organization" and noted the business model is one Domain has pursued "very successfully for many years."

As of now, the company has five employees but plans to expand to 10 by the end of the year by adding to its Waltham, Mass., headquarters. Syndax also maintains a small facility in San Diego.

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