Amarin Corp Plc (AMRN)

[HinduKush]

It was the JELIS trial yokoyama 2007:
https://documentcloud.adobe.com/link/review?uri=urn:aaid:scds:US:38094a0e-ade0-47f6-bb63-fb982ba396bb
Let sput one nail inthe generics coffin: this did not prove their case in any way:
++JELIS was 70% female (predominantly postmenopausal like Kurabayashi
++This was a trial of statin plus/minus epadel (98% on statin)
++There was No PLACEBO ARM


IT DOES NOT RELATE IN ANY FASHION to what Vascepa is claiming to do uniquely in the TG>500 mg/dl population.
Please note the lipid changes in the JELIS trial
++The TG changes are PROPORTIONAL to the baseline elevation. In both the LDL differences are blunted by the pre-existence of the statin. No one can ever claim this shows that it is obvious that EPA as Epadel could lower TG and not elevate LDL from this.
++Generics now try to shift the focus on the obviousness of the LDL effects of EPA to JELIS, but these inventors certianly did not have the idea of EPADEL as a stand alone therapeutic agent for TG>500mg/dl, that spares LDL and lowers ApoB at all. MARINE was published 2011 (though earlier abstract data was present in 2010 when it was heralded as a breakthrough: https://www.medscape.com/viewarticle/733304)
++In fact Japanese patents from 2010 show their thought process was focused on statin plus agents for CV event prevention and how to emulsify omega 3 preparations for better absorption than LOvaza NOT using high doses of highly purified EPA for TG>500mg/dl lowering. [Witness JP2017137361A JP2014240418A google patent search]
++Almost every MARINE related Amarin patent has an embodiment that speaks to lowering TG>500mg/dl AND LDL lowering AND ApoB lowering
The generics conveniently leave out the ApoB part (and focus on LDL) because the prior art of Kurabayashi is so utterly inadequate in establishing anything vis a vis ApoB lowering.Incidentally the generics brief doubles down on both MORI and KURANAYASHI and HAYASHI...
++Genetic studies have observed that Triglyceride-lowering LPL variants and LDL-C–lowering LDLR variants are associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB --A unique feature of EPA as Vascepa in the Marine trial in TG>500-1500 mg/dl).Ference et al : Association of triglyceride-lowering LPL variants and LDL-C–lowering LDLR variants with risk of coronary heart disease JAMA. 2019;321(4):364-373. doi:10.1001/jama.2018.20045
Thus, the MARINE trial which addressed this population of recalcitrant hyper-Trigyceridemia elevation (>500mg/dl) and showed that Vascepa exhibited BOTH LDL neutrality and ApoB lowering effects that were unique and was/has not been matched by ANY prior art before its publication.
++Toth missed his opportunity as to why TG>500mg/dl as chosen as a cut off in the literature (not by Amrn). It was not only because the incidence of pancreatitis rises above TG=5600mg/dl. It was for many other reasons:
(2) “An upper value for ‘normal’ fasting TG of 1.7 mmol/L (150 mg/dL) is sometimes defined; when considering non-fasting TG concentration, determining HTG prevalence is more difficult since there is no accepted cut-point. However, in normolipidemic subjects, post-prandial TG values rarely exceed 4.6 mmol/L (400 mg/dL) even post-fat challenge.” [Witness :Clinical review on triglycerides by Laufs ,Ginsberg and others (Ulrich Laufs, Klaus G Parhofer, Henry N Ginsberg, Robert A Hegele European Heart Journal, Volume 41, Issue 1, 1 January 2020, Pages 99–109c, doi.org/10.1093/eurheartj/ehz785) was a state of the art Triglyceride review that summarized all available POSA understanding in 2020.]
Hence another reason for choosing a 500mg/dl cut-off.
++No drug was different -the generics try to fudge the issue by saying statins could reduce LDL and that fibrates niacin etc are in a different category. I summarize:
• Because the prevailing published mechanism of TG lowering (2000-2020) has always believed that it involves peripheral conversion of VLDL via IDL to LDL and that this process is saturable, and dependent on LPL activity, that there is no reason for a POSA from pre 2000-2011 to expect ANY drug to NOT increase LDL in the process of lowering TG’s, especially so when the TG’s are above 500 mg/dl (MARINE population)
• Treatment efficacy and choice of drug is heavily dependent on the level of baseline severity of hypertriglyceridemia. In this context, ALL TG lowering drugs at the time of filing of the patents under litigation, were differentiated from EPA because EPA was the ONLY medication able to lower severe TG elevations without incurring LDL elevation (probably because it blocked hepatic synthesis of VLDL in liver as well as inhibiting excessive VLDL LPL-mediated breakdown to LDL) and lowering ApoB also.