I am almost sure that the company has already paid attention to my findings. Be patient. They will weigh it carefully prior to taking any action.
Thank you, Kole.
I emailed John Thero and got through. I believe that MDs in Amarin will review what I commented. Even their General Council may review the findings.
Finally, a bottom is coming. negative PDUFA on Dec 20 (a delay is 100% sure, just what kind of delay) has no big impact now.
Thank you for your kindness.
I believe that there is a positive by FDA setting up a historical high bar: Vascepa won't have any competitive RX fish-oil-based product coming in sight, if not forever then for a long long time. Vascepa enjoys a very strong "exclusivity" without any exclusivity status. AZN just throw $300M into the OMTH mass.
I hate lawsuits generally, but not this case. FDA is well prepared, I believe. But getting 9 NO votes by employing the censored data leaves a black hole for lawyers.
The news of rescinding SPA discounted potential damages with a negative PDUFA on Dec 20. For most of us: want to sell, already sold; want to hold, already hold. A few dozen cents volatility, you have to take it.
Running to the end of REDUCE-IT marathon is 100% sure. My only hope is that the company can have some fund by any means.
Rescinding SPA is a natural outcome of the AdCom Meeting. What is anything else?
Does anyone has established connection with Amarin? If someone does, you may pass the above post to the company ASAP. In lacking of scientific resources, the company needs outside rescues.
Triglyceride, Placebo Data Only, ANCHOR Study
Screening (6 Weeks)____|__Randomized Treatment (12 Weeks)
No Treatment _________|___Placebo (mineral oil 4 mL/d)
* Triglyceride Level, censored in FDA’s Briefing
# Triglyceride Level, presented in FDA’s Briefing
| vertical bar, division of screening phase and treatment phase
Main Point: mineral oil issue was FDA produced smoking from the gun of data censoring (omitted all screening data and details of placebo data – only two points (with #, above), baseline and median, of placebo data been presented in Briefing, resulting insufficiency of showing the upward-linear pattern perfectly consisting with the screening phase). Placebo effect is the signal of HTG progressing. Reductions with Vascepa, vs. placebo, are real.
Inference #1: REDUCE-IT, so far so good -- based on 6.2% reduction in LDL-C, 21.5% reduction in TG, and 22.0% reduction in hsCRP in a 12 week timeframe, and CHD event rate reduced form 5.9% in FDA's early version of Briefing to 5.2% in FDA's Errata.
Inference #2: RUDUCE-IT will succeed – the effects of 6.3% reduction in LDL-C, adding on statin effect, in a 12 week timeframe and a CVD event rate reduction form 5.9% in FDA's Briefing to 5.2% in FDA's Errata leads to an estimate of 5%+ CVD events reduction yearly in REDUCE-IT (it was 3.8% yearly reduction in JELIS), and the reduction with Vascepa should be significantly greater than that with placebo.
Inference #3. Vascepa save lives. FDA: “one reported death with placebo in ANCHOR.” ANCHOR had 702 patients in total, in which 233 patients were with placebo (236 with V 2g/d and 233 with V 4g/d). One in 233 is 0.0429%, and one in 702 is 0.0142%, in a 12 week timeframe. Translating to annual death rate, it would be 0.186% with placebo only and 0.0615% overall. High or low? According to CDC, the overall death rate in US was 0.799% in 2011. In 2011, there were 597,689 death by heart diseases alone. In ANCHOR, all 4 CVD events were with placebo (233 recieptors) but none with Vascepa (469 recieptors). The significant elevations, in LDL-C and hsCRP, with palcebo, and the significant reductions with Vascepa implicates greater death rate with placebo that that with Vascepa. In US, the ANCHOR population is sized as 36M, every increment of 1% annual death rate means 360,000 more lives lost in one year. FOUR MOR YEARS without effective and safe tratment, thousands more death, with disease progressing, is possible.
"Humor"? How many Bio studies terminated by death in history? Hundreds.
"FDA: One reported death in ANCHOR with placebo" is not strong enough to be a signal but do be a hint of HTG patient does die with disease progressing in a 12 week timeframe (only 200+ placebo patients).Their triglyceride hiked 25% and LDL=C and hsCRP also hiked significantly in the same timeframe simultaneously. So death elevation in a multi year timeframe is possible in accordance with disease progressing in thousands placebo patients. When death count reaches a certain level, FDA will call for "CUT" loud and clear.
My main point is:
The issue of "Mineral oil altered placebo inertness" was made up by FDA -- FDA omitted all screening data and details of placebo data in the Briefing to AdCom -- AdCom. The placebo data presented the background signal of progressing in high triglyceride (HTG) patients -- highly consistent with screening data without any treatment.
BTW, REDUCE-IT could be stopped by death elevation, another possibility.
Main Point: mineral oil issue is the smoke from FDA’s data censoring gun. Placebo effect is the signal of HTG progressing. Reductions, by Vascepa, from placebo are real.
Inference #1: REDUCE-IT, so far so good, based on CHD rate reduced form 5.9% in FDA's early version of Briefing to 5.2% in FDA's errata. CHD rate moving higher with placebo, but moving lower with Vascape.
Inference #2. REDUCED-IT will succeed.
It is proven again and again by huge outcome-studies that lowering LDL-C consequences to lowering CHD rate and lowering death rate.
In ANCHOR, there was 6.2% reduction in LDL-C, vs. placebo, adding onto the already lowering LDL-C by the Statin effect, 21.5% reduction in TG, and 22.0% reduction in hsCRP in a 12 week timeframe. And higher reductions should be expected with longer timeframe. Therefore, lowering LDL-C alone could have already produced reduction in CHD event with Vascepa.
As I mentioned previously, FDA estimated CHD event rate #$%$9% in the Brief, but it became 5.2% in the Errata. Where are the two rates based on? In fact, no any outcome-study has been done in ANCHOR population -- REDUCE-IT is the historical first one. Thus, the two numbers, 5.9% and 5.2% were based ongoing REDUCE-IT. My take is that 5.9% was from while FDA reviewing ANCHOR application (REDUCE-IT stared in 2011, and the application reviewing would begin in mid 2013). Since REDUCE-IT has never unblinded till now, the rate only can be estimated based on all participates (placebo and Vascepa). The Errata should be most recurrent than the Brief itself (Oct 2013). Therefore, it is possible that the 0.7% reduction was happened in a timeframe less than 6 months. With HTG progressing, placebo could not reduce events but increase – only Vascepa can and should be much higher than that from all participates. Counting on negative rate-change with placebo, the yearly reducing rate on CHD events could be around 5% with Vascepa.
I will post Inference #2, this afternoon.
Main Point: mineral oil issue was FDA produced smoking from the gun of data censoring. Placebo effect is the signal of HTG progressing. Reductions, by Vascepa, from baseline are real.
Inference #1: REDUCE-IT, so far so good, based on CHD rate reduced form 5.9% in FDA's early version of Briefing to 5.2% in FDA's errata.
Inference #2: REDUCE-IT will succeed. (afternoon)
Before the start, I’d like to describe my image on FDA’s atitue towords ANCHOR approval: a man ate a parished orange (a.k.a. some TG-lowering drugs) with green and white fugus (bad outcomes), then he catagorically refuses to take a fresh (safe) and riped (effective) apple (oh, ANCHOR).
Let’s start. With the entirety of data, HTG disease progressing was the backgroud singnal in ANCHOR. HTG is one of the modern diseases, just as hypertenssion (high blood pressure) and diabetics (high serum glucose). Without treatment, it progresses naturally (it is well documented in literatures that HTG progrossing does correlate with diabetic progressing. Now, let’s throw the mineral oil issue (wrongfully supposed in FDA Briefing) into garbage. Without the smell of mineral oil, the part of ANCHOR data is stll useful.
Inference #1: REDUCE-IT does doing well -- so far so good. It is evidenced by the change of CHD rate from 5.9% in Briefing to 5.2% in the Errata of the briefing.
REDUCE-IT was started 1n 2011, the enrollment became over 3,000 in early 2012 as FDA accepted ANCHOR’s application. FDA has minitored REDUCE-IT closely. I suppose that CHD rate was observed #$%$9% as FDA reviewing REDUCE-IT application in 2012. But the briefing was out in this October. I suppose that 5.2% is a recurrent CHD rate. I.e, CHD rate reduced from 5.9% to 5.2% in a one year timeframe. What is the force driving the reduction? HTG disease progressing should drive the rate higher. I supposs that the lower CHD rate is primarily drived by 6.2% reduction in LDL-C, 21.5% reduction in TG, and 22.0% reduction in hsCRP in a 12 week timeframe (higher reductions should be expected with a one year timeframe). I can use linear extrapolation to predict the numbers but rather not to do that due to consideration of satuation possibility.
(To be Continued)