Amarin Corp Plc (AMRN)

[HinduKush]

The line between moderate and severe TG elevation is arbitrary and not driven by any underlying science and therefore the concept of treating TG>500mg/dl is the same as treating TG<500mg/dl and that drawing a distinction mechanistically and therapeutically for the treatment of these populations is false. DU

The TWO populations argument is central to the factual errors of deduction that Judge Du made in deriving prima facie obviousness

As much as I can glean from my research, the 500mg/dl differentiation was chosen by evoultionary consensus for the following not exhaustive list of reasons:

(1) The clearance of triglycerides from plasma is saturable when plasma triglyceride levels exceed approximately 5.65 to 7.91 mmol/L (500 to 700 mg/dL). Because the prevailing published mechanism of TG lowering (2000-2020) has always published 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)
(2) It has been shown in clinical experiments that an upper value for ‘normal’ fasting TG of 1.7 mmol/L (150 mg/dL) can be 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. Hence another reason for choosing a 500mg/dl cut-off.
(3) Another reason why 500 mg/dl became a cut-off in separating forms of hypertriglyceridemia is that pancreatitis rises markedly in incidence as a complication when TG’s exceed 500 mg/dl upward.
(4) When the literature regarding connection between high TG’s and cardiovascular disease is reviewed e.g the Munster heart study and the NHANES data set, it sub-stratifies high TG’s and shows that the CV event rates climb rather steeply above 400 mg/dl and hence one more reason for looking at greater and lesser than 500 mg/dl as a cut-off.

References:
++Henry Ginsberg [Ginsberg, H. N. (2001). Hypertriglyceridemia: new insights and new approaches to pharmacologic therapy. The American Journal of Cardiology, 87(10), 1174–1180. (Ginsberg one of the pre-eminent POSA'a of the 2008 to date era)
++Clinical review on triglycerides 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)
++Chait A, Eckel RH. The Chylomicronemia Syndrome Is Most Often Multifactorial: A Narrative Review of Causes and Treatment. Ann Intern Med. 2019;170(9):626-634. doi:10.7326/M19-0203