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What PCSK9 Is Telling Us About Drug Discovery

Friday’s news about the real-world effects of PCSK9 drugs continue to reverberate. It’s worth going into the topic again, but from a wider view of genomics-driven medicine, because this is currently one of the biggest strategies for drug discovery in the industry.

The reasoning behind this is pretty compelling. If you comb through the human population, you’re going to find a lot of genetic variation. Some people are going to have loss-of-function mutations, and some (probably fewer) will have gain-of-function ones (it’s generally easier to mess a protein or pathway up than it is to make it work more than it already does). If you can assign these mutations to various phenotypes in the people who carry them, or alternatively, if you can spot various interesting phenotypes and work back to particular mutations that brought them on, you have data that cannot be obtained any other way. You can generate animal genetic models all day long (and people do), but no one’s going to deliberately produce crops of human babies with selective gene alterations just to see what happens. Nature, though, has run such experiments for us.

That, by the way, includes embryonic lethal mutations (which is what you get a fair amount of the time when you do knockout gene animal experiments). A good number of miscarriages and failed attempts at pregnancy are likely due to such mutations, although these studies are still in their early stages. But looking at living adults still gives you plenty of genetic data to deal with, since (at a fine enough level) every single one of us is a mutant compared to someone else. There are, of course, a number of rare diseases that are absolutely driven by genetic mutations, often in a single glaring important unmissable gene, and these are the subject of a lot of interest these days. The rare-disease model is that if you can address these, the small (often extremely small) patient population can be offset by a very expensive drug, so long as said drug has major meaningful effects. And the chance of getting such effects is improved greatly by knowing exactly what kinds of cells to screen in, which exact patients to enroll in your clinical trials, etc. (The offsetting factor is that the drug targets suggested by many (most? all?) of these rare disease can be very difficult to attack by traditional drug discovery means, so you may increase your chances in the clinic at a cost of decreasing your chances of ever getting there).

But outside of the obvious Mendelian diseases, the great majority of such mutations are silent, or nearly so; the challenge is to pick out the meaningful ones. That is nontrivial. GWAS (genome-wide association studies) have been run in all kinds of populations, comparing patients with a known disease versus controls, in the hopes of picking out such mutations. It is a fearsome statistical challenge, with many opportunities to get things wrong, because there are very few mutations that have a large effect (and the patients with such mutations tend to be very rare). Most of the time, what you pull up is a net full of genes that seem to have some association, but none of which can be said to be causative (or protective) on its own. The hope in the early days was that we’d find some heavy-duty signals for drug discovery against things like Alzheimer’s or diabetes, but there just aren’t many such discoveries to be had. For every disease that has a real genetic smoking gun (like the prototype genetic disease, sickle-cell anemia), there are far more of them that have fuzzy multivariate changes in relative risk, at best.

But PCSK9 by itself is indeed meaningful – from a drug discovery standpoint, it’s probably the most actionable of the mutations discovered by modern sequencing. The handful of patients who are double-recessive for nonfunctional PCSK9 have extraordinarily low levels of LDL (the so-called “bad cholesterol). You may know your levels from your own blood work, but whatever they are, I’ll bet that your LDL isn’t (say) 14, which is what you’d see in a human PCSK9 knockout. These patients also have greatly reduced chances (up to 90%) of heart disease versus “normal” human controls. It’s no wonder that the industry jumped on these results as soon as they came out.

Jumping on them wasn’t all that easy, though. PCSK9 is one of those (many) targets that doesn’t have a small-molecule binding site on it that controls its function. The most straightforward way to lower its functional activity was to raise an antibody against it and use that as a therapy. These days, a significant portion of the best-selling drugs in the world are antibodies, and that number has done nothing but grow over the years. Several companies were able to come up with good PCSK9 antibody candidates, and Regeneron (joined later by Sanofi) and Amgen made it into the clinic first. Pfizer was there as well, for some time, but had to drop out of the race due to a problem that shows up in the antibody business – raising immunity to the therapeutic antibody itself. It’s rather hard to predict when and if that’s going to happen, as Pfizer’s example shows – they certainly wouldn’t have plowed ahead into such large trials if they’d known that would happen to them.

But as with any drug target, you have to ask whether or not you can hit it to clinical effect, but also what the size of the results will be once you do. It can be a bit like the old story about the guy who’d lost three cars while betting on filling inside straights in poker – twice because he hadn’t made his hand, and once because he had. The human data from PCSK9 looked pretty compelling, though, so the results of the first major outcomes trial (which Amgen reported on Friday) were eagerly awaited. And awaited not only by the medical community, but by insurance companies, because the newPCSK9 antibodies present an unusually stark contrast in costs compared to their alternative (cheap generic statins). Are they worth it? A lot of prescriptions for them are getting rejected by insurance companies, and Amgen is arguing that these rejections are more arbitrary than evidence-based.

That’s where the arguing is now, because the Amgen study, while successful, was not all that compelling. Yes, the relative risk fpr the composite cardiovascular endpoints used in the study went down, but not by as much as observers were hoping for (15% reduction versus 20 or 25%). And when you get down to overall mortality, there was no change at all, which has to be a disappointment. Amgen has been arguing that this was a relatively short study, and that the first measurements were also taken at a relatively early point in the treatment, and that the overall trend is for better numbers as the treatment goes on (which may well continue). But while these points may be valid, it’s a little rich for Amgen to be making them, because they designed this trial themselves, presumably to generate the most compelling results in the shortest amount of time. The fact that they’re having to make such arguments at all is a sign that the trial definitely did not come out the way that they’d hoped – you can be sure that the plan was not to have to say “Well, gosh, it’s really not bad if you look closely”.

So here’s a big question: did the genetic basis for the whole PCSK9 discovery and development effort lead people down the wrong path? Given the human mutation data, should we have expected better data? I’d argue, from Amgen’s trial design, that they did indeed expect more than they got. Recapitulating a true genetic knockout pharmacologically is not easy. An antibody is probably your best shot, at least under present conditions, but it still isn’t going to flatten things down like a defective gene will, and perhaps that’s what we’re seeing here. Update: and keep in mind, having a gene knocked down all through development is never going to be quite the same as hitting that same pathway in an adult.

There’s some irony here, because the effect of statins on overall mortality and morbidity seems to have more going on than just their effect on LDL. Statins have a number of other effects in humans, some beneficial and some not, and some of the beneficial ones are not well understood. So we have a classic attempt at a targeted small-molecule drug that works better than it should, probably because it’s not quite as selective as planned, versus an antibody, which is probably very selective indeed, but may not be quite delivering on its promise. That’s the drug business for you – and note that determining both of these has taken a great many years and a great huge pile of money, time, and effort.

What does this tell us, then, about genomics-based drug discovery? PCSK9 is about as compelling a story as we’re likely to see in this space, and if it has indeed come up a bit short, that’s food for thought. To be fair to Amgen, they may well be right about the continued improvements over longer-term therapy, in which case this story may have a better ending. But the slam-dunk game-winning ending is already gone. That may be the main lesson we can draw for now – here’s a terrific case, and it still didn’t blow everyone away when it finally got to multiyear human therapy. Everyone who’s following genetic-based clues to human therapy (a big crowd indeed) should keep this in mind.

47 comments on “What PCSK9 Is Telling Us About Drug Discovery”

  1. bhip says:

    I wouldn’t leap to any conclusions re: the value of human knockouts for picking targets in drug discovery.
    The 15% reduction in the relative risk for the composite cardiovascular endpoints was in pts already on a high dose statin- their cholesterol levels were fairly well controlled in the absence of the PSK9 ab. I wonder what the benefit would be in the absence of statin co-treatment (this would be the valid comparator to the human knockout).
    The other variable that is different in the study vs. the human knockout is time. I also suspect that with longer treatment times, the benefits of the ab will be more apparent. Classic pharma thinking re. clinical studies- quickly & efficiently get a wrong (or incomplete) answer.

  2. Algirdas says:

    So, when is vaccine going to be available? Vaccinating newborns seems like the way to go.

    1. SW says:

      Vaccinating newborm against their own protein? That’s not how vaccine works.

      1. Algirdas says:

        Would you care to enlighten me precisely how this vaccine works, then:

        I mention newborns specifically to make the anti-PCSK9 intervention most similar to the genetic knockout: a population of people with no PCSK9 present in their bloodstream throughout their life histories. Vaccine still leaves developmental effects untouched, of course, but this will have to wait until practical human engineering arrives on the scene.

        1. NJBiologist says:

          Over the years, a number of vaccines have been prepared around autoantigens. Zona pellucida antigen is a long-running favorite (vaccines would be contraceptive). However, I don’t think any have yet made it past monkey research. I think the usual counterargument is a generalized worry about an autoimmune response.

          1. Derek Lowe says:

            Yeah, no one wants to be the first to set off something hideous in the clinic. . .

        2. Some idiot says:

          This is way out of my area, so it is likely that ignorance will abound in this post. But…

          I take your point 100 % about knocking out the protein early to more closely mirror the knockout. The same thing occurred to me. However, it is something that I would be cautious/nervous like hell about, since we now only have a relatively small amount of data on the “mab knockout”. Are there any long-term problems? It would be a bit tragic to find out 20 years later that it caused something drastic that wasn’t immediately apparent…

          One could argue that the “wild type knockout” shows that this is not the case. However (and here I am so far out of my depth that a snorkel will not suffice…!) what if those with the “wild type knockout” had other compensating changes (quite possibly a range of them, i.e. not readily visible to analysis), which negated (largely or totally) any negative effects?

          The short version is that it would need really, really good long-testing to make sure that it is ok first. It is one thing to silence with a mab, since you can just stop taking it if there are serious side effects. But if you make a vaccine against it, well, you are permanently turning off that particular light.

          The short version: on the basis of what we know now (and are likely to know in the course of the next 10 years or so) would I give such a vaccine to my child? No bloody way. And I should add that I am actually very much pro-vaccines…!

          1. Eric says:

            I’m also not an expert in this area but your comments seem on-point to me. One also has to ask – who would ever pay for, conduct, and analyze a study like this? Even in at-risk populations CVD rarely appears before the 40s (typically much later). Immunizations in newborns would require 40+ plus years to see actual benefits on hard endpoints although LDL reductions could be observed early.

        3. AC says:

          An immune response could also kill the cells producing PCSK9.

    2. Metacelsus says:

      Or in the more distant future, gene editing to completely knock out PCSK9.

  3. ScientistSailor says:

    Derek, do you think the genetic validation for PCSK9 is better than for NaV1.7?

    1. HTSguy says:

      The NaV1.7 story is much more complicated and indirect than you might initially suspect:

  4. anon says:

    “PCSK9 is one of those (many) targets that doesn’t have a small-molecule binding site”

    We may be right saying so by looking at the crystal structure but does it mean a small molecule will never bind? A conformational change in the protein?

    1. anon also says:

      While I do not speak for Derek, I would presume that “does not have a small molecule binding site” Is short for “Current research indicates that a protein activating/deactivating small molecule binding site has not yet been identified, and based on the scope of the research done to date it is unlikely that one will be identified in the near future. That does not exclude the possibility, of course, but current signs point to no”

      1. Argon says:

        “That does not exclude the possibility, of course, but current signs point to no”

        Indeed. The Magic 8-Ball for drug discovery research makes for cloudy predictions.

      2. Toby says:

        I thought Pfizer had a small molecule against PCSK9 that lowered LDL in animals, see link above.

  5. road says:

    Technically, PCSK9 is a serine protease that requires its catalytic activity for processing and secretion. If you could block that with a small molecule it could work. But many have tried and nothing’s worked yet…

    1. Derek Lowe says:

      I didn’t have time to go into this morning, but that’s the thing – for the most part, coming up with hits against a serine protease shouldn’t be all that difficult (if you’re willing to try mechanistic inhibitor head groups). But no one made much headway against PCSK9, from what I can see, which argues that it’s a tough one.

      1. David Borhani says:

        PCSK9 is not your usual serine protease. Its only known substrate, if I’m not mistaken, is itself.

        PCSK9 auto-proteolyzes once. Let’s say your serine protease inhibitor is bound, preventing PCSK9 maturation. As soon as the inhibitor unbinds, bingo, PCSK9 chews off its pro-peptide, and the inhibitor is no longer “active.”

        1. Hap says:

          Doesn’t that argue for a covalent inhibitor, though? If PCSK9 can’t get off the lock, it won’t be able to start itself up. On the other hand, that means that lots of the normal covalent binders won’t work (eventually, you can retro-Michael, for example, and once it starts, you can’t stop it) and if a covalent binder is that permanent, it has to be really selective or there’ll be trouble.

          1. David Borhani says:

            Yes, Yes, and Yes. Therein lies the rub…

        2. road says:

          All good points, and correct AFAIK. I was merely refuting the point that Derek made that PCSK9 “…doesn’t have a small-molecule binding site on it that controls its function.”

  6. HTSguy says:

    To make life even more complicated, the rest of your genetic makeup changes the effect of even severe Mendelian childhood phenotypes:

    doi: 10.1038/nbt.3514

    1. HTSguy says:

      typed too fast: genotypes, not phenotypes

  7. Morten G says:

    It isn’t that hard for nature to get a gain-of-function mutation but current sequencing technology pretty much ignores them (to the best of my knowledge). There are genes with copy number polymorphism; more copies of the gene, more functional protein.

    1. Anon2 says:

      Not sure if I completely understand this comment: are you implying that most gain-of-function mutations are due to copy number variation (CNV)? I don’t think that is a common viewpoint. In any case, NGS readily detects CNV.

    2. MrRogers says:

      Most geneticists wouldn’t call a CNV a gain-of-function mutation. Generally you reserve that for (at least) expression in a different place/time. More commonly, you’ll see it refer to mutations that result in new regulatory connections (loss of inhibitor binding or gain of scaffold binding are both common) or, occasionally, new enzymatic function.

  8. Barry says:

    Let’s examine the assertion that PCSK9 is the most compelling case for a drug target from sequencing. “There are, of course, a number of rare diseases that are absolutely driven by genetic mutations, often in a single glaring important unmissable gene, and these are the subject of a lot of interest these days.” Among these must be counted CML (chronic myelogenous leukemia). A single mutation (forming the “Philadelphia Chromosome”, coding for the unnatural kinase BcrAbl) is cleanly and uniquely causal to the disease. That’s a level of certainty we rarely see. And of course Gleevec–although it was tested and launched as an “orphan drug” for a rare disease–has been worth >$billion/year for a long time.
    The mass market for a PCSK9 blocker is still conjecture. BcrAbl blockade is the shining paradigm for a human mutant driving Drug Discovery.

    1. Derek Lowe says:

      Good point – I should make it more clear that my statement applies to non-small-market conditions.

    2. Mol Biologist says:

      Barry, I do like how your logic fly. A couple years ago I already discussed it at Linkedin Digital Health Group regarding drug-able potential of PCSK9. IMO the drug would not have any big effects in clinical population either for heart disease neither for stroke. Genetic isolate of Tibet Highlanders have a missense mutation in the EGLN1 gene, which encodes prolyl hydroxylase 2 (PHD2), and Tibetan adaptation to high altitude becomes the fastest process of phenotypically observable evolution in humans.
      However, it is unlikely that only this single mutation could lead to the mechanism of adaptation. They have low level of hemoglobin in blood and do not care about oxygen changes as much as the rest of human do. It is also proved that clinical impacts of small molecules or PHD inhibitors are quite limited. So, in case of PCSK9 it is a high chance that it is derived from specific population or genetics isolate. The carriers have low LDL due to other reasons which make them do not care about lipids as much as the rest of human do.

    3. Mol Biologist says:

      Barry, your logic is flying on right pass. Similia similibus curantur. I think at least one orphan disease may be treated by same antibody. But for sure, it is not Familial Hypercholesterolemia (abbreviated FH),

      1. Mol Biologist says:

        And for sure not for Prader-Willi syndrome. Patients have already low level of PC1 (encoded by PCSK1) due to prolonged deletion and lack of chromosome region with critically important players mostly of those are ncRNAs.

  9. Amg-anon says:

    DL – for all of your useless pontification. Amgen shares back upto $ 180 and rising. Take that and think about the health care business as a whole.

    1. c says:

      Is this comment satire? AMGN has not recovered from Friday’s 10 point loss in the numbers I am looking at.

      1. NJBiologist says:

        Maybe we found out who Agilist works for now…?

        1. Hap says:

          No…sounds more like a bitter daytrader. Agilist was much better at management-speak.

    2. Derek Lowe says:

      If you know of a place where I can sell AMGN at $180, please let us all know, because right now I can buy it for $169 and change.

    3. Jim Hartley says:

      A most unwelcome comment to an otherwise rational discussion.

  10. Amg-anon says:

    Chill out. Like dropping 10 points is a big deal.

  11. Amg-anon says:

    Chill out. Like dropping 10 points us a big deal.

    1. drsnowboard says:

      so the “$180 and rising” was just your internet being 5 days slow? Good luck with your day trading career

    2. Duane Schulthess says:

      It is a big deal if PCSK9 was supposed to be your next $10 bil asset! What else does Amgen have in its pipeline? This case is a warning shot across the bow of the industry, and I get very concerned looking at the gene therapies emerging targeting alternatives for insulin or any area with effective cheap generics. You can’t beat free.

  12. Me says:

    I don’t know anything about distribution (In the PK sense) of antibodies – any good info regarding PK of the mAbs vs physiological distribution of PCSK9?

  13. PrivilegedScaffold says:

    While it maybe an oversimplification to state that scalable chemistry is cheaper than scalable biology (in terms of producing small molecules vs. antibodies) it feels like from a financial viability perspective this is a case where the drug companies should have taken the final drug price in to consideration when giving this project the greenlight. With cheap and effective statins on the market for decades the PCSK9 inhibitors were already fighting a huge uphill battle in terms getting insurers to pay for it. It seems like Pharma-giants failed to take this in to consideration and now they’re paying the price.

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