Rapamycin Pilot Treatment Trial for ME/CFS

https://www.simmaronresearch.com/rapamycin-trial


The First Biomarker-Driven Treatment Trial for ME/CFS
Subsets Mean Success
Until now, the heterogeneity of the patient population and the lack of a reliable biomarker to diagnose and prognose ME/CFS has thwarted clinical trials for both non-approved FDA drugs as well as repurposed agents.

We have recently identified elevated levels of inactive ATG-13 as a testable and targetable pathway for treating symptoms of post-exertional malaise.

Biomarker to Treatment Trial
Rapamycin therapy inhibits mTOR and reduces autophagy disruption. We believe that a subset of patients may have chronic mTOR activation that can lead to the symptoms of ME/CFS. By taking rapamycin, the mTOR inhibitor, we hope that these people may see a significant reduction in symptoms.

We will track symptoms and autophagy markers in this study.

 

https://twitter.com/user/status/1723371505126412788

 

Encouraging, and something that definitely needed to be trialed but no control group and an 18month to two year study time is deeply frustrating, even with positive results there will need to be more studies and more studies before patients have any chance of getting their hands on the drug...

why not include a control group? Is there any good reason?

 

That’s encouraging. Their ATG13 work has been discussed here.

The trial size is big (n=100) or it’s at least relatively big for the fact that it isn’t placebo controlled and that there has hardly been any mTOR and ATG-13 research in ME/CFS.

Regarding @V.R.T. 's question on why there isn’t a control group, being an uneducated patient I can only speculate, but from what I can tell more researchers are adapting the stance that such studies can be used to create evidence for abnormalities in ME/CFS, i.e. use a drug trial to create evidence for its use and then take things from there, rather than creating evidence first and then trialling more rigorously. Scheibenbogen is following a similar path.

Of course now even in the unlikely case of positive trial results one has to wait at least 2 (this trial)+2 (an extra placebo-controlled trial) years, or something similar, but that would be the case anyways, because currently there isn’t much evidence that mTOR and ATG-13 play a role in ME/CFS so to have any grounds, to get funding, to do a large placebo controlled trial one would probably have to do another 2 years of research in any case. In that sense this trial is basically just these 2 years of research (with the big caviat of drugs possibly causing harm which lab work wouldn’t). At least that’s how I see it without having proper knowledge of the field. I also know that some people will probably dislike this approach as they’d first like to see somewhat bullet-proof evidence of mTOR/ATG-13 irregularities and then going straight to placebo-controlled trials.

The biggest problem I see is that the majority of pharmaceutical trials yield negative results (however this applies more to placebo controlled trials, non placebo-controlled trials often make any claims without providing any knowledge) and when they do so, they often do so without providing further context and knowledge and as a consequence often halt further research in similar directions and as such have an overall negative impact on other pharmaceutical companies. With that I hope the trial will look to the answer the following questions (and probably some even more important questions I'm not smart enough to think about):

• How many ME/CFS patients have irregularities in mTOR and ATG-13 (vs healthy and sedentary controls) and do they differ from other ME/CFS patients in any way (in terms of symptoms, onset, illness duration, severity or other markers)?
• What are the effects of Rapamycin on these irregularities within this trial?
• Were there markers of neuroinflammation? How did these correlate to other markers, including mTOR, ATG-13 (INOS, NO, ROS, protein aggregation/microclots?) or what ever else might be relevant and what was Rapamycins effect on them?
• What other effects did Rapamycin have?
• Are there any correlations of the above to exercise, PEM, cognitive function and sleep?
• (The main question on whether such a drug improves the quality of life of ME/CFS patients will remain unanswered as the trial isn’t placebo controlled.)

 

I imagine Simmaron simply does not have the resources to do a full trial with a control group (their annual revenue is about half a million dollars), so they are doing this trial which looks like it basically collects data from a few doctors who are prescribing it. They are collecting data on serum ATG-13 and other proteins, before and after, so there is something objective there (but the big question will be if there is any correlation between ATG-13 levels and severity, which hopefully this trial will give more data on). This seems like a good start to me, given the resources they have.

 

Doesn’t look like it.

 

I think the fact that they are looking at an objective outcome (ATG-13 in serum) makes it different, especially if they can correlate ATG-13 with severity before treatment begins (it would also be great if they did more work to compare ATG-13 in patients and healthy controls, since all they have published is about 10 of each, but maybe that's ongoing). Seems like this is better than just having various patients try it and no data collection at all.

It's very frustrating that no one is doing a RCT for aripiprazole. Seems like an obvious one for OMF (and better than LDN or Mestinon).

 

We can only hope that this "trial" will give them more insights in the underlying pathophysiology. I admire them for trying although the setup doesn't look that promising.

 

When I look at the list of side-effects, I wonder how many of us could even tolerate this drug if we had the chance to try it?

 

I know understandably so that every thread is usually filled with jadedness & a very heavy dose of cynical analysis (I’m at fault I’m sure being one of them).

Just wanted to point out that it’s great to see Mayo Clinic as a clinical participant in this for a clinical trial in ME, after years of dismissive behavior. That to me, is also a sign that things are moving. Just wanted to call-out, and I think sometimes it’s hard to acknowledge progress.

 

it is likely (I didn’t check links) a phase 2 a) trial, pilot study, which means they are testing the drug as an open-label to the study population to assess safety and effectiveness, and potentially dosage. We do know this drug is used for other purposes, but it hasn’t been tested for ME. A pilot study is needed to get funding for a larger sample and placebo-controlled trial.

Good clinical trials take time, unfortunately but we all want them to be performed with the highest standards of science with what we know at this time, and as for every drug trials, we must start with a pilot, then bigger studies with double blind, randomized trials as appropriate.

This drug gets me curious and excited, but who knows where it will lead us? Only through great science will we find out, and I know that Simmaron is to be trusted to find answers to whether Rapamycin could be helpful to some of us or all of us, and why.

 

My question would be why they want 100 patients.
No useful efficacy data will come out of this without controls.
So the only useful outcome I can see is evidence of an objective effect of the drug on metabolic tests relating to mTOR.
I would expect that to show after no more than two weeks and if it is consistent to be evident from about 20 cases at most, maybe 10.

Is the Mayo Clinic involved? I didn't see that.

 

From what I can tell, one of of the clinicians involved in the trial is from the Mayo clinic.

here is a quote from the frequently asked questions page about the trial:

In order to enroll in this trial you must be a patient under the care of the participating clinicians: Dr. David Kaufman MD, Dr. Daniel Peterson MD, Dr. Bela Chedda MD, and Dr. Stephanie Grach MD.

here is Dr. Grach's webpage at the Mayo:

https://www.mayoclinic.org/biographies/grach-stephanie-l-m-d-m-s/bio-20536370#!

It says that she trained with Dr. Lucinda Bateman.

 

This isn't actually the case. In this sort of situation going straight to a double blind controlled trial would be reasonable. If this is just a study of pharmacodynamics - effects of drug on pathways - then I do not see the reason for the size.

When I looked at rituximab for RA I did a tiny trial of 5 patients to show a biologic effect and went straight to a definitive double blind controlled trial with 160 patients. This study does not even appear to be a registered trial.

 

So it looks as if she is probably a fellow (senior trainee) aged about 30 who has recently joined Mayo or returned after Bateman Horne.

 

Rapamycin has been trialed by many and doesn’t really work. Potentially rapamycin PLUS lithium ( maybe 300mg) might work. I’ve posted on this before regarding a potential mechanism for this so I won’t repeat here. Plus there was a successful n=1.

 

I will be interested to hear the rationale for their study design, and look forward to results. I wonder whether they wanted 100 people to get an opportunity at trying the drug, versus 50 got it and 50 didn’t to gain wider knowledge about response to start with, then move on to the blinded studies if there is positive findings.

I am unsure whether budget was also a factor in their decision, whether there are additional costs to double blind, such as preparation of the drug.