I'm not a specialist but I think there are some stapled peptides that do show appreciable uptake, so the blog post is not a complete history; this review reports bioavailability of up to 70% for some agents.

Nielsen DS et al. 2017. Orally Absorbed Cyclic Peptides. Chemical Reviews.

https://sci-hub.ru/10.1021/acs.chemrev.6b00838

> this review reports bioavailability of up to 70% for some agents

To save us some skimming, could you specify which ones? (The review covers cyclic peptides that are absorbed by all mammals.)

There are several - I’m not sure why you say cyclic peptides are somehow distinct from other peptides regarding their bioavailability?

All peptides face similar challenges with absorption; the cyclic peptides simply have less liability to proteolysis.

The text covers dozens of agents with varied biochemical properties.

It’s a great read but is this really the history of oral peptides?

Yep, I think it is. The point is there's almost no history of oral peptides, other than stomachs destroying them.

FTA: "So to summarize the state of the art in oral peptide delivery: there are exactly two FDA-approved products that use permeation enhancers to get peptides into your bloodstream through your GI tract. Both achieve sub-1% bioavailability. Both required over a decade of development, thousands of clinical trial participants, and hundreds of millions of dollars."

Would a sublingual dose be possible/more effective? Research in other (um, yeah, medicinal!) compounds shows that it can be an effective pathway to the bloodstream rather than trying to survive the digestive system.

Sublingual is even harder. The sublingual mucosa is thin but selective. It strongly favors molecules that are small, lipophilic and uncharged. Semaglutide is about 8-10x too big, highly polar and charged.

Injection is really the only method with any substantial bioavailability. BUT, low (<1%) bioavailability does not necessarily mean useless.

> BUT, low (<1%) bioavailability does not necessarily mean useless.

Can you say more about that point ?

If the drug has a relatively low marginal cost of production, and the stomach just breaks down 99% of it without side effects, you can just manufacture 100x more, give it orally, and eat the cost of the 99% that gets lost along the way.

Injectable Semaglutide/Tirzepatide (>99.8% pure) are currently sold at a profit from China for around $2-3/weekly dose. Rybelsus (oral semaglutide) is sold at roughly the same cost per milligram, even though it's made in FDA-approved facilities (you just need to take >= 40x more milligrams per month, bringing it to $1000/month in the USA)

So manufacturing oral doses 100x higher than injectable seems to be economically viable.

It would be hilarious if people wound up snorting or boofing their GLP-1s (≧▽≦)

Insufflation for medicinal purposes if it works and doesn't cause harm seem like a win. Less needles == more use.

Ancedotal but it's really hard for me to do insufflation because of the discomfort. Of course if my life depended on it I could probably do it but otherwise I'd rather not.

Here is a list of ways bioactivity is achieved in 6 cases via 7 mechanisms:

Cyclization + N-methylation — lipophilicity, protease resistance (cyclosporine)

D-amino acid substitution — protease evasion (desmopressin)

Permeation enhancers — transient tight-junction opening or membrane fluidization (semaglutide/SNAC, insulin formulations)

Extreme potency — tolerating <1% bioavailability (desmopressin)

Minimizing size to di/tripeptides — exploiting PepT1 active transport (collagen hydrolysates)

Prodrug masking — protecting reactive groups, intracellular unmasking (S-acetyl-glutathione)

Local buffering — pH microenvironment control (semaglutide)

One I take, PEP19, apparently is unique in being naturally bioactive. Evidence is early stage, but I get noticably better sleep with it (by some non-drowsiness mechanism), taking 6mg, 3x the recommended dosage for sleep, but the higher dose may promote fat burning and fat browning at night (only 1 study). It only has 10 residues which apparently avoid having typical cleavage points, fragments may retain bioactivity, and it has extreme potency in very small doses so any absorption means a lot.

Despite a plethora of peptides, successes are not common.

I'm not sure why the hims investors ever thought that this was legal

They probably didn't, they just took the bet that this was one of the crimes that are currently legal, like crypto scams, environmental crimes, bribery, and tay evasion for the rich.

Hims has donated $1M to the current administration, which supports this theory

Some of the most profitable ventures this century have been objectively illegal, but when you know you won't go to prison for violating the law, why would you care to follow it?

The process of chlorinating water was first done illegally.

Also:

  human dissection (grave robbing)
  translating the Bible into English
  silk production outside of China (death penalty for exporting worm eggs)
  rubber production in Asia (seeds smuggled out of Brazil)
  the Underground Railroad
  heliocentrism
  AIDS treatment (see Dallas Buyers Club)
  Needle exchange programs for IV drug users
  Ridesharing/airbnb/napster (obvious ones)
  SF gay marriage licenses (in defiance of CA law)

Translating the Bible into English was not illegal. I very much doubt Bede or the monks of Lindisfarne were breaking the law!

The same for heliocentrism. No one took Copernicus to court.

With silk and rubber the smuggling was illegal, the actual cultivation was not

Grave robbing was illegal (and still is) but dissection was not.

Needle exchange was illegal in some US states but was legal in many other countries.

Reference to support the claim that translating the bible into English was banned (William Tyndale was executed for doing it): https://nobimu.no/en/subject-articles/banned-translations-of...

You can nitpick that "the church executing people for it" is not exactly the same as "illegal" but that's missing the point.

> The process of chlorinating water was first done illegally.

I tried to find a source on this but it doesn't seem to be true? The first chapter of this book describes the history of chlorination: https://upload.wikimedia.org/wikipedia/commons/f/fd/Chlorina... (which is a source Wikipedia cites) and it doesn't appear to mention anything about illegally chlorinating water. After looking in that book I asked ChatGPT to find a source for the claim, and it reported the claim was false. Chlorination was initially controversial but I can't find anything claiming it was illegal?

It probably is legal at the moment, but the rules may be changed to make it illegal. But also Uber and Lyft were super illegal when they were invested in. To some extent, YCombinator partners are on the record[0] supporting the idea of their startups doing illegal things.

Generally they'll frame this as challenging outdated regulations, but they acknowledge that the founders whose strategies they fully support sometimes come into office hours and discuss how they're worried that the strategy puts them at risk of going to jail.

There are different kinds of illegal, and Hims/Hers may end up getting blocked from their current business model, or they may end up entrenching new ways for consumers to get affordable care. The jury is very much still out.

0: https://www.youtube.com/watch?v=Hm-ZIiwiN1o&t=8m46s

Pretty sure it's illegal. You can get peptides (even GLP-1's) legally from various sources for "Research Purposes", but they're marked as "Not For Human Consumption" (even though, on the sly, I'm sure they're aware people are buying these for human consumption and they provide purity tests etc.) What makes it illegal though, is when you say it is for human consumption, or worse market it as a treatment for a disease. That's when you actually need FDA approval.

Compounding pharmacies generally operate outside of what we typically think of when we think of "FDA approval".

> Hims/Hers may end up getting blocked from their current business model, or they may end up entrenching new ways for consumers to get affordable care

Well, no: the thing that's a lot cheaper is a placebo at best, and they were just referred to the DOJ for prosecution.

The rest is more expensive

Hims offered semaglutide for $99/month. That’s a 90% discount on unsubsidized consumer prices for injectable semaglutide. I also don’t see any evidence that they sold a placebo, but I’m just catching up now, perhaps I missed where they’re selling something with a different active ingredient which does not work.

> Hims offered semaglutide for $99/month. That’s a 90% discount on unsubsidized consumer prices for injectable semaglutide.

It's not a 90% discount. Novo charges $350/mo or less.

I've since read TFA, as well as many other articles, official correspondence, and case law around the issue. I understand that without the additional ingredients of SNAC/sodium caprate/sodium caprylate, the bioavailability is probably too low to have a clinical effect at oral doses <15mg/day.

I read the actual FDA referral to the DOJ. They don't mention anything about any of what this article touches on. It's not clear that the referral makes correct claims about anything illegal going on. In statements, the FDA says that compounding pharmacies "cannot state compounded drugs use the same active ingredient as the FDA-approved drugs". That's a very brand-new interpretation of rules, and might not stand up to judicial scrutiny. In the context of "shouldn't investors have known that Hims business model is illegal??" -- it makes sense that investors couldn't have known ahead of time that the FDA would claim this.

https://www.fda.gov/inspections-compliance-enforcement-and-c...

i haven't read the article. is the question, can hims ship a clone of 25mg oral wegovy? yes, it can.

> ... at oral doses <15mg/day.

well it's not a clone of rybelsus, it's a clone of wegovy 25mg. so i suppose it will be bioavailable at 25mg.

> That's a very brand-new interpretation of rules

this is true. Tidmarsh, the whole Novo Nordisk deal with Trump, it's now about, well we'll do the patent enforcement we didn't want to do before. The simple fact of the matter is, these are lifestyle products, so it's not so black and white if they ought to have the same patent and payment protections as typical therapeutics.

Not sure why you're being downvoted, it was clear they hadn't based on their post, and they admit they didn't.

The charitable assumption is that investors weren't aware it was a problem.

Investors, or management?

I am bored to tears by this and it is simultaneously heart-breaking. My MD friend wasted $100K on MicroStrategy, ignoring my advice when he asked for it a couple months ago, and he's like "It's fine I'm not 65." and then proceeded to explain he absolutely should hold it because Trump will add it to Bitcoin strategic reserve.

Been following the market for 30 years and I've never seen loss per share > $10. They lost $42/share. Didn't make a dent in our conversation, I think he just ignored it twice.

Appreciate the perspective on the risk of dubious formulations. Consequences are far more than cosmetic.

Informative article but I feel like it could have benefited from a paragraph about what Hims is. I had never heard of them before.

An online pharmacy that advertises pretty aggressively, with men being the target audience. Hair loss, erectile dysfunction, that sort of thing.

https://en.wikipedia.org/wiki/Hims_%26_Hers_Health

wait till you discover soviet bioregulators (peptides by dr khavinson). all designed for oral.

great read!