Has Anyone Tried Omipalisib (GSK2126458) for Longevity Purposes?

#1

GSK2126458 (also known as Omipalisib) is a dual PI3K/mTOR inhibitor originally developed for cancer and fibrosis. Mechanistically, it’s similar to rapamycin in that it inhibits mTOR signalling, but it also targets the upstream PI3K pathway, offering a broader inhibition of the IGF-1/AKT/mTOR axis.

In longevity research, it’s starting to gain attention. In the Ora Biomedical “Million Molecule Challenge,” GSK2126458 topped the leaderboard by extending median lifespan in C. elegans by a remarkable 63%—far more than rapamycin or metformin in comparable models. That kind of result obviously caught my attention.

Given the growing interest in compounds that modulate these pathways, and the fact that rapamycin is already used off-label by many in the longevity community, I’m wondering:
Has anyone here experimented with GSK2126458 (Omipalisib) for longevity or other purposes?

Would love to hear any anecdotes, protocols, side effects, or thoughts.

Taking rapamycin is already considered a bold move—this is another order of magnitude beyond that. But the data is intriguing, and I can’t help but feel there might be something here.

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#2

It looks interesting with a shorter half life. However, what I like about Rapamycin is that it has had a lot of use and therefore the safety profile is quite clear.

https://publications.ersnet.org/content/erj/53/3/1801992

Abstract

Phosphatidylinositol 3-kinases (PI3Ks) and mammalian target of rapamycin (mTOR) play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Omipalisib (GSK2126458) is a potent inhibitor of PI3K/mTOR.

A randomised, placebo-controlled, double-blind, repeat dose escalation, experimental medicine study of omipalisib in subjects with IPF was conducted (NCT01725139) to test safety, tolerability, pharmacokinetics and pharmacodynamics. Omipalisib was dosed at 0.25 mg, 1 mg and 2 mg twice daily for 8 days in four cohorts of four subjects randomised 3:1 to receive omipalisib or placebo (two cohorts received 2 mg twice daily).

17 subjects with IPF were enrolled. The most common adverse event was diarrhoea, which was reported by four participants. Dose-related increases in insulin and glucose were observed. Pharmacokinetic analysis demonstrated that exposure in the blood predicts lung exposure. Exposure-dependent inhibition of phosphatidylinositol 3,4,5 trisphosphate and pAKT confirmed target engagement in blood and lungs. 18F-2-fluoro-2-deoxy-d-glucose(FDG)-positron emission tomography/computed tomography scans revealed an exposure-dependent reduction in 18F-FDG uptake in fibrotic areas of the lung, as measured by target-to-background, ratio thus confirming pharmacodynamic activity.

This experimental medicine study demonstrates acceptable tolerability of omipalisib in subjects with IPF at exposures for which target engagement was confirmed both systemically and in the lungs.

https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/omipalisib

what research is there as to the side effects of omipalisib

ChatGPT said:

​Omipalisib (GSK2126458) is a dual inhibitor targeting the PI3K/mTOR signaling pathways, currently under investigation for its potential in treating various cancers and idiopathic pulmonary fibrosis (IPF). Clinical and preclinical studies have identified several side effects associated with its use:​PubMed+3PMC+3ASH Publications+3

Common Side Effects

  • Gastrointestinal Issues: Diarrhea is frequently reported. In a Phase I cancer trial, 8% of patients experienced grade ≥3 diarrhea, and in an IPF study, it was the most common adverse event .​PubMed
  • Skin Reactions: Rashes occurred in up to 74% of patients in some studies, with 5% experiencing severe cases .​EMBL-EBI homepage+1PubMed+1
  • Fatigue: Reported in approximately 21% of patients .​

Metabolic Effects

  • Insulin Resistance and Hyperglycemia: Omipalisib has been associated with dose-related increases in insulin and glucose levels, indicating potential insulin resistance .​UCL Discovery+1ERS Publications+1

Cardiac Effects

  • QT Interval Prolongation: Preclinical studies in dogs showed that omipalisib prolonged the QT interval and, under certain conditions, led to arrhythmias like Torsade de Pointes in 20% of subjects .​PMC

Tolerability

While omipalisib has demonstrated pharmacodynamic activity, its tolerability varies. In some studies, 42% of patients required dose interruptions due to adverse events . However, short-term dosing in IPF patients showed acceptable tolerability .​UCL Discovery+1gsk-studyregister.com+1EMBL-EBI homepage

Conclusion

Omipalisib’s side effect profile includes gastrointestinal disturbances, skin reactions, fatigue, metabolic changes, and potential cardiac effects. These findings underscore the need for careful monitoring and further research to fully understand its safety and efficacy.​

My Conclusion

It strikes me that there is limited research with humans and what appear to be worse side effects.

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#3

Well, c. elegance is a start wrt. longevity. But tons of stuff works in worms and not further up the evolutionary tree. The natural next move is mice ITP. Until then, I’m staying on rapa. As John says, rapa has a long term safety record, and we know at least a little about dose dependent side effects. This new drug is terra incognita in that respect. But even in short to medium term, we’d like to at least see some effects on biomarkers. It’s definitely an interesting molecule, but too much for my personal risk tolerance at this point, as all we have is c. elegance and mechanistic speculation. We need to see some longevity data starting in middle aged and older mice. Has this been submitted to the ITP? That’s what I’d start with. Until then, it’s just rapa for me.

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#4

I would love to see this molecule in the next Robust Mouse Rejuvenation study.

I see Alpelisib on the ITP. It’s not the same as Omipalisib, but it is similar.

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#5

@AustraliaLongevity @John_Hemming @CronosTempi

The GSK2126458 molecule, also known as Omipalisib or GSK458, lies close to my heart because it was one of the compounds that my lab initiative discovered last year with very interesting lifespan effects. Shortly after that another lab, Epiterna shared similar data. I have now been project leading two research proposals around the compound together with different researchers. One proposal was sent to the ITP to test the compound in mice and the other one was sent to CIPT to test the compound in different strains of roundworms. I’m also collaborating with a researcher in Singapore, Kamil Pabis, who is conducting experiments in flies. I have also recently launched another research project in flies (more on that in the future). On top of this I have started some discussions to test the compound in yeasts and human cells. So lots of data will come in the future. If someone knows someone else who may help with generating data around the compound please reach out!

Regarding human use then I would be very cautious to start experimenting with this compound. The compound is not FDA approved as Rapamycin and the human data is no near close to rapamycin. But I’m very curious to test the compound in humans if the data in multiple species are promising.

Here is an interesting image that I created to the ITP proposal.

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The thing I have started to think more about is that maybe the dose protocol needs to be either decreased or increased later in life to have a good impact also on maximum lifespan. So there is potential here for dose protocol optimization for sure.

PS 1. One very interesting thing with all these experiments is that we will get hints on how strong the hypothesis is that inhibition of mTORC1 leads to good effects and inhibition of mTORC2 leads to detrimental effects.

PS 2. Here you can find all lifespan data from Epiterna on the GSK molecule

PS 3. Here you can find lifespan data on PI3K inhibitor Alpelisib in roundworms

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#6

Congrats, Krister, you certainly came up with a very interesting molecule. However, I must confess I am rather disappointed with the pace of longevity research in general.

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#7

I fully agree, it’s very frustrating that things go so slow forward. One thing I have learned throughout life is not to wait for other people to do the things that I really want to be done. My view is that it really sucks to get old, suffer from diseases and then one random day be forced to die against your own will. I have seen my parents die, relatives die, friends die and other people die and it has never been a pleasant thing. I can not just accept this and keep watching this sh*t happening to others and eventually myself. This is why I have dedicated my life to trying to solve the puzzle of aging in a serious way together with other dedicated people and organizations. The more people who get involved in this the better the odds that we hopefully will find a solution before we die. So if there are people out there who want to help out just reach out!

Below is a pipeline that I have been developing for a time for the different combinational therapies which the Rapamycin Longevity Lab will develop in the future. I also think we really need to rethink how things are done in a traditional way and try to find much more efficient ways.

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In the below clip from vitalism.io I talk a bit more about the mission with the lab initiative.

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#8

Wow - yes, it’s basically just an investigational drug right now. It seems just phase 1 study from my quick search. As we see all the time - most drugs (I think like 70% of drugs) still fail in phase 2 studies, so a very high probability that this drug will not make it through safety testing.

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#9

Yes, the phase 1 trials are interesting but the thing to keep in mind here is that the dose is most likely way too high in these trials because the purpose here is to use it for treatment of disease and not for slowing down aging. My guess is therefore that the dose that may work better for longevity is a very low intermittent dose than a daily high dose. Let’s see where things land when more data comes but even if the case will end up that the safety data is bad then this is great useful data for other compounds that are developed. Every data point has its value in the overall longevity puzzle.

Here is another study in humans on the compound

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#10

ITP is currently testing Alpelisib. I’m glad you pushed Omipaliosib to them. Have you sent it to LEVF? I emailed them about it hoping they do it in the next RMR, but I think you contacting them would hold more weight.

From what I understand it has a shorter half life than rapamycin so the dose protocol would need to be different. It seems very promising so trying a lot of different variations seems worthwhile.

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#11

Yes likely once a week or so given then half life being shorter than rapamycin. Given it has stronger effects, it might even be once every two weeks.

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#12

What can we do to help?

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#13

@AustraliaLongevity Yes, I agree, it will be very interesting to see the effect on Alpelisib in the ITP. If you stumbled upon some interesting data on it then please share it.

Great that you have contacted Aubrey de Grey about proposing the GSK molecule to the RMR. I have also talked to him but it was more on an overall perspective where I asked if he is open to proposal to the RMR and he said yes. I also met him at the ARDD conference last year and talked about the next RMR study and what treatments they planned to use. The thing that can be good to keep in mind is that he is not so interested in interventions that just slow down the aging process. His goal is to find interventions that reverse aging and/or repair damage. The GSK molecule is not aligned with this and more aligned with slowing down aging. My own personal view is that the best longevity effect is probably achieved when powerful slow down aging interventions are combined with reverse aging interventions.

Thanks for asking about what possible things there are that people can help out with. I see lots of possible things but the biggest thing that I feel is slowing down the research progress is the funding part of it. It takes lots of time to try to get funding so here things need to be done in a more efficient way. If we as a group of people can start to collaborate around that part and find ways to accelerate the funding process then I’m confident that things will start to take off. I have some ideas on how things can improve and I experiment a bit also around this to see what may work better than the approaches I have tried out. We can start with an initial call to see if we connect and explore opportunities that align with your interests. What do you think about that?

#14

Aubrey and I disagree on this. I think improving mitochondrial efficiency is the reversal of aging. He doesn’t. He does not explain why, but that’s life.

#15

We can give that a go if you want.

#16

@John_Hemming: Aubrey de Grey has extensively discussed mitochondrial dysfunction in aging, but his approach differs from simply improving mitochondrial efficiency. He categorizes mitochondrial damage as one of the seven types of aging-related damage and focuses on repairing it rather than enhancing efficiency. His work emphasizes removing accumulated damage rather than reversing aging through metabolic optimization. If you’re curious about his perspective, you might find his discussions on mitochondrial mutations insightful.

@AustraliaLongevity: Great! I send you my calendar and you can pick one time which works for you.

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#17

I think I do fully understand his perspective. I always put a lot of effort into trying to understand why people disagree with me as that is how I can learn most effectively.

What people miss is the link between mitochondrial efficiency and gene expression (inclinding mRNA splicing). That includes Aubrey.

In fact it is the failure of homeostasis of the body that drives aging rather than damage per se. Hence homeostasis needs to be fixed.

An excellent example of this is elastin and other parts of the ECM which is why skin function is such a good test of attacking the key aging pathways. The same applies to wound repair. That is why I think my application to the UK’s Food and Nutrition Committee for an intervention to accelerate wound repair is quite a good path through the regulatory route. I expect them to be mildly difficult, but actually an intervention accepted to accelerate wound repair would be quite helpful.

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#18

I feel I’m humble around this topic because we don’t yet fully know what will work and not when it comes to radically extending human lifespan. Maybe you are right, vice versa or that you two are both wrong. Let’s see what the data will show in the future. Looking forward to hear more about your work in the topic and I wish you all the luck with your intervention that you are developing :pray:

#19

In the end the proof of the pudding is in the eating.

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#20

Yep send the calendar to me in a private message. I’d be happy to have a discussion to see if there is anything I can do to help.

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