Still Here, August 19: Links and transcript

Summary

In this episode of Still Here: A two-way between Miles Griffis and Betsy Ladyzhets comparing and contrasting Long COVID and ME clinical trial designs for drugs targeting immune dysregulation and viral persistence.

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, JAK inhibitors and drugs targeting viral persistence
• Outro

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

Mentioned in this episode (in order of appearance):

• The Sick Times: Three clinical trials for Long COVID are testing JAK inhibitors to treat immune dysregulation
• The Sick Times: No “easy home runs”: Early Long COVID trials of Paxlovid and monoclonal antibodies failed, but the treatments still have potential
• The Sick Times: Research updates, July 8
• The Sick Times: Invivyd Chairman Marc Elia: The bureaucracy is killing people with Long COVID
• Still Here: February 25: Links and transcript

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: In this episode, we’re featuring a two-way between Betsy and Miles, talking about their latest features on clinical trials for Long COVID and how they’re designed, specifically about JAK inhibitors and trials targeting viral persistence.

And we’ll get into Betsy and Miles’ two-way after a quick musical break.

[instrumental segment of theme song plays]

The Sick Times: Three clinical trials for Long COVID are testing JAK inhibitors to treat immune dysregulation, No “easy home runs”: Early Long COVID trials of Paxlovid and monoclonal antibodies failed, but the treatments still have potential (1:05)

Betsy: You might have seen that The Sick Times has been publishing a series of features about clinical trials for Long COVID, looking at trials testing different promising treatments, as well as how they are designed.

Our first two stories in the series focused on trials testing the drugs BC 007 and rapamycin.

Our most recent stories are about JAK inhibitors and trials targeting viral persistence.

Miles reported the feature on the three JAK inhibitor trials, which are targeting immune dysfunction, and I covered efforts to repurpose acute COVID-19 treatments like Paxlovid and Pemgarda for Long COVID.

Similar to our prior episode on BC 007 and rapamycin, Miles and I are talking about both stories in sort of a two-way formatted conversation, as well as some of the distinctions and challenges in testing them as Long COVID treatments.

So the trials for these drugs tackle distinct Long COVID hypotheses.

Miles, can you share more about how the JAK inhibitor trials are responding to the hypothesis that Long COVID is driven, at least in part, researchers think, by immune dysregulation?

Miles: Yes, so this has been a theory that I feel like has been a quieter theory [explaining Long COVID] under viral persistence and latent virus reactions, gut microbiome, these other things.

You know, as we look at this series, it’s important to remember that a lot of these theories can exist together.

So while these drugs, which are called JAK inhibitors, are targeting potential immune dysregulation, it is also possible that they could help in other instances of viral persistence that would allow the body to sort of get out of a cycle of inflammation and autoimmunity, perhaps, and then give the body an opportunity to fight if there is possibly some kind of viral persistence happening.

So essentially, JAK inhibitors are these really powerful drugs that are used for a lot of autoimmune diseases. So the ones being trialed treat things like Crohn’s disease, arthritis, eczema, a bunch of different things.

And these are all pretty new drugs.

So that’s also one interesting aspect of them is they’re — [they] all came out about, I think the first one was 2012, so pretty new in the landscape of drugs.

And I think there’s 11 approved drugs right now that fall under JAK inhibitors.

The idea is that these drugs can help treat immune dysregulation by blocking the JAK/STAT pathway.

And essentially, that’s a really complex cell communication route that helps regulate molecules involved with immune responses and inflammations, aka cytokines.

Essentially, what they do is block this inflammation from happening.

There’s four different main JAK/STAT pathways, and these drugs target specific ones, JAK1, JAK2.

So scientists are trying to figure out what makes the most sense for Long COVID. And to get there, they’ve found that there is a lot of inflammation in people with Long COVID by doing these larger, like, blood tests that are really complex, not readily available in labs.

You know, this very high tech process that looks at molecules really, really specifically.

And that’s one way that some of these trials are using as an outcome measure — like, check these before the trials and check them after to see how these drugs are working, which pathways they’re addressing and more specific outcome data that some Long COVID trials have not had in the past.

So it’s definitely a huge step for Long COVID trials.

So on the flip side, there are also antiviral and monoclonal antibody trials responding to the hypothesis that Long COVID is caused by viral persistence of SARS-CoV-2.

Betsy, how do the trials you’re looking at target this hypothesis?

Betsy: Yeah, so I imagine most people listening to this probably know what we mean when we say viral persistence, but just to give a quick summary, the idea is that either the SARS-CoV-2 virus itself or pieces of it, or possibly its genetic material, get stuck in different parts of the body and are continually making copies of themselves.

So that leads to this issue called viral reservoirs, which is build-up of these virus pieces or virus copies over time.

And that can lead to all kinds of dysfunction, contributing to symptoms, possibly contributing to inflammation or doing things like reactivating latent viruses.

So it really intersects with a lot of other areas of Long COVID underlying biology.

And of course, if you have like copies of SARS-CoV-2 or pieces like its spike protein that are continually getting copied, then antiviral drugs that are meant to combat the coronavirus would help to tamp down on that and then ideally lead to improvement with symptoms.

So that’s kind of the theory, but unfortunately it’s a lot more complicated than that.

I think a lot of tests have specifically found the coronavirus’s spike protein, but it’s not entirely clear — like, is it just a spike protein or is it the entire virus?

One of the researchers who I talked to, Nancy Klimas, who’s at Nova Southeastern University in Florida, made the point that an entire virus is harder to tackle with treatments than just a spike protein.

These are kind of important questions to figure out, as well as, “Where are the reservoirs? What parts of the body are they in?” Because different treatments target different organ systems or different parts of the body.

“Who has viral persistence?” Studies generally show that a decent proportion of people with Long COVID appear to have viral reservoirs that can be measured with things like complex blood tests, but not everybody. A lot of studies have found around that like 25 to 35% mark, but we’re still figuring that out.

It’s also possible that once we have better tests that are more specific and targeted to this question, the percentage actually might be higher.

There’s a lot of unknowns there and all of that makes it difficult to identify who exactly is the best candidate to try one of these treatments.

So Miles, in your story looking at the JAK inhibitors, you looked at three different clinical trials.

Can you talk a little bit about what those are and what they’re testing?

Miles: Yes. It is pretty unique to see three different drugs being tried at once.

We haven’t really seen this level of, I guess, diversity in a treatment like this for a while for Long COVID.

I think there’s been some with viral persistence and looking at [that], but it’s really cool to see this very specific subgroup, this class of drugs, have three ongoing trials.

The biggest one is called Reverse-LC and they are studying baracitinib. Its brand name is Olumiant and it is a JAK1 and JAK2 inhibitor, and it treats arthritis, hair loss, and interestingly it’s the first JAK inhibitor approved for COVID-19.

So there are some studies early on in the pandemic that found it through AI, that it could be a beneficial treatment for COVID-19.

They did a large clinical trial on it and it proved to be effective for treating acute COVID-19.

So researchers of Reverse-LC decided that they wanted to trial it for Long COVID.

It has 550 participants.

It’s a phase 3, so this is the biggest of these three JAK inhibitor trials, and it has four different sites that are recruiting across the U.S. So you can learn more in the story about where those are.

There’s a lot of excitement around it. However, it will not have its data until 2027, so it’s a while off.

In contrast, the other two will have their results a little bit sooner.

The next biggest one is called LC-Revitalize.

It is international, so it’s recruiting in multiple different countries — in Africa, in South America, North America, and Europe. So it has a lot of reach, which is really unique.

I haven’t really seen any other clinical trial that’s this wide and international, and they’re intentionally doing that because of the impact and the burden of Long COVID outside of the U.S. and Europe.

So it’s a platform trial, which is a really interesting and sort of faster way to see results.

It’s also a phase 3 so there’s placebos but they’re testing two drugs at once.

One of them is a JAK inhibitor called upadacitinib or Rinvoq and that is a JAK inhibitor that treats the one JAK1 pathway, and is approved for autoimmune conditions, including Crohn’s disease, ulcerative colitis, and rheumatoid arthritis.

They are going to be testing over 300 people on this and another anti-inflammatory drug in tandem, so they’ll have two different arms and they’re going to test that for three months. And they’re going to see how people respond to each drug, and then they can adapt the trial from there, so if neither are showing any significant improvement or the safety profile is bad, they can stop either drug and trial a new drug, and they’re looking at these multiomics as outcomes. So it’s a very advanced trial that will tell us who responds versus who does not.

Also, like the last trial, [the researchers] got to this drug by looking at artificial intelligence.

Interesting that there are two different drugs of the same class that came from AI.

The last study is called Clear-LC.

It’s the smallest. It’s a Phase 2 and they are looking at a drug called abrocitinib, which also inhibits JAK1, and it treats eczema.

This trial has about 90 people in it, is their goal.

They came to it not through AI, but through doing these different blood tests that were from the [NIH] RECOVER cohort, looking at blood of people with Long COVID, and they were able to find these higher levels of inflammation and looked to see what could treat these specific pathways that were activated and it was another JAK/STAT.

A lot of people I spoke with were encouraged that these three different groups all came to the same class of drugs from slightly different ways and that they’re all trialing them at the same time.

Betsy: Yeah, no, it’s really cool to see, and really exciting — especially the different pieces about how they’re going to measure success with the drugs. Definitely aligns with patterns that I think all of the stories in this series have talked about, with researchers getting more intentional about how they design these studies.

Like rapamycin, which another piece in this series looked at, JAK inhibitors are immunosuppressing drugs.

They kind of tamp down on the immune system.

How does the clinical trial designs for these three studies address that?

Miles: Yeah, so JAK inhibitors are really potent and powerful drugs, and they come with something called a black box or box warning. And this means that they can cause, uh, really severe side effects, long-term health issues, and even death.

So these are really intense drugs. There’s been other clinical trials for the specific diseases and conditions that these drugs have been approved for and the benefits of taking these drugs outweighs the risk for some of them.

However, they have these really long criteria for getting on them.

So people who have like cardiovascular issues, clotting issues, and many, many others are excluded because these drugs have been found to increase the risks of those.

They’ve been found to be safe, like, with this exclusion criteria, and now these trials will assess the safety of them in Long COVID. And a lot of readers, I’m sure, are probably curious of — you know, COVID can cause clotting issues and cardiovascular issues.

So this is definitely something that researchers are paying close attention to while screening for these trials and being very selective because the drugs come with so much risk.

Betsy: Yeah, I think this is also something that came up as you were talking to people who have tried these drugs on their own.

So what were some of the things that you heard from those interviews and from those case studies?

Miles: Yeah, so to get on these drugs, a lot of people either get them prescribed — they’re really, really expensive, so they’re really hard to access.

They’re about several thousand dollars a month. Some can be like $8,000, $7,000 [a month].

There are, like, drug saving programs for some people, but they’re really hard to get approved because they’re usually one of the further things that would be approved by a insurance company.

To get on them, you have to do a lot of different tests.

You have to make sure you don’t have, like, any active infections or [are] getting any live vaccines because since they suppress your immune system, you can be more vulnerable to other infections. You have to do a lot of blood work. You have to go over your medical histories. So they can be really hard to access, but some people have been able to access them.

Some people I spoke with also had autoimmune conditions like Crohn’s or eczema and got the drugs because of those conditions pre-existing Long COVID.

Some found that it treated those conditions really well, but it did nothing for their Long COVID.

One of the main sources of my story has shared her experience with Rinvoq, one of the treatments being trialed, and she had a full remission from a very severe ME for almost 20 years, and she accessed the drug through doing a lot of tests that showed that she had these raised cytokines and inflammation. [She] was able to get the drug approved and measured her own cytokines after and they all went down to normal levels after her first trial.

She’s working on a case study of that now, but it led to a lot of excitement around this treatment, and there have been many other people with ME who have tried these drugs.

There was a small sort of, like, survey retrospective that I mentioned in the article and about half of the 36 people had significant benefits from different JAK inhibitors.

These are unpublished results, just sort of like a survey from patient-led researchers, but an interesting data point.

Unfortunately, some people in that survey had to stop taking the drug because of very severe side effects and other things I mentioned, and they noted that some were seeing improvements in Long COVID, so it was unfortunate that they had to stop taking them.

So these drugs are complicated, because even if they might work for some people with Long COVID, their risk factors and side effects and criteria to take them may exclude people with Long COVID in the future if they become found to be effective.

Betsy: Yeah, it’s very complicated, and it seems like it’s a bit of a different situation than the antiviral therapies that my story talks about, which are generally found to be pretty safe at this point.

Millions of people have taken Paxlovid and it’s a widely safe treatment. Although people do have to think about potential interactions with other drugs if they’re being prescribed it, but overall, [it’s] very safe to take but seems to not have such a big impact on people’s symptoms in the same way that we see with some of these case studies for JAK inhibitors and for also things like rapamycin.

It’s kind of an interesting difference.

Miles: So unlike these JAK inhibitor trials that are ongoing, [where] like, we still don’t really know a lot of information on them, we do have some results that are completed of trials with Paxlovid and the monoclonal antibody AER002, and they didn’t show the results that many in the community were more hopeful [for].

What did researchers say about these trials?

Betsy: So there are two studies with Paxlovid that have reported full results, have published scientific papers with a lot of detail about their findings, and so these were two studies — one was from researchers at Stanford and one from researchers at Yale, and both looked at the drug for 15 days. So that’s a longer course than people typically take if they’re prescribed Paxlovid for acute COVID.

That course is usually five days, but it’s still relatively short in the grand scheme of chronic illness that some people have had for five years or more at this point.

That’s one of the kind of main points that comes up when I’ve asked researchers and patient advocates, like, “What’s your reaction to seeing that both of these trials did not find that the 15-day course of Paxlovid alleviated symptoms, at least as far as these trials picked up with their study designs?”

And so people have generally not been very surprised by that outcome.

I think the kind of overall consensus is that even assuming viral persistence may be a major factor in symptoms for a lot of people, a 15-day course of an antiviral medication is not necessarily going to have a huge impact when somebody maybe has been sick for years and has these long-term reservoirs or long-term damage that reservoirs have contributed to, right?

That’s one of the big questions.

Another question is, who was included in these trials?

These studies, as I mentioned — we don’t necessarily have like a clear, agreed-upon biomarker to determine who has viral reservoirs of SARS-CoV-2 or its components, so these trials are not necessarily recruiting focused on that. As well as questions about measuring success — what kind of outcomes measures are being used?

I think all of this is still a work in progress for many researchers in terms of what makes the most sense.

I also spoke to a person with long COVID, Amy Engebretson.

She is a physician and she also helps write the Long COVID Weekly Newsletter and she happened to be a participant in the Yale study, and what she noted is that the placebo that was used in this study as well as other Paxlovid clinical trials was a drug called ritonavir which is, if you take Paxlovid, right, there are like two sets of pills.

So one is the nirmatrelvir, which is the new drug that Pfizer designed that specifically is meant to combat SARS-CoV-2.

The other one is ritonavir, and ritonavir is an antiviral that’s been around for a longer time. It’s used also in things like HIV treatments and so when you take Paxlovid, your course includes both of these, and the antivirals are meant to kind of help each other out.

When these clinical trials were set up, they included ritonavir in the placebo arm.

I think one of the main reasons why it seems like they might have done this is because the metallic taste that many people get with Paxlovid is associated with ritonavir.

So there’s kind of an interest in like if the study is being blinded, they don’t want people to know if they got the drug or the placebo, they still get that metallic taste either way.

However, as Amy Engebretson pointed out, ritonavir is still an antiviral. It still has antiviral properties, so it might still do something for some people who have viral persistence going on.

She actually thinks that was the case for her.

She found that ritonavir approved her symptoms and she actually said that she’s still taking it now that she’s no longer part of the trial.

I did ask the researchers for both Stanford and Yale’s studies, is this something that they’ve thought about? As we’re recording this, they haven’t gotten responses to that yet, so maybe we’ll have to update this.

It’s not something that I’ve seen come up in other commentary about these trials, but I think just speaks to the complexity of these studies where designing for one thing, like making sure the study is blinded well, might cause challenges in another area.

And every trial is like an iteration on this theme.

So the more papers we get and the more that we learn, I think the better that researchers will be able to design other studies in the future.

Miles: So how are these new trials now responding to those questions raised from the prior results?

And do they reflect sort of like a different research atmosphere for Long COVID treatment drugs than they did two years ago?

Betsy: They definitely seem to reflect the complexity a little more.

One thing that researchers are thinking about is this question of who is the best fit for a given trial, which as you mentioned also kind of applies to JAK inhibitors, of wanting to try and make sure that people are the right fit, that they’re not necessarily going to have safety issues.

So in the case of something like Paxlovid or [a] monoclonal antibody, it would be trying to look for people who have viral persistence.

Current studies aren’t really doing this yet, but it’s something that researchers are thinking about as they design upcoming trials.

Another thing that researchers are doing is trying to look at a lot of potential outcomes measures and then seeing what maybe best reflects success with the treatment.

This is the case with the trial of sipavibart, which is a monoclonal antibody made by AstraZeneca.

It’s something that is approved in the EU and a couple of other countries for people who are immunocompromised to take as a COVID prevention measure.

And this trial in Florida is studying it as a Long COVID treatment.

So one of the things that that trial is doing is they’re doing a lot of testing, asking people different kinds of questions about their symptoms, as well as things like a six minute walk test and a NASA lean test, which is a common test for dysautonomia.

The idea is, as Nancy Klimas has put it, to do a lot of tests for this trial, so that for future trials, we don’t have to do as many because we know which ones work or which ones maybe are reflective of improvements in symptoms as well as changes in the underlying biology.

And that trial is collecting biospecimens from people who are participating.

So they’re getting things like blood samples.

And the researchers will be able to study that afterwards, look at changes in a people’s underlying biology as they’re trying this monoclonal antibody treatment, and other researchers will have access to those biospecimens as well.

So another thing that researchers are thinking about at the moment is collaborating with people who have Long COVID and making sure that trials are accessible.

One example of that, I think, was with Yale’s study, they used a decentralized model so people could participate from around the country.

How has that come up for the JAK inhibitor trials?

Miles: Unfortunately, all three trials require in-person participation, largely because of, I think, all the blood testing and stuff you have to do for the criteria to make sure you don’t have anything that the drug can make worse.

I think, yeah, people will be slightly disappointed because it’s hard to take part.

Some of these trials did have some patient participation, Reverse-LC, the one trialing baricitinib.

They met with Patient-Led Research Collaborative, other reps from ME Action and other patient-led groups.

They had a high degree of collaboration based on the Patient-Led Scorecard, which is a metric that PLRC uses to gauge how much collaboration there was with people with lived experience.

Another person I spoke with for Clear-LC, the smaller study, they met with other patient researchers who did their own sort of trial before this on another JAK inhibitor, just sort of warning and telling them about their experiences, what went well, the side effects they had, etc.

Betsy: That’s cool, yeah.

Looking forward for these trials, do these researchers have a sense of when they might have results to share or what else are you looking forward to as we keep following these?

Miles: Some of these studies have private funding, so it’s outside of the government.

They are thus at very low risk from being interrupted. There’s also some interesting stuff going on in some of these that have support from other places.

So Pfizer is providing drugs, some funding for Clear-LC, the one on abrocitinib, which is called Cibinqo.

That’s cool to see that Pfizer has supported and provided drugs and placebos for a bunch of the other studies that Betsy was looking at too.

Betsy: One actually interesting detail that I found as I was finishing up the antiviral story is that Pfizer is working on testing a next generation antiviral, which is kind of like the next Paxlovid, essentially.

And one of the secondary outcomes in their clinical trial for how effective that drug is, is, “Do people develop Long COVID after a COVID case?”

Because as we know, there have been some questions about that with Paxlovid.

It’s cool to see that the company is learning from that and added this as a facet of their next round of trials, although it’s not a long treatment, but we know that preventing new cases of Long COVID also is important.

And another company that’s getting more involved with Long COVID research also is Invivyd, which makes the monoclonal antibody Pemgarda, also called pembivart.

And similarly to sipavibart, this is a monoclonal antibody that is meant to be preventative.

So people who are immunocompromised are eligible for it in the United States.

And so it’s like you can take it, I believe it’s supposed to be every six months, potentially.

And so that company, similarly, is working on studying the drug as a Long COVID treatment.

They haven’t announced actual trials yet, but a few weeks ago, they put out this announcement that they have a new study group called SPEAR that involves Marc Elia, who is the chairman of the board of Invivyd and also has personal experience with Long COVID, which he wrote about in an op-ed for The Sick Times a few months ago.

So he is involved as well as Michael Peluso, Amy Proal and Dave Putrino. And I believe Akiko Iwasaki from Yale as well, so just like a really star-studded group of researchers.

And it seems like they’re going to be collaborating to look at some of the questions on things like biomarkers and ideally design new trials.

Also notably, they are including post-vaccine syndrome as well as Long COVID in this project. So I think that’s a bit unique compared to some of the other trials that have happened so far. And Invivyd is working on next-generation monoclonal antibodies, too.

A lot of exciting stuff in the near future and in the further-term future.

I almost got a little overwhelmed with it as I was working on my story.

I just keep being like, “And there’s another trial I have to add. And there’s another drug I have to add,” which is like a good place to be.

It’s sort of exciting, compared to a couple of years ago when there were almost no clinical trials.

Miles: Yeah, it’s at a pretty exciting time.

One quote that really stuck with me from my story was from Elisa Kava. This was about the JAK inhibitors, but I think it could kind of apply to all these different treatments.

She said, “The fact that there are all these trials studying the same class of drugs is extremely significant for the field. I think that’s why I’m so enthused not just for the trials themselves, but what it means about the growing level of confidence in tackling Long COVID and other IACCs.”

We’re definitely in a much different place than we were a couple of years ago.

And there’s a lot of exciting prospects on the horizon.

James: Thank you both so much for talking about the clinical trials.

And hopefully this provides more insight [for folks] into the features that you wrote, which are really densely reported.

Outro (28:37)

James: So you can read both the features on The Sick Times website at thesicktimes.org.

And that’s all we have for you today.

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.