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Cardiovascular Disease

The Genomics Revolution Shows Up Late, But Shows Up

Robert Plenge has an excellent overview of the PCSK9 story up on his site; I recommend it. His take may sound different from mine at first, but I think we’re actually in agreement on a lot of important points. I said that “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,” but Plenge’s focusing more on the first half of that sentence. And he’s right about that – this target really is the best story we have so far in what I think we may start calling the new genomics era of drug discovery.

That era has been a while getting off the ground. Longtime drug researchers will remember that it was all supposed to take off like a rocket back around 1999 or so, when the human genome was sequenced. That was indeed a weird period, because a lot of people figured that if you hadn’t boarded said rocket in time, you’d find yourself stranded on a desolate planet bereft of all drug targets and all hope. Some rather silly decisions (in retrospect) were made on that basis, but the fear was very real, as were the hopes on the other side of the issue.

But as that PlengeGen post details, PCSK9 is indeed the real thing, and just what people were expecting to find back then. He’s right that the gene was basically unknown before 2003; no one had studied it and no one cared, because no one knew what it did or that its function could be important. From that flat standing start, a drug was on the market in 11 years, which by real world drug industry standards – particularly in cardiovascular disease – is about as fast as we can possibly go. People outside the business might well look at that and be aghast (in fact, that seems to be the reaction driving a lot of the “Burn down the FDA” sentiment). But it wasn’t the FDA that made this take 11 years; it was (once again) the flippin’ science.

If you take someone through the whole process, showing them what had to be done at each step and what the issues and pitfalls were, the timeline becomes a lot more believable. The first report of PCSK9 mutations in humans were gain-of-function, which (as mentioned before) is unusual. The people with these mutations have far worse LDL profile than normal, and that’s an interesting result, but it by no means guarantees that loss-of-function mutations would turn around the other way and have a beneficial effect. The report a couple of years later of just those sorts of mutations is what really jump-starting things – that was proof that something good could happen by knocking down PCSK9 somehow.

Then you get to the “somehow”. Do you do it with a small molecule? The PCSK9 protein has a serine protease functionality in it, so people thought that it might be approachable that way, but for many reasons that just didn’t work. Time spent, and that took care of the plausible small molecule approaches, so it’s on to antibodies. Then you have to take those antibodies, once you’ve generated a good one (which doesn’t happen overnight) and validate the whole approach in one of the animal models for lipoproteins. Takes time, and you can’t skip it or speed it up much, not and get actionable data that’s worth starting a human clinical program around. A big cardiovascular program is going to chew up many hundreds of millions of dollars in the clinic at the barest minimum, so you’d better be sure that you’re making the right call. The first humans didn’t get dosed with such an antibody until 2010, and that’s not because people were dragging their feet, and the first Phase III study results didn’t get generated until 2013, which for a long, slow process like cardiovascular disease is just about as fast as you can go. And even then, those numbers didn’t address real-world outcomes (mortality and morbidity); we only got those this year. If you can find a way to speed that up and still generate something meaningful, go collect your billion dollars. Frankly, a lot of the calls for FDA reform start to sound to me like “But we don’t care about meaningful”.

PCSK9 therapy was approved as quickly as it was (as the Plenge article details) on a surrogate endpoint: LDL levels. We’re fairly sure that those are connected to cardiovascular disease, but lowering them through a different mechanism (like this one) might or might not partake of the benefit that we’re seeing. You don’t know. That’s what the outcomes data this week addressed, and it’s true that the big picture is that yes, people were right – targeting PCSK9 really does work the way we thought it did. (The flip side, which I emphasized in my own post, was that it may not be working quite enough, compared to expectations). Surrogate endpoints are going to be crucial for slow-running diseases in the clinic, and this is one of the best example we have so far. Try finding one for Alzheimer’s, though, if you have few spare billions and a brave heart.

So there’s a case to be made that this target really is the dawn of the era that we all thought was dawning years ago. I can appreciate the celebratory tone of Plenge’s post, but at the same time, if you’d told people back in 1999 how things had worked out, they would likely have been (at some level) horrified that (a) it took until the mid-2010s for something like this to happen and (b) that this is the main example that we can point to, and that the landscape is not littered with similar stories. That brave new world is not the one we live in, though, and for the one we’re in, this is a good result and we should make the most of it.



28 comments on “The Genomics Revolution Shows Up Late, But Shows Up”

  1. the next big thing says:

    One point worth noting is that assuming there were no commercial barriers or adoption or safety issues, ie everyone in the world could safely pin their LDL to 40, then cardiovascular disease would still be the leading cause of human mortality.

    LDL is now for the first time shown to be a risk factor which when treated gives therapeutic benefit. But it is by no means the complete story of cardiovascular disease.

    1. bhip says:

      A very reasonable observation. However, even if the LDL story was the end all & be all, the pts being treated with PCSK9 ab in that study were already on statins & their LDL levels were fairly well controlled (~92 mg/deciliter).
      As we know, (like everything else in life), successful drug development is about timing. If the PCSK9 ab arrived before the statins, they could have been a huge hit. As it stands, in the face of largely effective generics, the LDL ship has sailed for its largest pt. population. Another example of this axiom, hepC drugs still in development are dropped in the face of very efficacious drugs already in the market place which are essentially curing the disease,

  2. anonymous says:

    When it comes to lowering your LDL, how “low” is too low? I mean I worry if your LDL goes low, is there any repercussions or we do not know? We know that when your sugar goes low you have lightheadedness and other symptoms. Will someone enlighten me on this?

    1. Peter Shenkin says:

      I believe Derek’s earlier post mentioned that humans with the knock-out mutation have a low incidence of cardiovascular disease but no known problems of the sort you’ve described. But of course, they may have compensating mutations elsewhere that takers of this drug do not have. We don’t know.

  3. Emjeff says:

    Derek, I’m not sure you’re completely on-base when you say the FDA is not to blame for an 11 year delay. That would only be true if you believe that every regulation that FDA promulgates is absolutely necessary, and that FDA reviewers are completely competent to evaluate new science. I, for one, do not believe that at all.

    1. Derek Lowe says:

      The earlier stages, though (the years leading up to the clinical trial) were not regulated by the FDA. I mean, there are such things as GLP/GMP, but you need something like that just to make sure that your manufacturing is legit.

    2. Eric says:

      Evidence for your belief? If you don’t have any, then your assertion has no more value than mine that the FDA is the tightest organisation on the planet and accelerates drug discovery.

    3. Loren Ipsum says:

      An 11 year “delay”? The gene’s function was only discovered in 2003. From that “flat standing start” it took 11 years to get a drug into the market.

      This is a phenomenally rapid time, as Derek noted (as as anyone with a modicum of experience in molecular biology would tell you). What could the FDA have POSSIBLY done to speed this timeline up?

  4. JJ says:

    It’s been pointed out before, but I haven’t seen a definite answer: what do people make of the lack of any improvement in risk of death?

    Compared with a substantial decrease in both heart attack and stroke, that seems odd. And raises the question of whether that heart attack/stroke risk is somehow unlinked with deaths – or whether the drug is generating some other, subtler hazard that offsets reduced deaths from heart attack and stroke?

    1. Barry says:

      The experiments-of-nature (human homozygous mutants) have had low (sometimes very low) circulating LDL concentrations from birth. The clinical subjects have had their levels depressed into the “normal” range for a matter of months after years in which they were uncontrolled. It may take years of treatment to cut into the mortality numbers.

      1. JJ says:

        Sure, there’s a difference between PCSK9 (or any target) suppressed from conception, and suppressed for a few years late in life. But the question then is, why would we see a sizeable effect on heart attack and stroke, but none at all on deaths?

        A disconnect between LDL and deaths is one thing. A whole string of other things have to happen for LDL to translate into survival benefit. But reduction in heart attack, or in stroke, ought to reduce deaths in itself.

    2. Anon says:

      Risk of death will always remain at 100%.

  5. Imaging guy says:

    Another example might be the discovery of CCR5 antagonist (Maraviroc) for HIV infection. People who has got homozygous mutation in CCR5 gene (found in Caucasians but not in Africans) are resistant to HIV infection (1,2). However, the drug does not produce as dramatic effect as PCSK9 inhibitor. Since a patient (“the Berlin patient”) with HIV infection and leukemia who received bone marrow transplant from a donor with CCR5 mutation was cured of HIV (3), I guess Maraviroc is not effectively blocking HIV attachment to CCR5.

    1. another guy says:

      The reason maraviroc was not widely used is due to tropism. Often the HIV-1 virus is only able to bind to the CCR5 co-receptor, however sometimes the virus has the ability to bind to the CXCR4 co-receptor and basically find a way around maraviroc. So the physician has to order a tropism test first to see if the HIV-1 in the patient will be susceptible to maraviroc. Other classes of antiretrovirals do not require additional testing other than the standard resistance test at baseline. Checking off one more test on the form may not seem like a big deal, but in practice, it makes a big difference in how drugs are used.

  6. Anon says:

    Just wait till you see the impact of Big Data in 10 years: “Is this all we have to show from it???”

    1. Anon says:

      The one hope is that Big Data will be cheaper (relatively) than Genomics.

  7. Mol Biologist says:

    Back to the roots. Initial screening which was done by researchers from the University of Texas Southwestern Medical Center in Dallas did show reduction of LDL by almost 30% only for heterozygotes carriers from Afro-American Ancestry. In whites reduction of LDL level was twice less and no loss-of-function*? But most important homozygous or two alleles carriers with extremely low LDL (40 mg/deciliter) were found only in African Females one in USA and one in Zimbabwe. IMO the founder effect of this rare mutation (loss-of-function) would have desired phenotype only with specific genetics/genomics background. And again carriers of mutation* have low LDL due to other reasons which make them do not care about lipids as much as the rest of human do.

  8. Curt F. says:

    he PCSK9 protein has a serine protease functionality in it, so people thought that it might be approachable that way, but for many reasons that just didn’t work. Time spent, and that took care of the plausible small molecule approaches, so it’s on to antibodies.

    My mind is still reeling from a very implausible-sounding paper that reports an amazing thing: a small-molecule inhibitor of PCSK9 translation. Pfizer folks apparently found a small molecule that specifically stalls the translation of a nascent PCKS9 peptide while it’s still coming off the ribosome.

    1. Mark Thorson says:

      Wow! What an interesting approach. Think of all the mAbs that might be replaced with oral drugs. The potential is staggering. Pfizer sure got their money’s worth on this project. I wonder how their molecule can be so specific? I wonder what limitations this has — if you look hard enough, can you find something which will do this for amyloid precursor protein, presenilin-1, etc.?

    2. Mol Biologist says:

      Dr. Hobbs and Dr. Cohen did outstanding work and they founded 32-year-old aerobics instructor from a Dallas suburb — healthy, college educated, with two young children. Nothing out of the ordinary, except one thing. Let’s switch from genomics and look to biochemistry. I will point one thing which may be out of your current scope but can you imaging if this lady is not “loss-of-function” carrier but instead she has two functional alleles, This biochemical activity gave her unbelievable advantage to be healthy despite on everything. Which we are or general population of modern people mostly lost this functionality under evolutionary pressure.
      French carriers have worst phenotype/genotype and we are in the middle of “loss-of-function” so we do have pretty reasonable habitus until we aged on screwed up our lifestyle. How this small molecule may approach us for healthy living? But if we picked up a difficult scenario and try to understand the biological mechanism of action, we can apply these antibodies/knowlege in rare diseases patients or create new working medications.
      Anemia in beta thalassemia patients (genetic isolate) is horrible side effect but there is an advantage to resist infection of malaria plasmodium.
      Same story with high LDL levels yes, it is a side effect but who knows what advantages we got?

      1. drsnowboard says:

        Outstanding gibberish

        1. ThomCat says:

          I read that for content, not grammar. Not smooth, but readable.

          Now, bearing in mind that I’m a lay observer and not a chem, bio, or genetics edu or industry participant, could someone tell us what’s wrong with MolBio’s content?

  9. Mol Biologist says:

    “If you want to tell people the truth, make them laugh, otherwise they’ll kill you.”

  10. Insilicoconsulting says:

    Anyone who had a good genomics background or simply a rational mind never expected miracles in 1999-2000. I was privy to discussions about obtaining Celera draft data due to a push by the “Top Leadership” who indeed had this fear of being left out.

    But sense prevailed and we sensibly decided not to pay millions of dollars for an early peek. Overall though the target based approach in general has been under fire, thus genomics too. Better late than never.

  11. Chris Phoenix says:

    I’m not sure whether this will be just a complicated way of saying “I don’t care about meaningful,” but it seems likely that clinical trials would cost a lot less with a less careful FDA. That would allow more drugs to be tried, and tried earlier.

    “Takes time, and you can’t skip it or speed it up much, not and get actionable data that’s worth starting a human clinical program around. A big cardiovascular program is going to chew up many hundreds of millions of dollars in the clinic at the barest minimum, so you’d better be sure that you’re making the right call. ”

    How much faster would it have gone, from the start of the animal validation step, if a cardiovascular program could be run for tens of millions?

    What would you lose in a bargain-basement cardio trial? You’d lose statistical power, for sure. You’d probably lose some monitoring for side effects. On the other hand, in a mythical world where there was no regulation and everyone was well-intentioned and competent, if the result of your small cheap trial was “can’t tell yet, but it doesn’t seem to hurt anything” you’d just add more people until you either decided it was a bad bet, or got a statistically significant answer.

    Consider that, in this mythical world, there probably wouldn’t be a need for formal “phases” of the trial process, with separate design process and approvals for each phase. How much would that speed things up? What, if anything, would be lost?

    1. Nicholai says:

      In your not so mythical Trump FDA, you have a lot more false positives, and a lot more people exposed to nasty safety events that were undetected in small populations. The FDA for the most part does a good job and their feedback is mostly reasonable. After what Pruit did to the EPA, I shudder to think how much snake oil will be approvedin the next 4 years . Be careful what you wish for you might get it

      1. Chris Phoenix says:

        Please don’t make this about politics. My question isn’t political.

        I’m well aware, as I’m sure every reader here is aware, that a faster less careful FDA would mean a tradeoff between more bad drugs and faster discovery and approval of good drugs. My question was asking for quantification of one factor of one side of the equation.

  12. Big Fresdie says:

    I can’t figure out how a genetics story, with contrasting loss and gain of function mutations, has anything to do with genomics. I get it, anytime a gene is implicated we have to say genomics or Francis’ 70 billion $ bet on “post genomic sciences” looks bad…but PCKS9 is an old fashioned human genetics story. For heavens sake it was discussed two editions ago in Thompson and Thompson! No GWAS in the tank.

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