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Top-Line Data Expected September 2019 for BETonMACE Phase 3 Cardiovascular Outcomes Trial for Apabetalone


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Message: How to best promote apabetalone?

Some good discussion over the weekend embedded in the Agoracom glitches regarding promoting/differentiating apabetalone. One big challenge for Resverlogix is that the evolution of RVX-208/apabetalone does not follow a linear path. A simple linear path is 1) we know our drug target and are patient population; 2) we have a drug for aforementioned target and we know what clinical endpoints it modulates in animal models and should modulate in humans; 3) we consistently show in early human Phase 1/2 clinical trials that the drug is safe and modulates aformentioned endpoints; 4) large Phase 3 trials confirm safety and efficacy.

The history of apabetalone is far from linear. It was first discovered in a small molecule screen as a drug that elevated apolipoprotein-AI synthesis and secretion in cells, and was shown in a primate model and early human clinical trials (i.e. Phase 2 ASSERT) to elevate circulating apoAI and HDL. ASSERT results were announced 7 years ago in Nov 2010. Phase 2 SUSTAIN and ASSURE were launched in 2011 on the basis of RVX-208/apabetalone being a novel agent to increase apoAI/HDL, promote reverse cholesterol transport and reduce atherosclerotic plaque. Hence the obvious comparison to HDL-raising CETP inhibitors.

However, a linear path was not in the cards for apabetalone. Between April 2012 and June 2013, things changed. The drug target of apabetalone was revealed to be a BET bromodomain inhibitor in April 2012. Positive SUSTAIN results were revealed in August 2012, which confirmed the ability of apabetalone to elevate circulating apoAI, HDL-cholesterol and large HDL particle number and supported the RCT hypothesis as the mechanism of action. The plan to spin out RVX Therapeutics (now Zenith Capital Corp/Zenith Epigenetics Ltd) was announced April 2013 and completed in June 2013. Then.....the top-line results of ASSURE were announced in June 2013, which revealed that apabetalone-treated patients were not statistically different from placebo-treated patients for changes in apoAI, HDL-cholesterol, or the IVUS measurments total or percent atheroma volume. OK....BET bromodomain inhibitor, Zenith spin-out, postive Phase 2 results, negative Phase 2 results.

Then came the post-hoc analyses of ASSURE. Sept 2013: Plaque reduction was better in ASSURE in patients on rosuvastatin compared to those on atorvastatin. Plaque reduction was better in ASSURE in those patients with low baseline HDL. Nov 2013: Plaque reduction was better in ASSURE in those patients with high baseline hsCRP, and 5-point MACE are reduced by apabetalone in the high hsCRP population. Furthermore, apabetalone reduces hsCRP levels. Virtual histology-IVUS suggests that the plaque in apabetalone-treated patients is less vulnerable to plaque rupture. OK....so high hsCRP, low-HDL, rosuvastatin is the way to go, right?

Then came the post-hoc analyses of combined ASSURE/SUSTAIN. Jan 2014: When the total population from ASSURE/SUSTAIN is combined, there is ~55% reduction in incidence of 5-point MACE and an even greater reduction in MACE incidence in the high baseline hsCRP subgroup. July 2014: An even more robust MACE reduction is observed in those patients with diabetes. Furthermore, blood glucose was lowered in these diabetic ASSURE/SUSTAIN patients. Sept 2014: In the combined ASSURE/SUSTAIN population, apabetalone significantly increased apoAI, HDL-cholesterol, large HDL particle number and HDL particle size. OK, so let's add diabetic patients and effects on blood glucose into the mix now too.

Then in 2015 came more analyses of Phase 2 trial data showing that apabetalone reduces alkaline phosphatase and that in chronic kidney disease subjects in ASSURE/SUSTAIN that apabetalone improved the eGFR. Also, that patients with elevated alkaline phosphatase levels had increased incidence of MACE. Further analysis of human data/samples and follow up experiments disclosed in 2015 and beyong using microarray to explore gene expression and proteomic analysis revealed that inflammation, coagulation, complement pathways, innate immunity, cholesterol/fatty acid synthesis, monocyte recruitment, migration and activation, macrophage function, inflammatory signaling and plaque stability are also modulated by apabetalone and may contribute to cardioprotection. OK, got it. Alkaline phosphatase, kidney function (eGFR), inflammation, coagulation, complement and a lot of other new stuff plus all that other stuff announced in 2013 and 2014.

Then came more trials/programs. They launched a complement mediated disease program in Sept 2015........still waiting on any one of those trials to start (i.e PNH). August-Nov 2015 featured the announcment of the BETonMACE clinical steering committee, trial commencement and start of dosing. Then in 2016 they announce a renal clinical advisory board, and did a Phase 1 pharmacokinetic study in New Zealand that supported making plans to initiate a Phase 2 Renal trial in early 2017.........which is still in limbo and currently not estimated to start until Dec 2017. Then there's the Fabry trial program announced May 2017 that is now listed as not starting until April 2018. OK. So it's a cardio drug (HDL/RCT/plaque), and its a renal drug (ALP, eGFR), and its a diabetes drug (glucose), and its an anti-inflammatory drug, and its useful for complement pathway mediated disorders, and useful for Fabry's disease. Got it.   

Then there are the mysterious pending changes to BETonMACE in 2017. Involvement of USA patients? Amendment to BETonMACE trial protocol to appease FDA recommendations (i.e. number of patients, trial length, duration of patient dosing, number of target MACE events)? Changes to BETonMACE futility analysis timing from 50% of original 250 events to an unknown point between 50% and 75% of events? 

And of course there's the new analysts, new website, the plans for the other lead compounds....but I won't get into that.

So how does Resverlogix promote itself and apabetalone when the path of its lead drug is anything but linear and there are so many unknowns? Have they differentiated themselves from the CETP story sufficiently? What are the best ways for them to communicate? Blog? News releases? Webcast quarterly updates? Investor/R&D Day event? Publications? Yes, there is baggage with apabetalone. But the once defeated apabetalone has risen again and is now in the driver's seat to be a revolutionary epigenetic drug as the first BET bromodomain inhibitor to succeed in a Phase 3 cardiovascular outcomes trial. And the non-linear path of apabetalone has positioned it as a game changer in many other diseases as well. With no other selective BET bromodomain inhibitors in clinical trials, and all other non-selective BET bromodomain inhibitors in clinical trials (Phase 1 or 2 only) being used for oncology indications, there really is no competition for apabetalone right now. We are all cheering for Resverlogix, but I doubt that I am alone in feeling that the team needs to step up its game. Let's hope good news is around the corner as we close out Q4.





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