Comparisons: Amgen then and Amgen now; Amgen now and Regeneron now

Here’s another recent event where pharma players find themselves boxed in by the success of their own scheme.   Let’s use the framework provided by Dr. Goldberg’s Merck Manual entry as background to a legal problem.  Note that the Merck Manual listing breaks down the diseases within the heading, “Dyslipidemia (Hyperlipidemia).”[1] Then the article breaks down the category, dyslipidemia/hyperlipidemia, into sub-categories Primary and Secondary. “Primary” refers to genetic causes and “Secondary,” to “lifestyle and other factors.”  The next category down (the “sub-subcategory,” if you will) lists the different diseases, FH and what were formerly known as “FDB” (APOB) and “FH3” (PCSK9). Familial Combined Hyperlipidemia (“FCH”) is also here … along with several other diseases.

Hyperlipidemia, Familial hypercholesterolemia, LDLR, APOB and PCSK9, p.Arg3558Cys, FCH, FH3, FDB

Now here’s the confusion. When Amgen first applied for FDA approval for its drug Repatha, it requested that the drug be available to patients with primary hyperlipidemia.  This was rejected. It was however approved for a subcategory, the heterozygous form of FH. (For this discussion, we’ll set aside the CardioVascular Disease [CVD] component of the indications. I’ve limited my analysis to the FH portion.) Without the prior linguistic manipulation,this clear rejection, de jure, would have excluded the FDB, the FH3, the FCH, and the others. But the pre-FDA linguistic maneuver[2] did take place and the FDB and FH3 were effectivelyredefined as “FH,” and so, de facto, the FDB and FH3 were “included” in the FDA’s approval … but not FCH. FCH was not part of the linguistic maneuver. So legally, what would be the difference between Amgen’s inconspicuous promotions for FDB sales and a hypothetical, conspicuous attempt at FCH sales? Is an FH promotion that silently includes those formerly defined separately as FDB on-label? Would an explicit “FDB” promotion still be on-label? If yes, then would promotion of FH-indicated drugs to the FCH be on-label or off-label promotion? The line has been blurred through deliberate, scientific obfuscation, and the increased market for FH drugs is made up of this linguistically manufactured grey area. How is this question even possible if the FDA is the ultimate authority? Who really decides what underlies an FDA drug indication?

Now as it turns out the indication for Amgen’s drug has expanded to include, not just FH, but now Primary Hyperlipidemia as a group.[3] So what? For example, imagine I arrive at a fruit stand and when the vendor is not looking, I secretly place apples under oranges within a box labeled, “oranges.” I next offer $5 for all the fruit on the table.  Why not? What have I got to lose? If he says, “No, but you can have that box of oranges for $5.” I grab the box of oranges – and with it, the apples I have previously slipped in. Is it a legal purchase just because I get away with it?  If I had slipped a peach in the box of oranges, would that have been equally “legal”? In fact, if I pre-decide the contents of the box and the vendorremains unaware, what fruit would not be “legally” available to me? If I somehow manage to convince myself that it was legal yesterday, what do I do if the vendor then explicitly makes a new offer, “I’ve got a better deal for you today. I’ll give you both the oranges and the apples together for the same $5.” If it had already been legal and aboveboard yesterday, what has just happened today? If legal, what basis would there be for considering this to be a new deal? What reason would I have to be pleased with the offer? If it is not a new deal, why would the vendor say anything at all? 

  1. If I explicitly acknowledge that a new and better deal has been made, I imply a difference from the previous deal.
  2. What is that difference?
  3. The vendor did not intend for me to take the apples yesterday.

The very fact that the vendor makes the new $5 offer tells me that I was never offered the apples the first time. Acknowledging the fact that there is a newdeal, I also acknowledge that I simply stole apples in the last deal.

If the FDA tells Amgen that they can now market to all those with primary hyperlipidemia, as opposed to the previous indication which restricted them to FH, was it previously legal to market to the other members of primary hyperlipidemia, FDB and FH3? Has anything changed at all? (The emphasis here and in the passages that follow are mine.)

FDB is a disorder which is clinically and biochemically indistinguishable from familial hypercholesterolemia (FH), a disease caused by LDL receptor gene mutation. This was demonstrated by the fact that approximately 3-5 % of FDB patients are incorrectly diagnosed as FH (Weisgraber et al. 1988). ~ Vrablik[4]

That was in the year 2000. How far have we travelled? Just a short while ago, pre-2011, calling the APOB mutation carriers “FH” instead of “FDB” was outright misdiagnosis. Now no one is the wiser. But FCH? That would be going too far evidently. Note that the reason why only 3-5% of the FDB patients are incorrectly diagnosed is because FDB is much milder than FH. Most don’t pass the industry’s recommended circumstantial scoring system. Vrablik continues,

However, reviews dealing with the comparison between FH and FDB homozygotes and heterozygotes showed that hypercholesterolemia, which arises from the genetic condition, is generally milder and more variable in FDB (Miserez and Keller 1995). Furthermore, the development of atherosclerosis is delayed in comparison with FH patients (Brousseau et al. 1995, Tybjaerg-Hansen et al. 1998, Če.ka et al. 2000).[5] ~ Ibid.

So FDB and FH are known to have very different degrees of severity. A demarcation between types of diseases has an increased medical value. Does this demarcation increase or decrease the financial value of a stock trading on Wall Street? Precision limits the range of targets, but expansion resists limits, resisting precision in the consequence. Precision is important to disease identification, imprecision to marketing expansion ­– in which of these directions do we travel when we conflate FDB with FH? Who decides? Pharma puts practicing doctors on a “need to know basis.” Below, pre-2011 (2008), FH and FDB are clearly two separate diseases. Again, they also involve two different degrees of severity.

Familial hypercholesterolemia (FH) and familial defective apoB 100 (FDB) are characterized by increased plasma low-density lipoprotein cholesterol (LDLc) levels and risk of coronary heart disease (CHD). FDB is clinically indistinguible from FH. … We conclude that the FDB lipoprotein phenotype was significantly less severe than that observed in FH carriers of LDLR gene missense ligand-binding domain mutations. ~ Ejarque[6]

Have doctor’s been put on a need-to-know basis?

Shouldn’t differing degrees of severity, not to mention differing disease mechanisms, merit a doctor’s specific awareness?  Why would the historical record be altered to the point that it serves more as an eye patch for the doctor than additional light on the patient?  If altering the scientific record for profit is above the law, then there is no limit to the damage that pharma can do.

Here is a paper published in 2018.

Recently homozygous FDB patients were identified. Hypercholesterolemia was less severe in these subjects than in patients homozygous for FH, in which the LDL receptor is defective. ~ Schaefer[7]

The message is the same. FH and FDB are two different diseases, with different mechanisms, and crucially, with different degrees of severity. It is not just the recent push for “precision medicine” but just plain common sense that tells us that genuine medical practice opts for preserving detail and not removing it from the scientific record. If Big Pharma can re-define diseases through a publication strategy, removing detail and creating grey areas to capture more sales, pre-FDA approval, then both the FDA and the practicing physicians remain on a “need to know basis,” where the “need” is profit … a profit threatened by a doctor’s improved vision.By controlling medical instructions, the manipulation subordinates the role of the physician to that of pharma’s full profit potential.

FH, Primary Hyperlipidemia, Repatha, Amgen, FDA

With the weakened diagnostic scoring systems in place, and genetic testing downplayed, all those who merely share characteristics with genetic FH are effectively renamed “FH.” This captures a significant number of those with merely secondary hyperlipidemia. However, for argument’s sake and for the present purpose, let’s just talk about Primary Hyperlipidemia and the FDA indications.

With FH, a definition of specific genetic inheritance met a specific FDA indication, while the prevailing literature had already slipped out of its genetic constraints as the disease name stretched over a broader range of conditions.  Genetic-based medicine is touted as “precision medicine” and FH is supposed to be caused by a narrowly defined genetic inheritance. Science and medicine pursue ever finer detail in the pursuit of precision, but the marketing here thrives on obscurantism, a wide shadow cast over neighboring definitions. How far and wide this shadow prevails depends upon limiting its extension just short of becoming conspicuous.

As far as FDB and FH3 are concerned, what has changed with Amgen’s new indication? With Goldberg, et al’s, linguistic maneuver, the expanded indication is a fait accompli – no one is the wiser. FH has become FDB and FH3 … but not FCHFCH, in fact, is on some publications’ “exclusionary criteria”[8] – IE, it is regarded as misdiagnosis to take the FCH for FH, just as it was once regarded as misdiagnosis to include the FDB as FH.  Why not also conflate the FCH? I’ll speculate a little here.  First FCH is the most common of the genetically caused dyslipidemias, with a prevalence between 1/50 and 1/100. The resulting inflation of FH prevalence would be very conspicuous. Second, FCH was described by the same Nobel Prize winner in the 1973 publication which is often cited for the prevalence of FH. In short, FDB and FH3 are still new and relatively unknown. FCH, on the other hand, was widely publicized alongside FH – 45 years ago; it is easier to manipulate information regarding lesser known, newer diseases which are not yet entrenched in textbooks or among older, experienced physicians.

But setting aside that speculation, what matters in the present argument is the fact that there is a heading called Primary Hyperlipidemia.  Sometimes FDB, FH, and FH3 had their own heading assigned, “Autosomal Dominant Hypercholesterolemia.” However, regardless of the category heading used on a given occasion, FH, FDB, FH3, FCH, were once distinct “mathematical sets,” each demarcated, separated and categorized with an equal rank within a given literature and disease hierarchy. Then an organized, orchestrated, Pharma-funded linguistic conflation of the diseases took place.

We can also see Amgen’s linguistic-legal confusion when we bring in Regeneron’s current indication for its drug, Praluent.  When Amgen’s changed indication is set next to Regeneron’s current indication, is there a legal difference? Regeneron’s drug is restricted to the subcategory, HeFH[9]; Amgen, is now able to promote to the whole category, Primary Hyperlipidemia, which not only includes HeFH, but FDB and FCH. If Amgen is only now permitted by the new indication to include the APOB and PCSK9 carriers, is Regeneron forbidden to do the same without an indication for Primary Hyperlipidemia? If so, was it legal for Amgen to promote to such before the indication change? If permitted, why wouldn’t Regeneron be able to promote to FCH as well?

Hyperlipidemia, Familial hypercholesterolemia,  FCH, FH3, FDB, Regeneron, Amgen

Who is in control if Big Pharma is allowed to cherry-pick and fund authors willing to go along with a language strategy and completely redefine diseases before they reach FDA consideration?  Big pharma is.

Regeneron report,  Familial hypercholesterolemia, LDLR, APOB and PCSK9, p.Arg3558Cys, FCH, FH3, FDB, FH prevalence

There are many issues here, but this portion of my analysis is concerned with mostly one.

If the FDA is going to approve a drug for “FH,” how many drugs would be sold … with this new definition? … or that old definition? If the APOB mutations are milder than the LDLR, do they both share the same risk-benefit profile in regard to risky treatments? For investors, what is the addressable market?

All these are important questions. But first things first. The issue of whether to include or exclude FDB under the definition of “FH” is an issue for the medical community and the FDA to decide. I’m not saying that such is not important. It is. However, we are doing something more elementary here: we are trying to compare apples with apples, and not apples with oranges. The violation I outline here is with simple linguistics and math. Stretching the definition of FH over FDB and FH3 and controversial p.Arg3558Cys and then setting the result alongside previous studies that did not stretch the definition must be accompanied by both a detailed explanation and a routine breakdown of the mathematical adjustment.

In another way of looking at this, FH-as-LDLR+FDB+FH3 is indeed an increase over FH-as-LDLR-alone. Likewise, a whole pie is larger than one of its slices. If this is to be more than a meaningless truism, some explanation would be useful here. Perhaps we could use a map of the differing FH definitions, where readers could zoom in and out of the different dimensions afforded by phenotypic versus genotypic perspectives, and the differing clinical scores of their constituents. Who is included with one definition but excluded with another? This might be useful as an exercise in clarification. But there is no legitimate prevalence comparison here. For a prevalence comparison to take place, the types which actually underlie the sets must first be identical. As it is, we are really comparing linguistic usage.


[1] See https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/lipid-disorders/dyslipidemia.

[2] The conflation begins at least as early as 2011.

[3] https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125522s014lbl.pdf

[4]  “Major Apolipoprotein B-100 Mutations in Lipoprotein Metabolism and Atherosclerosis,” 2000, M. VRABLÍK, R. ČE.KA, A. HOŘÍNEK

[5]   Also, note that the 1998 citation in the above refers to some of the same authors of the Danish reports. They will change their minds and eliminate this observation, after pharma-funding.

[6] Evaluation of clinical diagnosis criteria of familial ligand defective apoB 100 and lipoprotein phenotype comparison between LDL receptor gene mutations affecting ligand-binding domain and the R3500Q mutation of the apoB gene in patients from a South European population, 2008, Ejarque, et al. https://doi.org/10.1016/j.trsl.2007.12.001

[7] Homozygous Familial Defective Apolipoprotein B-100: Enhanced Removal of Apolipoprotein E–Containing VLDLs and Decreased Production of LDLs, 2018, Shaefer, Scharnagle, et al.  https://www.ahajournals.org/doi/abs/10.1161/atvb.17.2.348

[8] For example, Molecular Basis of Autosomal Dominant Hypercholesterolemia: Assessment in a Large Cohort of  Hypercholesterolemic Children. Anouk van der Graaf, et al. and Diagnosing familial hypercholesterolaemia: the relevance of genetic testing. Van Aalst-Cohen, et al.

[9] https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=446f6b5c-0dd4-44ff-9bc2-c2b41f2806b4