The First Battle, Won

By George ForrestTechnology

The First Battle, Won

How SNAC turned semaglutide into a tablet — and why 99% of the dose still never arrives

In September 2019, semaglutide became the first GLP-1 medicine millions of patients could swallow instead of inject. The chemistry that made it possible didn’t defeat all three battles from the last article in this series — it found a way to sidestep one of them entirely. What’s left is a genuine engineering achievement, with a genuine limit.

By Ibumix · 6-minute read

On 20 September 2019, the US FDA approved Rybelsus — oral semaglutide — as the first GLP-1 receptor agonist available in tablet form rather than as an injection [1]. Approval rested on the PIONEER clinical trial programme, which showed the tablet lowered blood sugar more effectively than two established comparator drugs, sitagliptin and empagliflozin, with an average incidental weight reduction of around five pounds — though the tablet was not, at that point, approved for weight management [2].

That approval didn’t happen because someone had solved the three battles set out in the previous article in this series. It happened because one piece of chemistry found a way to avoid fighting two of them the way anyone would expect.

A different way through Battle One

Rybelsus is co-formulated with an excipient called SNAC — salcaprozate sodium, shorthand for a molecule that would otherwise need a chemistry degree to pronounce. As the tablet dissolves, SNAC creates a small, temporary protective microenvironment around the drug, buying it enough shelter to survive long enough to be absorbed [3].

The surprising part isn’t that SNAC offers protection. It’s where the absorption then happens. For decades, pharmaceutical scientists assumed the small intestine was the only realistic site for absorbing a peptide — the stomach was just somewhere a drug had to survive, not somewhere it could actually get through. SNAC demonstrated that, under carefully controlled conditions, semaglutide absorption occurs predominantly in the stomach itself [3]. Rybelsus doesn’t so much win Battle Two — crossing the intestinal wall — as change which battlefield the fight happens on.

Researchers did not need to absorb all of the drug. They simply needed to absorb enough.

Winning small, winning enough

Here is the number that makes this story remarkable rather than simply successful: at the marketed 3 mg, 7 mg and 14 mg doses, Rybelsus has an estimated absolute bioavailability of just 0.4–1% [4]. Put another way, of every hundred molecules of semaglutide a patient swallows, somewhere between 99 and 99.6 never reach the bloodstream at all.

That would be a failure for almost any other drug. It isn’t one here, because semaglutide is potent enough that the sliver which does get through is sufficient to lower blood sugar meaningfully. It is, as the first article in this series put it, a story about absorbing enough — not absorbing everything.

The instructions that make it work

SNAC’s protective effect is local and short-lived, which is why Rybelsus only works if it’s taken exactly as directed: first thing in the day, on an empty stomach, with no more than 120 ml (about 4 fl oz) of plain water, followed by a wait of at least 30 minutes before eating, drinking anything else, or taking other oral medicines [5]. Steady-state blood levels take four to five weeks of daily dosing to build up [5]. Miss the routine on any given day, and an already small fraction of the dose gets smaller still.

None of this makes Rybelsus a lesser achievement. It is the reason patients have been able to take a GLP-1 medicine as a tablet at all, rather than an injection. But the instructions are also a window into how much precision is still being asked of patients, every single day, to make a single-digit-percent absorption ceiling work at all.

One battle won, not three

It’s worth being precise about what SNAC actually solved. It helped semaglutide survive and absorb in the stomach — a workaround for Battles One and Two together, rather than a defeat of either on its own terms. It did nothing for Battle Three, staying active long enough in the blood to matter; that battle was already won separately, by redesigning the semaglutide molecule itself to resist the enzyme DPP-4 and bind to albumin, as the first article in this series described.

Two separate pieces of chemistry, solving two separate problems, bolted together into one tablet. That’s a fair description of most oral peptide breakthroughs to date — and it’s also why SNAC’s trick doesn’t automatically transfer to every other peptide medicine. A drug that needs to be absorbed intact somewhere other than the stomach — insulin, for instance, or larger antibody-based peptides — needs an answer built for a different battlefield entirely.

The next piece in this series looks at a different route past Battle Two: an absorption enhancer that works not in the stomach, but in the small intestine itself

Sources

  • [1] Novo Nordisk / FDA. FDA approves Rybelsus® (semaglutide), the first GLP-1 analog treatment available in a pill for adults with type 2 diabetes. 20 September 2019. prnewswire.com
  • [2] PIONEER clinical trial programme summary — oral semaglutide vs. sitagliptin and empagliflozin. beyondtype1.org
  • [3] RYBELSUS® (semaglutide) Prescribing Information — SNAC (salcaprozate sodium) co-formulation and stomach-predominant absorption. FDA label. accessdata.fda.gov
  • [4] RYBELSUS® Prescribing Information — estimated absolute bioavailability of 0.4–1% at 3 mg/7 mg/14 mg doses. accessdata.fda.gov
  • [5] RYBELSUS® Prescribing Information — dosing instructions (empty stomach, ≤120 ml plain water, 30-minute wait before food/drink/other oral medicines; steady state at 4–5 weeks). accessdata.fda.gov

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