Rocketman2,

There are many ways to put the Vascepa story into perspective. Your inquiry about how Vascepa affects apabetalone isn't limited to Vascepa. For type 2 diabetics, the SGLT2 inhibitor class and the GLR-1R agonists have really shown their cardioprotection via MACE reduction in recent CVOTs. So if and when apabetalone gets approved, it'll need to compete with other drugs already proven to reduce MACE in diabetics like SGLT2 inibitors and GLP-1R agonists. As for Vascepa, I'll offer my perspective. I'm sure others have additional excellent viewpoints as well that I hope they'll share.

Patient population: In REDUCE-IT, ~70% of patients were enrolled on the basis of secondary prevention (i.e., patients had established cardiovascular disease) and ~30% on the basis of primary prevention (i.e., patients had diabetes mellitus and at least one additional risk factor). At baseline, the median age was 64 years, LDL-C was 75 mg/dL, HDL-C was 40 mg/dL and triglyceride (TG) was 216 mg/dL. Baseline BETonMACE patient data shows that there is some overlap in the REDUCE-IT and BETonMACE patient populations. Not an exact match but plenty of overlap. High plasma triglyerides are a common feature of diabetes. As discussed below, it seems that the MACE reducing effects of Vascepa are not entirely due to modulating TG. I'm sure Amarin would like to market Vascepa to patients with TG<150 mg/dL, but they may need to run another clinical trial for that. To be determined with the FDA. Similarly for Resverlogix, apabetalone may benefit patients outside of the BETonMACE patient recruitment criteria, but additional clinical trials are likely necessary to expand into other patient populations. Overlapping patient populations (i.e. patients with diabetes) may contribute to some competition between Vascepa and apabetalone.

Endpoint/MOA: Vascepa was originally approved for lowering of plasma triglycerides (TG). REDUCE-IT enrolled patients with TG >150 mg/dL and less than 500 mg/dL. Vascepa lowers plasma TG, but it is pretty clear from REDUCE-IT that the MACE reducing effect of Vascepa extends beyond just modulating the plasma TG endpoint. Other potential mechanisms include various antiinflammatory, antioxidative, plaque-stabilizing, membrane-stabilizing properties and possibly others. So although lowering TG was the original endpoint/MOA target for Vascepa, it is clear that the story is much more complex than that. Sound familiar? Apabetalone increases apo-AI/HDL-C in patients with baseline low-apo-AI/low-HDL-C; however, the apo-AI/HDL raising effect of apabetalone is somewhat modest. There are many other beneficial effects of apabetalone that extend beyond apo-AI/HDL-C to account for the MACE reduction. Bromodomain-2 selective BET inhibition affects several pathways as detailed by Resverlogix. For both Vascapa and apabetalone, there may be too much beneficial stuff going on to pinpoint to just one modulated endpoint/MOA. This complexity is both a gift and a burden. Great for efficacy. Difficult for explaining its effects. Although much of the focus of Vascepa is on TG and of apabetalone is on apo-AI/HDL, both are clearly acting via multiple other mechanisms as well. As far as I know, apabetalone doesn't affect plasma TG and Vascepa doesn't effect HDL. How much overlap is there in the mechanisms of action between Vascepa and apabetalone? Yet to be determined. Probably some, but my guess is that the modulated pathways are different enough such that patients can safely and effectively be treated both drugs. Similar logic for the SGLT2 inhibs and GLP-1R agonists. Co-administration of these with apabetalone is possible.

Competing drugs: There are other purified/concentrated omega-3 products in the clinical pipeline. This would directly eat into Amarin's Vascepa market, but this shouldn't affect Resverlogix and apabetalone. Apabetalone is still the only BET inhibitor in clinical trials for anything other than oncology and one of only two bromodomain-2 selective BET inhibitors in the clinic (Abbvie has a Phase 1 oncology BD-2 selective compound). Lots of competition in the LDL-C space (statins, PCSK9 antibody, PCSK9 antisense, ezetimibe, bempedoic acid). Lots of SGLT2-inhibitors and GLP-1R agonists in the diabetes space. Possibly competitors on the way in the purified/concentrated omega-3 space. The one huge advantage of Resverlogix and apabetalone is that they have no competition right now.

Apabetalone still has blockbuster potential. That hasn't changed. Perhaps Amarin exemplifies how hungry clinicians (and the market) are for novel MACE reducing drugs. If apabetalone hits its mark in BETonMACE, then hopefully Resverlogix will match, if not exceed, Amarin's stock performance and clinical reception.

BDAZ