RVX-208 (apabetalone) was the first (and only as of right now) BET bromodomain inhibitor brought into clinical trials by Resverlogix. However, it wasn't known at first by Resverlogix that RVX-208 was a BET bromodomain inhibitor. After Resverogix discovered this, they began their BET bromodomain program including the design of a number of new BET bromodomain inhibitor scaffolds, with each scaffold giving rise to likely hundreds of compounds. Resverlogix formally announced the BET bromodomain mechanism of action of RVX-208 after they established this BET inhibitor discovery platform and subsequent to this announced MOA spun out Zenith. The same BET bromodomain inhibitor discovery platform gave rise to compounds currently owned by both Resverlogix and Zenith.

Don has stated that they have at least 2 follow on molecules to RVX-208 for cardio and renal applications (and possibley compliment-mediated orphan diseases). These follow on molecules were likely derived from both the prior characterization of RVX-208 as well as the knowledge gained from the BET bromodomain inhibitor platform. So although RVX-208 was serendipitously discovered to be a BET bromodomain inhibitor, the realization of RVX-208 as a BET inhibitor was the reason for the establishment of Zenith.

IMO, the two primary differences that distinguish Resverlogix from Zenith at this point in time are 1) the disease targets (Resverlogix: cardio, renal, diabetes, compliment disease; Zenith: cancer and autoimmune); and 2) the selectivity of the BET bromodomain inhibitors (RVX-208 and potentially follow on molecules selective for the 2nd bromodomain, whereas lead compounds for Zenith ZEN 3694 and ZEN 3717 are pan-inhibitors that potently inhibit both the 1st and 2nds bromodomains of BET proteins). Zenith and Resverlogix and Zenith may or may not differ in the scaffolds for their lead compounds. However, both Resverlogix and Zenith are using second generation BET bromodomain inhibitors unlike the ongoing BET inhibitor cancer trials by Constellation (CPI-0610), Oncoethix (OXT015), Tensha (TEN-010) and GSK (GSK525762) that are all cancer Phase 1, Phase1/2 trials and are all diazepine scaffold based pan inhibitors binding strongly to both the first and second bromodomains. However, there is some concern based on a recent study of JQ1 in mice that these diazepene based BET inhibitors may have deleterious effects on memory formation due to their ability to readily cross the blood brain barrier to inhibitor to inhibit BRD4.

Zenith seems to have a rather large toolbox of customized BET inhibitors of different scaffolds that can target the first bromodomain, the second bromodomain, or both. Furthermore, they have both reversible (non-covalent) as well as covalent (irreversible for the life of the BET protein) inhibitors. They have many other tricks up their sleeve that they've talked about (like patient gene signatures to predict response to inhibitors and knowing which cancer drugs work best in combination with their BET inhibitors for cancer) and likely many that we don't know about because they've been in this BET inhibitor game longer than most. However, there is competition in the second generation BET bromodomin inhibitor field. Companies like Abbvie, BMS, Bayer and Incyte have ongoing Phase 1 cancer clinical trials that are using second generation BET inhibitors as well and these trials just started earlier this year and won't have result readout until likely 2017 or 2018.

So the success of RVX-208 will very likely have a positive impact on Zenith for two reasons. First of all, the royalty stream. Secondly, RVX-208 was the basis for the start of the BET inhibitor platform of Zenith, so success of RVX-208 validates the potential of BET inhibitors for treating human disease, appeases the FDA and other regulatory bodies about the safety of these BET inhibitor scaffolds, and most importantly establishes the credibility of Resverlogix/Zenith for running a top notch BET bromodomain inhibitor program.

Perhaps Resverlogix is more important to Zenith than vice versa. However, both are running cutting edge BET inhibitor progams. At this early stage in the BET inhibitor clinical trial game, any of the companies running BET inhibitor trials can boost up or pull down the other companies depending upon meeting trial endpoints and patient safety. Resverlogix, Zenith and the other companies' BET inhibitor programs may sink or swim together at this stage of the game.

Best regards,

BearDownAZ