If you are following the media frenzy on GLP-1s, you have likely noticed a new pivot by pharmaceutical companies to rush out oral options. Is that the answer we are all looking for? Let’s start by discussing the players involved.
1. Lilly
Eli Lilly is the maker of Tirzepatide, which is marketed as Mounjaro for Diabetes, and Zepbound for weight loss. Tirzepatide is a once-weekly injectable that works by attaching to the GLP-1 receptors in the brain and gut as well as the GIP receptor, which affects insulin. Tirzepatide has one of the best side effect profiles and weight loss at 15% in recent studies.
Lilly is heading the pack with their oral GLP-1 called Orforglipron. Orloforglipron is already in phase 3 of its trials and is ramping up manufacturing capacities for a release expected in 2025. The weight loss with Orloforglipron taken once daily is similar to Zepbound at a 9.4-14.7% loss in 36 weeks.
2. Novo Nordisk
Novo Nordisk is the maker of Semaglutide — a once daily injectable which is marketed as Ozempic for Diabetes and Wegovy for weight loss. This drug peaked at about 10% weight loss at higher doses. Novo has been in phase I trials for an oral agent called Amycretin.
Amycretin hits the GLP-1 receptors and the Amylin receptors which is new. The weight loss in phase one was fast and significant — 13.1 % in twelve weeks on a 100mg daily dose. The GI side effects were high at 87.5%, so they will be working on that issue, but it looks very promising.
Novo Nordisk is also studying an Oral agent called Monlunabant, an oral cannabinoid receptor 1 (CB1) antagonist. On September 20, results of the phase 2a trial showed mild to moderate neuropsychiatric side effects, primarily anxiety, irritability, and sleep disturbances with higher and more frequent dosing. They are still working on dosing to mitigate these, but it was concerning as we have not seen these particular side effects in this class.
3. Pfizer
Pfizer was in the process of developing a weekly GLP-1 called Danuglipron and decided to switch to making an oral version of it. It is currently in phase I trials, but this is interesting since they have never been in the GLP-1 race.
4. Roche
In December of ’23, Roche bought Carmot therapeutics for $2.7 billion and is currently working on a once-daily oral medication that hits the GIP and GLP-1 receptors, similar to Tirzepatide. This medication is currently in Phase I.
5. Viking Therapeutics
The biotech company, Viking Therapeutics has started to work on a GLP-2/GIP medication and is in phase I. The weight loss is very low at 3.3 % which is much lower than its competitors.
6. Structure Therapeutics
Structure is another biotech company that has oral GLP-1 medication in phase II trial. The weight loss is modest at 5.5 %.
Oral Agents vs. Injectables
Although taking a pill versus giving a shot may sound enticing, there are some pitfalls. First, it is daily vs. weekly injectables. Second, because it is oral, there tend to be more GI side effects. Since they involve nausea, vomiting, and diarrhea, you can lose the pill through your vomit, or by releasing it in your stool.
Additionally, there are very specific rules about taking the pill. It must be on an empty stomach with no more than 4 oz of water, and you must wait 30 minutes before eating. You cannot crush or chew the pill. And you must follow this protocol every day.
Finally, the pill has much lower weight loss than injectables, averaging about 5% or less. This is one reason why the previously released oral Semaglutide under the brand name Rybelsus was not very popular. Clinical studies showed only 5-8 pounds in 6 months. Of course, the newer agents are much stronger, however with that comes higher GI side effects, so we will have to wait and see what the finished products look like.
On a positive note, oral medications cost less to make, and are easier to manufacture as well, which should help supply chain issues and availability.
References:
- Goodwin, K. BioSpace News. March 28, 2024. “Will Oral Weight-Loss Drugs Break Open an Already Lucrative Market?”
- Taylor, N.P. Biotech. September 11, 2024. “Novo Nordisk hails remarkable weight loss result for dual-acting oral drug in early trial.”
- Eka Melsonet al. What is the pipeline for future medications for obesity? International Journal of Obesity (Feb 1, 2024)
- https://wwrew.pfizer.com/news/press-release Pfizer Provides Update on GLP-1-RA Clinical Development Program for Adults with Obesity and Type 2 Diabetes Mellitus Monday, June 26, 2023.
- Medscape Medical News: New Oral Weight Loss Drugs: Where Are We and What’s Next? Larkin M. June 5, 2024. https://www.medscape.com/viewarticle/new-oral-weight-loss-drugs-where-are-we-and-whats-next-2024a1000ak8
