Zenith NYAS Symposium notes

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Zenith's BET Inhibitor ZEN-3694 is Currently Being Evaluated in Multiple Oncology Clinical Trials

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Zenith NYAS Symposium notes

posted on Apr 29, 2016 12:50PM

Some notes of mine from the NYAS webcasts yesterday for Zenith Epigenetics' presentation by Eric Campeau. Resverlogix's presentation by Ewelina Kulikowski can be found here. Both were great talks that were extremely science heavy that justified current ongoing and planned trials. This was not an investor conference, so no info on regional deals, recent personnel changes, financing, follow-on drug candidates or trial timelines. Enjoy!

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Zenith Epigenetics at NYAS 4/28/16 presented by Eric Campeau

Great overview of the vast amount of pre-clinical data from cell culture and animal studies for ZEN-3694 supporting its use in the ongoing Phase 1 Prostate Cancer trial. We've seen a lot of this recently in the Zenith Corporate update slides and posters available on the Zenith website. Eric gave an overview of the trial design for the two Phase 1 trials and emphasized that ZEN-3694 is now "IN" and no longer "entering" clinical trials. 1 of 6 sites now active.
Eric did a good job explaining how ZEN-3694 is efficacious against prostate cancers that are both enzalutamide-sensitive and enzalutamide resistant (androgen receptor-dependent or -independent). Thus, depending on the type of prostate cancer, ZEN-3694 can be used as a stand-alone treatment or synergisticaly with enzalutamide. Eric also emphasized that ZEN-3694 synergizes with several other anti-cancer agents for various types of cancers. On the subject of synergy, Eric listed that ZEN-3694 synergizes with Keytruda (anti-PD-1 immunotherapy agent), suggesting that ZEN-3694 has applications to the immuno-oncology field as well.
Eric specifically discussed some key changes elicited by ZEN-3694 in different types of prostate cancers. For example, ZEN-3694 is efficacious in the enzalutamide resistant LuCAP 35 CR PDX prostate cancer model (collaboration with Eva Corey at Univ. of Washington). ZEN-3694 decreased candidate NF-kB dependent bone metastasis signature in PC3 (bone metastasis-derived) prostate cancer cells. ZEN-3694 decreases survivin MRNA and induces apoptosis in H660 neuroendocrine prostate cancer cells. ZEN-3694 induces p57/Kip2 tumor suppressor in androgen-sensitive VCaP prostate cancer cells both in vitro and in vivo.
Eric emphasized that Zenith has identified favorable outcome pharmacodynatic marker screen comprised of a six-gene signature observed in the response of whole-blood treated with ZEN-3694. These six genes include Myc, Bcl-2 and four others. I'm not sure if this included prostate cancer, but did include diffuse large B-cell lymphoma (DLBCL) and acute myeloid leukemia (AML). This can help identify likely responders to the drug prior as part of a patient screening. I'm not sure if they have a screen like this for prostate cancer, or if this was just for leukemias.
When asked about potential ZEN-3694 side effects, in light of those observed with other pan-inhibitors such as OTX-015 and JQ1, Eric responded that the degree of side effects from pan-BET inhibition is likely influenced by the type of scaffold, half-life of compound, compound affinity for target, and compound tissue distribution. JQ1 and OTX-105 are of the old benzodiazapine scaffold, whereas ZEN-3694 is an entirely different next-generation scaffold. Thus far, they are not seeing much toxicity with ZEN-3694 in various animal models as opposed to the toxicities observed with these other pan-inhibitors. My note: Zenith also has covalent inhibitors and BD1 vs. BD2 selective inhibitors that will offer different approaches, efficacies and side effects as opposed to pan-inhibitors, but this was not discussed today.