Dr. Patrick Soon-Shiong (“PSS”) is in the running for the world’s most interesting man. He is the 2nd wealthiest medical doctor in the world. His wife was in MacGyver.1 He owns the Los Angeles Times. He’s a part owner of the Los Angeles Lakers. He was a mentor to Kobe Bryant. He’s listed as the inventor on more than 1200 patents.2 He’s the first surgeon to perform a whole pancreas transplant. We are all inadequate in comparison.

Most recently it has become apparent that he is a surrogate for the Make America Great Again (“MAGA”) movement, or at least wants MAGA royals to think highly of him. He’s the ultimate cockblock of the LA Times editorial board.34 It shouldn’t be surprising that the South African born man of Chinese dissent who is a proud Los Angeleno has a unique perspective, and has lot to say about a lot of things.

Recently, he participated in a public flattery session on X with his bud, Elon Musk, where Elon begins the symposium by extolling the virtues of GLP-1’s:

This all perked up my ears that lead me down a rabbit hole. The most interesting man in the world has a GLP-1 in his back pocket? In phase 3 trials? Why does he call it a GLIP-1 and not a GLP-1? Have I been calling it the wrong thing all of this time!? WTF!?

I then found a X message from over a year ago that I flagellated myself for not seeing before:

Digging into PSS history with GLP-1 led me to the year 2011. At the same time Oprah was trying to lose weight on a 21 day vegan cleanse, PSS gets into the GLP-1 (or GLIP-1?) game.5 Flush with $2.9b from his sale of blockbuster pancreatic cancer drug Abraxane in 2010, he purchased ConjuChem, a struggling Canadian biotech that was developing CJC-1134-PC, one of the first GLP-1 to be developed for weekly dosing.

The gem of ConjuChem, to PSS at the time, was their Drug Affinity Complex (DAC™) and Preformed Conjugate-Drug Affinity Complex (PC-DAC™). It wasn’t the catchy names and groundbreaking trademarked acronyms that caught his attention, it was the technology of being able to extend the half-life of drugs by binding the drug molecule to albumin, which keeps the drug active in the body for a longer duration. PSS saw the potential in a lot of drug classes where frequent doses are necessary.

For a moment let’s imagine a parallel universe where PSS brought a life changing GLP-1 to market before Novo Nordisk and Eli Lilly. PSS is the richest man in the world, the epidemic of obesity has been conquered, and Elon Musk is kissing PSS’ ass on X. But that’s not the world we live in. What the hell happened to CJC-1134-PC?

The molecule proceeded with three clinical trials conducted between 2011 - 2013, one of which was unceremoniously terminated due to a “business decision.”6 Maybe it wasn’t a very good drug after all?

In June 2021, Changshan Pharmaceutical announces a joint venture to develop the drug (now referred to as Ibenatide).7 In September 2021, Changshan announces a phase 3 trial.8 There haven’t been any updates since. Maybe it’s not dead, but it doesn’t really sound like something PSS should brag to Elon about.

Desperate for more clues, I watch a one hour and eighteen minute podcast on YouTube that only confirms PSS status as the most interesting man in the world. One might say I don’t have a lot going on in my life, and that person would be correct.

Then at the one hour, twelve minutes and forty nine second mark, PSS says the magic words “No one knows this, I have a GLIP One in Phase 3… I’m coming out of stealth in about two months… (insert statements about curing all of humanities biological limitations…) …my job is to make it affordable to anyone who can afford it.”

At that point, I may or may not have shit myself. PSS is going to overtake the GLP-1 market with something all fat asses can afford? Do I need to sell my Altimmune & Lilly stock?

Deflated like a nitrous balloon after a Blink 182 concert, my PSS GLP-1 trail seems to have dried up. What clues have I missed? I looked at the messages on X again, hoping to find a glimmer of hope.

Oh, wait! Praise the Lord, PSS left a few cookie crumbs for me! He has a phase 3 GLP-1 asset? It’s effective at lowering A1C at a dose of .2mg?

A bit of Googling and conversing with a very random dude on Stocktwits (thanks Water03!) led me to a little known Chinese biotech startup, PegBio. Founded in 2008, with no known connections to PSS save for a common ancestry, I see they have a drug in development called Visepegenatide and scroll through a very long article from The Lancet.9

Is it a GLP-1? Check.

Does it have a super low dose? What is 150 μg in mg? Whoa, .15 mg? Yes, that’s nothing and pretty close to 1/10 of 2mg.

Is it in Phase 3? Kinda… in China. 600 patients. No one died or complained of gastrointestinal issues. Though I think it’s illegal to complain about things like that.

Ok, I think this is it. Is it a good drug? Eh, it’s good at lowering A1C. For really fat people, they’ll “lose some weight.” Is this the world changing drug that will make PSS king?

On November 21, 2024, an article from the esteemed journal “The Bamboo Works” indicates that PegBio needs cash. It’ll IPO on the Hong Kong Stock Exchange any day now, after raising $143m in cash over its lifetime. Needing to raise cash doesn’t seem to be consistent with PSS having an ownership stake. However, ImmunityBio diluted shareholders last week to raise $100m, so perhaps PSS is hard up on cash.

This is either it, or I need to start my search over again. One thing I do know is I’ll be saving a few Yuan to buy some PegBio if / when it goes IPO.

Two thirds of U.S. adults take prescription drugs, and the vast majority of those are in pill format.1 It hasn’t been until this GLP-1 revolution that subcutaneous injections have become a relatively common administration of medicine. Drugmakers are working on pill based versions of existing GLP-1’s and in new small molecule versions. I’ll attempt to explain how these work and why pills vs. injections.

Peptides

Peptide drugs are typically injected subcutaneously, which is relatively shallow below the skin. A peptide is a linkage of amino acids (organic chemicals) that create a structure that can fit into cell surface receptors. These receptors then signal to the body to perform some function. Pharmaceutical peptides, like GLP-1 agonists, tend to be complex structures that are very similar in structure to the hormones made by our own bodies.

Amino acids are the building blocks of protein, which our digestive tract quickly breaks down. The structure of the molecule is also typically too large to easily permeate the gut / blood stream barrier. Most GLP-1 drugs are between 29-42 amino acid linkages. The average amino acid has a molecular size of 110 Daltons, so the size of GLP-1 drugs is between 3190 - 4620 Daltons. Molecules of less than 600 Daltons efficiently pass through the gut / blood barrier,2 so peptides tend to be too large to efficiently find their way into our blood stream. Due to these factors, administration of peptides in pill form doesn’t work very well. There are a number of inventions that show promise in circumventing these challenges (and a good future article for me to write!).

Small Molecules

Nearly all oral drugs are small molecules. These are non-organic chemical structures that are quite a bit less complex than peptide structures, can be effective in interacting with cell surface receptors. Small molecules are being developed to perform similar functions to peptide based GLP-1 agonists. The inorganic structure isn’t degraded by our digestive system. The small size (between 500-599 Dalton, 4-9x smaller than GLP-1 peptides) allows it to pass through the gut / blood barrier and enter our blood stream.

Advantages of Peptides

The complex structure of a peptide can be designed to interact with multiple receptors. For example, Mounjaro / Zepbound / Tirzepatide (all the same peptide) interact with both GLP-1 receptors and GIP receptors. The structure of Tirzepatide causes the molecule to interact with GIP at a rate of five times higher than it does with GLP-1 as the structure is molecularly very similar to GIP, and less similar to GLP-1.3 The functionality of a peptide is greatly enhanced over a small molecule due to this flexibility.

Our bodies are very effective at removing foreign materials, so native peptides (peptides produced in our bodies, typically our pancreas) have a short life span to perform their function. Advances in peptides allow a much longer half life, both by being able to sit in a deposit under the skin and be slowly released, and more importantly to be able to bind to albumin in the blood stream and avoid being removed by the liver. Current GLP-1’s are typically weekly administration vs. the daily administrations of previous generation GLP-1’s.

Advantages of Small Molecules

The big one is taking a pill instead of an injection— most folks don’t like the idea of having to take a weekly injection. The small molecule GLP-1’s under development are taken daily.

Making a small molecule drug is an easier process than a peptide. It is linking fewer chemicals together in a streamlined process that already exists to make other drugs on a mass scale. Peptide production is a more complicated process, and the facilities to make the peptides and package them are in short supply. It is conceivable that small molecule GLP-1’s could be considerably less expensive than peptide GLP-1’s.

A peptide that is diluted into liquid has a limited shelf life and needs to be stored in a refrigerated environment at a relatively constant temperature. A small molecule can tolerate a large range of temperatures and has a much longer shelf life. These qualities make them much easier & less expensive for the supply chain and much simpler for the patient.

The Known Unknowns

The focus on GLP-1’s as a weight loss tool is clearly understood as very powerful & effective at quickly reducing body weight. We also know that in order to maintain a certain weight, these are long term / forever drugs, like blood pressure medication or statins tend to be. However, the long term impact of this class of drugs is not known because they haven’t been in existence for very long.

We are starting to understand that currently available GLP-1 drugs cause both a loss of fat mass and lean mass, such as muscle and bone. Weight loss through diet and exercise also cause a loss of fat and lean mass, typically a ratio of 25% lean mass to 75% fat mass.4 This makes sense because when our bodies have excess fat, there is an associated muscle & bone infrastructure needed to support the weight. Most GLP-1 drugs have shown a higher lean mass loss than diet and exercise alone. A single agonist GLP-1 has shown up to 40% lean mass loss in a 72 week clinical trial.5 The body requires more energy when there is a greater amount of lean mass compared to fat mass, so a reduction in lean mass will reduce metabolic rate. A reduced metabolic rate means the body requires fewer calories to maintain equilibrium weight. Those who discontinue the drug will be in a position to have less muscle while fat is relatively rapidly regained, likely in a worse physical condition than if they hadn’t taken the GLP-1 drugs in the first place. It is not known how lean mass is impacted over a longer term than 72 weeks.

We also do not know how small molecule GLP-1 agonists will impact lean mass loss. We do know that GLP-1’s cause people to consume less calories, which leads the body to use energy stored within the body, such as fat and protein. An agonist that only interacts with the GLP-1 receptor seems to be more likely to cause a greater proportion of lean mass loss than those with multiple agonists. Ozempic / Wegovy (Semaglutide) only interacts with GLP-1 receptors and has the 40% lean mass loss at 72 weeks as previously mentioned. Multi-agonists such as Tirzepatide (GIP & GLP-1) and Pemvidutide (GLP-1 and GCGR) appear to be able to maintain lean mass at a higher rate. Tirzepatide has a lean mass loss of approximately 29%,6 where Pemvidutide has an industry leading lean mass loss of approximately 21%.7

Which Is Better?

My prediction is peptide-based GLP-1’s and similar agonists will in the long term be the gold standard for this class of medicine in terms of body composition. The elderly, health nuts, and those with health conditions where loss of lean mass puts them at a higher risk. Small molecules have the potential to bring this class of medication to a wider demographic, and additional small molecules may be able to address some of the downsides of single agonist weight loss medications. Both are needed to address the obesity epidemic.

Disclaimer: This article is intended for informational purposes only and does not constitute medical or financial advice. It is essential to consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment. While I strive to be factual at all times, I cannot guarantee the accuracy of these statements.

Why would competitors freely trade amongst each other? Perhaps what they invented isn’t a strategic priority for them, or perhaps they have another drug in development that has greater promise. Ultimately drug developers want their efforts to come to fruition and generate revenue, whether it’s them or a competitor that ultimately brings it to market.

Chugai Pharmaceutical Co. is a Japanese drug developer that is owned 65% by Roche, the Swiss pharmaceutical company that is the sixth largest in the world. Chugai developed Orforglipron, a small molecule GLP-1 receptor agonist, which is able to be administered in a daily pill format. As of the date of writing this, the GLP-1 market is dominated by peptides, which are best administered by injection.

In 2018, Chugai sold a worldwide exclusive license of Orforglipron to Eli Lilly’s diabetes division. Eli Lilly paid $50 million upfront with high single digit / low double digit royalties (~7+% royalties). Back then, GLP-1’s were primarily utilized for type 2 diabetes management, and it was a minor class of drugs in comparison to the many medications available to type 2 diabetics. GLP-1’s were understood to help with weight loss, but not to the extent that we now understand.

As the majority owner of Chugai, Roche has the first right of refusal to Chugai’s developments. In 2018, they passed on Orforglipron, allowing it to be sold to a competitor. Roche has a significant emphasis on diabetes care, so it’s quite interesting they decided to skip on Orforglipron, even if it were just for the type 2 diabetes market.

At the time of licensing, Orforglipron was pre-Phase 1 clinical trials, so the ultimate chance of success was low without human trials for safety & effectiveness. Today we know that in completed Phase 2 trials, Orforglipron has shown effectiveness in both weight loss and improved blood sugar control. The bet has paid off so far for Eli Lilly.

Eli Lilly has multiple phase 3 trials underway for Orforglipron with a potential launch in 2026. It is anticipated to be the first oral small molecule GLP-1 to launch, which will likely bring this class of drugs to an even larger demographic at perhaps a lower price than current options. It has been predicted that Orforglipron will have $8.3 billion in annual sales by 2030.1 There’s no guarantees it’ll make it through Phase 3 trials as it is estimated that only 58% of drugs in Phase 3 trials are ultimately brought to market.2 However, I’d be willing to bet that Eli Lilly has a much higher success rate for advancing Phase 3 assets than the average.

Between 2018 and 2023, Roche along with every other big pharma woke up to the promise of the GLP-1 market. Roche acquired clinical stage biopharma company Carmot in December 2023 for $2.8 billion up front, plus up to $300 million in milestone payments, where it obtained three GLP-1 candidates:3

- CT-388 is a subcutaneous weekly administered GLP-1 / GIP and is currently in Phase 2 with a projected completion date of 5/31/2026.

- CT-996 is a once daily oral small molecule GLP-1R that is currently in phase 1.

- CT-868 is a daily subcutaneous GLP-1 / GIP for type 1 diabetics currently in phase 2.

If any of these drugs are ultimately successful, the earliest launch would be in 2029. Is CT-996 going to be more effective, safer, or more tolerable than Orforglipron and the other oral small molecule GLP-1’s in development? Will CT-388 offer any advantages to its injectable competitors?

Roche could have been a dominant player in the GLP-1 space by having the first oral small molecule GLP-1. The current GLP-1 leaders Eli Lilly and Novo Nordisk are the highest valued by market cap in the big pharma industry, and Roche could have moved up a few spots from its current position of the #6 largest. Instead, Eli Lilly will continue to build its dominance in the space.

I wonder at what point the person at Roche responsible for the decision to pass up Orforglipron realized they had made a serious error of judgment?

Disclaimer: This article is intended for informational purposes only and does not constitute medical or financial advice. It is essential to consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment. While I strive to be factual at all times, I cannot guarantee the accuracy of these statements.

I’ve noticed that articles on the subject tend to be very simple and not very objective or well researched (primarily mass media publications) to very complicated scientific journal articles, and not a lot in the middle. It is my goal to build a resource where the more complicated parts of this world can be understood by anyone who cares about it.