A brief history of oral peptides
seangeiger.substack.com
seangeiger.substack.com
Nielsen DS et al. 2017. Orally Absorbed Cyclic Peptides. Chemical Reviews.
To save us some skimming, could you specify which ones? (The review covers cyclic peptides that are absorbed by all mammals.)
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.
I'm saying there are peptides on that list that are bioavailable to non-human mammals.
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."
Injection is really the only method with any substantial bioavailability. BUT, low (<1%) bioavailability does not necessarily mean useless.
Can you say more about that point ?
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.
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.
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)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.
You can nitpick that "the church executing people for it" is not exactly the same as "illegal" but that's missing the point.
While there were bans or a requirement for authorisation of translations of the Bible in certain times and places (mostly the 1300s to 1500s) the first translations of (parts of the) Bible into English had been done centuries before this, some as early at the 7th century. This makes them some of the oldest written works we know of in English at all. They were also done by the church.
> You can nitpick that "the church executing people for it" is not exactly the same as "illegal" but that's missing the point.
When did this happen? Tyndale was tried and executed by the secular authorities in a place where there were no laws against translating the Bible.
The earliest translations into English were done by the Church.
>Needle exchange was illegal in some US states but was legal in many other countries
I'm not sure what your point is here
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?
I do still disagree for the following reasons:
- Jersey City started chlorinating in 1908; Maidstone, England started chlorinating in 1897 and Lincoln, England started chlorinating in 1905. So Jersey City wasn't the first to chlorinate their water.
However, Jersey City seems to be the first deployment in the United States, so perhaps that is what you meant. If this were the only issue I would concede the point.
- This was a civil matter and not a criminal matter.
- The dispute wasn't whether chlorination was legal or acceptable but whether it was sufficient to deliver "pure and wholesome" water. The city wanted them to build a sewer. The utility didn't really dispute that there was a water quality issue but they built a chlorination plant instead of building a sewer (while the lawsuit was still ongoing).
- The water utility won. They demonstrated that chlorination was sufficient.
That's the impression I took from Wikipedia and this writeup: https://www.dolmetsch.com/chlorination_history.pdf (Starting on page 4)
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.
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
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...
> ... 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.
No. RTFA. Feed it into an LLM with the first thought off the top of your head. Skim it quick. Whatever. (tl;dr: the clone skips the ingredient that makes the contents bioavailable)
indeed, the only evidence that the clone is missing the ingredients is the guy read a Reuters article about it, and asked the chatbot (presumably) to do research. the clones in this sector are pretty faithful. i'm going to chalk it up to, "declined to elaborate" doesn't mean, as the author insinuates, that Hims has a bad clone, i think they just didn't answer the question and there's nothing more to this.
this is coming from my place as knowing a lot about this sector and the simple fact of the matter is, they just make a clone and they do it faithfully.
It's not a 90% discount. Novo charges $350/mo or less.
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.
Do they actually make a proper assessment? Questionable, they’re going based on the lies you tell them over text and video. Here’s your script for your dick pills, come back soon!