Chicagoest wrote: "Both ZEN-3694 and RVX-222 Synergize with other treatments to achieve their outcomes. Are Zen-3694 and RVX-222 additives that must always be used with other therapies? Must they be specifically designed for each combination? Can BET Bromodomain Inhibition be targeted with any therapy? Can it be successful independently as in reverse cholesteral transport?"

In the case of RVX-222 (aka RVX-208 or apabetalone), one goal is to treat cardiovascular disease. With the exception of the early Phase I trial and the Austrailian Diabetes Trial, both of which were only 1 month long, all other trials have been at least 12 weeks in duration in patients with a significant risk of cardiovascular disease. Most patients who are considered to be at high-risk for cardiovascular disease and under the care of a physician are likely already on a statin. Statins act primarily on LDL, whereas RVX-208 affects other clinical endpoints (HDL, inflammation, complement, coagulation (thrombosis), etc). So if the patient population in a clinical trial has high LDL necessitating statin treatment, of course they are going to be taking a statin since RVX-208 doesn't affect LDL and LDL is a well-established risk factor. It is unethical and a huge burden to provide proof the RVX-208 can replace a current standard treatment as opposed to using it as an add-on therapy, especially when the affected endpoints for the two drugs are different. Furthermore, the post-hoc analyses of SUSTAIN and ASSURE have pointed to potential synergy with rosuvastatin vs. atorvastatin, and have also identified patients with diabetes, low-HDL and high baseline hsCRP as superb responders to RVX-208. In regards to patients with diabetes, very likely they would already be taking a diabetes medication. One must remember that even with statin treatment and even with drugs to treat diabetes, there is still substantial residual risk for cardiovascular disease. This is where RVX-208 comes in to affect HDL, inflammation, clotting cascades, etc. to substantially reduce this residual risk. Long story short, if you have other risk factors that RVX-208 is known not to affect, then you should be getting additional treatment for those risk factors beyone RVX-208 alone. However, whether RVX-208 would ever be approved/prescribed to treat an isolated low-HDL condition or an isolated diabetes/pre-diabetes condition is an unanswered question. Perhaps. But right now, the high-risk cardiovascular diabetic BETonMACE Phase 3 population is a better bet to see an effect (MACE reduction) in a relatively short time frame (average treatment period 18 months). Start there. Then expand to other indications/patient populations.

For the upcoming Complement Mediated Disease trial in PNH patients, it is unclear whether they will be on any other therapy or if it will be RVX-208 alone.

As for ZEN-3694, they've shown lots of pre-clinical data that ZEN-3694 and other Zenith compounds work great on their own and also works synergisticlally with some other drugs depending on the model system and disease. At least one of the BET-inhibitor targets, BRD4, is directly involved in the resistance mechanisms of several types of anti-cancer therapies. So, imagine you have patients who were responding to their standard anti-cancer therapy but begin developing a resistance to this drug. Bingo, this creates a pool of eligible patients for a novel add-on therapy to restore sensitivity to the other cancer drug. Alternatively, maybe for certain refractory cancers the patients never positively responded to the cancer drug. In these cases, it is likely that ZEN-3694 might be used on its own. In either case, these patients are excellent candidates for Phase I/II trial to see how BET-inhibition overcomes the resistance or treats refractory cancers. Of course, they first need to do the shorter term safety and pharmacokinetic trial.

On a side note, I asked Sarah today "Any update on the closing/completion of the Zenith Epigenetics Ltd/Zenith Capital Corp arrangement that was anticipated to be 2/1/16?" and she responded "The company has decided to close the Zenith reorganization after the clinical trial has commenced to avoid any delay to the launch of the trial."

Hope that helps!

BearDownAZ