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Replies to post #281287 on Amarin Corp Plc (AMRN)
06/18/20 1:51 PM
The FDA continued in a full sweep to declare they no longer considered elevated trigs a risk factor...A position held by the AHA the ADA and the NIH..They followed shortly by reneging on the SPA they had granted Amarin...that new scientific evidence indicated EPA's ability to lower CVD event risk was unlikely..Central to FDA's turn about was that trig lowering did indeed raise LDL-C and FDA held that only LDL-C was a legit bio marker for CVD event risk..
In summary, based on the above prior art it was completely unexpected to observe an 8.5% decrease in Apo-B when patients with TG levels above 500 mg/dl were administered 4 g of 96% pure ethyl-EPA. Also, based on the fact that the MARINE trial (Bays et. al. Am. J. Cardiol. (2011) 108:682-690) shows the criticality of the 4 g per day dose, as opposed to the 2 g per day dose wherein no Apo-B effect was observed, and based on the importance of lowering Apo-B in these patients, it is concluded that Applicant has effectively shown unexpected results for his invention.
"Toth et al included a retrospective analysis from more than 80 million medical records included in the Optum database. Toth et al found 23,181 patients with elevated TGs (fasting TG > 150 mg/dL) who were on treatment with statin drugs for dyslipidemia. The authors matched an equal number of patients without elevated TGs (TG < 150 mg/dL and HDL > 40 mg/dL) who were on statin treatment using propensity score matching. Both groups had been treated with statin agents for at least 6 months and had pretreatment measurement of lipid values. Toth et al demonstrated a 26% increase in major adverse cardiovascular events in patients with elevated TGs despite treatment with statin agents. (Toth PP, Philip S, Hull M, Granowitz C. Association of elevated triglycerides with increased cardiovascular risk and direct costs in statin-treated patients. Mayo Clin Proc. 2019;94(9):1670-1680)
“There is an emerging body of evidence demonstrating that plasma TGs are independent risk factors for cardiovascular disease...Ference et al evaluated genetic mutations in lipoprotein lipase (LPL), a key enzyme in metabolism of TG. Genetic LPL mutations that decrease enzyme activity led to an increase in plasma TGs and cardiovascular risk. The authors concluded that, for every 50-mg/dL TG lowering, there was an associated 18% lower risk of cardiovascular disease. Importantly, after adjusting for differences in ApoB levels, TGs were not independently related to cardiovascular risk. Thus, differences in ApoB, not TG levels, may directly account for the observed lower risk of cardiovascular disease. To achieve a 10-mg/dL reduction in ApoB, the TG level must be reduced by 70 mg/ dL. In comparison, the same ApoB reduction could be achieved with only a 14 mg/dL reduction in LDL-C level. This may explain the previous inconsistent cardiovascular benefits seen with fibrates, agents that reduce plasma triglycerides. In other words, in the presence of statin medication, there needs to be a very large reduction of TGs to move the cardiovascular risk-reduction needle. Navar controversially argued that the ApoB decrease seen in the REDUCE-IT trial was minimal (decreased by 2 mg/dL in the treatment group vs. a 4-mg/dL increase in the placebo group) and that the benefit of eicosapentaenoic acid seen in the REDUCE-IT trial was likely due to non-TG, non-ApoB-related, off-target effects."
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