Syracuse babies part of worldwide RSV medication test

[00:00:00] Host Amber Smith: Upstate Medical University in Syracuse, New York invites you to be "The Informed Patient" with the podcast that features experts from Central New York's only academic medical center. I'm your host, Amber Smith.

The Food and Drug Administration recently approved a new medication for the prevention of respiratory syncytial virus, which can cause serious disease in babies and toddlers. This drug was first tested on babies in Syracuse, in a trial overseen by Dr. Joe Domachowske. He's a pediatric infectious disease specialist and professor of microbiology and immunology at Upstate. "The Informed Patient spoke with Dr. Domachowske last fall about RSV and his study of this medication as it was working toward FDA approval.

Welcome back to "The Informed Patient," Dr. Domachowske.

[00:00:49] Joe Domachowske, MD: Thanks very much. It's exciting to be here and to talk about this topic in particular.

[00:00:54] Host Amber Smith: I understand you're close to wrapping up the last phase of your trials, and you're now seeking FDA approval for the study medication. That must mean that your study showed that this medication works, is that right?

[00:01:07] Joe Domachowske, MD: Everything indicates that it works extremely well. And it's very safe. It's very exciting time because if this meets its promise, we can change the landscape of RSV infection.

[00:01:18] Host Amber Smith: Well, can you give us a summary of what phase 1, or the first part of this trial involved?

[00:01:24] Joe Domachowske, MD: Yeah, back in 2015, we did the very first phase 1 trial, and there were about 90 babies enrolled in this trial. Phase 1 is very low enrollment, and it really was a dose selection study to make sure that we were giving the right dose and to do some safety information as well. We were the only site in the Northern Hemisphere to enroll any babies. We got three babies before it closed, to enrollment at the beginning of RSV season. Most of the rest of them were enrolled in the Southern Hemisphere.

[00:01:56] Host Amber Smith: So this is an international trial?

[00:01:59] Joe Domachowske, MD: Absolutely. All of the studies, phase 1, 2, and 3 are international studies.

[00:02:05] Host Amber Smith: So what did phase 2 focus on?

[00:02:08] Joe Domachowske, MD: Phase 2, we looked at the preemies who were born 29 to 34 weeks. A term pregnancy goes out to 40 weeks. So these are later preemies. And they're not eligible for the currently available prevention medication that we have. So enrollment for this particular group was a little bit easier because many of these folks wanted access to this type of medication for their infants, but they didn't have it, according to the standard of care. So we began that study in November of 2016, and it continued for one calendar year. It was almost 1,500 babies. And we found an 80% reduction in RSV medically-attended lower respiratory tract infection. And that means going to their own private doctor, going to the ER (hospital emergency department) or being hospitalized.

[00:03:01] Host Amber Smith: Eighty percent is huge, right?

[00:03:03] Joe Domachowske, MD: It is. This is the most common reason why infants are hospitalized in the US, and really everywhere else in the world. So to see an 80% reduction from this phase 2 clinical trial was so impressive.

[00:03:16] Host Amber Smith: And then phase 3, what has that been about?

[00:03:19] Joe Domachowske, MD: There are three phase 3 studies. One is finished, and two of them are going to be done in the next month or so. The first one, and I think the most important one, was the one we did in the preemies, the same group as the phase 2, but more efficacy information. We always collect safety information. That particular phase 3 study also included a subgroup of high risk infants because they were defined as high risk based on having congenital heart disease or chronic lung disease from their prematurity. So the effectiveness of the particular medication in that group and that phase 3 was almost identical to what we saw in the phase 2.

[00:04:08] Host Amber Smith: Can you explain, it's called nirsevimab, is that how you say it, the study medication?

[00:04:14] Joe Domachowske, MD: That's it's name, yes. Nirsevimab. Yep.

[00:04:16] Host Amber Smith: So can you explain how that compares with a medication that's already available for RSV prevention?

[00:04:24] Joe Domachowske, MD: The current standard of care for the highest risk newborns for RSV prevention is an antibody medication called palivizumab. That medication has to be given every month during RSV season, or during the period of time when a baby's potentially exposed to RSV, in order to maintain that protective effect. Because of cost issues and other related logistical problems, we really have only focused on the highest risk infants for receiving that particular medication. In 1998 when it was first available, we gave it to all of our preemies, even preemies that were born at 34 1/2 weeks, close to term. But gradually over time there's been increased restrictions to its use, largely because of the cost.

[00:05:22] Host Amber Smith: So, nirsevimab, when was it discovered or created?

[00:05:27] Joe Domachowske, MD: Nirsevimab was a product of two discoveries that were made in back in 2014. The first discovery, which made my jaw hit the floor, I was sitting at the RSV International Conference in Argentina -- which was beautiful -- and I was listening to a protein chemist describe one of the proteins that sits on the outside of the RSV virus. And I thought, 'I'm a clinical pediatrician. I do clinical research. I'm not sure a protein chemist, I'm going to even understand what's going on here.' But everyone in the room listened to this guy's story and what he discovered, and everyone was just sitting there with their mouths open saying, "Wow."

So what he discovered was that we'd been working on the wrong protein up until 2014. What happens is, if you envision the RSV particles themselves, they have these things sticking out the surface of the virus. And if you think of them as sort of daggers with a handle. As soon as those daggers touch a cell to try to infect a cell, the handle of the dagger flips, and the whole confirmation, the whole structural component of the protein changes. We need to have antibodies to protect us based on the pre-fusion, before this dagger touches the cell, not afterward. And we'd been working on the confirmation of the wrong protein for decades. So that was the first thing that happened.

The the second thing that was discovered right around the same time was that if we take any antibody, these monoclonal antibodies in particular, and we change the part of the antibody that attaches to the cell. Not the part that attaches to the virus, but the part that attaches to the cell. If we change it by just three amino acids, very small changes, it can enhance the half-life of these molecules from 19 days out to more than 120 days. So now we have the potential of making a very high neutralizing antibody against really whatever we want, that will last a fairly long time, out to five months, maybe longer. So nirsevimab is the first product that's taken advantage of both of these technologies and these discoveries. The company also refined the virus binding part of this antibody so that it's about a hundred times more neutralizing than palivizumab, the product that we're using right now.

[00:08:09] Host Amber Smith: Wow, that's interesting. So does it prevent RSV infection entirely then, or does it just prevent the babies from becoming severely ill?

[00:08:20] Joe Domachowske, MD: It clearly prevents hospitalization or lower respiratory infection caused by RSV. And there's some indications -- we don't have the final phase three information yet because two of the three studies are not closed up yet. We haven't finished them yet. And so the data are top secret until those last few pieces of information are collected. So at the very least, it prevents lower respiratory tract infection, reducing hospitalizations by 80 to 85% compared to a placebo. And we know that it's very, very safe because when we use the placebo to compare, the side effects from the placebo are identical to the side effects of this medication. So that's how well tolerated it is. Babies are used to having antibodies around because they make their own. And this is a completely human antibody. It's just made in a test tube instead of in the person. So we make it and refine it, and we give it to the babies. And because it has such a long half life, the expectation is we can give one dose, and it will protect these babies for five to six months. That's an RSV season for all of them.

[00:09:34] Host Amber Smith: So it's meant to be a preventive. Could it be used to treat a baby that's already sick with RSV?

[00:09:41] Joe Domachowske, MD: I suspect not. And the reason I say that is related antibodies have been developed over time -- including palivizumab -- have been tried as adjunctive therapy to treat RSV, and there isn't a single study from any of those other types of antibodies that indicate that that's the right path to take. Will those studies be done with nirsevimab? Probably. But they will be small studies, and I don't think there's going to be very high expectations for it to offer anything, once the babies are infected or once an older child, for example, would be infected. We still don't have any effective treatment for RSV, unfortunately.

[00:10:20] Host Amber Smith: Is there any benefit to a baby getting RSV? Assuming it's a mild case, that is, would RSV strengthen their immune system for life, or offer any sort of lasting protections?

[00:10:33] Joe Domachowske, MD: RSV is an interesting virus as far as the immune system goes, because the first infection does tend to be the most severe. But we get reinfected throughout our whole lifetime. And older children, young adults, they tend to get maybe a little bit of a cold, not typically severe unless it triggers their underlying asthma, and then of course, they can get into some trouble. But it's not until the other extreme of age, the elderly folks, where RSV causes severe problems again, where the rates of hospitalization in people over 65 years of age from RSV are second only to those for influenza as far as respiratory infections go.

So does getting RSV really do much as far as additive protection year after year after year? I think it probably does, but it's not one of these infections where you get it once and you never have to deal with it again. Like chickenpox, you get it once and most people are considered to have lifetime immunity. Measles, you get measles or measles vaccine, you're considered to have lifelong immunity. But RSV is more like strep throat. You get it once, and it doesn't do you much good, as far as being susceptible to getting strep throat again. You can get infected over and over again, and your immune system just doesn't kind of do what it needs to do to completely prevent you from being infected again.

[00:12:02] Host Amber Smith: I know your trials have obviously focused on children, babies, but RSV can be a deadly infection in the senior population as well. Do you know, or do you think that nirsevimab would work in seniors the same way it does in babies?

[00:12:18] Joe Domachowske, MD: I think that the logistics of doing that would be very difficult, bordering impossible, because the amount of the antibody that would have to be given is essentially based on weight. And so, our studies, for one of them, we gave the kids the nirsevimab two seasons in a row, and some of them got up to about 10, 11 kilograms, which is, you know, 22 pounds or so. And that still was a large enough volume that we had to divide it into several different shots. We couldn't give it all in one injection. So if we take that one year old, that 10 kilogram one year old, and we magnify them into an adult and say, "What is this dose that's going to be needed?" It's almost prohibitive to be able to deliver that type of dose.

But there are some strategies. Certainly we learned a lot about monoclonal antibodies with Covid and how they can be both preventative and, in some cases, effective at treatment. So there are some strategies that are being developed using a similar antibody structure and antibody system that may offer that type of treatment or prevention in elderly adults as well.

[00:13:35] Host Amber Smith: This is Upstate's "The Informed Patient" podcast with your host, Amber Smith. I'm talking with Dr. Joe Domachowske. He's a professor of pediatrics and microbiology and immunology at Upstate, and he's the principal investigator for a series of clinical trials about a new monoclonal antibody designed to prevent respiratory syncytial virus, or RSV.

Now, counting all the phases together of the studies that you've done on this from all countries, how many different babies participated in these trials?

[00:14:09] Joe Domachowske, MD: Internationally, I think altogether, more than 150 different clinical trial sites, in over 80 different countries. There were around 4,600 babies studied, for all of the phase 3 trials, the single phase 2 and the single phase 1 trial. So we have the safety information and efficacy information on nearly 5,000 newborns and young infants.

[00:14:38] Host Amber Smith: And in general, what was involved? Was it blood draws, or vital statistics? I mean, what did you do with the babies?

[00:14:46] Joe Domachowske, MD: They would come in. We'd make sure that they fit the definition for the particular phase of the protocol. Phase 1, there's always more blood being drawn, unfortunately, because we really have to get a good sense for the stability of the product, of the medication in the blood. And we were also looking to see if the babies would generate antibodies against, the antibody. Because then if the antibody's being neutralized by something that the baby's developing, it will stop working. So that was also a concern.

So for the phase 1, they did get six blood draws over the course of the six months that they were on the active phase and being followed. Anytime they got a sniffle, a sickness, any kind of respiratory anything, we asked the parents to notify us, and we'd bring them in, and we'd swab their nose and their throat to see if they had RSV as the cause. So it's asking families to do a lot.

The phase 2 and phase 3 are a little bit less burdensome, as far as the number of blood draws go. Those kids, every time they had a respiratory illness, we'd have to ask them to come in so that we could collect the swab and test them, because that was the clinical outcome we were most interested in: did this antibody protect them from RSV? And was this cold or other respiratory infection that they had, was it being caused by RSV, or was it being caused by something else?

[00:16:11] Host Amber Smith: Were there any adverse events during the trials that concerned you?

[00:16:16] Joe Domachowske, MD: Well, the trials were all placebo controlled, so the side effects or the reactions that the babies had, I didn't know if they had gotten a placebo saline injection, or if they got the monoclonal antibody injection. And the types of injection, local injection site complaints that we see with other immunizations weren't as frequent from nirsevimab. There was a little bit of maybe swelling or injection site tenderness for a day or so. But when we did unblind everything and we compared the placebo to the medication itself, the side effect profile was identical. So it's basically as safe as giving a saline injection.

[00:17:01] Host Amber Smith: Now, you enrolled the first two infants in the world to receive this investigational medication, more than seven years ago. What can you tell us about these babies?

[00:17:13] Joe Domachowske, MD: These are amazing kids. They're twin girls. They're now seven years old and they just finished up the Covid 19 vaccine trial that I was doing for pediatrics because they, their family is all very much engaged and interested in clinical vaccine research.

But when they were born, they were born middle of December of 2014, and my site wasn't quite up and running yet, but I was talking to the parents because I figured, if we could get up and running and have all of our regulatory requirements fulfilled, this is a perfect family and a perfect circumstance where we could enroll both of these newborn girls. They were born a little bit premature. They were born at 33 weeks gestation. Twins are often born a little bit early. And it was the first or second week of January, 2015. I brought them to my office because I didn't want them in the clinic, being exposed to other kids who are coming in sick. In my office, tiny little girls, put them on a makeshift bed on my desk, did their physical exams, drew their blood and gave them these doses, their first dose, the first two ever, first two babies ever to get this particular antibody product happened right by me, right in my office, oh, seven years ago. It was very exciting.

[00:18:37] Host Amber Smith: Was it difficult to persuade their parents to participate?

[00:18:41] Joe Domachowske, MD: I don't see my job as a clinical trial investigator as persuading. I like to give information, talk about potential of new products that are available and the potential that we gain information even if this stuff doesn't work. And, I knew this family very well, because they were both teachers in the area, and my kids both had one of them as their teacher years ago. The dad actually went on to become a respiratory therapist and was well aware of the potential consequences of RSV, especially in premature infants. So, they basically came to me and said, "When are you going to have an RSV prevention trial?" So it was not difficult at all to recruit them for this.

The third baby, which, we enrolled three altogether before RSV season started that year. And once RSV season started, the sponsor for the study asked us not to pursue additional enrollment because they wanted all of the kids to be RSV naive, and there would be potential for them to have been infected already. So, the third one, the dad is a physician, and he heard about it because he heard me talking about it, and he had a premature baby girl, who he came up to me and said, "What do you think? Do we fit the inclusion? And can we come and talk with you maybe about participating?" So that's how it happened.

[00:20:10] Host Amber Smith: Can you explain the main differences between clinical trials for adults and clinical trials for children?

[00:20:18] Joe Domachowske, MD: Well, I guess I do it naturally. But explaining it and talking about it is very important because children by definition, are a vulnerable population when we're talking about clinical research, just like pregnant women would be considered in that category. When we have a vulnerable population, we need to add additional layers of ensuring protection for their safety and their wellbeing. And the Institutional Review Board, the IRB, is responsible for making sure I, as a clinical trial investigator, take care of those issues with my clinical trial participants and keep their information private and keep them safe. Above everything else, it's patient privacy, patient safety. So anytime there's a volunteer, we need to take that into consideration and for vulnerable volunteers, there's additional regulatory requirements that need to be fulfilled. For example, if the intervention is more than minimal risk and doesn't really offer the possibility of a true benefit, it's more for the advancement of science for example -- that's not a clinical trial that likely would be approved by the IRB unless there was other contexts that said it's important to do so. So, there are some nuances and some fine print about doing clinical trial work in vulnerable populations. We've been doing this now for nearly 30 years. It's changed. The regulatory requirements certainly have changed, I think all for the better. But we have to be well trained. I have to make sure my team is well educated and know the protocol back, and forth and upside down, so that we are doing exactly what we're expected to do and we're keeping our babies safe.

[00:22:16] Host Amber Smith: Do I understand correctly that decades ago children were excluded from clinical trials because researchers had the feeling that they're a vulnerable population, that it would protect them by not enrolling them in any trials. And, what happened to change that?

[00:22:36] Joe Domachowske, MD: Well, gradually and really very slowly it became clear that there are certain medications, certain interventions, and certain opportunities that would be uniquely important for children. That wouldn't really be relevant to study in a phase 1, phase 2, and phase 3 kind of way in adults. But at the time, we needed to have phase 3 studies in adults. You know, we're talking about decades ago, in the US at least. And we needed to have something that was FDA approved before we could suggest doing a trial in young children with that same product. It had to be proven safe and effective In the adult age group. That's no longer the case, although depending on what the product is, what it's meant to prevent or what it's meant to treat, there may be instances where the FDA still requires at least a phase 2 trial that's completed in adults before they will allow a phase 1 trial to be started in children.

This one's an exception. The FDA identified nirsevimab before it was even named that, back in 2015 as a breakthrough medication. As we progressed, this changed into a fast track designation because the FDA recognizes that this has the potential to meet an unmet public health need for the pediatric population.

[00:24:05] Host Amber Smith: So maybe that'll change the timeline. I was going to ask you to kind of walk us through what you expect the timeline to be with the FDA in terms of approving nirsevimab as an RSV preventive.

[00:24:18] Joe Domachowske, MD: Yes. We expect what's called the biologic license application to go in within the next several weeks. So we're talking about sometime in October of this year. And typically, once that BLA (biologic license application) is submitted to the Food and Drug Administration, they have nine months to review it and get back to the sponsor or the manufacturer with comments, critique, "oh, we need to do this," "we need to tweak this," "we don't have enough data about this," "can you redefine this?" I mean, these applications are enormous and provide granular information down to the last detail. And the FDA reviews it, granular, down to the last detail. So nine months is a long time for the review. And once the response goes back to the person or the agency that has submitted the application, they have six to nine months to develop a response, unless the FDA is asking them to do another clinical trial, another phase 3, for example, and then they'll give them longer.

So you can imagine that whole process can take years and years and years. Typically for a product that enters phase 1, that does make it through all the way through a phase 3 and is shown to work, and be submitted to the FDA, typically, once it's submitted, it will take about a year, to a year and a half, for final approval -- if the FDA decides to approve it.

The agreement with the FDA -- because this is a breakthrough designation and fast track designation -- is that everything should be wrapped up within nine months. So it compresses the timeline, but does not change the vetting procedures. All the same review still happens. It just happens in a compressed way. And we've learned exactly how much these things can be compressed if the FDA drops absolutely everything and only focuses on one issue with the Covid, because our vaccines became available within a calendar year for adults, at least, from the time those first phase trials were started. We're not talking about that type of fast track for RSV. But the review will happen much quicker than it would have otherwise because it has these special designations.

[00:26:40] Host Amber Smith: So nirsevimab is not technically a vaccine. It's monoclonal antibodies. If it is approved by the FDA, would the American Academy of Pediatrics still list it on its vaccination recommendations for children?

[00:26:56] Joe Domachowske, MD: I suspect they will. The one big difference between how nirsevimab is expected to be handled compared to how palivizumab was handled when it was FDA approved back in 1998 is that rather than having guidance come only from the American Academy of Pediatrics Committee on Infectious Diseases, nirsevimab will be reviewed, and guidelines will be developed for how we should be using it by the Advisory Committee on Immunization Practices, the A C I P, so that federal agency that reviews and offers advice to the Centers for Disease Control, where the CDC director then signs off, or disagrees and comes up with a different plan.

We didn't have those A C I P type of a review for palivizumab, and I think it did result in some underuse because of concerns about cost, not safety, but cost. Every context that it was studied and showed that it worked. It just requires monthly dosing. The A C I P involvement in the review of this, I think folks are generally familiar with A C I P (Advisory Committee on Immunization Practices) now because we hear it so much when one of the Covid vaccines finally got FDA authorization for use. Then, of course, the separate review happens by the A C I P, and they would make the recommendations to the CDC director, and the CDC director would finally say, "Yep, push the button," and then vaccine was shipped, right?

So, that, I think, is a much better process because we have the federal agency review and the guidelines that we have for how to implement it will be crystal clear. It also has the potential for being included in the entitlement program, which is called the Vaccine For Children program, which says at the federal level -- this is entitlement, so it can never go away -- that these particular vaccines, if approved, would be available at no cost to those who are underinsured or not insured at all for everyone who lives in the US under age 19. So that would include all of these babies, if the VFC referendum is passed when the A C I P makes their recommendation.

[00:29:13] Host Amber Smith: I know that pediatricians have been seeking a reliable preventive, basically since respiratory syncytial virus was discovered. And your trials have shown that this monoclonal antibody works. So at what point do you and the rest of the research team celebrate?

[00:29:30] Joe Domachowske, MD: We've started to celebrate, because of the potential, but really, we've got a lot of work to do because if we're not careful, this monoclonal antibody will not reach its potential and its promise. So we've been very clear with the manufacturer that they have to price this like a vaccine, not a biologic, not like palivizumab. This has to be affordable, and it has to be available to the world because RSV, yeah, it causes severe morbidity. In the US we're talking about almost 2% of our birth cohort hospitalized every year for RSV infection. At our children's hospital, it counts for 10% of all of our hospitalizations, and it's only happening in the wintertime, but 10% of all hospitalizations are for RSV. It's huge. And to have something with that promise to have an 80% reduction, with that impact, and not be able to use it would be criminal. And we really need to be careful that this is vetted the right way. That's why I'm so glad the A C I P will be helping us develop the guidelines. I'm hoping for a VFC vote, because that will make sure that there's no disparity as far as who is going to get it, and it's going to be available to all babies, not the haves or the have nots. That's just not fair.

[00:30:47] Host Amber Smith: Well, Dr. Domachowske, I really appreciate you making time to tell us all about RSV and this new preventive medicine you've been studying.

[00:30:54] Joe Domachowske, MD: It's my favorite thing to talk about.

[00:30:57] Host Amber Smith: My guest has been Dr. Joseph Domachowske. He's a professor of pediatrics and microbiology and immunology at Upstate specializing in pediatric infectious disease. "The Informed Patient" is a podcast covering health, science and medicine, brought to you by Upstate Medical University in Syracuse, New York, and produced by Jim Howe. Find our archive of previous episodes at Upstate.edu/Informed. This is your host, Amber Smith, thanking you for listening.