Amarin Corp Plc (AMRN)

[HDGabor]

JL-

Thanks.

As it is started to be scientific, this post is definitely not a counter argument, just points for consideration.

assumption that trig lowering would lower CVD event risk..An assumption that was held by many MDs in the CVD field..

As you wrote TG effect on CVD was (and is still) an assumption only, TG was / is a suspect, but wasn't / isn't a validated (accepted, confirmed, etc.) marker of CVD event.

If this "assumption" was indeed correct then the "new science" clause in the SPA rules would have required "New" (dated from the commencement of the SPA) scientific evidence that trig lowering would not lower CVD event risk. ... FDA invalidated the SPA on the grounds of three CVOTs...ACCORD, AIM-HIGH, and THRIVE...all of which according to FDA, showed that Trig lowering, did not lower CVD risk...Well to say that was creative on FDA's part is putting it mildly..None of these trials were focused on trig levels and their effects on CVD event risk...All of trials were failures on some level and actual subset of moderately high trigs in one trial did suggest trig lowering might reduce CVD risk..

Nobody knows that any assumption is correct or not till it will be confirmed or refuted. Meanwhile these study weren't about TG, gave additional information (but not a definite answer) about add-on therapy and TG "role". None of these trials suggest trig lowering might reduce CVD risk none of the subset of moderately high trigs (as a standalone parameter, not as together with low HDL) suggest trig lowering might reduce CVD risk. (There were subgroup analyses of interest:)
- ACCORD-Lipid: TG>=204 mg/dL (upper tertile) results on primary endpoint: fenofibrate + statin 11.1%, placebo + statin 12.8%.
- AIM-High: TG 198-400 mg/dL results on primary endpoint: Niacin ER + statin 17.0%, placebo + statin 17.5%
- HPS2-THRIVE: TG ≥151 mg/dl event rate of primary endpoint: niacin/laropiprant + statin 13.9%, placebo + statin 14.8%.
Please note: these were the result of TG alone subgroup (not with HDL), similar to ANCHOR.

Meanwhile these subgroup results did not give a definite answer, increased the uncertainty of TG role / effect. The DMEP noted / advised that the ACCORD-Lipid and AIM-HIGH studies, while not designed to address this specific gap in knowledge, would provide important information on the incremental benefit of adding a second lipid-active drug to statin therapy during the pre-IND meeting (July 14, 2008).

Although levels of non-HDL-C correlate with risk for CVD in some studies, we are not aware of any prospective, controlled clinical trial data demonstrating that pharmacological reduction of non-HDL-C (or TG) with a second drug in patients with elevated TG levels at LDL goal on statin therapy significantly reduces the residual risk for CVD. The AIM-HIGH, ACCORD, and IMPROVE-IT studies, while not designed to address this specific gap in knowledge, will provide important information on the incremental benefit of adding a second lipid-active drug to statin therapy.

Best,
G