Wednesday , June 23 2021

The REDUCE-IT test of Amarin: Something wrong? – Amarin Corporation PLC (NASDAQ: AMRN)



Import

I hope everyone reading it has basic knowledge of Amarin (AMRN), its unique Vascepa product, and the REDUCE-IT or CVOT cardiovascular discount study. Furthermore, probably everyone knows that the recent disclosure of AMRN's positive results from REDUCE-IT, with significantly negative cardiovascular events or MACE, decreased by about 25%.

I bought AMRN in the range of $ 10-11 in the morning that released the top results and got an article on Seeking Alpha as soon as possible. Since the stock had spoiled the low single digits for a long time, I was not sure whether setting a target price of $ 15 In the following year was aggressive or attentive. Well, traders have shown me cautious, at least for now. Keeping my discipline, which was to wait for the presentation on Saturday with more complete information about REDUCE-IT at the annual meeting of American Heart Ass, I ran between $ 15 and $ 20. I have no place in AMRN since he first got to $ 20 and has no plans to go much or a little.

AMRN is facing two generic companies not settled with it, as did Teva (TEVA). These are the workshops of Dr. Reddy (RDY) and Hikma Pharmaceuticals (OTCPK: HKMPY). The latter also does, or did, business in the US as West-World. Both RDY and HKMPY have filed ANDA with the FDA and are in the early stages of the dispute with AMRN. It is therefore likely that Vascepa could have general competition until January 2020, when its most basic drug / pharmaceutical product patent # 8188146 expires.

Now I want to get to some of my first thoughts about CVOT REDUCE-IT, as discussed in NEJM, a supplement to it NEJM article, and in a short "logic and design" 2017 article.

I want to point out at the outset that I am not excited to present these initial remarks. I would have preferred it to be absolutely clean, at least at first reading.

A placebo that may not be a placebo at all

The REDUCE-IT multi-year study of 8000+ patients with high dose eicosapentaenoic acid or EPA was designed to transfer Vascepa from a specialized product for very high levels of triglycerides in routine use for patients at high risk of developing a CV event. AMRN plans to request a reinforcement of the label for Vascepa so that it is appropriate for some common populations to reduce the risk of MACE and also reduce the risk of CV death.

Given the known benefit of statins for most CV patients, REDUCE-IT's main case was to study Vascepa as a statin supplement. Vascepa was given as two large capsules twice a day. The placebo group received a preparation containing mineral oil.

Mineral oil is a problem for me, for reasons I will show below.

What is mineral oil?

Berkeley Wellness, in collaboration with the University of California School of Public Health (Berkeley), provides the following general description of this agent:

Like petroleum jelly, mineral oil is a cheap by-product of refined crude oil to produce gasoline and other petroleum products.

Mineral oil is sold in OTC and is commonly used for skin as the blog says:

Like petroleum jelly, mineral oil is an effective softener that forms an oily layer on the skin that traps water. So is a common ingredient in moisturizers and other skin care products; some people use mineral oil directly from the bottle to cure dry skin.

What about the chronic consumption of mineral oil? The piece of blog is addressed to this:

Is it okay to consume mineral oil as a laxative?

We do not recommend it. Mineral oil, taken orally, acts as a laxative due to its lubricating effect. it also helps the stool to hold the water so it remains soft. Sometimes it is temporarily encouraged for people who have pain caused by hemorrhoids or anal fissure or after rectal surgery. However, it may have adverse effects, especially fatty leakage from the anus and malabsorption of fat-soluble vitamins and carotenoids from foods.

"Bad Absorption" refers to incomplete absorption. The fat-soluble vitamins are A, D, E and K. The mineral oil can also inhibit the absorption of certain drugs, such as statins.

So, although the amount of oil was low, giving it for years, it seems to me that it is not a placebo.

So I have serious questions about the basic design of this study. So I have to make a warning, that is, I do not know what the FDA and the clinicians said about this issue. I will refer to placebo as a "placebo" to remind readers of my point of view, which is just me at this point. Also, as I repeat later, this is an investment article. All concerns are important. The truth will come out after the FDA does its thing next year. As a trader, it is to look at mineral oil as an active agent and not a real placebo. If I'm wrong, then what happens is that I can lose another move in the stock, including a possible takeover.

But if I'm right, I might lose a big sell-off.

Here is why I worry that mineral oil may have harmed the health of the placebo / placebo group.

Did the mineral oil prove to be confusing?

Some police work has led me to raise this question. I went to the tables in the supplement associated with the above. On page 40, Table 6 shows 23 undesirable effects that may be related to Vascepa. Few were statistically different between Vascepa and placebo. They were

  • diarrhea, 2.1% more common with placebo
  • constipation, 1.8% less common with "placebo"
  • anemia, 1.1% more common with placebo
  • peripheral edema (swelling of the feet), 1.5% more common with Vascepa.

Of these, the P value, a measure of whether a comparative difference could have occurred due to a change, was too low (ie convincing that the result is not due to chance) for diarrhea, constipation and swelling.

Since anemia was of marginal statistical significance and edema was more common with Vascepa, I would concentrate on diarrhea and constipation.

Guess what? These are exactly what you would expect if the mineral oil had a clinical effect on some people. More diarrhea, less constipation. What we do not know about it is whether the mild effects on GI function occurred in more than two percent of patients with petroleum oil. In other words, could 'placebo' harm to patients' health rather than act as pure placebo;

So far, this is just a question. Now at p. 38 and in Table 4. This gives lipids and other parameters. With this, I see a more immediate problem.

The placebo group may have taken anti-statin

Using the Hopkins method to measure LDL cholesterol (in mg / dl), are some of the Vascepa numbers:

  • baseline: 85,8
  • month 4: 83.6
  • year 2: 85.5.

Thus, a mild initial drop, then no change in steady state after 24 months for treatment.

Now look at the same numbers for the placebo group:

  • baseline: 86.7
  • 4 months: 93.7
  • year 2: 96.1.

Within just 4 months of the onset of "placebo", for unknown reasons, the LDL-cholesterol level in these patients increased by 7 units or 8%. Due to the mild initial difference in LDL-C, the 2-year difference between Vascepa and placebo was greater than 7 points. It was 10.1 points. Looking at "placebo", it is as if the placebo group went into a mild lipid-lowering agent and reduced LDL-C by 10.1 / 93.7 or 10.8%.

I guess there is no unknown reason. I suspect that mineral oil prevents the absorption of the statin and that the design of the test was defective in order not to correct it.

In addition, and according to the fact that there is an anti-statin activity, statins reduce a measure of inflammation known as C-reactive protein or CRP. This was also affected by "placebo". For this purpose, Vascepa reduced the CRP (listed in Table 4 as hsCRP) from 2.2 mg / L) from 2.2 in the baseline to 1.8 and in the two follow-up studies. However, the placebo group did not act again as if it had received an inactive agent, indicating these numbers:

  • baseline: 2.1
  • year 2: 2.8
  • last visited: 2.8.

Finally, while perhaps not of clinical significance, EPA levels were measured in the EPA group and the placebo group. Of course, from the initial stage to the study conclusion, EPA levels in the Vascepa group increased from 26 to 144 (micrograms / ml). However, EPA levels decreased in the placebo group, from 26.1 to 23.3. This is a drop of 10.7%. Could this, I wonder, perhaps have played a small role in the adverse health effects of the placebo group?

Its authors NEJM The article addressed it.

Comments from the article on this topic

From the final unity, the discussion, the writers minimize this issue by saying, in full:

Secondly, if the mineral oil in placebo affected the absorption of statin in some patients, this could have contributed to differences in outcomes among the groups. However, relatively small differences in LDL cholesterol levels among the groups could not explain the 25% lower risk observed with icosapent ethyl, and a post-hoc analysis suggested a similar lower risk regardless of whether there was an increase in LDL cholesterol among patients in the placebo group. Although JELIS was designed as an open label placebo placebo study, it showed a 19% lower risk of ischemic attacks with statin plus EPA than with statin monotherapy.

The JELIS study reported by the authors was a Japanese study that led AMRN to believe that REDUCE-IT had good reasons to succeed.

I have to be careful when I comment on a study that I have just read. Authors know the details many times better than what they said. They can invest mentally (at least) in the study. We would all like to succeed and thus open up an important new therapeutic method.

That being said, here are my thoughts on the subject as a retired cardiologist with some experience in this field.

He does not love it NEJM comment on mineral oil as a placebo

I am not convinced that the authors gave a complete picture.

First, let's say that it is quite reasonable that about 10% changes in LCL-C, CRP and EPA levels are not enough to cause a 25% reduction in MACE. But what if they are enough to explain perhaps a 10% reduction in MACE? In this case, what would clinicians do with a 15% reduction in MACE? What will the FDA say? This is a big difference, given the competition from the inhibitors of ezetimibe and PCSK9, and most probably from pipeline medications later on. Also, such important results, such as a 20% reduction in the mortality of the curriculum vitae, may fail to achieve statistical significance.

Secondly, the authors report a "post-hoc" analysis. This is a retrospective, unspecified look at the data. I am skeptical about this. This is because if I read the sentence properly, they ignore the fact that if the placebo group was actually a placebo, LDL-C and CRP might have changed very little in 4 months and throughout the study . Thus, some patients would have seen reductions in LDL, some would have remained stable, and some would have increased. What I care about is a pre-defined group comparison with the other group.

Third, this was a short article. Every word counts, and some and perhaps most of the writers want to say they are editing. Given that, why were they even bothered by JELIS? It is almost completely irrelevant to the interpretation of REDUCE-IT. different populations, different installments, etc. What survived in the final plan shows me that these are writers who are Vascepa's rebels. I could be wrong, but I write a stock market article that does not do scientific research and as investors and traders we have to think about what can happen without knowing with certainty.

What about the FDA?

The FDA will examine this study hard

If I had to guess, the FDA knew the design of the study. But if I paid some attention to using a placebo with placebo and its possible side effects if she showed a type of drug effect it's something completely unknown to me. We may never know that.

I expect the FDA to perform complex data analyzes that are beyond any analyst's ability to find at this point. As an example of an old set of burglaries, in the early 1990s, two companies simultaneously came up with drugs for septic shock. The companies were Centocor, which was later acquired by J & J (JNJ). and Xoma (XOMA), which is still hanging about $ 150 million. If I remember correctly, the medicine of each company went to an advisory committee, which was either unanimous or almost in favor of the safety and efficacy of the drug. You can imagine how loud the shares were trading. Thereafter, the FDA collected both drugs. What the FDA did was a careful and complex review of the data and decided that, clearly, the drugs were not effective, even if they were safe.

When I was in the industry, one of my roles involved reading the approval summary, or SBOA, of many approved, branded medicines. Basically in those days of cartoons, the FDA will send a box to the company with several hundred pages of its discussion and then it will be transferred to my home. Reports were reported from each section, from toxicology to one or two different statistical analyzes. I would like to read or look at at least every page, bypassing anyone, and use my knowledge at school level schools to try and watch how the FDA statisticians cut and cut the data. These people were good, really good. Apart from the good, they had all the details that were based on individual patient records that allowed them to make analyzes that foreigners can not do. I'm sure the FDA will hit through the REDUCE-IT results in complex ways and that the study will surely introduce the prescribing information. But…

My Bottom Line Here: We would not have guessed yet how the FDA will consider the REDUCE-IT study. This can be tough.

So, I just see the danger here in AMRN's commercial standards and in its final value.

Conclusions

AMRN is, in my view, dangerous from the start because of the two ANAs filed with the FDA that are the subject of disputes. With Friday's closing price of $ 21.05 and a market cap of about $ 6.5, AMRN needs years of big profits to just reach this level of profits.

My download for now is that REDUCE-IT needs a very careful study from the FDA. The strong results of the top-of-life CV that AMRN and the researchers highlighted would really be great if placebo was actually just a placebo. However, my reaction to the data I have seen is that the side effect profile matches the mineral oil in the placebo that exists in enough quantity to have affected the physiology of the GI of an unknown percentage of the recipients. The trend for more anemia in the placebo / petroleum group is also worrying. A lower hemoglobin level could predispose a patient with atherosclerotic disease to suffering from an MACE.

In addition, I read the relevant articles and completed more than once, but I did not see any reference to comparative changes in blood pressure. Did blood pressure even deteriorate slightly in the placebo group? Did this group end up receiving more antihypertensive treatment than the Vascepa group? And so on. Many questions, no answers. The FDA will know everything.

Εν ολίγοις, ίσως απροσδόκητα στους σχεδιαστές της μελέτης, η ομάδα του εικονικού φαρμάκου μπορεί στην πραγματικότητα να ήταν σε έναν παράγοντα που είχε αποτελέσματα παρόμοια με το φάρμακο. Αυτά τα αποτελέσματα με εντυπωσιάζουν ως αντι-στατινικά αποτελέσματα στα λιπίδια και έχουν προκαλέσει ανεπιθύμητες παρενέργειες GI. Έτσι, ίσως το μέρος της διαφοράς μεταξύ του Vascepa και του εικονικού φαρμάκου ήταν επειδή ήταν σαν να είχε χαμηλώσει η δόση στατίνης η ομάδα του εικονικού φαρμάκου. Εάν ναι, πόσο μεγάλο μέρος; Και πάλι, θα προτιμήσω: ένα σκληρό.

Δεν έχω καμία σαφή ιδέα για το πώς θα δουν οι έμποροι τώρα το AMRN, αλλά έχω μια σταθερή ιδέα ότι μετά από 10X, η AMRN είναι επικίνδυνη, δεδομένου του κινδύνου γενίκευσης. Χαίρομαι που έχω πουλήσει. Εάν εμπορεύεται υψηλότερα, εάν αποκτάται από έναν μεγάλο παίκτη, συγχαίρει για τα μακρινά. Η δική σας αληθινά θα παραμείνει στο περιθώριο και θα περιμένει πρώτα για σχόλια από το βιογραφικό βιογραφικό, αλλά αυτό που πραγματικά έχει σημασία είναι αυτό που ο FDA αντιλαμβάνεται. Νομίζω ότι όλα τα υπόλοιπα είναι εικασίες.

Και πάλι, εύχομαι η AMRN και η Vascepa να είναι οι καλύτερες. Ο κόσμος θα μπορούσε να χρησιμοποιήσει ένα ασφαλές και αποτελεσματικό νέο στοματικό παράγοντα για ένα μεγάλο, αναγκαστικό τμήμα του πληθυσμού.

Ευχαριστούμε που διαβάσατε και μοιραστήκατε τα σχόλια που θέλετε να συμβάλλετε

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Έγραψα εγώ αυτό το άρθρο και εκφράζει τις δικές μου απόψεις. Δεν λαμβάνω αποζημίωση γι 'αυτό (εκτός από το Seeking Alpha). Δεν έχω επιχειρηματική σχέση με καμία εταιρεία της οποίας το απόθεμα αναφέρεται σε αυτό το άρθρο.

Πρόσθετη αποκάλυψη: Όχι επενδυτικές συμβουλές. Δεν είμαι σύμβουλος επενδύσεων.

Σημείωση εκδότη: Αυτό το άρθρο περιγράφει μία ή περισσότερες αξίες που δεν διαπραγματεύονται σε σημαντικό χρηματιστήριο των ΗΠΑ. Λάβετε υπόψη σας τους κινδύνους που συνδέονται με αυτά τα αποθέματα.


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