Replies to post #128697 on Amarin Corp Plc (AMRN)

[rafunrafun]

Thanks. I'm watching but can't comment on any of it because in addition to being medically - scientifically challenged, I could not get my phone, tab and laptop to play the slides.

Even if the MOA, per JL is different, at the very least it will show that CVD is not only about reducing LDL. Also, I may be talking out of my ass, but in Marine / Anchor, hsCRP waa reduced by 36% / 22%, respectively. And CIRT is definitely about reducing hsCRP.

[IgnoranceIsBliss]

I would say that it's 10x more likely that it was stopped for futility than for efficacy, for two reasons:

- The null hypothesis doesn't exist for no reason, and
- In these CVD trials, the propensity these days to keep going despite crossing efficacy thresholds is very high. Especially when the primary is a composite MACE endpoint, and you'd want to try to get an impressive p-value on death by itself.

In other words, unlikely to be stopped for efficacy for the same reason AMRN bulls think that REDUCE-IT wasn't stopped for efficacy.

[oneragman]

AV,
While we have you here, I am sure a number of us would like your input on a couple of subjects. There were differences of opinion on how AMRN is calculating patient years. HG has calculated a different # using enrollment data. I don't question his calculations. Since they were differences with AMRN'S, there was speculation as to the difference. One was lost to follow up(not dropouts), which some were speculating could be 10% or more. There is a significant difference in PY, and any insight would be appreciated. The other point that came to light was that AMRN, in their patient year calculations, included patients even if they had an event. So if a patient had an event in 2013 and were still alive today, they would still be accumulating PY's. Is this normal for most trials?

[Biobillionair]

Regard mechanisms of actions: likely Vascepa would add additional benefit to methotrexate.

Methotrexate is an antimetabolite of the antifolate type. It is thought to affect cancer and rheumatoid arthritis by two different pathways. For cancer, methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis.[28][29] The affinity of methotrexate for DHFR is about 1000-fold that of folate. DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate.[28] Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis.[28] Also, folate is essential for purine and pyrimidine base biosynthesis, so synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.[28]

For the treatment of rheumatoid arthritis, inhibition of DHFR is not thought to be the main mechanism, but rather multiple mechanisms appear to be involved, including the inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine; inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells; selective down-regulation of B cells; increasing CD95 sensitivity of activated T cells; and inhibition of methyltransferase activity, leading to deactivation of enzyme activity relevant to immune system function.[30][31] Another mechanism of MTX is the inhibition of the binding of interleukin 1-beta to its cell surface receptor.[32]

https://en.wikipedia.org/wiki/Methotrexate

I doubt the trial set the bar as high as R-I for stop at interim.

BB