Avila: “Bond, Covalent Bond”

Posted in Portfolio news

Jus Singh doesn’t look much like James Bond, but he’s nearly as cool (see pic below). He’s the founder of Avila Therapeutics, a company we’ve backed that is focused on the discovery of targeted covalent inhibitors. When he and Roy Lobb started the company five years ago, it was abit of a crazy idea: while Big Pharma medicinal chemists hate irreversible covalent drugs (in large part, irrationally), if Avila could make them safe and selective in a systematic way we could open up a huge, relatively underexplored “drug space” with differentiated attributes.  In principle, Avila aspired to overcome the cultural/psychological bias against reactive warheads in Big Pharma, a bias that essentially prevented the latter from being willing or able to tackle the space.

Well, Jus and the team at Avila are well on their way to doing that.  In addition to making great progress on both their platform and pipeline, they have now published a great review of the field of covalent drug in Nature Reviews Drug Discovery.

The review summarizes the “resurgence” of covalent drugs and highlights their unique properties.  Here’s my crack the Cliff Notes version:

  1. Covalent drugs represent a significant portion of the current pharmacopeia.   3 out of 10 current blockbusters are covalent drugs, e.g., Plavix.  The top 26 covalent drugs have sales of >$30B in the US alone.  100′s of millions of prescriptions for covalent drugs are written every year.  So despite being traditionally despised by Big Pharma, there are lots of cases of safe and effective covalent drugs across antibiotics, oncology, gastro, CNS, and CV.  Importantly though, most were found by serendipity and screening rather than by design – Avila is hoping to change that.
  2. Unlike the reactive compounds that gave covalent drugs a bad name, today’s targeted covalent inhibitors utilize soft reactive warheads: weak electrophiles that become locally reactive in the context of the topology of a binding site.  In some ways, a common pre-requisite of a TCI is have a potent reversible scaffold to weaponize.
  3. Covalent, irreversible inhibitors have several key advantages over reversible drugs that lead to differentiated profiles:
    • Potency. TCIs tend to have very high ligand efficiencies (achieving high potencies with low molecular weights) because of their covalency.
    • Selectivity.  Because TCIs engage very specific amino acids in precise locations in the binding pocket, small changes between even close homologues can lead to exquisite selectivity.  For instance, the presence of a cysteine in specific location in one isoform can be strategically targeted to achieve selectivity vs other isoforms.  In addition, since a TCI will have an infinite off-rate, even reversible binding to other targets will diminish over time as the irreversible target acts as a ‘sink’ to drive selectivity further.
    • Pharmacodynamics.  The PK-PD relationship is decoupled with TCIs, so overall drug exposure in the plasma/tissues can be greatly reduced.  If inhibition via covalency is driven by Cmax, the PK can be short but still maintain once-daily dosing with less exposure.
    • Resistance.  Irreversible inhibition can help overcome weak or transient binding to drug-escape mutants, and Avila has shown potency with lots of the known clinical-resistance mutations.  Many of the latter increase the off-rate of reversible inhibitors; that obviously won’t work with an irreversible.

TCIs have enormous promise across a range of disease areas, and Jus’ recent review captures it well.  Its only a matter of time before Avila’s approach attracts a bunch of emulators.

* The title of this blog should be properly attributed to Avila and Jus – they actually coined the “Bond, Covalent Bond” tag line

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  • Mkarbarz

    There are plenty of targets that are open for this method. DPP-4 has a few compounds in development, as well as FAAH.

    Immunogenicity, however, is one area that their R&D will really need to tackle. Its one thing to do a SAD, or MAD. However, what happens to the covalent modified protein, and how is it cleared? Proteases may break up the protein, but conceivably, you now have a short peptide modified with a portion of a small molecule.

    Finding that high exposure, highly cleared covalent modifier is also attractive as well. Your cmax might be high enough to achieve inhibition, and then its rapidly cleared. In this case, the target is still inhibited till its cleared or the protein is turned over. Pretty attractive in some cases. Nice inhibition along with low potential tox.

    Some pharma companies are not that aggressive in regards to pursuing covalent modifiers, so its nice to see Avila try and fill this space. The premise is rather promising.

  • LifeSciVC

    Thanks Mkarbarz. Agree that immunogenicity is something to watch/study; I don’t believe any of the irreversible EGFR-kinase inhibitors have seen this (nor has Plavix to my knowledge). Do you know where this has been a real rather than theoretical issue?