Why point out all the previous valuations of CETP inhibitors, despite all but anacetrapib being deemed failures (anacetrapib is set to reveal topline data Q1 2017)? It used to be an easy comparison: CETP inhibitors raised HDL and RVX-208 raised apo-AI/HDL, albeit through totally distinct drug targets and mechanisms of action. Because they are both HDL-raising drugs, Resverlogix/RVX-208 has been tied to the fate of CETP inhibitors for over a decade (see this classic The Blunt Bean Counter - Resverlogix - A Cautionary Tale article).

The market gave HUGE valuation to these CETP drugs because there was and still is a huge need for HDL-elevating therapies to combat cardiovascular disease risk. Back then, RVX-208 was believed to simply be an apo-AI/HDL elevating drug and offering an alternative way to raise HDL via a distinct mechanism from the CETP inhibitors. However, the exact mechanism of action wasn't known yet for RVX-208.

Much has changed since then. Now, we know that RVX-208 is a bromodomain-2 selective BET inhibitor. We also know that in addition to the effects on apo-AI and HDL, that RVX-208 offers a myriad of other cardioprotective mechanisms due to the far-reaching effects of BET inhibition on multiple pathways. There is also mounting evidence that although the elevation of HDL-cholesterol by CETP inhibitors is much greater than that elicited by RVX-208, that these CETP-mediated increases don't seem to increase the functionality of HDL and aren't as cardioprotective as new apo-AI/HDL molecules created by RVX-208. But of course, this excitement for RVX-208 is counterbalanced by the failure of the Phase 2 ASSURE trial. Out of the post-hoc analyses for SUSTAIN and ASSURE, however, we now know that the target populations for RVX-208 are continuing to be refined beyond just low-HDL individuals to include those with diabetes, kidney disease and heightened inflammation (high hsCRP). There is also some evidence to suggest that there is synergy of RVX-208 with rosuvastatin compared to atorvastatin, which will hopefully be supported in the Phase 3 BETonMACE.

I don't think it was on slide 27, but I would have also liked to have seen them include a valuation for the recent SGLT2 inhibitors (Jardiance/empagliflozin, etc) and GLP-1 receptor agonists (Victoza/liraglutide, etc) since these glucose lowering diabetes drugs have now been shown to reduce MACE events in recent cardiovascular outcomes trials (CVOT). Resverlogix did include comparison of some of these in the comparison numbers needed to treat/cost to prevent one event slide of the Rodman & Renshaw presentation. There was a lot of excitement at the diabetes conferences when these CVOT Phase 3 results were disclosed for Jardiance/Victoza for the first time. Resverlogix has a chance to clear Phase 3 with a novel drug that has far reaching application to not just low-HDL individuals, but those with diabetes and kidney disease. A Phase 2 or Phase 3 BETonRENAL trial is scheduled to start in 2017, according to DM, and this will bring RVX-208 to the attention of the renal field if they aren't paying attention already.

One lingering concern for RVX-208 is the long-term safety of this novel drug. All BET inhibitors with the exception of RVX-208 are in Phase 1 trials right now. Most, if not all, are pan-inhibitors that aren't selective for the second bromodomain like RVX-208. However, no BET inhibitors and very few if any epigenetic drugs are been approved for clinical use. So this is still a high-risk, high-reward play despite BETonMACE being past the 10 month mark and the data safety monitoring board not having any concerns yet. But patients are going to be dosed for 1 to 2 years. So there is still a possibility that a big red flag may show up.

Long story short, I think these previous $8 billion to $13 billion valuations for RVX-208 are not too far off if RVX-208 clears the BETonMACE/BETonRENAL clinical trial hurdles of safety AND efficacy in the next 2-3 years. And who knows how the other RVX-208 indications (complement diseases, alzheimer's, other orphan disease) and follow-on molecules (7 promising molecules, close t confirming 2nd molcule/filing IND) will affect the valuation.

BearDownAZ