Mog, some extracts from the most recent coverage released today, take your time in reading the below;
I know you didn't even read one complete page from this coverage, so below are some highlighted points...enjoy shortyyy !!
Focus is also on REDUCE-IT where we believe Vascepa can show a benefit on final analysis in early '18,
We have reviewed recent literature and we highlight certain studies that support it, as well as studies highlighting mechanisms where EPA may provide benefit. We expect interim in ~Sep/Oct to continue as planned, and final results in early '18 where we believe it has favorable odds.
We currently have a positive view on whether Vascepa can show a favorable cardiovascular benefit in REDUCE-IT. At this time, we believe REDUCE-IT has a ~60% chance of succeeding, however our model more conservatively models only a ~25% chance (75% risk-discount)
Our view is that a higher baseline EPA level in the Japanese patients would have correspondingly benefitted the control group. Therefore, we believe the hurdle for the Epadel group to show a benefit with statistical significance would have been higher, not lower. We believe patients in REDUCE-IT with a lower background EPA level should derive a greater benefit.
JELIS Included Primary Prevention Patients: JELIS included both primary and secondary prevention patients (broad-based patient population), with ~5-6% of the patients having a history of myocardial infarction, ~15-16% with a history of angina pectoris, and ~5% with a history of angioplasty (CABG or PTCA). That is, most (~80%) of the patients were primary prevention patients. REDUCE-IT, on the other hand, is enrolling only secondary, high-risk patients. We believe this bodes well for REDUCE-IT because Epadel was able to demonstrate a benefit even in a lower risk patient population, and we believe we are more likely to see a greater benefit in higher-risk patients.
EPA Exerts a Multitude of Effects beyond TG-Lowering
Although we believe based on the literature that TG-lowering does indeed have a favorable impact on cardiovascular (CV) risk, EPA may confer additional benefits beyond TG-lowering, including: inflammation, endothelial function, plaque composition, plaque fibrous cap thickness, and platelet aggregation. Effects such as antiarrhythmic effects, vasodilation, and antiproliferation have also been noted from n-3 polyunsaturated fatty acids. While it is difficult to isolate each effect and determine its ultimate impact on a CV event, collectively they may exert a global and meaningful impact on CV risk that could tip the scale on an outcomes trial like REDUCE-IT in its favor. An entire review of all of its effects is beyond the scope of this report, but we highlight a few that we believe may have the most impact on outcomes: plaque regression, fibrous cap thickness, and inflammation
We have reviewed some of the latest literature on TGs and EPA, and we highlight several studies that we believe may be important in the REDUCE-IT thesis:
1) Genetic validation from two population-based studies that demonstrate that loss-of-function mutation in APOC3, which lead to significantly lower plasma TG levels and correspond with risk reductions in CV disease (both in NEJM 2014). Although these are only genetic studies and not studies that test a TG-lowering agent, we believe these studies help reinforce the relationship between TGlowering and CV benefit. EPA has been shown to reduce APOC3.
2) Post-hoc analyses of major outcomes trials, such as PROVE-IT and dal-
OUTCOMES, show that the patients with higher plasma TG correlated with
increased CV risk, most even after adjustment for covariates. Three of the (5) analyses showed that a 10 mg/dL decrement in TG reduced CV events by ~1.6%.
3) EPA may confer additional benefits beyond TG-lowering that may contribute to a CV benefit, including having positive impacts on: inflammation and plaque morphology. Recently, at AHA 2015, the CHERRY data showed that EPA + high dose pitavastatin treatment significantly reduced plaque volume v. pitavastatin alone in patients who received primary PCI.
Until REDUCE-IT Reads Out Final Analysis, JELIS is the Closest Proxy as an Outcomes Trial. We do not believe patients from Western societies should exhibit an impact on lipid parameters or on CV events any less favorable than the Japanese population.
CHERRY Data Suggests EPA May Have Favorable Effects on Plaque Regression:
At AHA 2015 in November, Ando et al. presented data from the CHERRY study investigating effects of EPA (1,800 mg/day) + high dose pitavastatin (PTV at 4 mg/day) treatment v. pitavastatin alone on coronary plaque regression and stabilization (Ando, K. et al. AHA 2015). The trial was a prospective, randomized, controlled trial that enrolled 241 patients who received primary percutaneous coronary intervention (PCI) using IB-IVUS in 6 hospitals. The primary endpoint was changes in coronary plaque tissue characteristics via IB-IVUS (integrated backscatter intravascular ultrasound). Secondary endpoints included: 1) changes in the volume of target coronary plaques, 2) changes in the lipid, fatty acid, and inflammatory profile, and 3) major cardiovascular events (cardiac death, myocardial infarction, PCI, and coronary artery bypass grafting). 122 patients were randomized to receive EPA/PTV and 199 to receive PTV only. 121/117 were included in the safety analysis, respectively, and 97/96 were included in the primary analysis, respectively.
EPA/AA Ratio. The investigators also noted that there was a significant inverse correlation between plaque volume and percent change in EPA/AA ratio (R=-0.323, p<0.001).
Interestingly, Matsuzaki et al. noted in his study of JELIS that that patients with high EPA/AA ratios trended towards lower rates of major coronary events v. patients with low ratios (HR=0.80, p=0.113). Though the trend was not significant, the incidence of cardiac death or MI was (HR=0.58, p=0.038). It is tempting to assume that the lower rate of CV
events is tied to the plaque regression that resulted from the higher EPA/AA ratio. While low EPA/AA ratio has been identified as an independent risk factor for ACS (Serikawa, T. et al., J. Cardiol. 2014, 63, 1, 35-40), the relationship between plaque regression and ACS is not definitively established though associations have been made.
As previously discussed, low EPA/AA ratio has been identified as an independent risk factor for ACS, and the low ratio has been associated with vulnerable coronary plaque morphology (correlation with fibrous cap thickness: r=0.37, p=0.002) (Wakabayashi, Y. et al. Eur. Heart J. 2014, 35, Suppl 1, 610). They showed on multivariate analysis that low EPA/AA ratio was independently associated with thin-cap fibroatheroma.
Collectively, we believe these findings are consistent with the notion that EPA can lead to higher EPA/AA ratios that have a favorable impact on fibrous cap thickness and plaque morphology, which may have a favorable impact on CV risk
Vascepa Known to Reduce hs-CRP, a Key Marker of Inflammation:
