To kick off a new year at The Sick Times, we’re excited to share a conversation looking ahead at future Long Covid research between Betsy Ladyzhets and Dr. Eric Topol, founder and director of the Scripps Research Translational Institute. Throughout the last four years, Topol has been a well-regarded commenter on Covid-19 and Long Covid, as he’s closely followed scientific developments and shared insights through social media and his newsletter, Ground Truths.
He spoke to Betsy about recent advances in Long Covid research, barriers holding up large-scale clinical trials, new funding recently announced for the National Institutes of Health’s RECOVER initiative, the Biden administration’s failure to acknowledge this crisis, and more. This interview has been lightly edited and condensed for clarity.
Betsy Ladyzhets: What would you consider some of the biggest advances in Long Covid research over the last year — any developments towards things like biomarkers and better understanding the mechanism of the condition?
Eric Topol: The most encouraging thing we’ve seen so far is the randomized trial of microbiome manipulation. It didn’t have a profound impact, but it alleviated symptoms across the board. And it was a well-done study, with a double-blind, placebo. But we don’t know if that’s going to hold up. [The study involved] several different bacteria species and some different glycans for so-called synbiotics, i.e. both pre- and probiotics. It was done in Hong Kong. So we don’t know, will that particular recipe work for people of all ancestry?
But it’s taken until this time, to have the first [clinical trial with positive results]. Symptom relief was the primary endpoint. So it’s encouraging. It also tells us, the microbiome is the real deal… But we need many different therapies. And we need potent therapies. This is a starter, this is hopefully, the beginning of an inflection point of getting validation of a number of useful therapies. I didn’t think the microbiome was going to be the first one to hit.
BL: Yeah, [the microbiome is] pretty complicated!
ET: Success is a function of who’s doing the trials. And to me, they have to be rigorous, they have to be large enough. That trial really fit the bill. We haven’t seen many trials with hundreds of people with double-blind, placebo control. So that’s been part of the problem. Most of the trials that have been done to try to help people with Long Covid are small, they’re not rigorous. Finally, we’ve seen one good one.
That’s my big hope in 2024: we’ll see many, many large trials that are well done — rigorously testing promising agents — and make up for lost time, because we’ve lost a few years here, of being able to come up with a treatment that works. So that’s what we’re working on [at Scripps Research] and trying to get that going. It’s not easy, because the funding that was coming out of the government was used for RECOVER. And you know, better than I, that that money was largely spent poorly, not getting any real traction on trials. [There won’t immediately be] more money coming out of the government for Long Covid. So, in order for us to get out of the box, we’ve got to get philanthropic funding, and that’s what we’re working on right now.
BL: What are some of the other barriers that would explain why we haven’t had many large clinical trials yet here in the U.S.? Funding, obviously, is a big one; what do you see as some of the other challenges?
ET: The U.S. hasn’t been too good at doing trials throughout the pandemic, frankly. Most of the large trials that got us quick answers, important answers were done by the U.K., in the RECOVERY group, and also by the WHO Solidarity trial. So we didn’t do many [in the U.S.] We did vaccine trials, but not for drugs, for treatment… It’s not a strong suit in the U.S., exemplified by RECOVER, which had a couple of years of all this, billion-dollar-plus in funding, and they didn’t get into trials.
The bottlenecks are the [pharmaceutical] companies. There are only a few startups that want to do trials, and they don’t have the funds. And then the large companies that could do trials, they don’t want to take the risk, or they don’t have a drug or various other reasons. Because so many clinical trials in this country rely on industry support, usually, we’re kind of in a tough position. A couple of the agents that have come to the fore, from startup companies — they can’t do a large trial.
Then, repurposing drugs. One of the drugs we’re especially interested in is rapamycin. That drug is made by Pfizer. But do they want to test rapamycin? No, not really, because it’s a drug that’s generic, so they get very little benefit out of it. Repurposing drugs is the fastest way to get to potential validated treatments for Long Covid. But companies might not find that at all attractive, because their mission is to find a drug that will increase their revenue rather than find a drug that will help the millions of people with Long Covid, unfortunately.
BL: I know this has come up too, with RECOVER, in this question of, what are they testing for clinical trials? That kind of a government program actually could look at repurposed drugs or could look at some of these other potential treatments that a pharmaceutical company is less motivated to look at.
And they announced just a few days ago that RECOVER has gotten an additional $200 million of funding to do more clinical trials. I don’t know if you’ve seen this yet. It was just shared around Twitter, with no details about what they’re working on or anything. (Editor’s note: Thank you to advocate Dakota for calling our attention to this news!)
ET: That’s really interesting, I didn’t hear that. That’s a sure thing?
BL: The NIH budget director, I believe, announced it in one of their committee meetings. I’ll send you the link. So, that’s a bit of news!
ET: Yeah, that’s great… One of the things you have to do here to do the trials, fast and economically, is to rely on digital decentralized trials. Unfortunately, the RECOVER people have never done that, they’ve never had one digital enrollment trial. And so that’s what we want to do [at Scripps], we’re trying to do these trials with 2,000 participants each, all remote. That is, anyone who has a smartphone could provide consent and their data and get the drugs that we would send to them. So that’s our plan: to go fast, large, decentralized, get the answers quickly. Unfortunately, that philosophy hasn’t been shared by RECOVER.
BL: Does that include the trial that Julia Moore Vogel is working on?
ET: Yes, exactly.
BL: She mentioned to me that it may be ready to launch soon, which I was glad to see.
ET: Well, it all depends on if we get the requisite funding we’re banking on. We’re in discussion, but we won’t be able to get going until we know we’ve got that funding.
BL: I see. What are some of the strategies — if you were to advise the advocates who are pushing for more funding from the government or trying to get more companies interested in this, what do you think they could work on to convince more players in pharma that Long Covid is worth attention?
ET: Well, sure, it’s worth their attention. I mean, you’ve got so many people who are suffering. And if they [companies] don’t get that, they’re missing out on a large population of impaired people. To me, it’s Captain Obvious that this is a big deal. Why some large pharma that would have a putative candidate drug wouldn’t get into this would be just crazy, because the potential helping people is so extraordinary.
The problem is that large pharma is looking for a novel drug. And that takes much longer to develop. So, I don’t know that you need to convince them how big this is in terms of, not just the population, but the disability that’s involved. But taking the risk — because there’s going to be drugs that are going to be tested that fail. There’s a risk. There’s not a biomarker yet, hopefully there will be. There’s a mosaic of symptoms, and there’s probably the need to partition people into different groups so that you don’t just test one drug across the board, but try to stratify the enrollment by symptoms to some degree.
So, I think there are some smart ways to get at this. But unfortunately, we haven’t seen any major pharma prepared to get into it at this point. We are going to try to get drugs out of these major pharma companies, which we think have tremendous promise, and for which they have not initiated trials, for one reason or another. We would probably have to hold the IND [Investiational New Drug application] ourselves, because they don’t want to take the risk. We know there are some agents that have promising features to test, but unfortunately, our enthusiasm is not shared by the pharma companies who make these drugs.
BL: Yeah. I know people often compare Long Covid to HIV, in the patient advocacy context. And I wonder how long it took — or maybe this is a historical question that we at our publication should look into — how that compares, timeline-wise to when these sorts of trials started. I guess one of the things that makes this challenging is the lack of a biomarker, or the lack of a clear mechanism to target, beyond [SARS-CoV-2] itself.
ET: It’s a good question about why this has been going on so long… Because you would have thought, by now, there’ll be many ongoing trials. In fact, I don’t know of any ongoing trials in the United States or abroad that are large at this point.
BL: Even RECOVER is pretty small.
ET: A hundred-person trial is not what I would consider adequate, because you could get misled that [results show a] negative, and it’s really a drug that has promise. Or it can be positive, and it’s not replicable. So I’m talking about trials of several hundred to a thousand for each arm. My understanding is that there’s a metformin trial that’s going forward, which is large. And I think it’s being predominantly enrolled in Brazil.
BL: I didn’t know that, interesting.
ET: Outside of that, I don’t know of any large trials ongoing. I may be missing some, but that’s all I know of. And that’s just pitiful. I mean, there’s just no excuse for that.
BL: I do wonder, to what extent the dismissal of Covid as an acute infection plays a role here. I was thinking about this a couple of weeks ago, because I went to an event that STAT News was hosting in New York City, and I was one of maybe three or four people in a giant room full of pharmaceutical industry folks who was wearing a mask. And this was early December, it was peak respiratory virus season. I wonder if this is something you’ve observed as well — the correlation between recognizing Long Covid and also recognizing the continued risk of [acute] Covid.
ET: I think that people have forgotten that there’s only one surefire way of not getting Long Covid, which is not to get Covid. And that includes getting Covid again, because as you know, while you may not have Long Covid on the first infection, it’s still possible with subsequent infections. There’s this pandemic fatigue that’s profound, and denialism, that, “oh, it’s just a common cold,” which is farcical.
The problem is that the vast majority of people want to just put this behind us. On the other hand, the virus has a totally different objective, which is to continue to infect people relentlessly, to find people who weren’t infected, and to reinfect people who have already been infected. And it keeps finding new ways to evade our immune system, the latest being this JN.1 variant that’s taking over the world really quickly. So it’s a mismatch: you have the humans that are basically ignorant, not realizing that this virus is fully with us and fully capable of global dominance quickly with a new variant…
And there’s a lack of respect for the virus’ toll on sickness, including Long Covid. It’d be one thing if this was just some small burden, [if the virus was endemic]. But what we’re seeing now — higher wastewater in many countries around the world, soaring hospitalizations in several countries — this is a serious issue that people just can’t seem to grapple with.
BL: Yeah, the psychological challenge of, we want to get it over with, but we can’t. Is there other research that you have been following, or that you are looking forward to following next year, looking more at questions of biomarkers or how exactly a coronavirus infection leads to Long Covid?
ET: It would be great if we had a biomarker because that would help to do trials, to have an objective measure of improvement. The problem is that there’s a long list of potential biomarkers, but many of them are not practical. You can’t [test for them] at scale, commercially, inexpensively. So that’s what we really need, and there’s a hunt that continues for that.
But you don’t necessarily need to have a biomarker to have an effective treatment. That’s one thing I think people don’t get, is that if you have a drug that has a “eureka” effect — you give it to people with Long Covid, and they quickly feel close to or as good as their baseline — it doesn’t matter that you don’t have a biomarker. We’ll take it. The more pressing goal is getting a treatment that works, the biomarker would be a bonus.
We may get one [biomarker] in the future. There are so many nominations of candidates, but I haven’t seen one that you could just get at your local lab, that would be easy to test. What we really need is something very practical.
BL: I know one of the challenges with people getting health care for Long Covid is this, “oh, all your labs came back negative,” response [from doctors]. Because the potential indicators are not things that show up in the standard screening panels. This is another ongoing challenge that I see from advocates I talk to, where they really want to be getting more funding for research, but also assistance for the day-to-day lives of people dealing with Long Covid. Even with successful clinical trials, treatments are gonna take a long time — and so, what do people need right now? That seems to be, not a hard question to answer, but [providing assistance is] a hard thing to actually make happen.
ET: Yeah, there are so many things out there that people think, “Maybe this will help, maybe that will help” [with relieving symptoms]. And there are so many people who have tried everything in that long list, from hyperbaric chambers to intravenous immunoglobulin, plasmapheresis… If something out of that list had a positive impact, it would have shined through pretty readily. The fact that we’ve not seen big benefits from the first list of candidate treatments, that helps to tell us those aren’t ones we can rely on.
What we have learned is a tremendous amount about the mechanism of Long Covid. There’s a hyperinflammatory state, driven by either a haywire immune system or an autoimmune component. And there’s also the microbiome involvement. So if we can get drugs that work [on these mechanisms], safely and potently, that seems to be our best shot.
The trials that we [at Scripps] want to get into in 2024 are those types of drugs. None of them have been tested yet in any significant group of people. When we applied to the government PCORI agency to do this, they said, “Well, there’s no data on these drugs and Log Covid.” There isn’t, that’s why we’re trying to do the trials. It’s a catch-22: if we had a treatment, we wouldn’t have to do the trial. It’s exasperating. You see the unwillingness to be logical here, to take the necessary risks, to benefit such a large number of people who are really hurting. I’m hoping it will turn around this year. We may not get all the answers, but if we just got one or two drugs that have a strong effect that would be phenomenal.
BL: Yeah, that makes a lot of sense. I also wanted to ask: I saw that you had signed on to the open letter that was published recently from PLRC and a bunch of other researchers. And I was curious if you had any comments on that effort, or just generally, what do you want to see the federal government improving here? I’m sure that could be a long list — what are your top priorities?
ET: The letter that Lisa [McCorkell] put together was important because the administration doesn’t want to acknowledge Covid… And that’s not good, because there’s this major problem that has to be addressed. So getting more priority and funds for [Long Covid research] is important. I certainly agree with the spirit of the letter. I didn’t know, although wouldn’t have changed my being a signatory, that there was $200 million more allocated to RECOVER… That’s great, if they only spend that wisely instead of wasting it.
BL: That’s the question, yeah. I’m working on another story about RECOVER, probably for early 2024. And I think that will be a major theme.
ET: They [RECOVER] could get a lot done. We think we can do big trials [of potential Long Covid treatments] for a few million dollars each. If we had that kind of money, we could run many, many trials. Again, the real difference here [at Scripps] is that we have an efficient method, relying on our digital infrastructure. And there’s no shortage of people with Long Covid that are willing to be in a trial. We know that.
BL: What else would you want to see from the government, whether that is nationally or at more local levels, to support people with Long Covid, or to at least better acknowledge this problem?
ET: Our president has never uttered the words “Long Covid.” And that, to me, is really bad. I don’t understand the reason why he hasn’t done that, but not acknowledging this large population of Americans who are suffering from Long Covid, to not address that right up front… He’s the leader, and it’s just unexplainable that he hasn’t yet. I still have optimism that he’ll have a wake-up call on this, but it’s really unfortunate. [The government’s response] starts from there.
(Editor’s note, added January 4: Biden mentioned Long Covid during a speech on the anniversary of the Americans with Disabilities Act in September 2022.)
HHS, they’re gearing up, they’ve hired a Long Covid director… That’s good. But [Biden] needs to say, “I’m on it, we’re on it, we know how important this is.” That would mean a lot to people, to know that it’s gone up to the president’s level. Otherwise, it’s like, does he even know that there are people who have Long Covid, and that he’s lucky he doesn’t? He and Jill have both had Covid, I don’t know how many times. Do they know about this? So, his acknowledgment would be a really good thing. And unfortunately, we haven’t seen it yet.
BL: I know that was a specific ask of the [PLRC] letter as well, for him to acknowledge Long Covid in a State of the Union speech or some similar kind of high-profile event.
ET: Not even speaking about it is a denialism that is intolerable.
BL: That was everything I had wanted to ask you about. Is there anything else you’re thinking about with regards to Long Covid research for the next year, or just anything else you’d want to share with readers of The Sick Times?
ET: I’m glad to see the new allocation [for RECOVER]. That’s a significant amount of funds… So maybe RECOVER can recover. I have to hope that that’s the case. But other than that, let’s just hope that this new year brings in a new enthusiasm to execute large trials, validate treatments that really work, and turn this around finally. It’s long overdue. We should have had effective treatments two years ago, not four years into the Covid-19 story.
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