Activity Transcript

Dorry Segev, MD, PhD: Hi everyone. I'm Dorry Segev. I'm a professor of surgery and population health and a transplant surgeon at New York University Langone Health. I'm also the director of the NYU Center for Surgical and Transplant Applied Research. Welcome to this program titled, "Why Do We Need Pre-Exposure Prophylaxis for SARS-CoV-2?"

I'm also joined and it's my pleasure to introduce Vineeta Kumar, who's a professor of medicine and a Robert and Cutessa Bourge endowed professor in transplant nephrology, as well as the medical director for the UAB Incompatible Solid Organ Transplant Program at the University of Alabama at Birmingham. Welcome, Dr Kumar.

Vineeta Kumar, MD, FAST: Thank you, Dr Segev.

Dr Segev: In this program, we have a few goals. One is to talk about the remaining unmet medical needs for COVID-19, to talk about what is pre-exposure prophylaxis or PrEP, who are the patients who might benefit from PrEP, and to give an overview of monoclonal antibodies that are available both in the US and the EU, and to give some context for evaluating this across the globe.

As we know and has become very obvious in the last couple of years, vaccines are the best strategy we have for defense against SARS-CoV-2 and COVID-19. However, some populations remain at risk, and those include those who are unvaccinated, people who cannot get vaccinated, such as those with a history of severe adverse reactions to the vaccines, and then those who do get vaccinated but are physiologically unable to mount an adequate immune response to the vaccine, and we'll talk about that population a lot in this program.

One of the ways that we've discovered that there are individuals who don't have adequate immune responses is through 2 years' worth of research studies where we've taken people who were vaccinated and measured both their antibody responses and T-cell responses, and we know that these are inadequate and that that inadequacy also correlates to inadequate clinical protection.

The first evidence of this, we actually published in JAMA in early 2021, right after the vaccines came out in the United States, where we studied solid organ transplant recipients who received 2 doses of an mRNA vaccine, as was the standard dosing in the United States, and we looked to see what the anti-spike antibody response was in these patients and how it compared to the general immunocompetent population.

What ended up happening was that the transplant patients had far lower chances of having any detectable antibody after vaccination, and even those who had some detectable antibody in general had lower levels of antibody than those who were immunocompetent. Now, they did have some vaccine response, many of them had some vaccine response, but it wasn't nearly as robust and impressive as what we had seen in the immunocompetent population.

This also correlated with much higher risk of breakthrough infections in transplant recipients as well. Again, further emphasizing the importance of understanding this reduced immunogenicity and incorporating more protections for our immunocompromised patients than for the general population.

For example, when we studied 18,000 fully vaccinated transplant patients across 17 transplant centers, at a time when 2 mRNA vaccines were the standard of care, and then we compared them to the general population, transplant patients had 82 times higher risk of a breakthrough infection compared to the general fully vaccinated population, and 485 times higher risk of a breakthrough infection with associated hospitalization or death, really emphasizing that not only were they at higher risk of getting COVID-19, but they were at higher risk of getting a very severe version of COVID-19 that would end them in the hospital, or even with mortality from that breakthrough infection.

Again, really emphasizing that while vaccines are the mainstay and still important in everybody, the adequacy of the vaccine response, there were some populations that would not have the same kind of adequacy as the general population.

There was a big study through the N3C consortium that looked at vaccinated transplant recipients and compared them to unvaccinated transplant recipients. Dr Kumar, do you want to tell us a little bit about this study and what its implications are?

Dr Kumar: 5:47 Absolutely, Dr Segev. The N3C, so that's National COVID Cohort Collaborative, that study, it's actually a data set from 36 sites across the United States, and what they did was to look at a cohort of adult patients that tested positive for COVID-19 between December 2020 and April 2022, so that was also covering part of the Omicron era along with the Delta era. They assessed the risk of complications post-vaccination in solid organ transplant patients vs solid organ transplant patients with unconfirmed vaccination status.

What they found was that over a median of 149 days after that initial vaccination, there was still a greater risk of mortality in the unvaccinated patients compared to vaccinated transplant recipients. The big message from the study, and there are a couple other studies since then that we've seen, is that while the relative benefit of vaccine is less in solid organ transplant patients than the non-immunocompromised population, solid organ transplant patients still exhibit significant benefit with vaccination compared to if you're a solid organ transplant patient and didn't get vaccinated, or an immune-compromised category patient and did not get vaccinated.

Dr Segev: However, after we discovered that 2 mRNA doses were often inadequate for our immunocompromised patients, additional discoveries came to remind us that with additional immune priming, we can improve the protection and the immunogenicity that our patients get from vaccines. Shortly after all of the data came out about 2-dose inadequacy, we published in Annals of Internal Medicine the first report that 3 doses might actually offer much more benefit to the immunocompromised than 2 doses.

With this and with several other trials that came out from Canada and France and Israel and other places, the standard became across the globe for the immunocompromised to receive 3 doses of an mRNA series rather than 2 doses, as the primary series. Not as a durability booster, but as the primary series of immunization in those who are immunocompromised.

There's been studies even of 4 doses, and one of the things that we're learning is that as we give people more doses, we can increase antibody responses. However, we reach kind of a point of saturation where we might get a little bit more antibody response, but we might not get more neutralization.

This has become particularly dramatic in the setting of the new Omicron variants. The new Omicron variants seem to require a lot more vaccine immunogenicity to achieve neutralization either in pseudo-neutralization assays or live virus neutralization assays, and this kind of seems to correlate with clinical protection as well.

The point is that in transplant recipients who had 3 doses with relatively low antibody responses, when they got a fourth dose, the antibody responses went up and the neutralization went up to some of the variants, but neutralization against the new Omicron variants did not increase. This emphasizes that still, as we are constantly chasing variants, there will be some instances where, while we see an increase in antibody detectability, we're not necessarily going to see an improvement in neutralization, and our patients will remain vulnerable in the context of those new variants.

Now, transplant patients, we've shown you a lot of data from that population because it's a particularly dramatic population in terms of immunosuppression, but transplant patients are not the only population that has been vulnerable during the COVID pandemic and during vaccination. Dr Kumar, do you want to tell us about other populations such as those with rheumatic and musculoskeletal diseases, and what has been found in those populations as well?

Dr Kumar: Absolutely, Dr Segev. Yes, while the majority of the patients that we treat are our solid organ transplant recipients, working at a very large tertiary/quaternary care center, we have multiple patients who are also on immunosuppression for other reasons. Rheumatologic reasons like lupus, which is very common, rheumatoid arthritis, or patients who have immune deficiencies like combined variable immunodeficiency.

What's common for these patients is still the 2 arms of the immune system. Either they're not making enough antibody, or they're not able to generate virus-specific T-cell responses by affecting B cells in the former case and T-cells in the latter case with the medications that are commonly used. While we would want the vaccines to be the universal panacea, there is still a subset of patients here that also have a very poor response. Dr Segev, is that sort of what you're thinking about in terms of some of these additional populations of interest?

Dr Segev: Thank you for going through some of that. Remind me, because we talk about antibodies all the time, where do the antibodies come from? How does one make antibodies when one gets vaccinated?

Dr Kumar: Tremendous question. There's a lot of different types of vaccines, live vaccines and attenuated vaccines, let's just stick for a moment with COVID, the ancestral COVID vaccine, which we know a lot about, and of course we have the bivalent vaccine now. In response to vaccination, there is a priming effect that happens. You're introducing some kind of antigenic stimuli, an antigen, a virus-specific antigen, that's not going to cause disease because it's inactivated, attenuated, but a foreign particle, foreign antigen nonetheless, that now you have T-cell recognition, B-cell priming, activated plasma cells, and then those make your antibody.

That entire process takes, at the earliest, a few weeks, so once you get a vaccine, you're not immediately protected. You have to cycle through all those steps of T-cell recognition of that antigen, the T- and B-cell crosstalk, the B-cell priming, the B-cell conversion to the early fast-acting plasma cells that ultimately make that antibody, which is why we tell our transplant recipients or our immune compromised or any of our general population, "Take the vaccine, still be careful. It takes 2 to 4 weeks before you are going to get a response." And as you showed eloquently in your data, longer for our immune-compromised patients.

Dr Segev: Great, and fortunately for those who don't make antibodies, as we've been talking about, all of these at-risk populations, you can make these in a lab and then administer them to people exogenously. We've seen throughout the pandemic the use of monoclonal antibodies, and the monoclonal antibodies can be used across different stages of the disease, all the way from before you even have been exposed to the disease through to when you have the disease and you want to use it as treatment. Can you walk us through the different stages of COVID-19 and the potential different utilities of these monoclonal antibodies?

Dr Kumar: Absolutely. For our audience, SARS-CoV-2 antibodies are at different levels, at different stages of the COVID-19 infection, if you will. Wouldn't it be wonderful if we just caught patients before they even were exposed to the virus and had an army of antibodies already in their system? That would be pre-exposure prophylaxis, where they have not seen the virus, not been exposed to somebody who has SARS-CoV-2, and they're purely in that protective space where if you gave them a load, then they are now, if they are faced with an infection, are able to have a pre-formed army. That's your PrEP, your pre-exposure prophylaxis.

Now, if you're not fortunate enough to have timed it right and you've been exposed to somebody, don't have the infection yet, so exposed but no infection, so that's post-exposure prophylaxis. Further up the chain then or further up the natural progression of that disease is you've been exposed, and "uh-oh," you now are starting to have symptoms, but you have early symptoms, mild enough symptoms, you can get intervention at that time. That would be your early outpatient treatment.

And so far, just to recap, we have availability of monoclonal antibodies in the pre-exposure phase, or once you've been exposed and have early symptoms phase. There are clearly antibodies approved and available for those 2 phases. At the present time, we don't have anything that's for sort of, I've been exposed, but not have infections yet.

Then, as you progress along that category of been exposed, have infection, it's not just mild now, the symptoms are getting worse. You are now starting to have other organ effects, not just the generalized constitutional ill effects that we get from any kind of virus exposure. Now you're starting to have moderate disease or more severe disease or critical disease, the monoclonal antibody, then at that point, it's not just monoclonal antibodies. It's monoclonal antibodies and additional things that you may need, especially if you're in the immune-compromised population. That just sort of is a snapshot of the different stages where you could be eligible for treatment with monoclonals.

Dr Segev: Great, and the 2 areas that we're going to focus on are pre-exposure prophylaxis, and one might think of this analogously. It's not physiologically the same, but analogously to vaccines, as the purpose of pre-exposure prophylaxis is to prevent the patient from getting COVID-19. Because once you get COVID-19, now you're in a completely different road, as you described, and then we'll also talk about the role of these monoclonal antibodies possibly in treatment as well.

Before we do that, do you want to give us a sense of, who are these immunocompromised vulnerable patients in whom we might be considering the role of, for example, pre-exposure prophylaxis with monoclonal antibodies?

Dr Kumar: Absolutely. The variety of patients that would benefit from these are not just the patients that we mentioned already, which are the solid organ transplant patients or patients with rheumatologic disease getting immunosuppression. It could be people with advanced untreated HIV. It could be patients with extremely high doses of corticosteroids that are part of their chemotherapy regimen, or they're getting alkylating agents or antimetabolites. It could be patients who have bad GI, ulcerative colitis or Crohn's, and are getting either TNF-alpha or other biologic agents that are extremely immunosuppressive and immunomodulatory. That's the other word, where you may not be truly immune suppressed, but you are interfering with either T to B-cell crosstalk or B-cell antibody production. These are all those subset of patients. There's a big list, and you can go online at the cdc.gov website and it gives you a big list of who would qualify. These are just some examples of the patients that fall in the category of immune compromised.

Dr Segev: The US has their own categories through the CDC. In the UK, the NHS has their list of categories of people who are immunocompromised, and this varies by different countries, and so wherever you're watching from, make sure you're aware of your local guidance of the patients that are considered through policy to be at higher risk, more vulnerable, and eligible for administration of things like monoclonal antibodies.

Let's go to the US FDA. There were emergency use authorizations given for some monoclonal antibodies. Do you want to tell us a little bit about the EUA for pre-exposure prophylaxis and the EUA for treatment?

Dr Kumar: Absolutely, Dr Segev. For our audience, this is where we're going to use some complicated pharmacologic names, so have your ears peeled for that. In the pre-exposure space, the approved monoclonal is tixagevimab plus cilgavimab. You will hear us refer to tixagevimab and cilgavimab as tixa and cilga, or T and C, or tix and cil. These are all used interchangeably. But this was the 1 monoclonal that was approved in the US and has retained in vitro neutralization activity against the Omicron BA.2 sub-variants. That's for the US.

Now, in the US for treatment, so this is people who have now had COVID infection, who now have symptoms, who then fall in the qualifying categories, the short form of the treatment agent for that is beb, bebtelovimab. And bebtelovimab actually has retained its in vitro neutralization, and also in clinical efficacy tracking since its release, extremely good neutralization activity across the spectrum of infection from mild to moderate disease, all the way to significant SARS-CoV-2 infection.

Bebtelovimab is available in limited supply in the United States, and because of that is definitely heavily regulated with a tiered system. The patients who then are infused with bebtelovimab are exactly the ones we're covering in this session, which is our immune-compromised solid organ transplant patients.

Dr Segev: Right, so in the US, pre-exposure, T and C, treatment, bebtelovimab. Now, what about in the EU?

Dr Kumar: In the EU, they led the way -- the casirivimab and imdevimab was the one that led the way, where it showed a significant reduction in symptomatic SARS-CoV-2 infection. It was about 2 and a half weeks, but the range was 2 to 4 weeks after getting infused, but this was all in the pre-Omicron era.

In the Omicron era, the dosage that was required to provide neutralization was not physiologically possible with the infusion that we were giving, but casirivimab and imdevimab led the way in being the PrEP for SARS-CoV-2 infection. We're back to just the tixa and cilgavimab in the US. That's the only one at the present time. Again, rapidly changing landscape.

Dr Segev: You said earlier with regards to T and C about coverage, retained coverage for BA.2. We're always chasing these variants, and probably there will be new variants at the time people are watching this that didn't exist at the time that we talked about this. Tell me a little bit more about, for example, BA.4 and BA.5 and what's happening with neutralization activity against these variants.

Dr Kumar: So thank you for bringing that up, Dr Segev. There's a beautiful New England Journal article that came out that showed us the mean neutralization activity of these monoclonal antibodies across the entire spectrum, from pre-exposure prophylaxis with that 1 agent, tixagevimab and cilgavimab, to multiple treatment agents. What's happened with the evolution of the viral variants, the amount of dosage required to provide neutralization activity has become higher and higher, where it's not safe to infuse that type of dose at the approved dose. For instance, if we take tixagevimab and cilgavimab, specifically, at the present time, the BA.4.6 is thought to be resistant to tixagevimab/ cilgavimab. In the US at the present time, the BA.4.6 is 11% of the circulating strain. Again, this is something that we're rapidly updating.

It sort of brings to mind that tixagevimab and cilgavimab, 3 months ago, had near universal in vitro activity against the circulating variants. Just in that short period of time, the resistant variant has increased from 2% to 4% to 6%, and most recently 11%. This is a call out to our audience to be constantly monitoring your own local environment and seeing what the rates are so that you can make the best decisions for your patients.

Dr Segev: Great. Let's just quickly talk about some of the big studies that helped us understand the role of pre-exposure prophylaxis. Let's first start with the casirivimab/imdevimab proof of concept study.

Dr Kumar: Absolutely. The casirivimab/imdevimab study was a study that infused this monoclonal in the pre-exposure primary prophylaxis category and compared it with patients who did not get the infusion, so that would be the placebo. They actually did get an infusion, but it was a placebo. When they compared these 2 categories, what they found was time to symptomatic infection, if that was the endpoint, so from exposure to the monoclonal infusion, not the infection, to onset of symptomatic infection in this population, they were able to show almost an 80% relative risk reduction in the group that got the casirivimab/imdevimab, compared to the group that did not get the monoclonal prophylaxis.

This really was a proof of concept in that it told us passive infusion of monoclonal antibodies was still protective, getting antibodies from patients who've had prior exposure to or prior infections with COVID-19. So it actually really had, in terms of the heterogeneity of the antibodies generated by this in vitro technique, it proved to be extremely effective, and that's what was the spirit or fueled the fire of further development of drugs in this area.

Dr Segev: That was great in the original study that you just talked about, and then there are data in transplant patients as well, that when this agent became available at the time, that the variants were sensitive to it. Transplant patients had impressive protection from this as well. However, as you've already reminded us, and as we know from the constant variant landscape, this is no longer recommended because it's not active against the Omicron set of variants. Now, in the world of tixagevimab and cilgavimab or T and C, do you want to briefly summarize the PROVENT study?

Dr Kumar: Absolutely, so the PROVENT trial was conducted among unvaccinated high-risk patients, and it showed a 77% reduction of infection in the treated group compared to the placebo group. What was interesting is that this protection stayed in place until almost 6 months, 180+ days, post-infusion. I can go into more detail, but the PROVENT study was also not necessarily in transplant or immune-compromised recipients. This was done in people who could not take the vaccine or were thought to have had a poor response to vaccine, and this was the group that was then given the infusion and then compared the placebo to it. That's the PROVENT study.

Dr Segev: An impressive demonstration that pre-exposure monoclonal antibodies can work when the variants are sensitive to those antibodies. The PROVENT study included some transplant patients, but then there were also several reports that came out shortly thereafter showing substantial reduction in symptom-free COVID-19, symptomatic COVID-19-free survival in transplant patients specifically as well. Two back to back in July, and in August of 2022 in Kidney International, and even several more thereafter, showing reduction, substantial reduction of Omicron infection at that time with those variants of Omicron.

Now, we've talked about this a few times. Do you want to tell us a little bit more about where the variants are shifting and what we're seeing in the US, for example now, and what we are expecting to see in the next few months?

Dr Kumar: Absolutely. Dr Segev, just to piggyback on the real-world data that you already mentioned in the KI study and the other one. What was also very important from those studies, was that we were able to find that also in solid organ transplant recipients, it was safe, and the rate of adverse events to tixa and cilgavimab were extremely uncommon. There were less than 4% and very mild. And in both of these studies there was only 2 patients, 1 in each study -- 1 developed a mild heart failure exacerbation and another 1 developed atrial fibrillation requiring cardioversion. So again, extremely well tolerated, even in the real-world experience.

Of course, as you are reminding us and reminding me to share again, that this is sort of in the era of the Omicron, and now with the Omicron variants coming through, as we just spoke, the BA.4.6 variant is sort of increasing in the United States, and this is thought to be resistant to the tixagevimab and cilgavimab, really sending a reminder to all of us that we have to remind our patients not just to rely on 1 modality for protection.

Get your primary vaccine series. Now there's the movement from the ancestral vaccine to the bivalent, so get your booster. Continue to mask, get your pre-exposure primary prophylaxis, and continue the "safe living" type of philosophy as much as you can. As hard as it is, there is a subset of our patients that are vulnerable, and while we all want the pandemic to hurry up and end, it is true for some, but it's not true for the others, and safeguarding them and helping them safeguard themselves is of primary importance.

Dr Segev: You mentioned the bivalent vaccines which recently came out, and that kind of segues us to future directions, right? Currently there are some outpatient treatment options. We've talked a lot about pre-exposure prophylaxis, but those who do unfortunately get COVID-19, can you talk a little bit about the current outpatient treatment options, and then what you might know in the pipeline for monoclonal antibodies, and maybe what you would wish for in the pipeline for monoclonal antibodies?

Dr Kumar: I love that question, Dr Segev. I will start with, what do I wish for? I just wish for sort of the moon. I wish for the pandemic to end, for us to have these amazing treatment options that nip this in the bud and don't let our patients suffer. The reality of it is not far, but we still have some ways to go.

So talking about what are our current treatment options available? We already talked about bebtelovimab, which seems to be the most effective, but because it's in limited supply, we have to then turn to other potential options. The available oral options for our infected patients with SARS-CoV-2 who have now the COVID-19 infection are 2: molnupiravir, and the other agent is the combination of nirmatrelvir and ritonavir.

The other outpatient treatment beyond the monoclonals and the oral agents is the IV option for remdesivir. If you are at an institution where you have the ability to provide the service, Monday through Sunday, 7 days a week, with at least 3 doses of IV remdesivir on 3 sequential days, that's another option. The drug is available. It's really having the manpower and having the support and the infusion center availability throughout the week that sort of becomes a rate-limiting step.

As far as pipeline, there are a couple. They're all in the treatment space. Ensitrelvir, which is a 3C-like protease inhibitor, it's actually being developed for oral treatment for mild to moderate COVID-19. If you go on the NIH website, you can see the study trial design for this. Another oral agent, and I'm really glad that now a lot of the focus is on oral agents as opposed to IV infusions, and now that some of these oral agents have worked and we know the pros and cons and how to optimize them, how wonderful is it that we can just call in a prescription for a patient and they can take it at home without having to come to a center or infusion clinic? Especially when they feel bad.

This new novel agent doesn't have a name yet. It is alphabet soup and some numbers, ALG-097558. It's also a 3CLPro inhibitor. It interferes with viral replication and it's also for treatment of COVID-19 infection. Then, as far as I'm aware, at the present time, other than where we have tixagevimab and cilgavimab, there's no other agent being studied in the pre-exposure primary prophylaxis category.

Dr Segev: Dr Kumar, it's been great chatting with you about all of the challenges that our immunocompromised patients have had, and the potential ways that we've risen through science to address some of these challenges and the continued challenges that we have.

Then, I also want to thank the audience who are participating in this activity, and hope that you've learned something today and that you've also enjoyed this conversation, and to please continue with the activity to answer the questions that follow and complete the evaluation so that we can design new programs in the future. Thank you, Dr Kumar.

Dr Kumar: Thank you Dr Segev. May we all continue to be trusted sources of information to our patients who look towards us to guide them through these tough times. It's been a pleasure. Thank you for inviting me and for us having the chance to have this conversation.

This transcript has not been copyedited.