Yes, pretty much off topic. However, as someone who has closely followed and currently invested in both RVX and ESPR, let me tie the path of Esperion's ETC-1002 to what may be in store for Resverlogix. Keep in mind that Resverlogix is still in conversations with the FDA regarding endorsing/approving Phase 3 BETonMACE and possibly including US sites in the BETonMACE trial. Esperion/ETC-1002 has had a pretty smooth path from a clinical trial/efficacy perspective; however, an extremely bumpy path from an investor/company valuation perspective. Let's see if we can compare/contrast and learn some lessons.

Starting with clinical trials.......ETC-1002, an ATP-citrate lyase inhibitor, has clearly and consistently shown that it can lower LDL in a mechanism completely distinct from statins. They have run several Phase 2 trials and now are running a few Phase 3 trials for long-term saftey, LDL-lowering efficacy, and cardiovascular event reduction. The mechanism of action and affected endpoint for ETC-1002 have been consistent and have established ETC-1002 as a strong clinical candidate for statin-alternative, statin-add on, ezetimibe add-on, and possibly ezetimibe/statin combo-add-on.

How does that path compare to Resverlogix/RVX-208? Well, as we know RVX-208 was first promoted solely as a novel therapy to increase production of new HDL by liver cells to effectively raise levels of functional HDL in the blood. Its mechanism of action and drug-target were unknown as it progressed through early clinical trials. Only late in the game was it discovered to be a BET inhibitor. During Phase 2 ASSERT and SUSTAIN, apo-AI and HDL were the primary endpoints of the trial and these endpoints were successfully modulated by RVX-208. Then came Phase 2 ASSURE, and compared to the statin-only placebo group, there were no group differences between placebo and RVX-208-treated for changes in apoAI, HDL, percent atheroma volume or total atheroma volume for the primary endpoint that included ALL patients. Significant differences were only observed in non-pre-specified post-hoc subgroup analyses of ASSURE (or ASSURE plus SUSTAIN patients combined) for atorvastatin vs. rosuvastatin, or only looking at diabetics, or only looking at high baselin hsCRP, or only looking at those with the lowest baseline HDL, or looking at 5-point MACE. Concurrent to and subsequent to ASSURE failure, many additional benefits of RVX-208-mediated BET inhibition were observed, affecting many other cardioprotective pathways. 

So from a clinical trial, hypothesis, and mechanism of action standpoint, ETC-1002 has traveled a much smoother path than RVX-208. 

Now for the investor/company valuation perspective. First off, how have competitors affected the share price. Until relatively recently, Resverlogix valuation was kind of tied to the hip to the success/failure of cholesterol ester transport protein (CETP) inhibitors, which also raise HDL. Both at one time were promoted as ways to raise HDL, which would decrease cardiovascular disease. RVX-208 effects on HDL were very modest compared to the huge effects elicited by CETP inhibitors. However, as the various CETP inhibitor cardiovascular outcomes trials each kept failing to show decrease in cardiovascular events, the clincial efficacy of CETP-inhibitor-mediated HDL changes and the validity of the HDL-hypothesis were questions. The above forementioned bumpy path for RVX-208 and the clincial failure of CETP inhibitors creates a lot of investor confusion. You have CETP inhibitors that raise HDL tremendously but have no effect on decreasing cardiovascular events; and you have a novel drug that only modesly affect HDL that fails to show plaque reduction in Phase 2 ASSURE primary endpoints. If you only followed Resverlogix/RVX-208 and CETP-inhibitor clinical trial results, and did not closely follow Resverlogix into the depths of the post-hoc analyses described above and did not follow the advances in the knowledge of the multiple mechanisms of action beyond HDL modulation, then you would rightfully question the future of RVX-208. Add to this the FDA "waffling" on participating/endorsing/approving (I'm not sure of the right word here) the BETonMACE trial, and I think its easy to understand why from an investor/company valuation perspective that there can be some pretty sour opinions (not me and most of us on this board of course!)

A similar exercise for Esperion and ETC-1002. ETC-1002 has been tied to the hip of another statin-alternative to LDL-lowering, the anti-PCSK9 antibodies. These PCSK9 antibodies are further along in clinical trials and already approved for LDL-lowering, ableit their expensive nature has resulted in various concerns related to payer/insurance groups covering these. This latter concern about pricing of PCSK9 antibodies kind of helped Esperion valuation at first. ETC-1002 offered a much more inexpensive, and orally available, alternative to the anti-PCSK9 drugs. As previously mentioned, the PCSK9 drugs were further along clinically and were already marketed for LDL lowering. So when Esperion met with the FDA to discuss the regulatory path forward, Esperion first thought that it has received some positive guidance that a Phase 3 LDL-lowering/safety trial would be enough for FDA considering approving ETC-1002 for being marketed for LDL-lowering. Result, we saw ESPR shoot about $100/share. Then, Esperion and/or the FDA communicated something differently......that effectively the FDA would like to wait until current anti-PCSK9 cardiovascular outcome trial(s) read out so that they can know whether or not the LDL-hypothesis (further LDL-lower offers clinical benefit) is still valid. FDA would consider approving ETC-1002 for cardiovascular risk reduction with a completed CVOT trial. A result of this FDA "waffling" on approving for LDL-lowering use, ESPR price craters back down to ~$14/share. Note: European-EMA was still on board with giving positive regulatory guidance for ETC-1002 for BOTH LDL-lowering and cardiovascular risk reduction. Fast forward to 2017, and the new "President" administration talks strongly of loosening FDA regulations/expediting approval. ESPR creeps up to $30-$35. But wait, on this past Friday the anti-PCSK9 CVOT Repatha/FOURIER trial reads out and shows kinda dissappointing effects on reducing cardiovascular outcomes, so ESPR drops down to ~$24. And then Monday morning, the FDA now changes course on ETC-1002 resulting the in the Esperion press release "Esperion Announces FDA Confirmation Regarding Regulatory Pathway to Approval for an LDL-C Lowering Indication for Bempedoic Acid" and the price shooting back up to $35 as of this writing. Long story short for ESPR.....the FDA and PCSK9 drugs have moved the share price more than clinical trial results.

So just to close.......there are a lot of lessons to be learned from Esperion about the fickleness of the market and share price. We are still waiting for clarity from the FDA for RVX-208. There is still another CETP inhibitor trial to read out Q3 2017: Anacetrapib/REVEAL. There are still questions about safety/efficacy for RVX-208. And of course there are loan/funding concerns for Resverlogix. We might see some wild swings both ways in the Resverlolgix share price depending on how there various issues/stories unfold. Of course, it is up to each individual investor to interpret the short and long-term implications of these events for him/herself.

DYODD and GLTA. 

BearDownAZ