Semaglutide is a peptide. Your stomach’s entire job is to destroy peptides.
It’s the whole point of your stomach. Your GI tract is a 30-foot disassembly line for proteins. Acid denatures them, pepsin cleaves them, trypsin finishes the job. The mucus layer on your intestines blocks absorption as well.
Anything that looks like a chain of amino acids gets shredded into fragments before it can reach your bloodstream. This is what’s supposed to happen. It’s how you digest food. It’s also the reason that for over a century, every attempt to deliver a therapeutic peptide by mouth has run into the same wall.
The first attempt at oral insulin was in 1922, one year after the protein’s discovery. Researchers gave patients the highest doses they could tolerate and got nothing close to the effect of a simple injection. That was a hundred years ago. Since then, thirteen different companies have tried to crack oral insulin. Nine decades of work, and not a single commercial product exists. Peptide drugs on average have oral bioavailability below 1-2%. For comparison, metformin, one of the most common diabetes drugs in the world, has oral bioavailability of 40-60%.
So when Novo Nordisk announced they’d figured out how to deliver semaglutide in a pill, it was a genuinely remarkable scientific achievement. They didn’t fully solve the oral peptide problem, but they just barely squeezed past it using a molecule called SNAC.
How SNAC Works
SNAC, salcaprozate sodium, was developed by a company called Emisphere Technologies over the course of decades. Emisphere started screening modified amino acid compounds for permeation-enhancing effects in the 1990s, eventually landing on SNAC as their lead candidate. Their first commercial product using SNAC was an oral vitamin B12, approved as a medical food in 2015.
Novo Nordisk partnered with Emisphere in 2007 and licensed the technology for their GLP-1 program. In 2020, Novo acquired Emisphere outright for $1.8 billion, assigned about a hundred researchers in Copenhagen to improving SNAC, and got to work expanding it across their pipeline.
SNAC actually does three things simultaneously:
It buffers the local pH in your stomach, which suppresses pepsin activation and protects semaglutide from degradation. It changes the polarity of the solution around the dissolving tablet, which prevents semaglutide molecules from clumping into oligomers, keeping them in their active monomeric form. It incorporates itself into the lipid membranes of your gastric cells, temporarily fluidizing them so that semaglutide molecules can slip through via transcellular transport.
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