I have been writing this blog for some time (!) That occurs to me on seeing this article in Nature Reviews Drug Discovery on oral dosing of peptide drugs – I say that because of this 2002 post on the very same subject, at the time directed towards the then-still-somewhat-hot topic of Judah Folkman’s endostatin angiogenesis inhibitor (which was itself a peptide). I pointed out that such compounds have a rough time in development as oral therapeutics, and of course, they still do.
That new article goes into useful detail on why that’s the case, but fundamentally it’s because our digestive systems are completely focused on breaking proteins down into tiny absorbable pieces, and not towards letting intact peptides into the bloodstream. Digestive enzymes, mucosal barriers, the permeability of the various membranes involved, the biases of active transport mechanisms: the gut really does not want to let foreign proteins into the vasculature, for a lot of excellent reasons that have been under pretty hard evolutionary pressure since our distant ancestors first had anything like a gut. You’re fighting against all that when you want your protein drug to be an oral therapeutic, which is why there are very, very few of them.
The review goes into the various strategies that have been tried over the years – trying to enhance permeability (as always, a double-edged sword of a strategy), ways to harden-up the protein structures themselves, delivery devices such as intestinal patches and hydrogels, etc. And it lists several proteins that have had extensive work done on them, with insulin probably at the head of the group. An orally available insulin could be quite useful, and many people have taken a crack at it with no one making it all the way through yet. That’s actually a double challenge – just getting insulin as an oral agent is already a massive challenge, but even if you manage that you face the well-known trickiness of insulin dosing in general. The insulin response is very strong, very fast, and very brittle. One of the main ideas behind modifying the injectable protein over the years has been to try to mitigate those effects so that the dosing is smoothed out a bit into a more controlled longer-lasting form. All attempts to modify its dosing (oral, inhaled, what have you) have to contend with that behavior.
There is, though, a recently approved oral form of semaglutide, a GLP-1 agonist for type II diabetes that was first approved as a once-a-week injectable. It’s an engineered analog of GLP1 itself, acylated and modified to be resistant to cleavage by the DPP-IV protease, among other things. The oral form is a pill with a rather large dose of SNAC (sodium salcaprozate), a salicylamide-derived permeation enhancer. Its mechanism of action is still up for debate, and it probably acts via more than one, but it does indeed seem to enhance uptake of peptides. For semaglutide, this happens in the stomach (rather than the small intestine) and there’s a U-shaped dose-response – that is, you have have too little SNAC dosed along with the drug and you can also have too much, for reasons that are also not really clear. It needs to be taken with water, first thing in the morning in a fasted state, with no food for 30 minutes. There are some gastrointestinal effects in some patients, as you might expect, and there is variability both from day to day in individual patients and between patients, which means that physicians need to work out the dosing in each case. But the drug is effective and safe – no worse than the injected formulation and certainly more convenient to take.
So don’t just immediately assume that it’s impossible to get an oral peptide formulation. But don’t assume that the problem has been solved, either – SNAC and similar compounds have been around for quite a while now, and they are nowhere near the universal answer. But this plan can work, once in a while, if you’re willing to put enough time into the development and the clinical trials.