Bezisterim seeks to intervene early in the inflammatory process.
There are “clinical trials”, “Clinical Trials”, and “CLINICAL TRIALS”. We in the ME/CFS world are used to small “clinical trials” that contain maybe a couple of dozen people, may or may not be placebo-controlled and randomized or not, etc., and are too small to tell us much but can spark interest and can lead to larger trials.
Then there are “Clinical Trials”: large, juicy trials that contain hundreds of people, are placebo-controlled, etc. but are not big enough to be definitive. Then there are “CLINICAL TRIALS”, which can contain thousands of people and are immediate standard setters.
The GIST
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Bezisterim seeks to intervene early in the inflammatory process
The Bezisterim ADDRESS-LC Clinical Trial that Solve M.E.’s recent webinar focused on is a big, juicy trial that is going to tell us much.
- Biovie, the drug company producing Bezisterim, glommed onto long COVID because the inflammation looked so much like what it had seen in Parkinson’s and Alzheimer’s disease. The trial leader, Biovie’s Dr. Penny Markham, has a close relative with longstanding ME/CFS.
- The trial, funded by the Department of Defense through the Congressionally Directed Medical Research Program, stands out in its expense ($13 million), its large size (over 200 people), and its rigor, including a 4-week pretrial period in which participants will be assessed to ensure they have long COVID.
- Plus, the Bezisterim trial may be the first time a drug company is testing a new (non-FDA-approved) drug in a major trial. Dr. Michael Peluso of UCSF believes the trial will be a trailblazer for long COVID – opening the way for other similar studies to take place.
- Bezisterim is unusual in that it seeks to turn off inflammation by interrupting very basic inflammatory pathways. Because the drug aims to regulate the immune system, not suppress it, it produces few side effects. Its ability to pass through the blood-brain barrier potentially allows it to reduce neuroinflammation. Plus, given recent study findings, its ability to stabilize insulin may be helpful in diseases like long COVID, ME/CFS, and fibromyalgia.
- Plus the trial will measure 400 biomarkers of inflammation/immunity, biomarkers of neurodegeneration, metabolic dysfunction, and DNA methylation (epigenetics) to learn more about long COVID and to find a “signal” that tells Biovie who will benefit.
- It can be a little hard watching long COVID get the big bucks while ME/CFS continues to get slim pickings, but the amount of money pouring into long COVID simply dwarfs that provided for ME/CFS. The way is long for the ME/CFS community, but everything we know suggests that advances in long COVID will ultimately benefit ME/CFS as well.
- Long-COVID patients between the ages of 18-64 with cognitive and fatigue problems who have had long COVID for less than 2 years can participate. Participants cannot have had ME/CFS/FM before getting long COVID. You cannot take LDN for a month before the trial.
- This is a “phase II” trial. If it’s successful, the company will move on to Phase III trials and attempt to become the first drug to get FDA approval for long COVID.
- Five trial sites are open now, but 19 trial sites will ultimately be available. The trial is moving fast and is expected to be complete by early 2026. Find out how to participate here.
The Bezisterim ADDRESS-LC Clinical Trial that Solve M.E.’s recent webinar focused on is the second. It’s a big, rigorously done trial that won’t give us the final word on this very intriguing drug, but if successful, it will open the door to the next trial and tell us quite a bit about long COVID in the process.
Solve ME/CFS Initiative President and CEO Emily Taylor talked with Dr. Penny Markham, the leader of the trial and a Senior Vice President at Biovie, the drug company which makes the drug; Dr. Michael Peluso, the co-creator of the LIINC project at UCSF and a very active long-COVID researcher; and Ezra Spier, a person with long COVID and member of the Patient-Led Research Collaborative.
Dr. Markham said Biovie started thinking about and working on long COVID around 2022. Markham, who has a family member with a 30-year case of ME/CFS, said that when Biovie realized that the inflammatory footprint of long COVID jived with what Bezisterim can do, it applied for funding to the RECOVER Initiative (but was denied). After pivoting to the CDMRP (Congressionally Directed Medical Research Program) – which is committed to funding high-risk/high-reward studies – the trial was funded by the Department of Defense for a cool $13 million.
(While it wasn’t highlighted in the webinar, this trial likely wouldn’t have happened without ME/CFS and long-COVID advocacy. Several years ago, Solve M.E. worked to get ME/CFS included in the Congressionally Directed Medical Research Program (CDMRP) which is committed to “high risk/high reward” research that the NIH, for instance, might not support.
Since that time, several million dollars in ME/CFS grants have been awarded. Then two years ago, ME/CFS advocates got ME/CFS and long COVID singled out as “high-priority” diseases, giving them first choice at the trough. That designation helped Biovie win its $13 million grant for a clinical trial. (That equals the entire funding the ME/CFS field gets from the NIH yearly.) )
The Trial
First, Ezra Speir, who knows the clinical trial long-COVID world, laid out how patients were involved in producing the trial, and why he’s so excited about this particular one. Indeed, while a large drug trial that addresses one of these diseases is noteworthy, the ADDRESS-LC trial stands out in a number of ways.
Dr. Peluso said that for the last five years, it felt like they were “banging their heads against the wall” in the long -COVID clinical trials sphere, but that seems to be changing. As he noted in a recent Health Rising interview, he believes the “first generation” of long-COVID trials has opened the door for a 2nd generation of trials, which features more drug company involvement and better trial designs.
Dr. Peluso felt, though, that the most important thing about this trial is that it’s being done at all. The new drug, the public/private funding partnership, the rigor of the trial, the exploratory measures, and the expense ($13 million-plus!) are showing that the long-COVID field has legs and has matured as a field. He expects the Bezisterim trial to lay the groundwork for similar trials to come.
Bezisterim
Indeed, the ADDRESS LC trial is not your usual long-COVID drug trial. Peluso noted Bezisterim is not a repurposed drug (the RECOVER Initiative is only studying repurposed drugs) but is a brand-new, yet to be FDA-approved drug, and an exciting one at that. This may be the first time that a drug company is taking a chance on testing a new, not yet approved drug in a major long-COVID trial.
Bezisterim seems a drug apart. It seeks to dig so deeply into our biology that it doesn’t fit common drug categories. Listed as an “anti-inflammatory and insulin sensitizing drug,” it potentially has such a wide-ranging effect that it fits into a number of drug categories, including anti-dementia, antiepileptic, antirheumatic, antineoplastic, antihyperglycaemic, antiparkinsonians, antiviral, and nootropic.
Plus, Bezisterim is attempting to get at something more fundamental than most immune drugs. It attempts to turn off (or tamp down) the TLR-4 inflammatory pathway which has been implicated in long COVID and ME/CFS. It’s ability to get through the blood brain barrier means it has the potential to impact neuroinflammation. Plus, its mission – to reregulate immune functioning (instead of to merely suppress it or increase it) – means it produces few side effects.
Dr. Markham explained how the spike protein of the coronavirus can turn on the TLR-4 pathway, but some evidence suggests this pathway may also be turned on in ME/CFS. The effectiveness of low-dose naltrexone – another TLR-4 inhibitor – provides another reason to think this drug might work in ME/CFS and fibromyalgia.
By taming the TLR-4 pathway, Bezisterim is able to calm broad inflammatory pathways such as ERK and NF-kB, which produce an array of inflammatory products (IL-1, IL-6, IL-8, TNF-α).
A long-lasting metabolic derivative of DHEA, Bezisterim is not only anti-inflammatory but is also “insulin-sensitizing”, and that’s potentially a big deal for ME/CFS, fibromyalgia, and long-COVID patients.
A UK Biobank study that examined more than 3,000 blood-based biomarkers found evidence of chronic inflammation, insulin resistance, and liver disease in ME/CFS. Likewise, studies suggest that insulin resistance may be common in fibromyalgia and long COVID. Peter Attia, MD has convincingly shown that problems with glucose regulation and insulin resistance underlie many major chronic illnesses.
Alzheimer’s / Parkinson’s Drug?
Biovie clearly has high hopes for Bezisterim as they chose for their first exploratory trials two of the knottiest diseases of all – Parkinson’s and Alzheimer’s. Their small, 7-month, randomized, double-blind, placebo-controlled trial of people at mild/moderate risk of Alzheimer’s delved deep into Bezisterim’s effect on biology.
While the small Alzheimer’s trial was not successful in significantly moving the needle on cognitive performance, improvements were seen, and Bezisterim was able to improve measures of metabolism, oxidative stress, inflammation, aging, and dementia. Gene expression studies suggested that Bezisterim was turning back the clock on many markers associated with Alzheimer’s, including neurodegeneration (lowered amyloid levels), biological aging, oxidative stress, dementia, metabolic, and inflammation. Plus, in Parkinson’s, the drug was able to improve fatigue/energy.
The ADDRESS LC Study
Bezisterim study design.
The ADDRESS LC trial is also uncommonly rigorous. The 12-week, 208-person study includes a 4-week screening period (to rule out other causes of cognitive problems or fatigue) and a 4-week follow-up period. Concerning symptoms, the trial is focusing on cognitive problems that have been validated in long COVID, and is assessing PEM and other symptoms, including a specific focus on tinnitus (:)).
Then there are the “exploratory measures” including over 400 biomarkers of inflammation/immunity, biomarkers of neurodegeneration, metabolic dysfunction, and DNA methylation (epigenetics). Biovie is assessing to understand the biological effects the drug is having, learn more about long COVID, and find a “signal” it can use to identify who benefits from the drug.
Now that’s a clinical trial!
An ME/CFS Note
Yes, the way is long for people with ME/CFS! It seems inevitable, though, that progress with long COVID will move ME/CFS forward as well.
It can be a little hard watching long COVID get the big bucks while ME/CFS continues to get slim pickings, but that’s where we’re at.
In the webinar, Ezra Spier reported how dismayed he was when he learned that his 3-year case of long COVID meant he couldn’t participate. I’m sure he can imagine how people with 10, 20, or more years of ME/CFS feel as they see the many long COVID treatment trials going on…without them.
There’s no denying that the way has been and is long for ME/CFS. Not taking into account the hundreds of millions of dollars a year long COVID is getting via the Congressional authorization to produce the RECOVER Initiative, the NIH, on its own, is spending over $100 million/year on long COVID. (It’s spending $13 million/year on ME/CFS.)
Good or bad, right or wrong, long COVID is where the money is at – and thank god that at least, it’s getting good funding. We must remember that every step forward for long COVID is also a step forward for ME/CFS. Every big, long COVID study or trial is a potential benefit for this disease.. Virtually every long COVID researcher says they have post-infectious diseases like ME/CFS on their minds as well.
If the long-COVID Bezisterim trial works out, the company plans to move to ME/CFS. After all, if the inflammation in long COVID is close enough to Parkinson’s/Alzheimer’s for Biovie to make the jump into long COVID, how much easier will it be for it to make the jump into ME/CFS.
Participating in the ADDRESS-LC Trial
Long-COVID patients between the ages of 18-64 with cognitive and fatigue problems who have had long COVID for less than two years can participate. Participants cannot have had a prior case of ME/CFS/FM. Participants cannot take LDN for a month before the trial or during the 12-week trial.
Unlike other clinical trials, Biovie is not letting the grass grow under its feet. There are no five-year waits for this study – it is moving with lightning speed. The trial has already begun, data collection is expected to be complete in November of this year, and the trial is expected to wind up in Jan 2026 (!).
This is a Phase II trial to assess efficacy and safety. If the trial is successful, Phase III trials to get FDA approval for the drug will begin.
Nineteen sites are planned (five are active right now). If you live near a site that hasn’t been activated, give it a bit of time, and the contact information will be posted.
Want to be part of the study?
Find out how to sign up here.
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Two big problems which bias the trial towards appearing to work when it actually doesn’t. The first is the 4 week followup, it needs to be a lot longer than that, at least 6 months, we need to ensure relapse doesn’t occur.
The second thing is trying to select patients who are more likely to just recovery with the less than 2 years requirement. There is no reason to do that and its a form of bias that is common. I also suspect they are going to require people walk into their clinic and not defend them from reinfection, further biasing towards mild patients and risking the trial results with noise from reinfections.
Despite their claims about learning from early trials it sounds like its the same errors we have been watching for years.
Interesting point about the possibility of a spontaneous recovery from people with shorter cases of long COVID. I hadn’t thought of that. If I remember correctly, after two years recoveries become rarer and rare. I guess they had to weigh that against the increasing likelihood of more things going wrong over time (???). As I remember clinic visits are going to be a part of the trial – maybe Ezra can chime in here – and home visits will take place as well.
They are learning, though. They’re being more careful about the participants in the study (4 week pretrial period – outside of the intramural study, I’ve never seen that before), and (my favorite) doing lots of exploratory studies alongside the trial.
“In the webinar, Ezra Spier reported how dismayed he was when he learned that his 3-year case of long COVID meant he couldn’t participate. I’m sure he can imagine how people with 10, 20, or more years of ME/CFS feel when they are shut out of the many long COVID treatment trials going on.”
I sure can, Cort – the lack of trials for ME/CFS is infuriating to me.
Thanks so much for covering the trial.
Ezra! You did such a great job at the webinar! I’m sorry I didn’t get more of your presentation in the blog. Thanks for commenting – and thanks for your support:)