Astellas' Bocidelpar - drug to restore mitochondrial function

John Mac

John Mac

Senior Member (Voting Rights)
Post has been moved from the "United Kingdom: ME Association news" thread

Mitochondrial dysfunction in Long Covid and ME/CFS

David Systrom, a pulmonary and critical care doctor at Brigham & Women’s Hospital, Boston, believes he has found answers through studying patients with ME/CFS, an illness that in many cases is precipitated by viral infections such as Epstein-Barr and bears many similarities to long Covid.

When Systrom studied the mitochondrial DNA of these patients it appeared to be normal, but after taking a deep look and conducting muscle biopsies, he identified abnormalities at the electron level, deep within the mitochondria.

“In both ME/CFS and long Covid it’s most likely that these are acquired forms of mitochondrial dysfunction, perhaps related to the initial infection itself or an autoimmune response to a virus or both,” Systrom says. “This impedes the mitochondrial machinery, but doesn’t affect the DNA itself, and it means the mitochondria then fail to generate appropriate amounts of ATP to serve the needs of the muscles.”

Systrom is now running his own clinical trial in both ME/CFS and long Covid patients, in partnership with Japanese drug company Astellas, which has developed a drug that aims to restore normal mitochondrial metabolism.

https://meassociation.org.uk/2022/06/mitochondrial-dysfunction-in-long-covid-and-me-cfs/





 
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Jaybee00 said:
https://www.fiercebiotech.com/biote...s-inks-180m-deal-bolster-mitochondria-rd-unit
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Astellas is hunting for small molecules that modulate target proteins through activation, stabilization or degradation, mechanisms that enable researchers to get at otherwise undruggable targets. The general concept has taken off in recent years, with companies such as Pfizer identifying protein degradation as a way to open up previously undruggable targets and betting big to enter the field.
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Sounds novel/ interesting, but does anyone have an inkling how promising this line of research is and how relevant to ME/CFS?
 
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The inclusion criteria for the Astellas Bocidelpar MECFS trial being undertaken by Systrom in Boston is not an MECFS diagnosis but is this

https://clinicaltrials.gov/ct2/show/NCT04855201

“Participants with reduced maximum oxygen uptake due to poor SOE, defined as peak exercise ([Ca-VO2])/[Hb]) ≤ 0.85 and VO2max < 85% predicted in the absence of a cardiac or pulmonary mechanical limit, determined by aCPET within 6 months prior to day 1 or participants with reduced maximum oxygen uptake due to poor SOE, defined as peak exercise ([Ca-VO2])/[Hb]) ≤ 0.85 and VO2max < 85% predicted in the absence of a cardiac or pulmonary mechanical limit, determined by historical aCPET within 45 months of screening and confirmed reduction in skeletal muscle citrate synthase activity”

So is it possible that there will be subjects included in the trial who meet this criteria but do not have an MECFS diagnosis?

Conversely, I imagine there will be MECFS -diagnosed patients who don’t meet this criteria?

I imagine they designed the criteria this way because they believe the drug will only work on a specific subset of MECFS patients?

Tagging @Snow Leopard as he is the resident expert on this stuff—thanks.
 
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There is nothing at that link to indicate that the trial, titled "A Study to Evaluate ASP0367 in Participants With Reduced Maximum Oxygen Uptake Due to Poor Systemic Oxygen Extraction", is designed to be one on ME/CFS. Has it been promoted as a trial for ME/CFS patients?
 
Actually after reading the Cort Johnson article I see this, which at least answers one of my questions

“Systrom stated that the 1,500 invasive CPETS he’s done over the years suggests that 20-25% of ME/CFS patients have enough problems with oxygen uptake to at least meet the criteria for the study.”

So it will only be a small subset of MECFS patients.

Im guessing that if they extended the trial to include all MECFS patients, then Astellas would be concerned that the trial would fail due to the inclusion of many non-target MECFS patients.
 
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Scanning that article I have no idea if Cort actually spoke to Systrom or Astellas about it or he has put the article together from information from other sources. But looking at the Astellas clinical trials website, they list it as "A study to evaluate ASP0367 in participants with primary mitochondrial myopathy", https://www.clinicaltrials.astellas.com/study/0367-CL-1201/

inclusion criteria includes
  • Diagnosed with primary mitochondrial myopathy (PMM), consisting of the following:
  • Molecular genetic abnormality (i.e., nuclear or mitochondrial) known to be associated with causing mitochondrial dysfunction (such as, but not limited to, mitochondrial DNA (mtDNA) single, variable deletions in chronic progressive external ophthalmoplegia (CPEO) and Kearns-Sayre syndrome (KSS); mtDNA m.3243 A > G common mutation in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS); pathogenic nuclear or mitochondrial genome variants demonstrated to cause primary mitochondrial disease), and
  • Participant reported symptoms (i.e., muscle weakness, fatigue and exercise intolerance) or physical examination findings of myopathy that are the predominant symptoms of the participant’s mitochondrial disorder.
So they are not selecting ME/CFS patients, they are selecting PMM patients.
 
Correct. Which is why I asked my question about how they developed the inclusion criteria. I’m guessing if they said all MECFS patients could be included, then the trial would fail because at most only 20-25% would respond (the target subset). But I wonder if they could have said 1. an MECFS diagnosis AND 2. Meet the above criteria. But perhaps there are people that meet the inclusion criteria who do not have MECFS?
 
Jaybee00 said:
Correct. Which is why I asked my question about how they developed the inclusion criteria. I’m guessing if they said all MECFS patients could be included, then the trial would fail because at most only 20-25% would respond (the target subset). But I wonder if they could have said 1. an MECFS diagnosis AND 2. Meet the above criteria. But perhaps there are people that meet the inclusion criteria who do not have MECFS?
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20-25% is better than the estimates for DecodeME which is only looking at a 10% subset with existing diagnosis. There should be quite a lot that fit this criteria especially if they are only looking for hundreds to thousands although it depends in how big an area and with what level of commitment. Still 20-25% isn't all that bad when the vast majority of ME studies done so far have been only accessible to the top 50% of capability.
 
Jaybee00 said:
And here’s a Guardian article that mentions the Astellas trial for MECFS and LC.

https://www.theguardian.com/science/2022/jun/26/can-our-mitochondria-help-to-beat-long-covid
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Is it the same trial? The Guardian one is about an Axcella trial, based at Oxford University in the UK, and the one this thread is about the pharmaceutical company seem to be called Astellas, and the trial is at Brigham hospital in Boston, US..

Is it the same company with different names in UK and US?
 
Andy said:
I'm not sure where that figure for DecodeME came from because I can tell you that it is definitely not true.
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It's the estimate for how many people have a diagnosis for ME in the UK out of the estimated sufferers. I raised a comment about a while back on the thread, it is the current estimate for primary sub selection for that study and actually its subselecting to about 2/3 of that in practice with hidden criteria in practice. So I guess around 6% is more accurate only that last one is clinical criteria.
 
But the two things are completely different.

Systrom apparently believes that 20-25% of ME/CFS patients have what is the selection criteria for this non-ME/CFS study, so for that subset to take part they would a. have to have an ME/CFS diagnosis and b. be tested to confirm a diagnosis of Reduced Maximum Oxygen Uptake Due to Poor Systemic Oxygen Extraction.

People who have a confirmed diagnosis of ME/CFS, are aged 16 and over, and are based in the UK can take part in the questionnaire phase of DecodeME. Our selection process then selects from those participants those we would like to donate a sample of DNA. We hope to be able to ask 25k (20k onset pre-covid, 5k onset post-covid). Why 25k? To provide robust results and because our funding limits us to that.

Of the two, DecodeME is recruiting nation-wide, with participation possible from home. For the trial being discussed in this thread, the testing needed to confirm the diagnosis is done via CPET, and then there is a CPET that is done at start and week 6, so I very much doubt that 20-25% of all ME/CFS patients could take part in this study - it would be more like a tiny fraction. [ETA: They are also only recruiting 40 participants. So a tiny tiny fraction.)

BrightCandle said:
with hidden criteria
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We have already explained why that is and that we will list the full criteria when we publish.
 
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Confusingly, the Guardian article mentions both the Astellas and Axcella trials (which are completely different). From the article:


“In both ME/CFS and long Covid it’s most likely that these are acquired forms of mitochondrial dysfunction, perhaps related to the initial infection itself or an autoimmune response to a virus or both,” Systrom says. “This impedes the mitochondrial machinery, but doesn’t affect the DNA itself, and it means the mitochondria then fail to generate appropriate amounts of ATP to serve the needs of the muscles.”

Systrom is now running his own clinical trial in both ME/CFS and long Covid patients, in partnership with Japanese drug company Astellas, which has developed a drug that aims to restore normal mitochondrial metabolism.“
 
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