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Outpatient COVID-19 Oral Treatments & Other Therapeutics · The SHEA Podcast

• 0:08
  SPEAKER_02: Welcome to the Rapid Response Podcast brought to you by the Society for Healthcare Epidemiology of America, SHA, promoting the prevention of healthcare associated infections and antibiotic resistance and seeking to advance the field of healthcare epidemiology and antibiotic stewardship.
• 0:23
  SPEAKER_02: I'm Dr.
• 0:23
  SPEAKER_02: Christopher Cernich, Chief of Medicine and Hospital Epidemiologist at the Madison VA Hospital and an associate professor of medicine at the University of Wisconsin School of Medicine and Public Health.
• 0:33
  SPEAKER_02: I will be serving as today's podcast moderator.
• 0:37
  SPEAKER_02: Discussion on the podcast does not reflect Shay's perspective, but facilitates communication of multiple perspectives and experiences as we go through this challenging time together.
• 0:45
  SPEAKER_02: Shea is excited to launch this episode of the podcast, COVID-19 updates for what we know now.
• 0:51
  SPEAKER_02: Today's discussion will focus on outpatient COVID-19 oral treatments and other therapeutics.
• 0:56
  SPEAKER_02: We are fortunate today to have two excellent speakers with us today, including Dr.
• 1:01
  SPEAKER_02: Monica Mahoney, who's a clinical pharmacy specialist in infectious diseases at Beth Israel Deaconist Medical Center, and Dr.
• 1:08
  SPEAKER_02: Jason Pogue, clinical professor in the Department of Clinical Pharmacy at the University of Michigan College of Pharmacy and Infectious Diseases, Clinical Pharmacist at Michigan Medic Center.
• 1:19
  SPEAKER_02: Thank you both for joining us today.
• 1:21
  SPEAKER_02: Why don't we go ahead and jump right into the discussion?
• 1:23
  SPEAKER_02: But first, I think our listeners would appreciate hearing from both of you as far as your backgrounds with therapeutics and treatments for COVID-19.
• 1:32
  SPEAKER_02: I know that this has been a very rapidly changing field and kind of giving a sense of how you guys have engaged with the process since the beginning of the pandemic, I think it would be very useful for our audience to hear.
• 1:42
  SPEAKER_02: Dr.
• 1:43
  SPEAKER_02: Mahoney, can we start with you?
• 1:44
  SPEAKER_01: Sure.
• 1:45
  SPEAKER_01: Thank you for having us on today.
• 1:46
  SPEAKER_01: So as you said, I'm a clinical pharmacy specialist in infectious disease at Beth Israel Deagonus Medical Center.
• 1:51
  SPEAKER_01: My role is in the outpatient ID clinics and also in OPAT.
• 1:56
  SPEAKER_01: So helping coordinate outpatient infusions for patients on long-term IV antibiotics.
• 2:01
  SPEAKER_01: Specifically for COVID, a lot of my efforts have been focused on administering vaccines.
• 2:06
  SPEAKER_01: So I was involved in many of our different vaccine clinics for both employees and patients.
• 2:12
  SPEAKER_01: In terms of monoclonal antibodies, maybe fortunately or unfortunately, I have not been involved with that just because we have a team approach and our OPAT director, Dr.
• 2:21
  SPEAKER_01: Dan Taupin, has taken the lead on that.
• 2:24
  SPEAKER_01: So a lot of what I comment on today, I do have to give credit for him for that.
• 2:28
  SPEAKER_01: But a lot of what we're going to talk about today, the coordination of outpatient therapeutics or infusions or different sites, is very applicable to a lot of what I help coordinate on a daily basis.
• 2:38
  SPEAKER_02: Yeah, I think we don't give pharmacists enough credit for all the hard work that they've they've done with our healthcare systems and getting our vaccination programs up and running.
• 2:47
  SPEAKER_02: We we would have been completely lost without pharmacy groups at every healthcare facility stepping up.
• 2:53
  SPEAKER_02: So I want to just thank you for doing that.
• 2:56
  SPEAKER_02: How about you, Dr.
• 2:56
  SPEAKER_02: Polk?
• 2:57
  SPEAKER_03: Uh yeah.
• 2:58
  SPEAKER_03: So first off, I want to thank Shay for inviting me here today.
• 3:01
  SPEAKER_03: And it's always great to have a conversation with Chris and Monica.
• 3:04
  SPEAKER_03: So I'm excited for this.
• 3:05
  SPEAKER_03: As far as my role, I honestly don't think there's anything special in my background related to COVID therapeutics that a lot of our audience probably hasn't been through themselves to a significant degree, right?
• 3:16
  SPEAKER_03: Like many, I've spent, unfortunately, the last two years closely following the literature, you know, helping our stewardship team develop and then edit and then edit and then edit and so on and so forth, both the inpatient and outpatient guidelines, just trying to help.
• 3:31
  SPEAKER_03: We have a great team in Michigan, just trying to help that team, you know, drink off the fire hose of data, try to make the best decisions for our patients as it relates to things like outpatient therapies, trying to monitor, you know, the activity of different monoclonals against the variants of concern and whether or not we need to be switching what we're doing, refining our criteria for high risk when you have different amounts of product.
• 3:54
  SPEAKER_03: Again, I don't think that anything special about me with regards to that.
• 3:58
  SPEAKER_03: I think that certainly ID pharmacists, ID physicians, it's what we've been doing for two years.
• 4:03
  SPEAKER_03: Certainly very vested in it, interested in it, whether by choice or by by force, you know, at this point in time.
• 4:09
  SPEAKER_03: But like I said, it's great to be here.
• 4:11
  SPEAKER_03: And I really look forward to our discussion today.
• 4:14
  SPEAKER_02: Well, thank you both.
• 4:15
  SPEAKER_02: So I think obviously we want to spend a significant amount of our time today talking about the new kids on the block, including the new oral therapies from Merck and Pfizer.
• 4:25
  SPEAKER_02: But before we kind of jump into that, there has obviously been some new developments with monoclonal therapy and with Omicron on the horizon.
• 4:32
  SPEAKER_02: I think there are also some issues that that we want to kind of dive into.
• 4:36
  SPEAKER_02: So, Dr.
• 4:37
  SPEAKER_02: Poe, can you provide us with the science behind the monoclonal therapies, including some of their efficacy data and the impact that they're having on patient outcomes?
• 4:47
  SPEAKER_03: Yeah, this is one I very much look forward to discussing, right?
• 4:50
  SPEAKER_03: Because while there have not been many things to celebrate with regards to therapeutics for COVID, the monoclones have certainly been the exception.
• 4:57
  SPEAKER_03: They have just been phenomenal compounds and helped so many patients.
• 5:01
  SPEAKER_03: So it's great.
• 5:02
  SPEAKER_03: So yeah, I think it's always nice to start with the mechanism of action.
• 5:04
  SPEAKER_03: I don't say that just because I'm a pharmacist and it's my job that I have to say that or I lose my nerd card.
• 5:10
  SPEAKER_03: But I do think it's important for people to appreciate the mechanism of action of these because one, I think it's a it's an interesting and unique mechanism, but also when we talk a little bit later about activity against variants of concern, it's important to understand why that could come into play.
• 5:24
  SPEAKER_03: So basically, the target, again, they're they're meant to be neutralizing antibodies, so similar to our immune cells that we might get from when Monica gives us our vaccine.
• 5:33
  SPEAKER_03: And really they bind to epitopes on the spike protein, largely in the receptor binding domain, but they don't all have to do that.
• 5:39
  SPEAKER_03: And the different monoclonals that are available will bind to kind of different target sites.
• 5:44
  SPEAKER_03: There's kind of a classification system surrounding that.
• 5:47
  SPEAKER_03: But the goal is ultimately the same as to neutralize the virus and prevent entry to into our cells.
• 5:53
  SPEAKER_03: So basically, we're trying to stop that initial interaction between the spike protein and ACE2, which leads to uptake into the cells.
• 6:01
  SPEAKER_03: And one thing that you'll see in the monoclonals we give today, we give combination therapy.
• 6:06
  SPEAKER_03: This is for a variety of reasons.
• 6:08
  SPEAKER_03: I think most notably is to ensure you're going to have binding to different active sites, even if there's slight mutations going on.
• 6:14
  SPEAKER_03: Hopefully, this can stop or slow the development of escape mutants as well.
• 6:19
  SPEAKER_03: And you just get some better kick out of it.
• 6:21
  SPEAKER_03: So we have a bunch of different products that are available.
• 6:23
  SPEAKER_03: They differ a little bit in some regards with regards to A, which epitopes they do bind to on the spike protein.
• 6:30
  SPEAKER_03: Again, that's a really important concept for the audience to think about and read about because this can lead to retained or lost efficacy in the setting of certain variants.
• 6:38
  SPEAKER_03: And so that's an important concept.
• 6:40
  SPEAKER_03: They can also differ a little bit with how they attract affector cells.
• 6:43
  SPEAKER_03: So again, how they kind of work with our immune system to actually stimulate removal of that virus.
• 6:48
  SPEAKER_03: And then with one we'll talk about a little bit later today, you can also make modifications to those compounds a little bit.
• 6:54
  SPEAKER_03: So you can modify the PK.
• 6:56
  SPEAKER_03: Notably, you can extend the half-life out, which allows you to get kind of a longer duration of therapy.
• 7:00
  SPEAKER_03: And we're going to come back to that.
• 7:02
  SPEAKER_03: But ultimately, they all have the same goal, right?
• 7:05
  SPEAKER_03: You want to neutralize the virus, you want to give these early in the disease course when you're still in that kind of viral phase predominantly, with the goal of stopping progression of illness, decreasing the need for hospitalization, decreasing the progression to potentially even death in that situation.
• 7:19
  SPEAKER_03: And the other thing I think is important to note, right, is that you can also speed up recovery time a little bit as well.
• 7:24
  SPEAKER_03: Again, a viral illness, as you might be able to hear, I actually have a viral illness myself right now, and you can speed that up by a couple of days.
• 7:31
  SPEAKER_03: My goodness, I'd like to shave a couple days off of this.
• 7:33
  SPEAKER_03: So I think that's an important patient-centered outcome as well.
• 7:37
  SPEAKER_03: And to date, like I said, because they've been shown to be remarkably effective in a variety of different settings.
• 7:44
  SPEAKER_03: I think the one that we're all most familiar with and probably use these agents the most in, are for outpatient treatment of mild to moderate COVID-19.
• 7:51
  SPEAKER_03: Basically, these compounds have been shown to decrease the need for hospitalization or progression of death by about 70 to 90%, depending on which trial, which is, I mean, honestly, phenomenal.
• 8:03
  SPEAKER_03: They also have a role in post-exposure prophylaxis.
• 8:06
  SPEAKER_03: And so patients who are exposed, whether it's to being in a nursing home or something, or they have a household contact who has symptomatic COVID, you can decrease the development of COVID-19 in those high-risk patients as well with post-exposure prophylaxis.
• 8:20
  SPEAKER_03: Again, great efficacy data there.
• 8:22
  SPEAKER_03: And then one thing I think it's also important to note and for our audience to be aware of, even though it's not a place that we use them a lot, particularly in the United States, due to what our emergency use authorization is for, but there are multiple studies now that actually show in seronegative, so those without their own antibodies in patients, that one of the monoclonal compounds, Casarivamabin and Devomat, or the regeneron cocktail, actually has been shown in multiple studies now to decrease progression to death or needing mechanical ventilation.
• 8:55
  SPEAKER_03: That's a pretty big deal.
• 8:56
  SPEAKER_03: So I think it's really important to keep that in mind.
• 8:59
  SPEAKER_03: Again, sometimes you could maybe stretch the verbiage of the EUA to use it in some of those hospitalized inpatients.
• 9:06
  SPEAKER_03: But the other thing I think I'd I'd love for our audience to know is that you can really do compassionate use for certain patients through Regeneron for these inpatients.
• 9:16
  SPEAKER_03: So if you have the right patient, you can look on their website and kind of follow that process.
• 9:21
  SPEAKER_03: But certainly, like I said, across the board, you see this just this great efficacy data.
• 9:26
  SPEAKER_03: And again, it's it's nice to see after all of the failed trials we've seen so far.
• 9:30
  SPEAKER_02: Yeah, I think you bring up a good point with that latter category.
• 9:34
  SPEAKER_02: And I feel like we've been kind of jumping through hoops with some of our patients who get admitted to the hospital for other reasons and test positive for COVID and mild illness, and we're really concerned about them progressing and trying to get them in patient therapy or coordinating a discharge and then having them go down to our infusion clinic right after the discharge.
• 9:54
  SPEAKER_02: It seems a little bit ludicrous that we have to kind of jump through these hoops, but I suspect every healthcare institution is kind of encountering some of the same issues.
• 10:03
  SPEAKER_02: I guess I wanted to ask one clarifying question.
• 10:06
  SPEAKER_02: Obviously, a lot of the post-exposure prophylaxis came from households.
• 10:10
  SPEAKER_02: The Blaze II studies were looking with the BAMLINIVAMAP, which you know has had its EUA revoked in nursing homes.
• 10:19
  SPEAKER_02: And I'm just curious as to whether there's been any additional studies that have come out of post-exposure prophylaxis in long-term care facilities with the monoclonals that you're you're aware of.
• 10:31
  SPEAKER_03: There is not anything in particular that I was referring to in that situation.
• 10:34
  SPEAKER_03: No.
• 10:35
  SPEAKER_03: And again, having the ability to use them in that setting, I think that again, it's just there as a potential option, even if it's not something that has been particularly done frequently.
• 10:44
  unknown: Okay.
• 10:44
  SPEAKER_02: Dr.
• 10:45
  SPEAKER_02: Mahoney, I know you said that you're not directly overseeing your monoclonal infusion program at your institution, but it sounds like you have a fair amount of insights into some of the logistical challenges and barriers you've encountered with setting up the program.
• 10:58
  SPEAKER_02: Do you have any advice or or kind of input for other healthcare facilities that are trying to get these programs up and running or thinking about getting them up and running based on your experiences at your setting?
• 11:10
  SPEAKER_01: Yeah, definitely.
• 11:12
  SPEAKER_01: As you know, Jason pointed out, these have phenomenal reductions.
• 11:16
  SPEAKER_01: So the want for these far exceeds demand at times.
• 11:20
  SPEAKER_01: So allocation and access to the products has periodically been an issue.
• 11:25
  SPEAKER_01: Currently, the allocation, I believe, comes from each state's Department of Health.
• 11:29
  SPEAKER_01: So you have to put in your order with them on a weekly basis.
• 11:33
  SPEAKER_01: And how much product you get back can potentially depend on what are the case rates or the positivity rate in your current area.
• 11:41
  SPEAKER_01: You know, if there are hot spots around the US, they might get preferential shipment there and possibly previous usage from the week before.
• 11:48
  SPEAKER_01: Another logistical issue that maybe we don't think about as much is having the personnel available to administer these products.
• 11:55
  SPEAKER_01: You know, this is an IV infusion.
• 11:58
  SPEAKER_01: We need someone to actually give the IV for the 30 or 60 minutes that it takes.
• 12:02
  SPEAKER_01: Then there's a monitoring period.
• 12:04
  SPEAKER_01: The patient has to be observed for another 30 to 60 minutes.
• 12:07
  SPEAKER_01: For most of these patients, they have active infection.
• 12:10
  SPEAKER_01: So there is PPE requirements.
• 12:13
  SPEAKER_01: You know, where are you going to have these clinics?
• 12:15
  SPEAKER_01: We're speaking from the institution standpoint, but we don't have to have clinics associated to hospitals.
• 12:21
  SPEAKER_01: You know, there could be home infusion centers that are administering these in the patient's home.
• 12:25
  SPEAKER_01: Down in Arkansas, I remember reading that community pharmacies were going to be giving the monoclonal antibodies for treatment.
• 12:31
  SPEAKER_01: So there are a lot of different areas that potentially patients could receive these.
• 12:35
  SPEAKER_01: So the infection prevention considerations and concerns of how do you set up, how do you isolate the clinic so it's not in an area that other people are getting other medical therapies?
• 12:45
  SPEAKER_01: Do you have separate entrances for the patients coming in?
• 12:47
  SPEAKER_01: Those all have to be considered and land out.
• 12:51
  SPEAKER_01: Because of some of these considerations, talking to other institutions in the Massachusetts area, we've been focusing more on the treatment approach rather than the prophylaxis.
• 13:02
  SPEAKER_01: And I know that other institutions are taking the same approach just because we cannot accommodate all the requests and all the need for treatment, let alone for the post-exposure prophylaxis as well.
• 13:14
  SPEAKER_01: So trying to coordinate and figure out where we can get the patient in to receive that infusion has been frustrating because we would love to accommodate everybody who gets referred to us.
• 13:24
  SPEAKER_01: Subcutaneous administration potentially could be an option if it's available for that monoclonal antibody.
• 13:29
  SPEAKER_01: Aaron McCreary's group out in Pittsburgh, they put out a wonderful paper.
• 13:33
  SPEAKER_01: But unfortunately, with the variant that's currently in circulation, though sub Q administration is not an option with the other monoclonal antibodies.
• 13:39
  SPEAKER_01: Mentioned home infusion companies.
• 13:41
  SPEAKER_01: You know, we thought that maybe they'd be a great way to take off some of the pressure from coming into clinics, from talking to the local ones while the want and the desire is there.
• 13:50
  SPEAKER_01: Again, they ran into issues with being able to obtain the product for administration.
• 13:54
  SPEAKER_01: And then if they actually have a patient that they could go to administer at the patient's home, they still have nursing needs.
• 14:00
  SPEAKER_01: You know, they need a qualified person who can go and set up the infusion, administer, monitor the patient.
• 14:05
  SPEAKER_01: And again, we need the PPE requirements, thankfully, now isn't as big as an issue as it was at the beginning of the pandemic.
• 14:12
  SPEAKER_01: So you ask, you know, what are some tips or tricks or resources that we can use for our listeners?
• 14:17
  SPEAKER_01: If you haven't been on SIDP, Society of ID Pharmacists website, they have a phenomenal monoclonal antibody toolkit.
• 14:24
  SPEAKER_01: It's free for all to access, written by people who are using and administering these.
• 14:29
  SPEAKER_01: So it's, you know, boots on the ground tips on how to optimize your therapy.
• 14:33
  SPEAKER_01: If you are a system or a network of institutions, you know, rather than each individual institution trying to figure it out for their patients, try to have a network approach, centralize the process, have maybe a handful of people that are responsible for coordination and referrals.
• 14:48
  SPEAKER_01: When you think about how the patient gets plugged into the system, you know, first they have to come up with uh, they have to endorse symptoms, they have to have a positive test, they have to be referred by their PCP, you know, figure out where else we can help out.
• 15:01
  SPEAKER_01: Does it have to be diagnosed by a PCP?
• 15:03
  SPEAKER_01: Can urgent clinics or freestanding diagnosis clinics take off some of the pressure of diagnosing these patients?
• 15:10
  SPEAKER_01: If they make the referral, you know, you do have to think about how do you get back to that physician if you can't accommodate them.
• 15:15
  SPEAKER_01: It's a little easier if you have PCP versus maybe an urgent care physician who's gone the the next day.
• 15:21
  SPEAKER_01: And I I think another important thing is realize that in addition to your own institution, where are other local areas that maybe patients can get monocholid antibodies?
• 15:30
  SPEAKER_01: Because if you can't accommodate them here, maybe you can still refer them to another site and they could go and get it there as well.
• 15:37
  SPEAKER_01: So I think you know, being a team player is going to be a very common thread throughout everything that we talk about today.
• 15:44
  SPEAKER_01: So it's really difficult to try to have just an isolated one institution approach to this.
• 15:50
  SPEAKER_02: That's great.
• 15:50
  SPEAKER_02: I think we'll definitely try to make sure we link to a number of those resources as well as others when we post this podcast.
• 15:58
  SPEAKER_02: But before we kind of leave the monoclonals, I do want to spend a little bit of time talking about the new AstraZeneca monoclonal.
• 16:06
  SPEAKER_02: And in particular, kind of what is its niche in therapeutic approach or more appropriately, prophylactic approach?
• 16:14
  SPEAKER_02: What patient populations or settings do we really want to think carefully about?
• 16:19
  SPEAKER_02: And then I guess most importantly, what's the prospects of Omicron taking over and the impact on the potential efficacy or lack thereof with this product?
• 16:30
  SPEAKER_02: Jason, do you want to jump into that really easy series of questions?
• 16:33
  SPEAKER_03: Oh, yes, very easy.
• 16:36
  SPEAKER_03: The next three hours for the answer to this.
• 16:38
  SPEAKER_03: No, I mean, this is such an interesting question because right, I think we were all like super excited last week by the the EUA for the AstraZeneca combination called EVU Shield, which is a fun name, but it's again it's just another combination of two monoclonals.
• 16:55
  SPEAKER_03: This one's Tixagebomab and Silgabomab, and yes, the pronunciations will be on the final.
• 17:00
  SPEAKER_03: The difference here is that again, this was for pre-exposure prophylaxis and immunocompromised patients who may not mount a response to vaccination.
• 17:08
  SPEAKER_03: So this is a huge, like unmet need, right?
• 17:11
  SPEAKER_03: We know, I mean, we already have the primary series as an extra dose of vaccine in this population.
• 17:17
  SPEAKER_03: We know that a significant proportion still do not mount, at least from a neutralizing antibody standpoint, a sufficient response to those.
• 17:25
  SPEAKER_03: And you know, they're forced to live their lives a little bit differently because of the risk that they're at.
• 17:29
  SPEAKER_03: And so, this the prospect of giving a pre-exposure prophylaxis, again, basically, as we talked about before, trying to give those neutralizing antibodies via the drug in this situation to have it on board in case they get exposed to COVID-19 is a huge deal, right?
• 17:45
  SPEAKER_03: And if you look at the clinical trial, I mean, it did really well in this pre-exposure prophylaxis trial.
• 17:51
  SPEAKER_03: Basically, it was an 80% reduction in symptomatic COVID with use of this combination.
• 17:56
  SPEAKER_03: And like we talked about a little bit earlier, right?
• 17:58
  SPEAKER_03: The key thing about this agent was that the half-life is three months.
• 18:02
  SPEAKER_03: So it had a tweak done to the compound so that it's a their three-month half-life.
• 18:07
  SPEAKER_03: And so you anticipate an extended duration of activity, six months or longer.
• 18:12
  SPEAKER_03: And so, again, that all sounds great, right?
• 18:14
  SPEAKER_03: And we are excited and we're trying to figure out okay, we're gonna have limited doses.
• 18:17
  SPEAKER_03: And kind of what you were talking about, Chris, is about how are we gonna prioritize which immunocompromised patient populations we're gonna get to in this.
• 18:24
  SPEAKER_03: And institutions have started that process and are doing it, and but it's super depressing that, like the week you have that conversation, right, and it's really emblematic of our fight against this just god-awful virus, is that the the week that this occurs, we find out that Omicron, the newest variant of concern, basically knocks out both of these compounds.
• 18:46
  SPEAKER_03: There might be some very modest retained activity of one of them.
• 18:50
  SPEAKER_03: And I think it's still an open question if a little bit of activity of one in the pre-exposure space might be enough, right?
• 18:57
  SPEAKER_03: Again, you're not necessarily worried about IC50s to the same degree in that scenario because again, you want some sort of effective concentration of compound on board in that situation, right?
• 19:08
  SPEAKER_03: And so if you're just trying to neutralize the first exposure, maybe that still has some effect, but I will tell you we're not optimistic, right, in that situation.
• 19:18
  SPEAKER_03: I think that it just kind of highlights our struggle, right?
• 19:20
  SPEAKER_03: It highlights the importance of knowing the variants of concern circulating and the impact it has on the various monoclonals, like Monica and Chris Lakia's already talked about.
• 19:30
  SPEAKER_03: And with Omicron already starting to take off, and again, probably by the turn of the year being the you know predominant thing that we're dealing with, I think it's important for our audience to know that you know you need to pay attention to how these monoclonals do in this situation.
• 19:44
  SPEAKER_03: And Omicron unfortunately renders BAMLANIBAMAB, Edis Evimab, much like things like beta and gamma did.
• 19:50
  SPEAKER_03: Unfortunately, Caseribimab and Devamab, which was in Devamab in particular, was always our stable one to these variants, but it knocks that out.
• 19:58
  SPEAKER_03: And our novel one that we just talked about, Tixagebamab and Silgabamab.
• 20:02
  SPEAKER_03: And so, really, the only option that you have that we currently have an UA for is going to be Citrovamab.
• 20:09
  SPEAKER_03: And as Monica so nicely discussed, you know, the problem there is one, I mean, we don't have enough of all of these, let alone enough of one of these to meet the demand that we need.
• 20:18
  SPEAKER_03: But two, is that again, you lose that beauty of being able to give it sub Q.
• 20:23
  SPEAKER_03: You have to go back to IV only, at least currently.
• 20:26
  SPEAKER_03: There are some IM data.
• 20:28
  SPEAKER_03: Um, there's an IM study for Citrobomap.
• 20:30
  SPEAKER_03: So hopefully maybe in the future that becomes an option.
• 20:33
  SPEAKER_03: But what I would say to kind of like transition our thought process here, at least from my standpoint, is that I think given that this can constantly change with the different variants, it really highlights the need for other therapeutic options, particularly if you're talking about outpatient use, thinking about oral, that aren't going to be impacted by these mutations that can occur to the spike, right?
• 20:58
  SPEAKER_03: And I think that one of the exciting things that we'll talk about moving forward here in a little bit is that that's that's the allure of these orals, right?
• 21:04
  SPEAKER_03: Is that in addition to them being oral options, they're not going to be impacted by spike changes that are there purposely or or that kind of evolve purposely to get around neutralizing antibodies?
• 21:16
  SPEAKER_02: Well, I'm amazed that you can remember the names of all these different monoclonals, let alone pronounce them appropriately or I think appropriately.
• 21:23
  SPEAKER_02: Dr.
• 21:24
  SPEAKER_02: Mahoney, I think you've kind of already touched on some of the logistics beyond kind of stratifying and identifying the appropriate patients and some of the concerns with Omicron, are there any unique logistical issues that you can think of with the long-acting monoclonals that we need to be aware of?
• 21:39
  SPEAKER_01: Yeah, definitely.
• 21:40
  SPEAKER_01: And before I answer that question, I just want to give a quick plug for people that if you have unique ways of administering or facilitating some of the monoclonal antibodies, definitely please publish them.
• 21:50
  SPEAKER_01: I remember I reviewed an article and it was on one specific monoclonal antibody.
• 21:54
  SPEAKER_01: I can't remember what it was, but at that time, my feedback was well, is this even pertinent?
• 21:58
  SPEAKER_01: It's not active in the current Circulating strain, but lo and behold, a couple of months later, it's now active on some of the subsequent ones.
• 22:05
  SPEAKER_01: So if you have IM injections, definitely publish that.
• 22:07
  SPEAKER_01: So then when we redo this podcast, we can talk about your wonderful data and new administration techniques.
• 22:14
  SPEAKER_01: But focusing on the pre-exposure, which I'm trying really hard not to pronounce the name, I think we have some additional possible freedoms that we can take because it's indicated for pre-exposure.
• 22:27
  SPEAKER_01: The patient shouldn't have the infection.
• 22:30
  SPEAKER_01: So potentially that opens up a lot of different facilities or places where we can administer.
• 22:35
  SPEAKER_01: You know, we don't need the full PPE.
• 22:37
  SPEAKER_01: We don't necessarily need the isolation because these patients shouldn't be infected with the virus.
• 22:42
  SPEAKER_01: But if we're targeting our immunocompromised patients, does that mean can we give it in our transplant clinics and our infectious disease clinics and our hemonical clinics in our infusion centers that already potentially have the capacity for administering and monitoring these?
• 22:55
  SPEAKER_01: I think a new consideration is going to be how to equitably give these medications, which patients out of your immunocompromised patients are going to be the first to receive it because absolutely we're going to have limitations in availability when it first comes out.
• 23:09
  SPEAKER_01: University of Nebraska Medical Center, they just released their algorithm on how to stratify patients, you know, immediately when the product is available, three months after it's available, six months, et cetera.
• 23:18
  SPEAKER_01: American Transplant Society ATS, they also came out with the stratification.
• 23:22
  SPEAKER_01: So more organizations are putting forth guidelines that you can review and adopt rather than reinventing the wheel.
• 23:28
  SPEAKER_01: So talking about the administration of these, this is a little different because these are intramuscular injections, right?
• 23:33
  SPEAKER_01: It's two separate injections.
• 23:35
  SPEAKER_01: There's 150 milligrams of tixagavimab and then 150 milligrams of silgavimab.
• 23:40
  SPEAKER_01: Two separate vials.
• 23:42
  SPEAKER_01: You don't have to reconstitute them, but you do have to draw them up into syringes, and then you have to give two separate IM injections.
• 23:48
  SPEAKER_01: Now, looking at the EUA fact sheet, it does say that gluteal is preferred, but it says preferred.
• 23:54
  SPEAKER_01: It doesn't say mandated.
• 23:55
  SPEAKER_01: So potentially we can give it maybe in the deltoid, maybe in other areas.
• 23:58
  SPEAKER_01: So that means pharmacists can potentially be involved in administering this product as well.
• 24:03
  SPEAKER_01: It does have to be stored in the refrigerator, you know, the vials before you use them.
• 24:07
  SPEAKER_01: Once you draw them up in the syringe, you have to use them within four hours.
• 24:10
  SPEAKER_01: So there's a different timing component associated here.
• 24:13
  SPEAKER_01: And then you have to monitor the patient for an hour.
• 24:16
  SPEAKER_01: And if you look at the EUA, you know, we don't know what the future holds.
• 24:19
  SPEAKER_01: Jason talked about the half-life of the medication, but potentially hinting that we might have to redose this every six months or every 12 months.
• 24:26
  SPEAKER_02: Oh that's wonderful additional information.
• 24:29
  SPEAKER_02: Thank you, Dr.
• 24:30
  SPEAKER_02: Bonnie.
• 24:30
  SPEAKER_02: Well, let's go ahead and kind of shift our conversation to the new kids on the block.
• 24:34
  SPEAKER_02: And obviously, Malniperavir, the Merck product, was narrowly approved by the FDA advisory committee a few weeks ago.
• 24:43
  SPEAKER_02: And my understanding is that the Pfizer product, Nermatrell, combined with Retonavir, should be undergoing advisory committee review in the next week or so.
• 24:52
  SPEAKER_02: Dr.
• 24:52
  SPEAKER_02: Poe, can we start with kind of an overview of the mechanism of action and the efficacy data with Molna Pyravir?
• 24:59
  SPEAKER_03: Yes, Dr.
• 24:59
  SPEAKER_03: Sharon, that was great.
• 25:00
  SPEAKER_03: You pronounced those drugs fantastically.
• 25:02
  SPEAKER_03: And again, I'd rather talk about the new kids on the block, the band, I think, than try to pronounce some of these, some of these names.
• 25:09
  SPEAKER_03: But here we are, alas.
• 25:10
  SPEAKER_03: And and so, yes, two-part question there.
• 25:12
  SPEAKER_03: And I actually want to start with a mechanism of action.
• 25:15
  SPEAKER_03: Again, you do note the trend here, but I think what's really important, I actually want to kind of take both of the novel agents together here a little bit, because I think it's important for people to understand, to really understand where these oral agents work and actually where the monoclonals work as well, is to really understand the life cycle of the SARS coronavirus too.
• 25:36
  SPEAKER_03: And so, just real briefly to talk about that, just to kind of show you the different mechanisms and why they have different mechanisms of action.
• 25:44
  SPEAKER_03: So we already talked about kind of that first step, right?
• 25:46
  SPEAKER_03: You got the spike protein that's on the SARS coronavirus 2.
• 25:50
  SPEAKER_03: It will attach to ACE2 receptors, and that kind of brings the virus into the cell.
• 25:54
  SPEAKER_03: And that's where the monoclonals are working, right?
• 25:58
  SPEAKER_03: They're trying to bind to that spike, don't allow it to get into the cell at all.
• 26:02
  SPEAKER_03: So that's kind of where that first mechanism of action comes into play.
• 26:06
  SPEAKER_03: But let's say we don't have that, we fail in that situation, and the virus gets into the cell.
• 26:10
  SPEAKER_03: So again, what do viruses do?
• 26:12
  SPEAKER_03: All they want to do is replicate, right?
• 26:13
  SPEAKER_03: That's their whole purpose and function in life.
• 26:16
  SPEAKER_03: And so it then starts that process.
• 26:19
  SPEAKER_03: So the virus goes in, it kind of dumps out its viral material, hijacks our ribosomes, right, and translates that virus out.
• 26:27
  SPEAKER_03: And what'll happen when that occurs is the first thing that comes out of that are really two large polypeptides.
• 26:32
  SPEAKER_03: They're called non-functional proteins.
• 26:35
  SPEAKER_03: And so you have these two big proteins, but they can't really do anything yet.
• 26:39
  SPEAKER_03: To make them functional, you got to cleave it down, make it smaller, getting it into these functional proteins.
• 26:45
  SPEAKER_03: And the process, again, we're always real clever in science.
• 26:49
  SPEAKER_03: The process is called proteolysis, which is going to knock that down into smaller peptides.
• 26:54
  SPEAKER_03: And then the enzyme that does this is a protease, right?
• 26:57
  SPEAKER_03: And so again, basically in SARS coronavirus two, the key protease of interest is called 3CL.
• 27:04
  SPEAKER_03: And this is kind of the big one that is the major protease.
• 27:07
  SPEAKER_03: There's another one as well, but it's not the main one.
• 27:09
  SPEAKER_03: And so when we come back to nermatrolvir or however you want to say that word, right, that L is like in the worst position possible to try to say that name.
• 27:19
  SPEAKER_03: But but again, when you get back to Nermatrolvir, we'll go with that one.
• 27:23
  SPEAKER_03: That's where it's working.
• 27:24
  SPEAKER_03: It's working on that protease.
• 27:26
  SPEAKER_03: But if the protease is not inhibited and you're able to get these functional proteins, then what happens is those functional proteins assemble and then replication occurs, right?
• 27:35
  SPEAKER_03: So that's where you get the replication of the RNA genome.
• 27:38
  SPEAKER_03: This is mediated by append RNA polymerase.
• 27:41
  SPEAKER_03: Again, that's not specific to SARS coronavirus too.
• 27:43
  SPEAKER_03: We know this mechanism, right?
• 27:45
  SPEAKER_03: A lot of our antivirals work as inhibitors of this RNA polymerase.
• 27:50
  SPEAKER_03: And in fact, remdesivir, a drug that you know might work a little bit in some patients, it's actually how it works as well, right?
• 27:58
  SPEAKER_03: It's also a RNA polymerase inhibitor, does a little bit differently, kind of our traditional chain terminator type situation, but that's how it works as well.
• 28:07
  SPEAKER_03: What's different about molten nuperivir is that it's a really, really good nucleoside analog, like really good.
• 28:15
  SPEAKER_03: Like it almost works as a better nucleoside than the nucleosides do themselves in that situation.
• 28:20
  SPEAKER_03: So when it gets inserted into that replicating genome, it doesn't stop the process.
• 28:26
  SPEAKER_03: It just keeps going on and going on, and then you have this new virus that has molnapyrovir in it.
• 28:31
  SPEAKER_03: And then when it replicates again, it starts to induce all of these errors in the replication process.
• 28:37
  SPEAKER_03: More molnapyrovir comes in, it messes up the base pairing.
• 28:41
  SPEAKER_03: And what happens is after a number of rounds of that, you get this functionally deficient virus that can't replicate, it can't do anything.
• 28:49
  SPEAKER_03: They call it like there's very dramatic terms for it, like error catastrophe that occurs in this situation.
• 28:55
  SPEAKER_03: But ultimately, it's it's a non-functional virus in that situation.
• 28:58
  SPEAKER_03: And that's really where Molna Pure works.
• 29:01
  SPEAKER_03: That's why it's a little bit different.
• 29:02
  SPEAKER_03: That's actually where some of the toxic concerns that Dr.
• 29:05
  SPEAKER_03: Mahoney will get to come into play as well.
• 29:07
  SPEAKER_03: But it's a little bit different from that standpoint.
• 29:09
  SPEAKER_03: And so those are the kind of life cycle.
• 29:11
  SPEAKER_03: And then just to kind of play out the life cycle, right?
• 29:14
  SPEAKER_03: Uh the last step in bowel replication is going to be the assembly of the viral structural proteins and the packaging of the viral genome into neuvrions.
• 29:22
  SPEAKER_03: And hopefully, we might have an agent that targets that in the future as well.
• 29:25
  SPEAKER_03: So understanding that process can really help you understand these drugs.
• 29:29
  SPEAKER_03: So, with that said, the question was really directed at Molneware.
• 29:34
  SPEAKER_03: And you talk about the efficacy data.
• 29:36
  SPEAKER_03: And is there efficacy data?
• 29:37
  SPEAKER_03: I think is the good question that comes when you try to do that.
• 29:40
  SPEAKER_03: And so I think for our audience, it's important to note that again, our data still exists in the form of press releases.
• 29:48
  SPEAKER_03: Or in the case of Molnew Purevere, because the adcom already happened, the advisory committee already happened, we got to see those documents.
• 29:56
  SPEAKER_03: So we saw Merck's submission, we saw the FDA's interpretation of those data.
• 30:00
  SPEAKER_03: But I think it's important to know that we don't know a lot of details about that data set, has not undergone peer review.
• 30:06
  SPEAKER_03: I think it's subject to change a little bit.
• 30:08
  SPEAKER_03: Don't be surprised if it does.
• 30:10
  SPEAKER_03: But what I think we do know is that what we know is really confusing.
• 30:14
  SPEAKER_03: And so again, Molna Pierre Vir is actually studied in two different trials.
• 30:18
  SPEAKER_03: One was in an inpatient hospitalized patient study.
• 30:22
  SPEAKER_03: That was actually stopped rather quickly for futility, not shockingly, right?
• 30:26
  SPEAKER_03: Because the antivirals, once they're in the hospital, not the best benefit of these.
• 30:30
  SPEAKER_03: But I think it's important to keep that in mind as you try to look at all the context of the data.
• 30:35
  SPEAKER_03: And then there's the outpatient study, and I think it's got some clever like move in, move out name or something like that, clever trial names that come with that.
• 30:44
  SPEAKER_03: And if you remember in October, right, we got this bombshell that was dropped, this game-changing press release that came out that said there was an interim analysis and the DSMB looked at the interim results.
• 30:56
  SPEAKER_03: The interim results showed a 50% reduction in the primary endpoint of hospitalization or death giving molnuper beer compared to placebo.
• 31:05
  SPEAKER_03: And that was such a dramatic effect, they stopped the study, right?
• 31:08
  SPEAKER_03: And if you looked at the rates in that press release, the event rate was 7% in the molnuperiver arm and 14% in the placebo arm.
• 31:18
  SPEAKER_03: And that was really cool and encouraging data when we saw it, because we don't have anything oral at that point in time.
• 31:22
  SPEAKER_03: Again, all the Paxlova data, which is much easier to say, all that data didn't exist yet.
• 31:28
  SPEAKER_03: We hadn't even had a press release with regards to that yet.
• 31:30
  SPEAKER_03: And so it was really encouraging.
• 31:32
  SPEAKER_03: But I will note that I think a lot of people thought it was weird when we saw that.
• 31:36
  SPEAKER_03: And what was weird about it was the event rate in the placebo group seemed bizarrely high.
• 31:42
  SPEAKER_03: That 14% number, if you look at any of the industry trials for outpatient therapies, the event rate's usually around seven, seven, eight percent, somewhere in that range.
• 31:51
  SPEAKER_03: So that was weird.
• 31:52
  SPEAKER_03: But again, it could have been patient population where they'd rolled any number of reasons.
• 31:56
  SPEAKER_03: So again, we waited.
• 31:57
  SPEAKER_03: And then over the Thanksgiving weekend, right before they had the actual advisory committee, the document came out, and then you got a new press release that said, Oh, full analysis demonstrated that that wasn't a 50% reduction, it was a 30% reduction.
• 32:13
  SPEAKER_03: Again, the Molneu Pierre arm stated 7%, but the placebo dropped down to 10%.
• 32:18
  SPEAKER_03: So again, again, 30% would still be significant, in my opinion, but it dropped down in that scenario.
• 32:24
  SPEAKER_03: But what was really odd about that is that when you looked at those data, right?
• 32:29
  SPEAKER_03: Because they presented those data, and if you did the math, what it basically showed was in the second half of that trial, again, after the interim results, all of the other patients who already enrolled, you know, they eventually followed them up as well.
• 32:42
  SPEAKER_03: There was absolutely no benefit to Molneperivir.
• 32:45
  SPEAKER_03: It was a 6% and a 5% event rate in Molnuperivere and placebo.
• 32:49
  SPEAKER_03: And oh, by the way, those percents are in line with that 7% number that we normally talk about in these trials as well.
• 32:56
  SPEAKER_03: And so, you know, you combine those data with the absolute lack of benefit in the hospitalized patients in a study that was stopped for futility, I think it leads to significant concerns of whether or not this agent is effective or not.
• 33:09
  SPEAKER_02: So before we kind of jump into some of the logistical issues and some of the concerns about the mechanism of action with Molnupuravir, can you speak to what we kind of know about efficacy data with PaxLVID?
• 33:23
  SPEAKER_02: And obviously we we haven't seen the actual data yet.
• 33:28
  SPEAKER_02: So I may be kind of asking you to cross a bridge too far at this point, but can you kind of speak to whether we're having some of those hanky data issues or reporting issues that we encountered with Mel DePurevir?
• 33:40
  SPEAKER_03: Yeah, good, it's a good place for that question, too.
• 33:43
  SPEAKER_03: And you are definitely asking me to go too far because I am going a hundred percent based off of a Pfizer press release here.
• 33:50
  SPEAKER_03: So again, that needs to be said.
• 33:52
  SPEAKER_03: There's not even a FDA ad pump document that I can read partial information.
• 33:57
  SPEAKER_03: This is a hundred percent coming from the company's press release.
• 34:01
  SPEAKER_03: So we need to keep that in mind.
• 34:03
  SPEAKER_03: But what I will tell you is the results, what we know or what we've been told to this point are honestly beyond anything that I could have hoped for with an oral agent in this situation.
• 34:13
  SPEAKER_03: And so if you look at the study, and again, this was over 2,000 patients in this trial.
• 34:19
  SPEAKER_03: What you basically saw, Chris, was uh almost a mab-like effect, a monoclonal antibody-like effect.
• 34:25
  SPEAKER_03: And again, the numbers made a little bit more sense.
• 34:27
  SPEAKER_03: So, again, primary outcome was comparing hospitalization or death in patients who got paxlovid.
• 34:33
  SPEAKER_03: I'm gonna stick with Paxlovid or placebo, and the rates were about six and a half percent-ish in the placebo arm, again, similar to what we would expect, and less than one percent for those that got acting, there's a 90% reduction.
• 34:46
  SPEAKER_03: And what was really encouraging about this, and to your point, Chris, is that we actually had an interim report from them too about a month ago, and this was what the numbers were like with about half as many patients.
• 34:59
  SPEAKER_03: And so it kind of held true in the second half of the study as well, which is really encouraging, right?
• 35:05
  SPEAKER_03: For fidelity of the data, for likelihood that this is a real finding.
• 35:09
  SPEAKER_03: They also, in that press release, I don't know if you saw it or not, but in that press release, they also have a kind of a standard risk population where they were using this drug as well.
• 35:18
  SPEAKER_03: So, again, not a high risk population, but either those that were vaccinated and had a risk factor or those that didn't have a risk factor for progression.
• 35:26
  SPEAKER_03: And at least directionally, you saw the same type of thing.
• 35:29
  SPEAKER_03: You saw a 70% reduction in the need for hospitalization.
• 35:32
  SPEAKER_03: So all of these things go together, and I think they're super encouraging information.
• 35:38
  SPEAKER_03: Again, huge caveats that we haven't seen any of these data yet, but these are these look like awesome data.
• 35:45
  SPEAKER_02: Thank you, Dr.
• 35:46
  SPEAKER_02: Mahoney.
• 35:47
  SPEAKER_02: I want to kind of shift, you know, making assumptions that one or both of these products are going to get approved or EUA, you know, authorized, at least in the short term.
• 35:57
  SPEAKER_02: Can you speak to some of the major logistical issues that I think we need to be starting to think about as healthcare institutions and specifically thinking about who can we give these to, who should we not give these to, where can they be distributed from?
• 36:15
  SPEAKER_02: And three, what are some of the the issues from kind of timing of administration and some of the burdens that we should be advising to the patients?
• 36:26
  SPEAKER_02: So, kind of a potpourri of logistical issues with these drugs that I'm sure you you've got concrete answers to at this point.
• 36:34
  SPEAKER_01: Oh, totally.
• 36:34
  SPEAKER_01: Yeah.
• 36:35
  SPEAKER_01: Easy questions and easy answers.
• 36:38
  SPEAKER_01: I wanted to start off by focusing on kind of just the actual medications themselves and how are we instructing patients to take these?
• 36:45
  SPEAKER_01: And when MOLU Pyrevere first came out, I'm like, oh my gosh, the pillboard, and you know, the the how are we going to instruct patients to take these?
• 36:52
  SPEAKER_01: And then lo and behold, you know, their matrios, like here, hold my beer.
• 36:55
  SPEAKER_01: You know, we have even more issues to deal with right there.
• 36:58
  SPEAKER_01: But backtracking, okay, MOLNU Pyrevere.
• 37:00
  SPEAKER_01: If you haven't looked at the formulation, so the dose is 800 milligrams twice a day for five days, but they only come currently as 200 milligram capsules.
• 37:09
  SPEAKER_01: So we're instructing patients to take four capsules twice per day for five days.
• 37:14
  SPEAKER_01: Now, the good news is that I think it's coming in a standard bottle of 40 capsules.
• 37:18
  SPEAKER_01: So that's going to be the entire treatment duration, but still that's a lot of pill burden for the patients to take for that short period of time.
• 37:26
  SPEAKER_01: Maybe in the future we'll have different drug strengths.
• 37:28
  SPEAKER_01: It'd be great if we just said, you know, one capsule twice a day for the five days.
• 37:32
  SPEAKER_01: But currently you get four twice per day.
• 37:35
  SPEAKER_01: Looking at the FDA adcom, you know, there's two kind of things that jump out that maybe we have to counsel patients on or have additional considerations on.
• 37:44
  SPEAKER_01: And I say maybe because there isn't too much data to back them up.
• 37:48
  SPEAKER_01: The first is teratogenicity.
• 37:50
  SPEAKER_01: Pregnancy screening is something new that we might have to consider or incorporate here.
• 37:55
  SPEAKER_01: If you look at the clinical trials, pregnant patients were excluded from participating in the trial.
• 38:00
  SPEAKER_01: And currently there is an observational pregnancy registry that if you and the patient decide that the benefit outweighs the risk and they go on the medication, you can enroll them in there.
• 38:11
  SPEAKER_01: But you know, there was contradictory information in some of the animal models.
• 38:15
  SPEAKER_01: So to be safe, no pregnant patients were enrolled in the trial.
• 38:19
  SPEAKER_01: So the recommendation right now is in a patient with regular menses or unreliable birth control to determine the last date of their menstrual cycle.
• 38:29
  SPEAKER_01: And if it's within four weeks, that's fine.
• 38:32
  SPEAKER_01: You can go ahead and give the medication.
• 38:33
  SPEAKER_01: If the patient has irregular menses or unreliable contraception or just cannot recall, then the recommendation is to do a pregnancy test in patients that have childbearing potential.
• 38:45
  SPEAKER_01: You know, where do we do this?
• 38:46
  SPEAKER_01: This is an oral medication.
• 38:48
  SPEAKER_01: We're thinking that potentially community pharmacists might be able to dispense it, or maybe we can mail the medication to the patient.
• 38:54
  SPEAKER_01: It doesn't have to be coming into a clinic to get an infusion, but where along that diagnosis to administration does a pregnancy test come into play?
• 39:03
  SPEAKER_01: So another step that we just have to factor in.
• 39:06
  SPEAKER_01: The other one is potential carcinogenesis.
• 39:08
  SPEAKER_01: You know, again, there were some animal models that weren't conclusive, contradictory evidence.
• 39:15
  SPEAKER_01: It was discussed in the meeting, but nothing was really decided on there.
• 39:19
  SPEAKER_01: But that has gotten out.
• 39:20
  SPEAKER_01: Patients might be asking about it, they might be aware of it.
• 39:24
  SPEAKER_01: So coming up with a way to address this or approach this in patients that do have questions is going to be another consideration to have.
• 39:31
  SPEAKER_01: So moving on to neurmatrilvir, this one, you know, pill burden is better.
• 39:36
  SPEAKER_01: It's only three tablets twice a day for five days, right?
• 39:39
  SPEAKER_01: Less pills until you realize that one of those three tablets is retonavir.
• 39:44
  SPEAKER_01: So you're taking a co-formulation of two tablets of nermatrilivir, 150 milligram tablets.
• 39:50
  SPEAKER_01: So take two of those plus a hundred milligram retonivir tablet, and you take that twice per day.
• 39:55
  SPEAKER_01: The good news is that based on the images that we've seen, I think these are going to be blister-packed.
• 39:59
  SPEAKER_01: So each of your, you know, morning and evening dose is going to come in that really easy to open hard aluminum plastic foil that I definitely don't cut myself on trying to get open, but at least they're trying to make it foolproof so that your patients can take their full AM dose and their full PM dose.
• 40:17
  SPEAKER_01: So a whole five-day supply will come in one box.
• 40:20
  SPEAKER_01: If you haven't picked up, the major downside is that it's co-formulated with rotonavir.
• 40:24
  SPEAKER_01: Rotanovir is a potent CIP3A4 inhibitor, which means drug interactions.
• 40:30
  SPEAKER_01: And that's oversimplifying it because as Jason and I were furiously texting last night and this morning, retonivir is a CIP3A4 inhibitor.
• 40:38
  SPEAKER_01: It inhibits other hepatic enzymes as well.
• 40:41
  SPEAKER_01: And if you're lucky, it actually has a little bit of induction as well.
• 40:44
  SPEAKER_01: But the one that we focus on, the major one, is that 3A4 inhibition.
• 40:49
  SPEAKER_01: So yeah, clearly huge nightmare.
• 40:51
  SPEAKER_01: And if you're on social media, all the pharmacists are flipping out for good reason.
• 40:55
  SPEAKER_01: If you go on up to date and you look at Ratanavir, there are over 100 red X, do not use, do not cross go, do not collect$200 contraindications, like actual contraindications with Ratanavir.
• 41:09
  SPEAKER_01: And that's just the category X.
• 41:11
  SPEAKER_01: You know, there's several dozens, if not 100 more, of the category D, which means that you have to modify the therapy if you're going to use a combination with Ratanavir.
• 41:20
  SPEAKER_01: And obviously, we're going to have access to every single patient's accurate, updated medication list, right?
• 41:26
  SPEAKER_01: But that's sarcasm, I don't think we're going to.
• 41:28
  SPEAKER_01: So trying to get that information from the patient is going to be difficult.
• 41:32
  SPEAKER_01: I think if we are working out of a health system and you have access, it's one of your internal patients, and you have access to their medication record, slightly more accurate.
• 41:41
  SPEAKER_01: But if you have a freestanding clinic and you're seeing this patient that you have no background information on, or perhaps the patient doesn't speak your language and they don't remember the medications that they're on, that's going to be challenging.
• 41:51
  SPEAKER_01: So I have a couple of tips that I was trying to brainstorm here.
• 41:55
  SPEAKER_01: Having access to a medication list is going to be key.
• 41:58
  SPEAKER_01: You know, calling possibly their community pharmacies to get an updated medication list.
• 42:03
  SPEAKER_01: If they're from a rehab or long-term care facility, getting that medication list.
• 42:07
  SPEAKER_01: Having a pharmacist embedded in your screening and coordination team is going to be key to review these high-level interactions that you should be on the lookout for.
• 42:18
  SPEAKER_01: So absolute contraindications, do not use with retonivir.
• 42:22
  SPEAKER_01: There are certain cardiac or anti-arrhythmic drugs like amiodarin or phleconide that you should be aware of.
• 42:26
  SPEAKER_01: Certain doax, you know, you can potentially predispose the patient to major bleeds.
• 42:31
  SPEAKER_01: Inhaled intranasal steroids, you know, when I have patients, boosted HIV medications, this one always flies under the radar.
• 42:38
  SPEAKER_01: Now we can argue five days of therapy, you know, is that really going to be significant, but I think it's something that you should still be screening for.
• 42:45
  SPEAKER_01: So those are ones that you should avoid.
• 42:46
  SPEAKER_01: There are others that we're going to have to catch and decrease the dose, you know, certain blood pressure medications, statins, antipsychotics, because it could lead to QTC prolongation.
• 42:55
  SPEAKER_01: So the list goes on and on.
• 42:57
  SPEAKER_01: The management of those interactions is going to be different depending on the degree of interaction, the dose of the concomitant medication, and what they're actually using that medication for.
• 43:05
  SPEAKER_01: You know, can we just hold that other medication while they're on the treatment with the Paxlavid?
• 43:10
  SPEAKER_01: Having a good drug interaction resource or screening tool is going to be key.
• 43:15
  SPEAKER_01: And I would add, use an HIV drug interaction one.
• 43:18
  SPEAKER_01: Those are usually more specific.
• 43:20
  SPEAKER_01: The one that I prefer is University of Liverpool, but there are others that you can use as well.
• 43:24
  SPEAKER_01: But the good news is that thankfully, that rotonavir interaction, the inhibition does appear to be short-lived.
• 43:30
  SPEAKER_01: You know, the onset is rather quick.
• 43:32
  SPEAKER_01: A couple of PK studies that I found is that usually it starts within 48 hours, the inhibition of starting that rotonavir, but that inhibition also goes away about two or three days after you stop the rotonavir.
• 43:42
  SPEAKER_01: So we're not talking a lengthy inhibition or interaction period just around the time that they're starting their Paxlovid therapy.
• 43:50
  SPEAKER_01: So a couple of larger questions here is what do you do if you have a patient that you're going to start on Paxlovid and they're already on a PK boosted HIV regimen?
• 43:58
  SPEAKER_01: You know, what if they have Cobacid?
• 44:00
  SPEAKER_01: Stat or retonavir as part of their regimen.
• 44:02
  SPEAKER_01: Can you not take the Paxlavid retonovir and instead substitute it with your HIV medication for at least one of those doses?
• 44:09
  SPEAKER_01: But then what do you do when they take their second dose?
• 44:12
  SPEAKER_01: Will that Paxlavid retonivir interfere with their HIV medication?
• 44:16
  SPEAKER_01: So trying to identify these issues before the patient gets the medication and talking to their HIV clinician or even determining if this is the correct medication, but the patient on maybe a monochline antibody is the way to go.
• 44:28
  SPEAKER_01: Additionally, what if they're on the opposite?
• 44:30
  SPEAKER_01: What if they're on an inducer like a rifamycin?
• 44:32
  SPEAKER_01: You know, you can't use that combination either because then you're going to decrease your doses of Pexlavin.
• 44:36
  SPEAKER_01: So I will stop with the drug interactions there because apparently this is not an all-day podcast.
• 44:42
  SPEAKER_01: But yeah, lots to consider, right?
• 44:44
  SPEAKER_01: I mean, I guess this is job security for myself and Jason and the other ID pharmacists, but yeah.
• 44:51
  SPEAKER_02: Yeah, I think that's been kind of the running story of this pandemic.
• 44:55
  SPEAKER_02: Just when you think you have something figured out, there's kind of layers and layers that that kind of continue to unfold.
• 45:01
  SPEAKER_02: And certainly we all have a great deal of optimism around the potential impact of the orals.
• 45:07
  SPEAKER_02: You highlighted a number of critical aspects that that are going to make administration of these orals not so straightforward.
• 45:14
  SPEAKER_02: And I can't say enough that institutions need to be looking at how they're going to control the assessment and distribution of these products.
• 45:22
  SPEAKER_02: And I agree with you that having pharmacies directly integrated into those processes is going to be critical for institutions to be thinking about.
• 45:32
  SPEAKER_02: Well, we have spent a tremendous amount of time talking, and I could spend at least another hour talking to you both about nuances here.
• 45:40
  SPEAKER_02: But in the interest of time, I think we'll we'll go ahead and kind of wrap up.
• 45:44
  SPEAKER_02: But before we kind of wrap up, I do want to open it up to see if there are additional issues or facets of these outpatient therapeutics that we didn't really kind of get to.
• 45:54
  SPEAKER_02: And maybe I'll start with you, Dr.
• 45:56
  SPEAKER_02: Pogue, first and then give Dr.
• 45:58
  SPEAKER_02: Mahoney some time to kind of close here.
• 46:01
  SPEAKER_03: That was awesome, Monica.
• 46:02
  SPEAKER_03: And that's a lot to go.
• 46:03
  SPEAKER_03: And again, it's a five-day drug interaction.
• 46:05
  SPEAKER_03: I don't think that you can overstate the weirdness that that's going to be in a lot of different ways.
• 46:10
  SPEAKER_03: The other thing that I would just highlight is that the coordination is going to be critical.
• 46:14
  SPEAKER_03: Remember, these come with a five-day window to start from the onset of symptoms.
• 46:18
  SPEAKER_03: And so it's just, there's just a dire need to coordinate this whole process.
• 46:23
  SPEAKER_03: And I'm really hopeful that we can succeed at it.
• 46:25
  SPEAKER_03: Again, as Dr.
• 46:26
  SPEAKER_03: Mahoney talked about, you know, who gets a mab?
• 46:29
  SPEAKER_03: If a mab is still an option versus an oral, is it is it going through the same place?
• 46:34
  SPEAKER_03: If I go get to a test and treat somewhere, do I only get one option but not the other?
• 46:38
  SPEAKER_03: I think there's a lot of weird things that need to be figured out.
• 46:42
  SPEAKER_03: And we really need to be spending those times to have those conversations now.
• 46:46
  SPEAKER_03: That I would just reiterate that fact.
• 46:49
  SPEAKER_02: Any additional thoughts?
• 46:50
  SPEAKER_01: Yeah.
• 46:50
  SPEAKER_01: So I do want to take a moment to talk about our community pharmacists.
• 46:54
  SPEAKER_01: Because when we heard that we're going to have these oral medications, I think immediately everyone thought of, okay, how can we use our community pharmacists to get these medications into patients' hands?
• 47:04
  SPEAKER_01: And with the Ninth Amendment of the PrEP Act, the Public Readiness and Emergency Preparedness Act, you know, pharmacists are allowed to order and administer COVID-approved or authorized medications as long as they are subcutaneous, intramuscular, or orally administered.
• 47:19
  SPEAKER_01: And we've seen how valuable they have been in giving uh COVID vaccines and boosters.
• 47:25
  SPEAKER_01: But I do want to focus on the current working conditions that a lot of our community pharmacist are having.
• 47:31
  SPEAKER_01: I know all of healthcare is burnt out, but I don't think a lot of time has been spent focusing or highlighting our colleagues in the community pharmacies.
• 47:39
  SPEAKER_01: Prior to the pandemic, they were getting their hours cut.
• 47:43
  SPEAKER_01: They were asking to do more with less.
• 47:45
  SPEAKER_01: They have insanely crazy metrics to fill, like how many prescriptions do you fill per day?
• 47:50
  SPEAKER_01: How long does it take you to answer a telephone?
• 47:53
  SPEAKER_01: How many flu vaccines are you giving?
• 47:55
  SPEAKER_01: Then all of a sudden, hours were cut, COVID vaccines were given.
• 47:58
  SPEAKER_01: We're in the middle of flu uh vaccine season.
• 48:01
  SPEAKER_01: When the first of the year rolls around, we're going to have prior authorizations that we're going to need for our standard maintenance medications.
• 48:08
  SPEAKER_01: If you're on social media, I encourage you to check the hashtag pizza is not working just to see some firsthand accounts of just how dire these situations are.
• 48:18
  SPEAKER_01: There are statistics that say every US citizen lives within five miles of a pharmacy.
• 48:23
  SPEAKER_01: We are the most accessible healthcare personnel just because you can walk up to us, you don't need an appointment, you can ask us questions.
• 48:30
  SPEAKER_01: But in the current working situations, there is no way for them to maintain their safe prescription, dispensing, drug interaction check purposes.
• 48:41
  SPEAKER_01: You know, they're still maintaining all of our patients on all of their medications, in addition to doing all these other extra things.
• 48:47
  SPEAKER_01: And it's unrealistic to think that they can also administer COVID tests and then provide these oral medications for our patients.
• 48:55
  SPEAKER_01: So I we have to be creative on how we actually get these meds to our patients.
• 49:00
  SPEAKER_01: Rather than leaving you on a doom and gloom topic, some potential solutions that we can have is, you know, look at some of the success that we have had with our mobile vaccine clinics.
• 49:10
  SPEAKER_01: Can we have mobile test and treat where you have these pre-packaged bottles?
• 49:15
  SPEAKER_01: You know, we said that it's going to come.
• 49:16
  SPEAKER_01: A five-day course is going to come individually packaged.
• 49:20
  SPEAKER_01: So can we have some kind of algorithm or some kind of protocol written out that symptomatic patients can come, they get tested, they can receive one of these medications, you know, with all the caveats that we talked about, drug interactions, pregnancy screenings, et cetera.
• 49:34
  SPEAKER_01: You know, can we get out into the hard-hit communities?
• 49:36
  SPEAKER_01: We talked about equity, reaching out to the patients, making sure that we are getting to them rather than relying on patients who are more medically literate and asking for these therapies.
• 49:45
  SPEAKER_01: Can we mail them to our patients?
• 49:47
  SPEAKER_01: That brings up an issue of our US Postal Service.
• 49:50
  SPEAKER_01: And now our service is slower than ever.
• 49:52
  SPEAKER_01: But, you know, if Amazon can do it, then can't our government figure out a way during a pandemic to get medications to people in need.
• 50:01
  SPEAKER_01: So I think we have an opportunity with these new medications to come up with new ways, better ways to get to where our patients are and where they need these medications.
• 50:12
  SPEAKER_02: Those are all fantastic points and really appreciate both of you coming on today.
• 50:17
  SPEAKER_02: Again, could have extended this easily by another hour.
• 50:21
  SPEAKER_02: And I'm sure we'll have an opportunity in the future to bring you back on as it becomes more clear about where these oral therapies slot in.
• 50:29
  SPEAKER_02: And I'm sure we'll also have other developments as far as other therapeutics to talk about.
• 50:34
  SPEAKER_02: So again, thank you both for sharing your expertise and insights with us today.
• 50:39
  SPEAKER_02: So this podcast can be accessed, the SHA's online education center, learning CE, under the Rapid Response Program, where you also find resources such as the SHA COVID-19 town halls.
• 50:50
  SPEAKER_02: If you're interested in becoming a SHA member, we have an opportunity for you to take$20 off your membership type using the coupon code LEARNICNCCE2022 at checkout.
• 51:00
  SPEAKER_02: This concludes today's episode of the Rapid Response Podcast.
• 51:04
  SPEAKER_02: Thank you for tuning in.