Three effective treatments for COVID-19 not (yet) in guidelines

Paul Sax: [00:00:02] Hello, this is Paul Sax. I'm Editor-in-Chief of Clinical Infectious Diseases and welcome to the Let's Talk ID podcast. Today, I'm delighted to be joined by Dr. David Boulware, professor of medicine at University of Minnesota, where he is in the Division of Infectious Diseases and International Medicine. He joined me around three years ago toward the start of the pandemic because as a clinical trialist extraordinaire, he had both personal experience running COVID-19 trials and also the broader perspective of how to evaluate treatments going forward. I've invited him back now as it's been, as I said, three years, and he has an important perspective on how we've done researching treatments for COVID-19 and what he's currently excited about and what we can expect in the future. David, welcome.

David Boulware: [00:00:45] It's great to be back. Thank you. Paul.

Paul Sax: [00:00:48] I'm going to start with Nirmatrelvir with Ritonavir, which everybody knows is Paxlovid. It's incredible how the brand name has really taken off. It is by far the most broadly used treatment and I'm really interested in your thoughts on the strength of evidence for using it now, in the current situation we are in, in the current pandemic.

David Boulware: [00:01:08] I mean, when you look back on the initial clinical trial that was published over a year ago now, the EPIC-HR trial, that was in the high risk group, the HR. Clearly there was a large benefit in unvaccinated high risk people for reducing hospitalizations and death. There's no doubt that that's highly effective. The EPIC-SR trial, which was the standard risk trial, that looked at standard risk people who were unvaccinated or higher risk people who were vaccinated, those data haven't really been made public, but are, in a press release anyway, that there was a trend towards benefit, but unclear of how it performed in those two groups. If you look at the US, there's an estimated probably 5% of the US population which has been uninfected and unvaccinated. The rest of us have either had infection and or been vaccinated and so that the population that was studied in doesn't really exist. And so it's being extrapolated very broadly to high risk populations that are mostly have some form of prior immunity either due to infection or vaccination. And so there's a little bit of a stretch that what the clinical benefit in that population is, you know, there's probably is a benefit. And so if you look at the case control studies of tens of thousands of people, this is something that you can show a statistical benefit perhaps, but the time to symptom resolution, which is really what most people care about, hasn't really been shown. And there's also case control studies of long COVID. But similarly, case control studies are not randomized trials.

Paul Sax: [00:02:36] Do you have knowledge about why the EPIC-SR study has not been published?

David Boulware: [00:02:40] I think twofold. One is that the data probably are not super supportive. And so if the data were supportive, particularly I think in the vaccinated subgroup, if there was like a trend towards benefit, the data probably would be public. But if the data are kind of not very supportive, I mean that's the only explanation I can have. That sounds a little conspiracy theory-esque, but that trial would have been great to just expand and have a larger sample size if the issue was just that there was a trend towards benefit, we needed 2000 people or 3000 people to show the benefit, then why not just expand the trial and get more data? The fact that it wasn't done suggests maybe some of the subgroup analysis were not very beneficial. But we don't know that.

Paul Sax: [00:03:20] And what about shifting to a much less commonly used drug, but I confess I have recommended it in some people who can't take Paxlovid, what about Molnupiravir? And I feel like, in fairness, I have to mention the brand name, which is LAGEVRIO, although nobody knows it, it's kind of kind of ironic. We have a lot of data on this treatment. What do you think?

David Boulware: [00:03:41] Yeah, the initial clinical trial was barely squeaked out a p value. If you consider loss to follow up as a failure, then there was a statistical difference in unvaccinated population, but some were seropositive and there wasn't a benefit in seropositive people in the initial trial. The larger UK panoramic trial I think is quite definitive. And so in 26,000 people there wasn't a statistical benefit as far as reduction in hospitalizations or health care utilization. It was an open label trial, and so there was a benefit as far as symptom reduction, that's a little bit hard to interpret. But it was four days, so it's a large effect where people felt better, faster. I'm a little skeptical that that's a real effect because in the move out trial, in a double blind trial, there was not a big reduction in symptom duration, and so in an open label trial, this could just be a placebo effect. That was a highly vaccinated population. I think the same would be true if you had prior infection and survived, that the benefit is quite minimal to none. The argument has been used, well, what about immunocompromised people? The immunocompromised people who were enrolled into panoramic trended towards doing worse. And so that's a little bit when they were prescribed molnupiravir.

Paul Sax: [00:04:49] It's really an interesting quandary because that time to symptom recovery, as you mentioned, was really dramatic. And it's more than has been seen in open label studies of, for example, oseltamivir for influenza. As the son of a psychiatrist, it made me think maybe the placebo effect isn't all bad?

David Boulware: [00:05:07] So that's the placebo effect is really what you're banking on with the hydroxychloroquine and the ivermectin. I took this medicine, I got better, and therefore it worked. And that's the great thing about a self-limiting illness where 99% of the patients are going to get better either regardless or despite what you do. And so that opens up a lot of possibilities for giving ineffective therapies that have no actual benefit.

Paul Sax: [00:05:32] And of course, there is the controversy about molnupiravir as mechanisms of action, that this might be generating harmful variants, it's got mutagenesis concerns. If I were to look at my crystal ball, I would say that treatment's probably not long for the COVID-19 guidelines. Briefly, we need to talk about remdesivir in the outpatient setting. And again, for fairness, I'm going to say it's VEKLURY, but remdesivir in the outpatient setting. Your thoughts?

David Boulware: [00:05:58] Yeah, I mean, the data were good. Once again, it was tested in unvaccinated population, had a large reduction in hospitalizations and health care utilization. The catch is trying to do it. And so our health system looked at this and this is really hard to do where you're giving multiple daily infusions to people.

Paul Sax: [00:06:15] Speaking of difficult to give treatments, your opinion about whether we'll ever have another monoclonal antibody-based treatment, either for treatment or prevention.

David Boulware: [00:06:24] There's certainly a need. For those who are immunocompromised, those with B cell defects that don't make antibodies, having a monoclonal antibody, you know, all the people on rituximab, that's a huge population that's at risk long term. And so having a monoclonal antibody for prophylaxis, there's a clinical need for that. What the companies have shown is that developing a monoclonal antibody is high risk because it may only be around for three months and so why are you going to spend tens of millions of dollars to develop a monoclonal antibody if it's going to be lost quickly? And so I think from the commercial side, the variants sort of stabilize and there's not much new variants that pop up. I don't foresee a company really pursuing the whole regulatory pathway to get approval for that because of just the expense versus the risk is not commercially viable.

Paul Sax: [00:07:13] I completely agree. It was very discouraging for them when Evusheld was no longer effective or recommended. Recently, three other treatments have demonstrated favorable results in clinical trials, but interestingly, none of the three is in our current guidelines, and two aren't even available. Why don't we start with a personal favorite of ours, which is pegylated interferon lambda. Help our listeners understand the clinical trial results, what they were when we first learned about them, and last, maybe say a few words of why it's not currently available as a treatment.

David Boulware: [00:07:44] What is interferon? So interferon is one of these compounds that help as part of your immune system. And the interferon lambda in particular is basically an antiviral compound. And so it boosts your intrinsic immune system's response to viral infections. This is something which is a host directed therapy. And so it's something that could be effective against a number of different viruses. And the initial company was looking at this for hepatitis Delta virus. But this is good for potentially any sort of viral infection where we don't have a treatment. And so they tried this out for COVID and basically it was in a randomized double blind placebo controlled trial. It was effective at reducing hospitalizations in E.R. visit was the primary outcome. Also, it was effective for reducing hospitalizations. And so when they looked at overall, it was 60, 60%-ish, I'm thinking. And then when they looked at the subgroups of like if you looked at the unvaccinated population, so just like the Paxlovid trial, basically it was about the same. It was sort of 89, 88% reduction in hospitalizations among the unvaccinated population. This is a one time injection. So it's kind of similar to the monoclonal antibody. It'd be difficult to administer in a health system. But the reason why I'm most excited about what the possibilities of this is, is it could be a really a broad spectrum antiviral for any sort of respiratory infection or viral infection where we don't really have a therapy for. And it would be great to have this within our toolbox so the next pandemic that rolls around, this is a possible therapy. And so I think that's currently today. Is it essential? No, but I think it would be great to have the next pandemic. And the fact it's not available, it's safe, it's clinically effective is kind of a shame.

Paul Sax: [00:09:23] I mean, it's interesting. As you mentioned, the clinical outcomes were excellent, significant reduction in hard clinical endpoints. Yes, it's given as an injection like monoclonal antibodies, but it's a subcutaneous injection rather than an intravenous one, which is much, much easier. And then the third thing is that it clearly worked across variants. The study was conducted over a period where there were variants coming and going and didn't seem to have any impact on the outcomes, which is very encouraging and I don't really sense that it would have much in the way of drug interactions. Now, once the study results came out, someone asked me whether it could induce autoimmune diseases and I suppose theoretically that could happen, but that wasn't reported in the trial. What can you share with us about the regulatory issues, if anything?

David Boulware: [00:10:06] Well, this is where the regulatory aspects are sometimes the bureaucracy is not great. And so typically for  a clinical trial, one is supposed to file an investigational new drug application, what's termed an IND application. The FDA then sort of looks at the protocol and the main thing is, is it safe to proceed? So that's the first sort of assessment. And then they also will give you feedback on the trial design and what they think and if you're going to apply for regulatory approval, like what they would suggest doing. The company had an IND for their own protocol, but the protocol that the main trial was conducted under, the TOGETHER trial, was done outside of the US, in Brazil, and so they weren't obligated to file an IND for that protocol. So they didn't. And so there was some reasons or why they might not have, it was an investigator-initiated trial, but you can still file an IND for an investigator-initiated trial with the FDA. If you don't file an IND, the FDA can choose to look at your data or they can choose not to. They're not legally obligated to consider the data. And so they took kind of a hard line of saying, well, you didn't file an IND. I'm not sure what they didn't like about the trial. It's a platform trial that reduced hospitalization, which is a pretty hard endpoint. It also reduced E.R. visits and hospitalization. So they viewed it basically as a phase two trial, which is kind of like a pilot trial. And this was a 1900 person trial - that's like one of the largest outpatient trials, probably the second largest after the panoramic trial. They sort of view this as a pilot trial is a little bit ridiculous, in my opinion.

Paul Sax: [00:11:36] Yeah, it's frustrating. I can say that when the data were presented, they were published in the New England Journal of Medicine and then presented again at the conference on retroviruses and opportunistic infections. And not surprisingly, there were questions from the audience about what's going on. And I think nobody, nobody really knows at this point.

David Boulware: [00:11:55] Yeah, so unfortunately, the company is basically dropping it because they're not going to repeat a new trial in the US of $100 million trial to show the exact same results. And so they've sort of dropped it and moved on, which is a major loss to patients in the US. I think withholding this therapy is a mistake, but they are interested in looking at broader respiratory viral infections and so they are going to redo sort of some trials probably outside of the US with the TOGETHER trial platform looking broadly at respiratory viruses. And so this is I think really great is the plan of if you come in with some sort of respiratory thing, it's thought not to be bacterial pneumonia. Can you send off your molecular testing for PCRs to figure out what it is? But in the meantime, give them an injection of this and then you figure out three days later or two days later, oh, it's RSV or oh, it's COVID. Oh, it's flu. And you have a potential broad spectrum antiviral that you're giving for these respiratory illnesses. And so that I think is quite exciting. There actually are following the correct paperwork, filing an IND with the FDA. And so maybe this will come back around and will be available. But I think instead of prescribing a lot of unnecessary antibiotics for viral pneumonias, this could actually be kind of exciting.

Paul Sax: [00:13:07] Yeah, that's very exciting. I'm glad to hear that they're moving forward with that trial on to the next treatment that's not available, at least not yet, ensitrelvir. And you can tell from the name it's another protease inhibitor. It's available in Japan. They did a study in low risk people with COVID-19. What did it show?

David Boulware: [00:13:23] Once again, quite exciting data in a relatively small trial. This is also presented at the conference on retroviruses and opportunistic infection. They showed once again sort of reductions in health care utilization and hospitalizations and also in symptoms of long COVID...

Paul Sax: [00:13:37] Blinded study.

David Boulware: [00:13:38] Blinded study. So a double blind trial and once again, a small study, I'm forgetting the exact numbers, 350 people or 400 people ish, relatively small trial, but had sort of significant results, had very good virologic effect as an effective protease inhibitor would be expected. And so this is a very exciting therapy. These data have been around for a while. The Phase two trial was completed quite a while ago. And once again, that therapy is not available in the US, which is also disappointing.

Paul Sax: [00:14:07] Yeah, I thought the data on symptoms of long COVID were among the most convincing data we've seen. That antiviral therapy could reduce long COVID incidence because participants were still under the blind when they were queried about it. And they did a broad range of questions of symptoms and there was a really significant reduction. And it makes sense that if you have an antiviral that is effective, that a viral induced post-infectious syndrome would have reduced severity. Very exciting data.

David Boulware: [00:14:36] That really helps for the proof of concept that early antiviral therapy is likely going to be helpful.

Paul Sax: [00:14:42] We're going to now move on to a personal favorite of yours I know, as a as a co-investigator in the study. So let's talk about metformin. Why was it even chosen as a COVID-19 treatment?

David Boulware: [00:14:55] There's a whole long backstory with metformin that in vitro it has some antiviral properties against a wide variety of viruses, and it's not a direct antiviral against the virus, but it's more on the host side, so it's sort of host directed therapy once again of down regulating pathways that relate to viral replication. And so metformin initially was identified by one of my Minnesota colleagues, David Ody, who does a lot of insilico modeling of various therapeutics and his model of viral pathways and what might work. And so he predicted early on while I was doing my hydroxychloroquine trial, saying that he didn't think that was going to work based on his model, and he was correct. But metformin was one of the things that hit of like, oh, like this is potentially positive. And so the next step was actually looking through our health system records, big data, querying people who are on metformin. So a lot of those people have diabetes, but you can, among people with diabetes, look at people on that therapy and control for other factors. Once again, the people who were on metformin had a lower reduction of progressing to severe COVID and being hospitalized. So that was one data set. And so we then worked with United Health Group and looked at their sort of research people and Optum and they queried their databases and similar results across multiple states where people who are receiving metformin had lower risk reduction for hospitalization.

David Boulware: [00:16:14] And so once again, observational data, case control data, not perfect, but it's usually you start with observational data and then you go to randomized clinical trials, not the reverse. And so with that prelim data, there was enough interest to get some funding, some private philanthropy, which is actually more interested in ivermectin at the time than metformin. But with that we said, well, we can do a factorial design trial and we can look at both of these at the same time. And so that was kind of the genesis. The Rainwater Foundation, who also supported some of the ivermectin work in the TOGETHER trial, to do a factorial randomized trial looking at three medicines in total. So it was metformin versus placebo and then another factorial randomization was ivermectin versus placebo, low dose fluvoxamine versus placebo, or just a placebo placebo. And so with that trial, we were able to look at three medicines for basically the same sample size to look at what the effect was when we gave immediate release, metformin that was titrated up over a couple of days.

Paul Sax: [00:17:12] It's a great study design and if you were betting on which one you thought was going to work at the start, which one would you have put your money on and what actually happened?

David Boulware: [00:17:23] Well, I pushed for the inclusion of fluvoxamine, so I was sort of on the fluvoxamine bandwagon and I was like, why are we studying metformin, there's no way this diabetes medicine is going to work. And so I was skeptical, but the PI was really sort of expertise on sort of weight and obesity and stuff like that. And so she was all in on the metformin and I was very, very, very skeptical. And it's kind of almost embarrassed to say, well, we're looking at metformin for COVID because from an ID doc perspective, it doesn't make any sense.

Paul Sax: [00:17:51] So what does the data show?

David Boulware: [00:17:53] So basically there's a big problem with pulse oximeters. It turns out that our pulse oximetry data were basically kind of junk in that there were unbelievable values and people going from like 70% to 100%, which might be their heart rate being reported. And so the pulse oximetry data were basically junk. And so the primary endpoint didn't work. And so if people sort of read down the abstract of the New England Journal paper and stop there, their conclusion would be this therapy doesn't work. As part of the other composite endpoint, and this was pre-specified, was to look at reductions in E.R. visits and hospitalizations and death. And so there was a reduction in E.R. visits and hospitalizations, a little over 40%. And then the hospitalizations, the primary endpoint was 14 days. That was probably, in retrospect, a mistake. And by the time of sort of 2021 and 2022, most trials are reporting 28 day hospitalization. There was not a reduction in 14 day hospitalization. There was a reduction in hospitalization by day 28. And so it went from, I think, 2.9% to 1.2%, which was statistically significant. But that's sort of a secondary endpoint. The numbers appeared in the New England Journal manuscript, but there wasn't a P value. But we did put the numerators and denominators hoping that people would do a chi-square test or Fisher's exact test and be able to be like, oh, the P value is 0.03, maybe there actually is a reduction in hospitalization by day 28. But the party line in looking at the abstract is, oh, it didn't reduce hospitalizations, so therefore we don't care. In retrospect, yes, we should have picked 28 day sort of hospitalization as the endpoint. But you design trials in the middle of a pandemic and you make choices as you do. And that was a mistake on our part. So you live and learn.

Paul Sax: [00:19:30] Can I ask you about the virologic data and the long COVID data

David Boulware: [00:19:33] The most incredible thing is there's actually a virologic effect. There's basically about a half a long reduction in viral load by day five. By day five, you're still titrating up the dose. And so people started at 500mg day one, 500 twice a day, day two through five, and then day six were up to 1500 milligrams a day. Day five is about a half a log reduction. And by day ten, it was sort of a little bit more than that. And so that virologic reduction versus placebo was sustained, which is different than with Paxlovid where there is a big biologic effect early through day five and by day ten, when you're off the medicine, you sort of converge back towards placebo and you're probably potentially at risk of rebound. In contrast with metformin, we saw actually reduced rates of rebound where the day ten level was not higher than the day five. And so we kind of defined rebound as if your day ten viral load shouldn't be higher than day five. So there was less rebound. There was a biologic effect. There's sort of a mild, modest antiviral effect. You know, half a log reduction is not quite as big as some of the protease inhibitors. But this is in a population where about half the people were vaccinated. The effect was larger in unvaccinated than vaccinated, in part because they have a higher viral load. It was larger than the effect seen with molnupiravir, which I think was 0.35 log reduction. It's only a $1 medicine. So I think certainly the value, the cost versus viral load reduction, certainly would favor metformin over molnupiravir. I think that's kind of exciting. And what does that mean? And so the bigger aspect is actually the long COVID data, which I think are quite exciting. With long COVID, the patients, the participants in the trial, were followed long term through ten months of after randomization, like a 300 day follow up, which is pretty extraordinary.

David Boulware: [00:21:12] And the loss to follow up was like 5%. Once again, pretty comprehensive data of the people who agreed to be followed more than than 28 days. I think about 10% didn't want to be followed. But of the people who wanted to be followed beyond day 28, really great follow up. And so there was basically was a 42% reduction in long COVID incidence over that time period. How we define it, it was sort of health care provider diagnosis of long COVID. I would say not the greatest. "What is long COVID" is quite hard to define. We said, well, they went to a health care doctor and they got diagnosed. And so it does speak to the population that this is about 10% of people that if they do have long COVID, they do have these symptoms that kind of persist and can linger. Nowadays, where people think about your risk of death and hospitalization, if you're vaccinated or you survive, prior infection is probably low. But if you've got a 10% risk of long COVID, like that's something I would want to avoid. And so I think metformin is quite exciting in that respect, where low cost medicine in a double blind trial and so all of that, you know, there's a 42% reduction that's pretty statistically significant. It's kind of surprising how little traction that's gotten. It's unpublished. So we'll see.

Paul Sax: [00:22:25] A lot of it has to do with the bottom line statement. In the New England Journal of Medicine paper, you look at the abstract and you look at the last line in the abstract, and none of these treatments was shown to be effective. But, you know, obviously the devil's in the details.

David Boulware: [00:22:39] That line was not written by the authors.

Paul Sax: [00:22:42] Let me put you on the spot. You now have access to these medicines. What would the guidelines look like? According to Dr. David Boulware.

David Boulware: [00:22:52] The 2 or 3 therapies, I think that are, I mean, four therapies, you've got protease inhibitors. So it would be nice to have two protease inhibitors available. For people with severe underlying immunocompromised, still protease inhibitors are going to be your first line choice. I think interferon lambda is a really quite appealing therapeutic. It'd be really interesting to also know like the long COVID data on that, but we don't have that. But my assumption with the protease inhibitors that both of those likely have a benefit for long COVID as well. And I think metformin, it's a low cost therapy, particularly in low and middle income countries that don't have access to the protease inhibitors and are not going to have realistic access for the foreseeable future, I think that's a very good therapy. In my dream world, if we could do a clinical trial, it would be to add a protease inhibitor to metformin. That's not going to happen in the short term. You know, just as with HIV therapy, if you have one antiviral, that's great. But if you have 2 or 3, can you get a better viral load reduction? And because the mechanisms of how metformin works versus the protease inhibitors, if you add those together, do you get a better viral load reduction and importantly, sort of avoid some of the rebound that's observed with Paxlovid? It's an additional $1.

Paul Sax: [00:23:59] It sounds like a very plausible clinical trial. And since we're not going to have the elimination of COVID-19, we're going to have a lot of time to study it. I just want to quickly talk about the cost. A colleague of mine, she was traveling abroad and got COVID and could get Paxlovid, but had to pay out of pocket for it. Thousand dollars. So these drugs are not cheap.

David Boulware: [00:24:24] They are not. Not yet. And I think you have to what's the absolute benefit for the person? You think about the number needed to treat, the number to reduce the hospitalization. And so it's all good and fine when sort of covered by the US government for US citizens here, but once we the pandemic ends and we transition back to the sort of the commercial health care model, HMOs and other health systems are going to be pretty aggressive at gatekeeping that you're 55 years old, there's no benefit in that population.

Paul Sax: [00:24:52] David, this has been a really fascinating conversation. I appreciate your insights on these studies. I always look for them. And as you know, because I email you regularly just to get your opinions. Thanks so much for appearing on our podcast today.

David Boulware: [00:25:05] Thank you very much for the invitation.