Orforglipron: The next big thing?


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Jul 4, 2024
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This category looked so sad and empty...

If the Phase three studies show that once daily oral orforglipron is at least as effective as injectable semaglutide, I can't help but think that it has the potential to explode and take over a huge percentage of the anti-obesity drug market. There is a massive untapped market of people who will not or cannot inject themselves, even using the auto injector pens, not to mention the people that don't have the capacity to properly manage dose calculation & reconstitution of research peptides. Taking a pill once a day is far more acceptable to the population at large.

Orforglipron is a GLP1-RA, but it is not a peptide, so will not require the dosing restrictions & will be significantly more bio-available than Rebelsus, for example. (Peptides are broken down by the digestive system, hence the injection delivery requirement.)

This April, a meta-analysis of three published Phase II Randomized Control Trials to date of orforglipron was published: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10896246/

At higher doses, it looks like there was a decrease in body weight of 8 - 9% over 36 weeks (without evidence of plateau), vs. 9.2% over 56 weeks in the Semaglutide STEP-1 trial. This is certainly close enough for it to be a viable choice, IMHO.

Eli Lilly's Phase III RCT comparing different doses of orforglipron to placebo with 3000 participants started last year and is slated for its first endpoint in September of next year.

(This is an editorial comment and is strictly my opinion: I think it's time for manufacturers of anti-obesity drugs to stop using placebo as the comparator in their RCTs. We know that all GLP-1RAs work, at this point. The trials need to be using other GLP1-RAs as the comparator. Think of cancer or blood pressure medication trials. It would be considered unethical to use placebos in one group. Instead, the comparison of new therapies is made against standard current therapies. Obesity is a life-threatening illness and should treated no differently!)

I don't know anything about the difficulty of the synthesis of this molecule, but I wouldn't be surprised to see our favorite overseas companies getting in on this, if feasible.
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comparing to placebo is a gold standard in medical research, they simply must do it
No. Comparing to a control group is required, but it doesn't have to be a placebo control group. It's 100% acceptable, even required, to compare a new treatment to the standard-of-care treatment.

For example, if I were testing a new oral medication for Type 2 DM, I might randomize the participants to receive either the new med or metformin, which would act as the control. It would be unethical to randomize them to a placebo when they have a serious disease with a known effective treatment. This is my argument for GLP-1Ras, too.
Well, here is a timely article with another answer to my hypothetical question: https://www.medscape.com/viewarticle/mounjaro-beats-ozempic-so-why-isnt-it-more-popular-2024a1000ckd

Why don't we see more head-to-head trials of competitor drugs? The answer is pretty simple, honestly: risk management. For drugs that are on patent, like the GLP-1s, conducting a trial without the buy-in of the pharmaceutical company is simply too expensive — we can't run a trial unless someone provides the drug for free. That gives the companies a lot of say in what trials get done, and it seems that most pharma companies have reached the same conclusion: A head-to-head trial is too risky. Be happy with the market share you have, and try to nibble away at the edges through good old-fashioned marketing.
No. Comparing to a control group is required, but it doesn't have to be a placebo control group. It's 100% acceptable, even required, to compare a new treatment to the standard-of-care treatment.
citation required ;)

World Medical Association. (2013). World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Jama, 310(20), 2191-2194.