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Zenith lands dough for bro, moves its lead cancer program into the clinic.Zenith lands dough for bro, moves its lead cancer program into the clinic BioWorld Online - 5 hours ago http://www.bioworld.com/content/zenith-lands-dough-bro-moves-its-lead-cancer-program-clinic Zenith lands dough for bro, moves its lead cancer program into the clinic By Marie Powers News Editor Zenith Epigenetics Corp. closed a $24.56 million private placement with its lead investor, Eastern Capital Ltd., by pricing 24.56 million common shares at $1 apiece. For starters, the funds will finance a phase I trial of the company's pan selective BET (bromodomain and extraterminal domain) inhibitor, ZEN-3694, in the lead indication of metastatic castrate-resistant prostate cancer (mCRPC). The shares are subject to a four-month holding period. Zenith reported that Eastern will hold approximately 47.76 million, or approximately 38.6 percent of Zenith's issued and outstanding common shares. Eastern also holds warrants to purchase about 2.05 million Zenith common shares. Last year, Zenith closed a private placement of 4 million common shares to Eastern Capital, also priced at $1 apiece. That offering allowed the company to complete investigational new drug (IND)-enabling studies and file the IND application for ZEN-3694. The first arm of the phase I trial – launching "immediately," according to Donald McCaffrey, Zenith's president and CEO – will test ZEN-3694 as a monotherapy in patients who progressed following treatment with Zytiga (abiraterone, Johnson & Johnson) or Xtandi (enzalutamide, Medivation Inc./Astellas Pharma Inc.). The open-label safety and tolerability study is expected to enroll about 44 patients who will receive escalating doses of the oral drug once daily in 28-day cycles, according to Thomson Reuters Cortellis. The second arm will combine ZEN-3694 and enzalutamide, administered together in 28-day cycles, in approximately 58 patients with mCRPC who either progressed on abiraterone but did not receive enzalutamide or are receiving enzalutamide and experienced prostate-specific antigen (PSA) progression in the absence of radiographic and/or clinical progression, according to Cortellis. Dose-limiting toxicities or treatment-related adverse events are co-primary outcomes for both arms of the study, which also will assess progression-free survival, circulating tumor cell (CTC) response rate, PSA and radiographic response rate and pharmacokinetics. CTC enumeration and tumor biopsies through the dose-expansion phase will be used to measure disease progression and characterize resistance. Zenith also developed a whole blood assay to measure the activity of ZEN-3694 on six markers so it could assess target engagement, gather information about the physiological properties and activities of the compound in humans and determine potential biomarkers for future studies. Zenith expects to have data in hand in the third quarter, McCaffrey said. The company already plans to move ZEN-3694 next year into one or more additional studies in other types of cancer affected by bromodomain inhibition. Zenith is a 2013 spinout of Resverlogix Corp., which a year earlier reported success in a phase IIb trial of its small-molecule BET protein inhibitor, apabetalone (RVX-208), designed to increase levels of high-density lipoprotein cholesterol in patients with atherosclerosis. (See BioWorld Today, Aug. 29, 2012.) In September 2015, Resverlogix moved apabetalone into the phase III BETonMACE trial, which expects to enroll more than 2,400 high-risk cardiovascular disease patients with type II diabetes mellitus and low high-density lipoprotein (HDL). About 15 percent of the patient population will also have chronic kidney disease, according to the company. The study is expected to take several years to complete, with a primary endpoint of time to first occurrence of major adverse cardiac events, or MACE. However, that didn't stop Resverlogix from beginning to partner up outside North America. Last year, the company, headquartered in Calgary, Alberta, with a U.S. office in San Francisco, inked a potential $400 million licensing deal in China, Hong Kong, Taiwan and Macau with Shenzhen (China) Hepalink Pharmaceutical Co. Ltd. The arrangement included an equity investment that gave Hepalink about 12 percent of Resverlogix's shares in exchange for rights in all indications in the covered territories. (See BioWorld Today, April 28, 2015.) The phase III program is the only late-stage trial in the field of bromodomain inhibitors, giving Resverlogix a huge lead, according to McCaffrey, who also serves as that company's co-founder, president and CEO. His assertion is borne out by Cortellis, which shows a dozen other companies with earlier-stage programs. 'WE HAVE SOME PRETTY GOOD NAMES BEHIND US' Splitting into two companies gave Zenith the oncology side of the assets – and more. "ZEN-3694 is not just a drug," McCaffrey told BioWorld Today. "It's an entire platform and we are developing other drugs for oncology and autoimmune indications. Although the company is only 3 years old, our knowledge of the biology is a lot older." BET inhibitors act by repressing expression of oncogenes, including MYC and BCL-2, that are highly expressed in many cancer cells, resulting in inhibited cell proliferation and induction of apoptotic cell death. Additionally, cancer progression may be driven by tumor cells that acquire super-enhancers to overexpress certain hallmark oncogenes. BET inhibitors selectively suppress super-enhancer-driven gene expression and have shown selectivity toward tumor cells. BET proteins also play a central role in the transcriptional program of oncogenes driven by gene fusions, translocations and mutations. Among its inhibitors of the BET domain are compounds targeting the proteins BRD2, BRD3, BRD4 and BRDT – each one also containing the first or second bromodomains, BD1 or BD2. Competitor molecules "hit everything," McCaffrey explained. "We have drugs that are very good that hit everything, as well, but we also have drugs in the platform that can be specific for any one of the 12 domains." For example, restoration of androgen receptor (AR) signaling is a hallmark of CRPC, and ZEN-3694 was shown to inhibit AR signaling in several preclinical models of CRPC, both in vitro and in vivo, including models of resistance to enzalutamide. Zenith's BET inhibitors also work "exceptionally well with checkpoint inhibitors," McCaffrey said, including those of programmed cell death protein-1, or PD-1, and programmed death ligand-1, or PD-L1. In mCRPC, for instance, ZEN-3694 works downstream of the AR, so while enzalutamide encounters resistance to the AR splice variant 7, "it's highly expected that we do not have that issue," McCaffrey said. That difference has attracted research partners such as Memorial Sloan Kettering Cancer Center, the University of California at San Francisco and Los Angeles and the University of Pennsylvania. "We have some pretty good names behind us," McCaffrey pointed out. With some 20 employees, Zenith is headquartered in San Francisco and has its R&D facilities in Alberta. Like Resverlogix, Zenith plans to advance some of its assets internally and "we are in discussions with various groups about partnerships," McCaffrey said. "The platform is extremely large, so trying to do it all on our own would be difficult." Zenith also has an ace in its back pocket. As part of the spinout, the company is entitled to the royalty stream from apabetalone across all indications, "which could be an exceptionally valuable asset, especially now that we have a phase III candidate and we're moving into additional indications," he added. Like Resverlogix, Zenith is forging a global path to market. The company has opened discussions with the FDA and initiated submissions to the EMA, and it's in early conversations in other regions on licensing rights to ZEN-3694 and future programs. Zenith is named for the point in the sky directly above a person's head, and McCaffrey expects the company to shoot "straight up" with the bromodomain technology. "We're not altering the genes but turning them on or off," he said. "It's a real game-changer." |
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