Given the Pearl study didn’t quite deliver what we hoped in terms of dosage and sample size, what would it take for us to crowdsource and fund a study?
Can anyone put us in the ballpark of the cost?
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I think the PEARL study required an investment of around $400k.
Given the positive press and success of the monkey study it seems we could get more aggressive.
I like your thinking here. Time to plan a PEARL 2 study. How do people think it should be modified given what we know in now.
@szalzala any interest on your firms’ part to iterate and repeat?
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Just to add, I know that at least three other Rapamycin clinical longevity - oriented studies are starting or have started…
- NUS Singapore study (Andrea Maier’s study)
- Buck institute rapamycin study (Eric Verdin mentioned this to me last December - not sure of the status or details)
- U. Wisconsin Everolimus study by Adam Konopka - Everolimus Aging Study (EVERLAST) Trial Begins!
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There’s also Dr. Brad’s study.
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YES! But we need a serious principal investigator first. And then fundraising takes time as shown by the time Brad Stanley took to raise, or how much @Krister_Kauppi is struggling to get $100k.
Also, in an ideal world we should do a multi arm multi stage trial: one common placebo (to save money) and several drugs tested in parallel (metformin, SGLT2, rapa, etc.)
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I think a PEARL 2 (+) in the US (as opposed to NZ or Sweden) may have more funding traction, given the increasing awareness and use of rapamycin here.
In an ideal world it would be significant better powered to measure some sort of efficacy, and much wider range of dosing strategies; eg. 5/10/15/20mg week, 10/15/20/25 every two or three weeks, Sirolimus and Everolimus, with established protocols for deviations from lipid or glucose measures (e.g. use of statins/BA/Zetia, or SGLT2/Met).
Total number of participants? 400 to 600?
This would, I think get excitement from the wealthier people already using rapamycin for longevity as it would help them refine their strategy so has an immediate benefit for them.
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You’ve got to find someone who has more than $100 million in assets (What’s less than a million to them?) to consider funding this IMHO. Unfortunately, the people I know with this level of wealth aren’t interested… yet.
Most people really don’t think you can extend your lifespan or health span outside of the normal sleep, diet, and exercise route. A few (with problems) are good with statins/metformin. Others are into supplements that treat deficiencies. It’s a rare bird that will try Rapa.
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Trials are 10x more expensive in the US, so there’s a tradeoff.
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There are new ways to do more “virtual” trials the way PEARL 1 was conducted which are much more cost effective. The PEARL study was something like $400K I believe (and people had to pay for their rapamycin, I seem to recall). Seems like for a moderate increase from PEARL 1 (to say $1.5 to $2 Million?) maybe we could do a PEARL 2.
Mostly this would be focused on Safety at higher doses, but some level of efficacy as can be measured in a 6 month trial (more biomarker work, as is being done in the NUS study).
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PEARL (1) was hobbled by the placebo approach. Realistically moving the needle on geroscience is unlikely to be possible via a placebo must that reducing cortisol levels is normally good for health.
XPrize are looking at n=1 crossover trials where measurements are made of an individual and then you look for improvement of those measurements post intervention.
With Rapamycin there are complex issues relating both to dosing and timing of doses. Interestingly in researching side effects I found more recently angioedema (swelling) as potential side effect that I was not aware of previously.
https://www.jacionline.org/article/S0091-6749(06)02419-5/fulltext
Dose-Dependant Angioedema Due to Sirolimus
We report two cases of angioedema, associated with increased sirolimus levels, due to inhibition of isoenzyme CYP3A4 by voriconazole, a potent anti-fungal agent which is commonly used in the setting of bone marrow transplant.
Urticaria is hives.
Interestingly also
Sirolimus associated with improved outcomes in refractory chronic spontaneous urticaria
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It seems like the placebo issues they faced (compounded rapamycin issues) could be easily addressed with enteric coated capsules (obviously with bioavailability validated prior to the study, in a reasonably large population of people). I believe NUS is struggling with this issue right now also - so they will have solved it by the start of PEARL 2…
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What is needed with Rapamycin I think is a good study probably from case reports to start out with to find out at what threshold angioedema happens. It depends where the swelling is, but swelling in the throat and/or intestines can be quite serious.
Although this is probably not that much of an issue for people taking intermittent doses as the treatment is normally mainly to discontinue the use of rapamycin until the swelling subsides it is still probably the primary source of a potential acute risk to life from taking rapamycin.
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Looking a little further at the questions of deaths from mTOR inhibitors I found this review from Feb 24
https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(23)00258-1/fulltext
It appears that there are some deaths from evorilimus treatment. These tend to be people chronically using the drug.
Although no serious adverse events were attributed directly to treatment with rapamycin or its derivatives in the studies on healthy individuals assessed here, it is important to note that in six studies, only single doses of rapamycin or its derivatives were given.29,32,33,35,37,69 Although single doses of drugs can be used to study pharmacokinetic and pharmacodynamic characteristics, short-term tolerability, and safety, this approach is insufficient to confirm long-term safety. In a study where doses of 2–6 mg/day were given for 48 weeks, a significantly higher number of adverse events were reported in the treatment group than in the placebo group; specifically, infections were the most common adverse events,41 in accordance with empirical data on the occurrence of bacterial infections in users of off-label rapamycin.70 In addition, in the EXIST-3 study, which included everolimus-treated patients with tuberous sclerosis complex, aged 2–65 years, the core phase (18 weeks)71 reported a tolerable safety profile and no deaths; however, the subsequent extended phase (48 weeks) of the same study reported two treatment-related deaths attributed to pneumonia and septic shock in younger patients (aged <6 years) after the data cutoff date.72,73
Five deaths due to serious adverse events suspected to be related to everolimus occurred in a study including postmenopausal women with breast cancer treated with everolimus (10 mg) and exemestane (25 mg) daily for 48 weeks or until disease progression, unacceptable toxicity, death, or discontinuation for any other reason; the causes of death were pneumonitis, bilateral pneumonia, and disease progression.74 In another study, treatment-emergent adverse events resulting in permanent everolimus discontinuation occurred in 33% of individuals aged 65 years or older and 17% of those younger than 65 years.75 These results stress the importance of assessing the long-term safety of such treatments in healthy individuals.
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Yes - infection is the key risk if you take these drugs at high levels, with no breaks (i.e. immune suppression). So it would be good to get proxy measures for immune function - e.g. TREGs, WBC, etc.
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I have just done some calculations assuming a half life of 60 hours as to what the steady state concentration of rapamycin is for 40mg per day were one to take a single dose and measure the peak concentration. That single figure in fact is just over 160mg.
40mg is AFAICs the normal maximum dose used chronically for immune suppression.
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Reading through the comments already posted, here are my thoughts:
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One of the major hurdles to enrollment was the placebo possibility - many potential participants were reluctant to enroll because they did not want to risk being on the placebo
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PEARL “Phase II” is already underway as an observational longitudinal trial. There’s no formal control or placebo group, however it’s going to be a much larger data set in terms of the number of patients. We’re monitoring some aspects, such as various biomarkers and subjective feedback/QOL. We’re planning on adding more advanced testing, but it’s been difficult to find the right testing (since we really didn’t get anywhere with methylation or glycanage during PEARL)
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I think observational trials are probably the best way forward when it comes to testing not only a single therapy, like rapamycin, but multiple different therapies across many combinations
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AgelessRx is setting our sights on the XPRIZE Healthspan. We’re still deciding if we have enough resources to be competitive. Hopefully we’ll make a final decision before the years end in order to meet some of the deadlines. Doing well in the XPRIZE should attract large amounts of investment interest
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Yes to participate in PEARL. There was a nominal $360 I believe charge.
Well, at least you KNOW people with this level of wealth, so that’s a good start😜
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