Read the fine print; consider the consequences

While browsing news, as I usually do, I encountered an article that the first “biosimilar” had been approved by the FDA. And a quick search led to a better webpage with more detailed information, even if it’s from the folks who will profit from this (stupid libertarians, do you think Novartis would put out this careful information without regulations? dream on). What’s that, I wondered. Generally being interesting in molecular biology and related biomedical issues I wanted to see what this is about.

At first, since the articles dealt with the general issue of a biosimilar drug and its approval process nothing much caught my attention UNTIL I noticed the new drug Zarxio is a possible substitute for filgrastim (Neupogen brand name). Now that is something that really interests me.

You see Neupogen is often given to people going through chemotherapy because their white cell counts, in particular, neutrophils, can drop to dangerous levels, vastly raises that person’s chance of infection, a condition known as neutropenia. Now that rings a bell because I have neutropenia, in fact a bit worse pancytopenia (shortage of multiple types of blood cells).

About 18 months ago I was diagnosed with myelodysplastic syndrome (MDS). In fact back then I figured by now I’d probably be dying. This wasn’t just a guess by my hematologist based on blood tests alone; I also had a bone marrow biopsy and dysplastic cells were discovered. Lights out time, no cure for this and it’s progressive. But my hematologist (also oncologist) referred to my condition as “smoldering” (which according to literature I found is a somewhat obsolete term), but basically that I had, at most, a slowly progressing form and therefore would probably die of something else first. So I take B12 and get blood tests every six months to see if it’s gotten worse and thus far, while still below normal, I’m not down to the abnormal levels (there is a gap between bottom of normal and top of abnormal which is where I am).  So who knows.

One problem with many medical conditions is we don’t (typically) test a “control group”, esp. when testing is expensive and invasive, unless it’s a drug trial or some other study. So do some/most/all people develop some degree of dysplasia in their bone marrow that goes unnoticed if they don’t get treated for any of the various diseases associated with abnormal marrow. Once when my mother was in the hospital I asked the doc who monitored her brain MRI if she had any damage – he almost laughed, basically everyone who is 95YO has some brain damage, mini-strokes and other conditions that just happen, but are subcritical. So, possibly this is the same thing – if you gave bone marrow biopsies (not something casually done) to a large group of people over 65 would how many would show some amount of dysplasia – answer, nobody knows. So is my condition just normal aging or something worse? Only by getting sicker will anyone know.

But back to Zarxio and biosimilar drugs. The original patented drug is a  granulocyte-colony stimulating factor, or G-CSF, which is derived from biotechnology (not mixing up chemicals in a factory like most “small molecule” drugs). A biosimilar is the same substance but produced through a different (and synthetic process). Now if this seems esoteric consider the well-known drug, penicillin. It was discovered as the natural product from a type of fungus that had anti-bacterial properties, i.e. an antibiotic. Originally the only way to product that drug was growing some of the fungus and extracted penicillin (and unfortunately getting other crap from the fungus which is the cause of most of the allergic reaction to penicillin). Human insulin was originally extracted from pigs and had some similar adverse consequences. Over time, once a useful drug has been found it’s desirable to come up with a better manufacturing process, one that is more controllable, produces a purer product (fewer side-effects), and, of course, usually, is cheaper, which the drug companies love.

That’s what the story of a biosimilar is. Instead of a biological process to produce the drug a chemical process is used, but the active compound is the same. Thus, it should (but needed to be proven) work the same. And that’s what Sandoz accomplished and the FDA just approved.

Hurrah, a drug that I might actually need is now more readily available. Now the big issue, right now, with Neupogen is that it’s very expensive (my sister took the drug during her chemo and fought with the insurance company to get it covered). So a biosimiliar drug might (remains to be seen, Sandoz may just price it to market, not get in price war) could be cheaper. For me that may not matter. As long as the Repugs don’t kill Medicare and I can afford to pay my supplemental and Plan D drug plan I could probably get Neupogen, so cheaper, nominally, doesn’t matter to me (it does intellectually, but not selfishly).

But here’s the thing and the reason in multiple posts I’ve advocated reading actual detailed papers, not just press releases; or at least, if not scientific papers then the full disclosure information sheets, not the dumbed-down stuff for public consumption (hey, if it’s your health learning some science and biology and technology and how to read more complicated papers is WORTH IT). So here’s the catch (isn’t there always one) for me:

Confirm the diagnosis of severe chronic neutropenia (SCN) before initiating Zarxio therapy. Myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) have been reported to occur in the natural history of congenital neutropenia without cytokine therapy. Cytogenetic abnormalities, transformation to MDS, and AML have also been observed in patients treated with filgrastim for SCN. Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia. The effect of filgrastim products on the development of abnormal cytogenetics and the effect of continued filgrastim administration in patients with abnormal cytogenetics or MDS are unknown. If a patient with SCN develops abnormal cytogenetics or myelodysplasia, the risks and benefits of continuing Zarxio should be carefully considered.

Got that? Well it may sound like impenetrable gobbledygook but if you had MDS (or the possibility of it) you’d be well-advised, instead of Jenny McCarthy consulting Dr. Google, to actually learn what this stuff means (trust me, it’s not that hard, but it does take work, start with Wikipedia, then harder stuff, then real science papers).

What this says, the bold but not unlined part, is that this drug (either the original or the biosimilar) is not going to halt progression to myeloid leukemia (otherwise known as get your affairs in order, you’re a goner). But worse, is the underlined part. While it doesn’t say anything necessarily bad, it does (as science usually does, i.e. honestly) say no one can say what the consequence of this drug is on your MDS (gets worse, gets better, stabilizes – nobody knows).

Now in some sense this is no surprise to me having fairly thoroughly studied MDS. The problem is that filgrastim is not a cure, it is known as a palliative. It counteracts what is wrong with you. Not enough neutrophils, filgrastim is like fertilizer, it triggers the growth of more. But it does NOT address why you don’t have enough.

What is wrong with me (and this is true for most cancer) is that my stem cells (no, not the ones religinuts freak out about, but HSC (hematopoietic stem cells), which we all have lots of are going bad for me. An stem cell reproduces itself, both to make more stem cells (for the future) and to differentiate into mature blood cells (what we need that triggered this growth). The trouble is, sometimes, one of those HSCs underwent a mutation (exactly what is not known and probably it is a set of multiple mutations, both in DNA and epigenetic factors). The new stem cell, derived from an existing one, is called a clone (again, no, not what the religinuts freak out about, a clone is just a copy, hopefully totally identical to the original). So I have good HSCs and now I have some bad HSCs (the clones of the original mutation from who knows when (could be decades ago) and who knows why: random chance (bad luck) or a mutagen (like smoking, or even BBQ, loaded with carcinogens). The trouble comes when the damaged cell stem is a little bit better at reproducing that the normal cells which means, over time, the abnormal cells become relatively more numerous, eventually driving out the good HSCs (and then it’s lights out). How fast this happens is based on complex genomic and epigenetic interactions not yet known (unfortunately unlikely to become known during my remaining life, this is tough research to do). So my bad HSCs produce dysplastic (aka bad, misformed) adult blood cells, in my case, most notably the neutrophils.

Now without enough neutrophils you don’t die directly from that, but you need to live in an isolation chamber or else some ordinary non-fatal disease will kill your because neutrophils are the soldiers that kill the ISIS bugs and without enough of them the bugs win.

So while Zarxio can, temporarily, compensate for some of this, it doesn’t get rid of the bad HSCs. So Zarxio might help you live longer, but that’s the operative sense, only longer, as this will eventually kill you (the reason my oncologist isn’t too worried about this is that at 68 something else will probably kill me first, but I may be “unlucky” in that since all my effort at diet and exercise has reduced my most likely death threat.

So, while undoubtedly this is more than you could possibly want to know, here is the takeaway. Learn about this stuff (it’s not easy, but you’ve learned harder things) and learn to read the information carefully (and also distinguish the junk that fools the anti-vaxxers and Jenny McCarthy, the Internet is NOT always right, gosh, is that a surprise). Critical reading to find good and accurate information (and even the best is not that great) is essential. And you need to do it. Don’t just trust the white coats (yes, trust them, and trust evidence-based medicine instead of woo), but find out for yourself. You’re not a doctor and don’t try to be, but you can get more from your doctor as an informed patient. And this is doable, not just for MIT grads with lots of background in molecular biology, but everyone.

Do it. Read the real detailed data. Understand it. And if you don’t look up the terms you don’t know and find out what they mean. You can do it and you should do it.


About dmill96

old fat (but now getting trim and fit) guy, who used to create software in Silicon Valley (almost before it was called that), who used to go backpacking and bicycling and cross-country skiing and now geodashes, drives AWD in Wyoming, takes pictures, and writes long blog posts and does xizquvjyk.
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