Still Here, August 11: Links and transcript

Summary

In this episode of Still Here: A two-way between Felicity Nelson and Betsy Ladyzhets comparing and contrasting the BC 007 and rapamycin Long COVID and ME clinical trial designs.

Find our Long COVID news and commentary podcast on Spotify, Apple Podcasts, Pocket Casts, Amazon Music, iHeartRadio, or listen below and jump to the start of the podcast transcript. We’re currently experimenting with our format, so this is an episode sans COVID trends focused on just one top story.

Jump to a specific part of the transcript:

• Intro
• 2-way: Clinical trial design, BC 007 and rapamycin
• Outro

Still Here overlaps with The Sick Times’ newsletter, which publishes weekly.

Mentioned in this episode (in order of appearance):

• The Sick Times: Clinical trials are testing cancer drug rapamycin for Long COVID and ME
• The Sick Times: Berlin Cures’ failed Long COVID clinical trial yields lessons on study design
• Research Square: Simmaron preprint on low-dose rapamycin clinical trial
• medRxiv: Erlangan preprint on BC 007 clinical trial
• The Sick Times: How volunteering to be a lab rat paid off

Additional audio in this episode: 

• Rude Mechanical Orchestra: Which Side Are You On? (orig. Florence Reece) 

Transcript

Intro (0:00) 

[Instrumental snippet of theme song, the Rude Mechanical Orchestra’s rendition of “Which Side Are You On?” begins playing.]

James Salanga: Welcome to Still Here, a Long COVID news and commentary podcast from The Sick Times.

[Instrumental ends]

Miles Griffis: Hi, I’m Miles Griffis.

Betsy Ladyzhets: And I’m Betsy Ladyzhets. We’re the co-founders of The Sick Times. 

James: I’m James Salanga, and I’m Still Here’s producer.

Miles: Many institutions are ignoring the ongoing COVID-19 pandemic and trying to erase the Long COVID crisis.

Betsy: But here at The Sick Times, we’re not. We’ll continue to bring you the latest Long COVID news and commentary each week.

Miles: Without pandemic denial, minimizing, or gaslighting.

James: And we’ll do that on our website, social media platforms, our newsletter and this podcast. [In this episode,] Betsy and writer Felicity Nelson will be talking about two features that they wrote about clinical trials for Long COVID and how they’re designed.

Those stories focus on trials testing the drugs BC 007 and rapamycin. And we’ll get into that two-way after a quick musical break.

[instrumental segment of theme song plays]

The Sick Times: Clinical trials are testing cancer drug rapamycin for Long COVID and ME, Berlin Cures’ failed Long COVID clinical trial yields lessons on study design (1:15)

Betsy: So in the last couple of weeks, The Sick Times has started publishing a series of features on Long COVID clinical trials and how they’re designed.

The first story in that series focuses on a drug called BC 007, also known as rovunaptabin.

And the second piece talks about a drug called rapamycin, which has long been used for organ transplants, cancer treatment, and other features like that.

So these two stories offer two distinct perspectives into clinical trial design.

I reported the BC 007 story, and I’m here with freelancer Felicity Nelson, who reported the feature on rapamycin.

We’re going to talk about each drug and some of the distinctions and challenges in trialing them as Long COVID treatments.

Thank you for joining us, Felicity.

Felicity Nelson: It’s great to be here.

Betsy: So could you maybe talk a bit about the history of rapamycin and what it’s been used for? Because I know it has kind of an interesting backstory.

Felicity: Yeah, it’s got a fascinating backstory that goes way back into the ’70s.

It was first discovered on a very remote island called Rapa Nui, which is also known as Easter Island. And a group of scientists went on an expedition from Canada to survey the island, and as part of that, they picked up a whole lot of soil samples.

Eventually, that got investigated, and they found that there was some bacteria inside those soil samples that produced a compound that they eventually called rapamycin, which is after Rapa Nui.

And this compound had really extraordinary abilities. It was an anti-cancer drug, and it also seemed to suppress the immune system.

Initially, they couldn’t really find any uses for it, because suppressing the immune system made it seem a little bit useless as a drug.

But when the ’80s rolled around, it turned out that suppressing the immune system was quite useful for transplanting organs, because you need to make sure that people don’t react, their immune systems don’t react to these organs that have been put in their body that aren’t theirs.

Nowadays, rapamycin is used in basically all organ transplant recipients.

There are drugs called rapalogs, which are very similar to rapamycin, and they’re used as anti-cancer treatments today.

One of the interesting twists and turns in the story was that the drug was almost lost to history after the pharmaceutical company that was investigating it abandoned the research.

But interestingly, a rebel scientist rescued the samples literally from the trash and eventually reignited interest in the research because he was so fascinated by it. And he also sadly developed cancer and used rapamycin to treat his own cancer, which is another whole fascinating part. And it seemed to work as well, although it’s hard to tell because it was just one patient.

It’s gotten even more interesting recently as a series of animal experiments in mice and worms and fruit flies have shown that rapamycin has tantalizing potential as a longevity drug. So in these animal models, it seems to make mice live longer.

Now there’s a couple of companies that are prescribing rapamycin for longevity to humans, and there’s a few studies looking into this.

They don’t yet have extraordinary results, but there’s a whole community of people who are, you know, really excited about rapamycin as a longevity drug.

Betsy: Fascinating. That’s so cool about how it was saved from the trash.

I feel like that’s the level of commitment that we need for Long COVID research, trying to hold on to these potential treatments, no matter what.

Felicity: Yeah, it’s amazing history, and it just goes to show that sometimes you need those scientists who really believe in their research to just hold on to it.

And you see that a few times in the history of science where scientists put their own life on the line and their careers on the line to really pursue something they care about.

And so tell me a bit about the history of the drug you were investigating, BC 007.

Betsy: Yeah, so not so much of a long history in this case, I would say.

But it’s based on around 20 years’ worth of research from a group of scientists in Germany into autoantibodies, which is this term for what happens sometimes in the immune system, where components mistakenly attack the body as if body parts are actually outside pathogens or outside invaders, and can lead to things like inflammation, cause all sorts of issues, because essentially the immune system is attacking when it shouldn’t be.

Autoimmunity now is one of the theories for Long COVID.

So research has previously been studying BC 007 for heart disease.

Specifically, there was one clinical trial completed in 2018 that found the drug was safe for treating chronic heart failure, and that it could neutralize a specific type of autoantibody that blocks something called G-protein-coupled receptors.

So those are molecules that are involved with a bunch of different functions in the body.

So these researchers have been studying BC 007 for heart disease, but then realized maybe it could also work for Long COVID.

And so that kind of led to the trials that have happened in the last couple of years.

We know that both of these drugs have garnered a lot of excitement in the Long COVID community.

What’s going on right now with rapamycin? I know your story covers two clinical trials that are underway at the moment.

Felicity: Yeah, that’s right. There’s two trials that have started. One is at Mount Sinai, and another one is at Simmaron Research. These trials look at Long COVID and ME.

Sinai’s trial is randomized and placebo-controlled, which is considered the gold standard and a good way of finding out whether the drug actually works for these diseases. Whereas Simmaron’s research isn’t randomized or placebo-controlled, which doesn’t mean it’s not useful.

It just means it can’t give us as much information about the efficacy of the drug. It can tell us things about biomarkers and other interesting information.

However, there has been some research release from Simmaron.

They’ve given us a sneak peek into their clinical trial via a preprint, which came out in June.

Of the 40 people with ME who were taking low-dose rapamycin over three months, around 70% showed improvements in fatigue, post-exertional malaise, and orthostatic intolerance.

Again, it’s hard to know what that means given the trial design, but it is promising and an interesting result that shows that we might expect some more interesting results down the line when these studies wrap up, which should be in the next year or two.

Betsy: I guess the early results [are] showing that it looks like it might help some people, but obviously a lot more research is needed to get more definitive findings.

So you mentioned Simmaron is also looking at biomarkers. Could you say more about what that process is like?

Felicity: Yes. So I spoke to a researcher at Simmaron and the chief scientist, I guess, can’t remember his exact title.

And they were both really helpful and talked through some of the mechanistic studies that they’d done in the lead-up to launching this clinical trial in humans.

And some of those mechanistic studies are very complex and all about various cellular processes that are going on and why they think rapamycin might be doing something useful in the cell to basically boost the health of mitochondria, which are the energy-producing organelles in the cells, little structures that just push out ATP, which is like energy molecules.

And their theory is essentially that these mitochondria, when they get old and dysfunctional, they’re not getting broken down fast enough in people with ME and they’re not getting replaced.

So basically they think people with ME have in their muscles these energy-producing cells that are just a bit sort of tired and not working properly.

Rapamycin might be able to help with that by speeding up the process called autophagy, which is where the cells sort of repair these old and dysfunctional organelles.

And what they found in their clinical trial was that the participants with ME who responded best to rapamycin were those that had a history of viral infection or reactivation or notable shifts in blood biomarkers that were associated with autophagy, which is that process we were talking about.

So that’s sort of interesting because it lines up with what they originally showed in their mechanistic studies.

If this finding holds up with further research, doctors might be able to use blood tests to screen patients for potential treatment with rapamycin, which would be really cool.

Betsy: You know, researchers really want to be able to pair the specific treatments that they’re testing with specific biomarkers that both could help select participants for a trial and then also help measure how well the treatment is working.

Like, that’s the ideal scenario, but we’re not really there yet with both the testing and the treatment options that we have.

So it’s cool to hear that Simmaron is looking at both of those things at the same time.

Felicity: Yeah, that’s one of the things that kept coming up is that if you don’t have a biomarker, you’re on the risk of accidentally lumping in a whole lot of different types of illness that don’t all respond to rapamycin.

If you’re not targeted enough, that could dilute the results and you might get a non-finding, when in fact the drug may help for a subset of those patients.

So that’s why it’s super important for us to find these biomarkers, because otherwise doctors aren’t going to feel comfortable prescribing these drugs because they just don’t know if they work well enough.

Betsy: Yeah, I feel like that actually transitions well into the BC 007 studies, because my reporting suggests that this is maybe what could have happened in the phase two trial run by the company, Berlin Cures, that produced this drug.

So let me talk about that a little more.

Earlier in the pandemic, there were some case reports suggesting that a handful of people with Long COVID were really helped by this drug. But of course, the case series is a very different type of evidence than an actual clinical trial.

It’s just a few people who are experimenting with something with the help of physicians and researchers.

So these reports led to two trials in Germany, one that was run by Berlin Cures, the company that produced BC 007, and one by a research center at the University Hospital Erlangen.

So the Berlin Cures trial was more of a large randomized controlled trial phase 2 study, including about 120 participants.

The Erlangen study was a smaller one with about 30 participants. That one was a bit broader in the measurements that it was using, and also was aiming to look at like safety signals and kind of a range of measurements.

With the trial run by Berlin Cures, I think — I feel like it’s sort of a well-known story at this point.

The trial ended really abruptly with a press release that was posted by the company in November of last year, where they essentially said, “Our primary outcome was not successful. We didn’t see a difference between the treatment group and the placebo group. And also we’re out of money and we’re not doing any more research.”

So that was basically the press release.

People were really disappointed and that was what led me to start looking into this and try to figure out what happened.

And of course, it’s difficult to say for sure because, you know, the company ran out of money, so there’s no like full report. There’s no scientific paper with these results yet.

But I was able to talk to some participants in the trial as well as outside researchers who kind of looked at the study design information that’s publicly available in places like clinicaltrials.gov.

So there are a few reasons why both participants and experts think this study may have maybe not necessarily been not successful, but maybe not [in the] best position to actually capture a more accurate outcome of how well this drug performs.

One goes back to this question about biomarkers. Berlin Cures was using a specific test that they developed of autoantibodies to screen people for the trial.

And one of the researchers who I spoke with, Artur Federowski at the Karolinska Institute, who is a long-time POTS expert and who has studied this type of dysfunction, basically called the test into question, said it might not be reliable.

And participants who were in the trial also noticed some potential issues with the test.

They said that some people who were really trying to get into this trial because they were so excited about this drug were potentially getting screened multiple times at like different study sites and essentially going over and over until they got a positive result, which suggests that perhaps the test was not the most reliable in screening people.

So that’s one kind of challenge that came up.

Another is that outside of that test, the study was rather broad.

So it included people who had a wide range of Long COVID symptoms, wasn’t really using other specific tests or biomarkers.

It may be that the study maybe could have been more specific in selecting participants who were likely to be helped by BC 007.

There are also some questions about the outcomes measures that the study used — that maybe they didn’t do a good enough job of measuring impacts on things like post-exertional malaise or other kinds of common symptoms.

They mainly used a fatigue score that has gotten some critique in the Long COVID and myalgic encephalomyelitis communities.

And there were some other issues that came up from the study participants that I talked to — things like really long study visits that may have led people to experience post-exertional malaise sort of while they were getting the infusion or while they were doing follow-up visits that were meant to be testing how the drug had impacted them, some issues with communication, lack of acute COVID precautions.

And there’s other stuff too that really didn’t make it into the full article. People were saying that trial staff were telling them that they could tell who got the placebo and who got the drug based on symptoms, which is just really not something that aligns well with the ethics of doing these trials.

So I think there are just a lot of potential issues that came up.

And it’s also of course hard to examine, like I said, because there’s no paper yet.

It might be that the study design was sort of not well suited to really answer that question of, “Is BC 007 helpful for people with Long COVID?”

Felicity: Interesting.

The people you spoke to, did any of them have positive experiences?

Betsy: Yeah. So there was one person, her experience is sort of the lead of the story, who had a really positive experience.

The participants were later unblinded, so people did find out which option they received.

And so it seems sort of mixed.

Also, the Erlangan study, which was the smaller one, did put out a preprint of its results in December and found that the drugs seemed to help some people. Bit of additional evidence, although that was a much smaller trial.

Felicity: And were there side effects?

Betsy: Both trials, the Berlin Cures one and the Erlangan one, found that the drug was safe and that there weren’t major safety issues. Although, of course, this is just based on the press release, which was very brief.

So hopefully eventually we’ll get more details about anything that might have come up from that trial.

Felicity: And this drug is to do with DNA targeting.

Is that right? How does that work?

Betsy: It uses, like, genetic material to target this specific cause of autoantibodies, basically.

Felicity: That’s super fascinating.

Why did they think that particular one was going to work as opposed to any other autoantibody? Because there are a lot of them.

Betsy: I think it’s just that this is the drug that they had available that had a previous trial from heart disease research.

And there was case reports of it working really well from like 2021-22, although I’m just kind of hypothesizing.

Felicity: Sure. Yeah, that’s super interesting.

I guess with my reporting on rapamycin, it was different because I think the clinical trials that are underway, it sounded like they were pretty robust.

The scientists I spoke to were pretty impressed with the way the Mount Sinai study was being run. It seems quite comprehensive.

The Simmaron research, it’s got some more limitations, but it didn’t seem to have the same issues that you’re mentioning with your trial.

Betsy: I mean, I think part of it is also a timing thing.

The Berlin Cures study, and I believe also the Erlangan one started in 2023.

So at that point, you know, there wasn’t quite so much known about the mechanisms of Long COVID and maybe not so many tests available.

So I think that’s something that researchers are really thinking about now, as we’re starting to see more trials start heading into the next few months or the next year.

I think researchers both have more tools available to them and have these earlier studies to learn from.

Whereas this BC 007 one, particularly the Berlin Cures study, was one of the earliest randomized control trials that has happened for Long COVID.

So I think it’s partially notable for that reason.

Felicity: I spoke to David Putrino at Mount Sinai about the precautions they’re taking to take care of patients while they’re involved in the trial, COVID precautions, lots of little things about the clinic that just make it — it sounds like a safe environment for people to be in.

And also the Simmaron Research trial was very remote, so people were doing it from home and weren’t required to go anywhere to participate.

So I think those things help people avoid crashes and other types of spikes that can make the data really hard to understand.

Betsy: Yeah, no, they definitely do.

I mean, multiple participants who I talked to who were in the Berlin Cures trial were saying, like, it was really exhausting.

You know, they were at these clinics for hours on top of also traveling from elsewhere in Germany or elsewhere in Europe.

So I think that’s definitely something that people who might be participating in these kinds of trials want to see is, you know, maybe it’s not possible to do like a remote framework for every single study or every single treatment, but at least that researchers are thinking about it and trying to make those accommodations as much as possible.

Felicity: And I think that’s one of the things that came up in my research was that if you’re going to try rapamycin, the doctors who are prescribing it outside of clinical trials make sure the patients are quite stable before they start, and also make sure the patients don’t start to feel better and then do more exercise and then have a big crash.

I think there’s a lot of complexity around how to make sure patients are stabilized and being monitored really carefully.

And that almost is fundamental to ensuring whether or not you can tell if the drug works, because if there’s something else going on, it’s much harder to tell there’s too much noise.

And one of the things that’s happened with rapamycin is because it’s available through longevity companies like AgelessRX and Healthspan, patients are going ahead and ordering it online.

Betsy: I know you talked to a few of those people for your story as well as some of the physicians.

So yeah, what were some of the things that you learned from them?

Felicity: Well, the patients who were going ahead and working with telehealth companies, there’s clinicians involved and there is monitoring involved.

But I think it’s a little different to working with a long-period specialist who is treating you and prescribing rapamycin as part of a comprehensive plan.

And those patients who were, I guess, going it alone and experimenting on their own had mixed experiences.

So some of them said it was helpful. Some of them had a miraculous improvement for a while and then after six months they couldn’t tolerate exercise and had to stop taking the drug. Some patients had massive side effects at the start and then had a huge level of improvement that then disappeared.

So it’s very strange.

And that was patients who were sort of self-experimenting as well as patients who were also getting prescribed rapamycin from a doctor.

My feeling is that it’s a drug that may help a few people, but there’s just a lot of chaos in the data, so it’s hard to tell.

Betsy: Yeah. I mean, I guess that goes back to why we need robust clinical trials and also biomarkers to help understand what’s going on in those trials and to help understand who might be a good candidate for this kind of drug.

Felicity: Sure, yeah.

There was one person we spoke to who anonymously reported having a significant crash after trying rapamycin.

And one doctor we spoke to was saying that patients with ME and Long COVID can be particularly sensitive to new medications.

And I think that’s something that patients would already be aware of is that if you’re going to try a new drug, particularly one that’s off label, it’s that there’s always comes with risks and you don’t know how you’re going to react.

And I guess the doctors that have experienced prescribing rapamycin are very careful about dosage and putting patients on the drug, and then maybe taking them off the drug or putting the dosage up very slowly and figuring out how it works for the particular patient.

Betsy: Yeah, definitely a lot to think about for the providers and the patients who are trying this.

One thing that we’ve also been following at The Sick Times is challenges with research funding under the Trump administration.

There have been a lot of issues with funding from the National Institutes of Health and other government agencies.

With Berlin Cures, that’s not quite so relevant because that research is all based in Germany, but the rapamycin trials are based here in the U.S.

So is that something that came up at all as you were reporting the story or something that you see impacting this drug in the future?

Felicity: So both rapamycin studies for Long COVID and ME were not relying on funds from the federal government, which was nice to hear.

And Simmaron Research is running on private donations.

It sounded like Simmaron Research was a bit strapped for cash and sort of awaiting more funding.

And I don’t know what the outcome of that was, but I didn’t get that feeling from Sinai. They felt a bit more comfortable.

So I don’t know. When you’re reliant on donations, it’s really just chance and things can be quite stop and start, which is why you want the federal government to be backing these trials, at least in part, because it just allows them to continue what they’re doing without so much jerkiness.

And that does concern me.

And I feel like as a community, we need to get better at supporting science and really donating money to scientific research, because it’s so important to know whether these drugs work, particularly as patients are already using them and doctors are already prescribing them.

Betsy: So what do you see as next for the rapamycin research?

Felicity: I think what’s next is waiting to see what these trials find, particularly the Mount Sinai research.

And that will inform whether or not this drug gets crossed off the list or gets picked up for further research.

I’m hoping that there’s a very clear finding, because that would be useful.

I feel like very strongly that in the next two years, a drug will be accepted as helping people with Long COVID and ME.

Just one —

Betsy: Just, like, one FDA approval would be so nice.

Felicity: Even if it’s not necessarily FDA approved yet, but just doctors go, oh yeah, we think this might help.

One thing that I was going to say is that this series that The Sick Times is doing on different drug trials is very exciting, because there’s a lot of diversity across different types of drug being looked at for Long COVID and ME.

And for the first time, I think ever we’re getting some real momentum happening with actual treatments as opposed to observational studies that show the same thing or trials that look into interventions that clearly don’t work, such as CBT and graded exercise therapy.

So I think that’s really exciting.

And I hope I can do another one [clinical trial].

So what’s next for BC 007?

Betsy: So this was a bit of exciting news that I found as I was finishing reporting this story.

A bit of behind the scenes as to how this happened — basically, I sent an email to Berlin Cures to the info email on their website, just saying, like, “Hey, I’m a journalist, I’m doing this story, like, here’s a bunch of information about this. Here’s some questions.”

And I wasn’t fully expecting to get a response because there hasn’t really been anything publicly shared about this company since late 2024, when they announced they were out of money.

But to my pleasant surprise, I got this email from a researcher named Oliver von Stein, who was previously the CEO of Berlin Cures.

And he explained that he’s now started a new biotech company.

It’s called APTA Therapeutics. It was just founded a few months ago.

And this new company has essentially acquired BC 007, as well as other assets from Berlin Cures, and they want to do more research.

It seems a little ambiguous in terms of exactly how and when they’re going to get started.

But he talked about wanting to support researchers who have expertise in Long COVID and other infection-associated chronic conditions in Europe, in Germany, and other parts of the European Union to do their own sort of smaller trials with the drug, like making it available for researchers to test, and basically learning more about that question of, “For whom does this drug seem to be useful?”

And then that would hopefully inform a larger trial that might be better set up for success than the prior Berlin Cures study.

And he also mentioned that APTA Therapeutics has access to the original data from the prior trial, and they want to get more analysis done on that, hopefully publish a paper, which has not happened.

Even just getting a paper with the full results, I think, could potentially be really helpful.

I hope to stay in touch with him and get more updates as he’s able to share them.

This is definitely a story we’re gonna look into as we go forward this fall.

Felicity: And is it likely that this drug will be available for people to use anytime soon?

Betsy: Not super soon. I would say, I think, even this research, von Stein’s sort of optimistic estimate was maybe the next year and a half.

They’re hoping to do some of these smaller investigator-led trials.

So that and then a trial and then eventually filing for approval, either in the EU or the U.S. or other countries, all of that takes a long time.

So I guess, unlike rapamycin, there’s no, like, off-label because it’s not available yet.

Felicity: Sure.

And what are your thoughts on which drugs should be trialled first?

Because I feel like the ones that are off-label make more sense because they can immediately get rolled out to patients worldwide, particularly the ones that are out of patent that are quite affordable.

Betsy: I mean, that’s true.

It’s hard to say because I think both really need to be happening.

Felicity: Ideally.

Betsy: Maybe that’s a cop out answer.

But I’ve been working on another story in this series about Paxlovid and monoclonal antibodies, which are obviously a big example of drugs that are already available and that people are trying.

There are some clinical trials on those.

So I don’t know.

I think different people, like, different researchers and patient-advocates kind of disagree about this.

Some people really want things to be available and some people really want novel stuff.

So I don’t know. [But] Really nice talking to you.

I think this is cool.

I feel like it’s nice that we have some kind of compare and contrast between these stories.

Felicity: Great to chat to you about your story and good luck with the next one.

Betsy: Yeah, thank you.

Outro (27:48)

James: So you can read Felicity’s story and Betsy’s story both at thesicktimes.org. And that’s all we have for you in this episode.

You can stay up to date with our continued coverage at thesicktimes.org and The Sick Times’ newsletter at thesicktimes.org as well.

[Instrumental theme song excerpt plays underneath the rest of the podcast]

Miles: We’ll continue reporting the information you need to better practice care.

Betsy: Solidarity with everyone still here. 

James: This podcast and The Sick Times are supported by you. You can help us keep this work going by donating on our website, and thanks again to everyone who donated to our summer fundraiser.

Still Here is a production of The Sick Times, a nonprofit newsroom chronicling the ongoing Long COVID crisis. 

Our theme song for this episode is the Rude Mechanical Orchestra’s rendition of Which Side Are You On?, originally by Florence Reece. I’m James Salanga and I produced this episode. Our engagement editor is Heather Hogan. Our summer intern is Delfi Marchese. Sophie Dimitriou designed our podcast cover art. And Miles Griffis and Betsy Ladyzhets are your co-hosts and The Sick Times’ co-founders.

Thanks for listening.