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Clinical Trials

Crossing Fingers

I’ve mentioned it in passing before, but it bears repeating: this is a really unusual moment in drug discovery. We have simultaneously more new modes of action for therapy coming on in the clinic than I can ever recall, and some older ones are getting reworked to join the action. This short overview is a good look at the topic. Things that many of these have in common are new interfaces between small molecule organic chemistry and biomolecules. We still have a lot of enzyme inhibitors and receptor antagonist drugs out there, but these classic mechanisms (which, you will note, depend mainly on our ability to gum up the works in the right spots) are being joined by protein degradation, gene therapy (CRISPR and others), exon skipping, attempts to go after various RNA species, more non-active-site targeting of proteins, a new wave of antibody-drug conjugates, and more.

One way to look at these things is as a triumph of what we now call chemical biology. I have a slide deck that makes the assertion that chem-bio is the way forward in general, so I’m already biased toward that idea (and the fact that I work in a department focused on that stuff has something to do with it, too). But I think there’s a good case that the tools of that field, and the mindset behind it, are important factors. There are a lot more cellular processes that we can imagine targeting than we ever have actually been willing or able to.

To be sure, some of these represent yet more ways to gum up the works. But I think that drug discovery has always been biased in that direction, because we’re inside cells that have had a billion or two years to work out some very slick processes and tune them up to concert pitch. Stepping in and making these perform even better is a real challenge, whereas throwing a spanner wrench into the gears is much more feasible. That has tended to make the central problem of drug discovery “What process should we beneficially shut down?” This accounts for the number of bounce-shot double-negative mechanisms that you see in this business: what we want to do is activate Pathway X, but the way that we might manage to do it is to inactivate some inactivating mechanism (kinase Y or protease Z) and thus set it free. Drug development, often enough, consists of fashioning just the right size and shape of spanner wrench and flinging it just so into the bewildering mass of cellular machinery in order to bring a particular set of gears to a grinding, screeching halt.

Gene therapy is the outlier of that bunch – it doesn’t work through a small molecule agent, and it is generally aimed at directly restoring function. What it shares with the others, though, is a great deal of what can only be called novelty. We really don’t know what’s going to happen when we step in and try to rewrite some little strech of a patient’s genome, in the same way that we don’t know what’s going to happen when we give them a bifunctional molecule that targets some particular protein for degradation. People haven’t had these things done to them before. And if there’s one thing for sure in this work, it’s that we don’t know a lot of the pathways and connections out there in the cells yet. Doing things to human cells (and to human patients) that you’ve never tried before is a way to uncover some of those, and experience has shown that not all the things you uncover are good.

That’s a roundabout way of saying that I hope that these new therapeutic modes actually make it through. Having so many new mechanisms under development at the same time increases the chances that something unexpected and unwelcome will happen. That post the other day on idiosyncratic toxicity is an example, and that’s just one of many possibilities. Some of those we have seen before (but can’t anticipate accurately) and some of them are things that we will be learning about for the first time.

That’s most certainly not an argument to slow down or steer clear; it’s the cost of doing business in early-stage drug research. And there are worse problems than having a lot of new, interesting, and exciting stuff hitting more or less all at once. But I will be very glad to see more degraders, CRISPR attempts, RNA mechanisms and so on make it further into human trials without anything weird happening. We need these new shots on goal, and I hope that we can take then as cleanly as possible. This is a big moment – let’s hope it continues.


16 comments on “Crossing Fingers”

  1. Barry says:

    Recently, CRISPR/Cas9 has been modified to recognize/bind gene sequences w/o cleaving anything, but blocking translation of the targeted gene. It would be exciting to be able to silence or down-regulate chosen gene–products selectively, reversibly. But getting such a blocker into cell nuclei in vivo is still daunting. The quest for small-molecule modulators of mammalian transcription factors has been frustratingly unproductive to date.

    1. SP says:

      Good example of chemical biology thinking. The homing function of the endonuclease can be separated and used as a tool independent of the originally evolved function, which you can then pair with other tools to do steric blocking, CRISPRi, CRISPRa, base editing, etc.

  2. Peptide Robot says:

    You really have a way with imagery, great article.

  3. anon the II says:

    I’m having a hard time believing that they called them spanners in Arkansas. That sounds kinda British to me. We called “justables” in southeastern NC. As in “Hand me that justable, so’s I can tighten this nut”.

    1. Derek Lowe says:

      Probably heard them called “Crescent wrenches” more when I was growing up, actually. But somehow “throwing a spanner in the works” is the industrial-action phrase that comes to my mind. A more American version of the phrase might involve throwing a monkey wrench, but actual monkey wrenches are antiques in my book (as opposed to similar-looking pipe wrenches)

      1. loupgarous says:

        My dad died and left us a whole box full of plumbing and other home improvement gear, including a big old monkey wrench. We used it to turn the antenna mast (a long joint of steel pipe) when weather required we re-orient it for better TV reception.

  4. small is better says:

    Derek, you say:
    “Gene therapy is the outlier of that bunch – it doesn’t work through a small molecule agent, and it is generally aimed at directly restoring function. ”

    What about risdiplam, an SMN-2 splicing modifier for SMA. I understand this small molecule designed to increase and sustain SMN protein levels in CNS…

    1. Derek Lowe says:

      Not gene therapy, in my book, which would be rewriting of the underlying DNA sequence. This is more in the RNA targeting class.

  5. Anonymous says:

    Maybe it’s a disagreement over terminology, but not all gene therapy is “rewriting” an existing genome. Some of it is additive, by inserting a functioning gene into cells with mutated, not properly functioning genes. E.g., Luxturna adds a functioning RPE65 gene into cells in the retinal epithelium where it gets expressed and restores vision to patients with Retinitis Pigmentosa / Leber’s Congenital Amaurosis.

    But, a general comment about gene therapy: the popular press sometimes makes it out to be a 100% fix, but it is not. Response can vary greatly from 0% to almost 100%. In cases where success is only partial, small molecule adjuncts can still serve a purpose. (Had to get in a plug for small molecule organic synthesis!)

    (I’m putting a link to Luxturna in my handle. Read the warnings and adverse reactions.)

  6. Curt F. says:

    OK, I agree we get to call all that stuff “chemical biology” as long as I further get to stipulate that:

    1. the invention of X-gal and IPTG were some of the greatest inventions of chemical biology even though they were first synthesized long ago (in 1964 for X-gal).

    2. perhaps to this day the greatest chemical biology invention ever was the dideoxy terminator technique for DNA sequencing. Thank you Fred Sanger.

    (I get sick of hearing about how fields of science are so new, when far more often it is only the neologism that is new, while the underlying ideas have been percolating around for decades.)

    1. Joe says:

      You might also argue that Gram staining was chemical biology. The idea of using chemistry to make biological discoveries has been around for hundreds of years.

      1. Jop says:

        Yeah, I am forever confused where the difference lies between chemical biology and biochemistry, biological chemistry, biophysics, biomolecular chemistry, biophysical chemistry, synthetic biology, medicinal chemistry, molecular biology, biotechnology, or whatever. One or two years ago, Nature Chemical Biology asked scientists what chemical biology actually entails, and got so many different answers depending on the scientists’ background. The actual science is of course the same as it was before and doesn’t care what name we give it.

        1. James Millar says:

          My girlfriend is studying psychology, and I’m consistently baffled about where each of the sub-disciplines end, especially the ones with with “neuro” in there somewhere:

          [Behavioral] neurology, [clinical | cognitive] neuropsychology, [cognitive] neuropsychiatry, [cognitive] neuroscience, neuropsychoanalysis, etc etc.

          Many of those also have a permutation with pharma- as well.

  7. 10 Fingers says:

    Can I also add a moment of appreciation for the new times for “old school” targets?

    There are some generally well-characterized classes of enzymes (say, serine hydroplanes/proteases) that are definitely druggable and certifiably hard. No matter how compelling the biological validation, it doesn’t make the fruit hang any lower on those branches. Yet, each success obtaining such high-hanging fruit changes how we think about the orchard.

    Beyond that we are getting incrementally better at growing and harvesting that fruit, overall (if I may overtax the metaphor). Many scientific disciplines are getting progressively better integrated and capable of collectively getting to the answer to a simple question: is there a drug here? CRISPR may not be a therapy for disease X, but it might be the best thing to point you at one most clearly.

    It has never been a better time to validate a target or pathway, and decide what kind of molecule might serve as a treatment to best help a patient. It has never been easier for a small company to find a niche population with an unmet medical need for which a validating clinical campaign could plausibly be undertaken, and do so in an environment where much of the technical capability required is commercially accessible.

    With due respect to the justifiable cynicism that working in this field creates, it is a glorious time to live up to the privilege of being able to make new medicines for people who have nothing.

  8. Jb says:

    Just like to point out that ‘gene therapy’ also means ex vivo modified cells. Arguably, something like CAR T cells have been the most successful gene therapy out of them all, even much more so, one could argue, than viral based gene therapies.

    mRNA therapies are also classified as gene therapies even though they do not affect DNA.

  9. Kent Matlack says:

    What a wonderfully conceived and written piece, Derek. Keep them coming, please.

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