133. Echinocandins Part 2: Rezafungin

Part 2 of 2 on Echinocandins! 

Tihana Bicanic gives a masterclass on Rezafungin, its use now and in the future, and gives an update on the relevant clinical trials and studies you need to know to make you a Master Echinocandologist. 

Alyssa and Jame are here too, but very much in receive-only mode. Listen in and find out why! 

Notes for this episode are found here: https://idiots.notion.site/132-133-Echinocandins-2d76a1ea09d8811f800ad3a446c6726e

Transcript

Jame 0:00

The following episode is the second part of our discussion on Kinic and focusing on Raise Fungi and its practical application. See part one for an overview of the EC can drug class in general. Hope you enjoy the show.

Speaker 0:12

Soon May the editing, editing come to discontinue Caspo fun gun. One day when the BDG is done, we'll take our leave and go.

Jame 0:23

Fine. Let's turn now to the new kid on the block. Raise fungi. So Raise Fungi is a new EC hand that has had its license bestowed upon it by the Cher in January, 2024. It is once a week. It is structurally similar to Anular Funkin and it's got activity against everything that we've just said before including Pneumocystis vei. But I be, it doesn't have a trial supporting that, but it's probably got some mouse study

Tihana 0:53

there are ongoing trials.

Jame 0:55

And this has generated quite a lot of interest. It's by NAP Pharmaceuticals, if I remember rightly, and they've been attending all the ID conferences and putting up a little poster and giving lots of product literature away because it's once a week. It's got certain advantages. It's in the therapeutic range for a large period of that time. It has. Implications for pac, similar to the long-acting glycopeptides and hospital at home and things like that. And of course, in terms of saving nursing time, it will be saving a lot of infusion time, even if you end up using it as an inpatient. The only downside is that it's super duper expensive, but there may be some other snags as to why we would want to use it or not use it. Over to you. Tihanna, your chance to cut loose and absolutely take ung into the cleaners or big it up depending on how you're feeling about this drug.

Tihana 1:53

Yeah, I mean, RESA Fungi. So just to go back, so what is its licensing based on? So it's licensing is based on two clinical trials. The STRIVE trial, which was a phase two trial and restore, which was a phase three trial. And essentially these were non-inferiority design randomized trial where Sung was pitched head to head against Casper Fungi. And then in the Casper Fungi Group there was an optional step down around day five to seven to Fluconazole. And as you mentioned with Sung, you have this high loading dose of 400 milligrams. On day one, and then you have this weekly dosing of 200 milligrams. And in this study, essentially Resif fungi was non-inferior to Casper fungi, on all sorts of measures, but conventionally in, for the EMA, I think it's just mortality. And then for the FDA, it was a composite of clinical resolution and improvement and mortality. Whatever indices you look at, it's non-inferior. The toxicity was comparable and as a result as you say, it received a license in the UK early last year. So one of the sub-analysis of these studies is they looked at time to culture conversion. So it's, PK is such that. it achieves this high, early high concentration and then this long tail, which lasts this half life of I think around 150 hours. I dunno.

Jame 3:38

Something like that. Yeah.

Tihana 3:39

So around five, six days,

Jame 3:42

days,

Tihana 3:43

And as you said, the pharmacodynamic target for a kind of cans, I think is a UC over MIC, is that right

Jame 3:52

that right? I think it might be different for Razor, but Alyssa you wrote its concentration dependent killing, but I think it's, you know how basically Amy Glycosides are concentration spending beta tums, or time over MIC and everything else is basically a OC over MIC. But some stuff is more concentration and some stuff's more, I think their kinda kinds are a bit more concentration, but actually for their PD targeting, even for aminoglycoside, Ucast are now using a UC over MIC PD indices, so I don't know that really it's every, if they're using that for everything except the beta lactams, they're probably using it for the EC

Tihana 4:27

Yeah, I think it's you see, Alyssa, have you got that in your notes?

Alyssa 4:31

I don't, but I think it's, is it a UC over

Tihana 4:33

I thought it was I thought it was a UC over MIC, but essentially it achieves obviously a high initial dose and therefore there's a matter of something like 24 hours versus 27 hours to caspo. As we've said, all these drugs are. Fungicide, but clearly Reza fungi has some trends towards quicker killing, which perhaps is not surprising given its higher front loaded dosing.

Jame 5:04

dosing.

Tihana 5:05

The question would be, and I think remains unanswered in the literature, is what happens at the tail end. of the dosing. Particularly as we talked about at sites that are difficult to penetrate. And for that, I think we still need some research and animal model data on whether the, At days five, to seven, whether perhaps there may be. Areas compared to daily dosing where that concentration above the MIC is not achieved, and therefore resistance might emerge. But at the moment, this risk is theoretical. There's absolutely no evidence of that. Now in terms of how, so it's licensed for invasive candidiasis and then there have been a number of follow up, sponsored by the company, cost effectiveness studies looking at, and One of the major arguments supporting its higher cost that the company gives is, that you use lower nursing time cost, the pharmacy costs.

Jame 6:05

Yeah. Less plastic, less carbon. There, there's lots of reasons for using long acting things. The only thing is that it's pricey.

Tihana 6:12

No, so what I was gonna say is they've always said why aren't we using it in our intensive care units? But what I've tried to explain to them is that in real world practice, especially on the ICU, these patients have a central line. There are so many drugs that are on daily iv and practically speaking, a weekly drug, we are just, as doctors and nurses not so used to giving it. There's the danger it might, be missed. There's not. So many antibiotics. I mean, what do we have? We've got dalbavancin, we've got not that many antimicrobials that we give weekly. So in practice, because the nurses are doing, all these other drugs. It's really an increment on their time that Doesn't, to my mind, justify using that. cost. The other analysis they did based on again, sub-analysis of their clinical trial data and serving investigators is could you in theory by using Reza Fun save on the time of ICU bed days or hospital admission? so I think where one should be using, resif fun in invasive candidiasis is for patients where you could facilitate stepping down and discharging them if that's the only thing that's keeping them in hospital. Now we know in practice that certainly in our context, around half of candidemias occur in the ICU. so often that's not the only thing keeping them either in the ICU or in hospital. However, for complicated invasive candidiasis, for example, we have used resin and others also in the published literature for things Like endovascular infection, endocarditis, bone and joint infection, where you are going to be treating patients for six weeks or longer.

Jame 8:07

Yeah,

Tihana 8:07

It then is a very attractive option to facilitate discharge and OPA that's liked both by patients and bot.

Jame 8:17

Oh yeah. And more locally to me I know that the Glasgow guys have been using razor fungi in their opat service but certainly the. The second this thing becomes generic, I think it will become the oat ec canon of choice. Just as when DBA Ankin becomes generic the use of other glycopeptides will go through the floor. Presumably in, certainly in the oat service, maybe not in inpatient medicine, but actually if all the evidence of DBA van and turns out to be as good as it looks so far, again, that might change within patient medicine as well. But we're talking about antifungals. We're not talking about antibacterials. I know that you hate hearing about them.

Tihana 8:58

We've actually just to say our own local experience of Reza Fungi, just to add, we've mostly actually been using it off license, and indeed we have published, and there'll be a reference listed, our experience of our first six cases. Of using it. And actually three, only two of those were for classical invasive candidiasis. The others and they were both bone and joint. The others where we've used it is we all know and experience in our practice, people with refractory mucosal, particularly esophageal candidiasis, either patients with HIV or I've had a liver transplant patient as well, particularly again, where there's less susceptible organisms such as glabrata or recurrent candidiasis in an outpatient setting. I also have used it in a patient with genetic chronic mucocutaneous candidiasis, and that's been published in the literature. These patients get recurrent. oral and sometimes also esophageal candidiasis that's due to a genetic immunodeficiencies. So I have a patient who's now on his. Fourth or fifth course of resin every three months because he will just relapse. So these are patients where, unlike what we discussed earlier. this is to do with admission avoidance, these are outpatients. We've also used it for chronic pulmonary aspergillosis. I've used it in one case in patients who were refractory or resistant, can be to azoles.

Jame 10:34

And do you still use it weekly? In that scenario?

Tihana 10:37

we were using it according to the broon regimen, which again has has been widely clinically used, but there hasn't been a particular clinical trial, just a small cohort study, but using it for two weeks every eight weeks and maintaining them on AALS throughout, as long as you can get them on a nasal, they tolerate. But there is actually a study that the UK is a site for that NAP MDI pharma running of using resin in this salvage situation for patients with chronic pulmonary aspergillosis who are refractory or resistant to azoles. And There are multiple recruiting sites, as far as I'm aware to that study. The other study when we talked about PCP, The other clinical trial that's just finished is called the RESPECT trial, which is looking at a comparison A placebo controlled double-blind trial of sung against Cotrimoxazole interestingly and also against posaconazole for prophylaxis in hemat oncology patients, either a ML or post bone marrow transplant. So essentially using sung to cover both for candida aspergillus. As well as pneumocystis compared to Cori and Poser. And that's finished enrollment. The results are not known yet, but This is going back to, Regan's activity against cyst of pneumocystis, for which there is actually, evidence from an animal model of efficacy, but no human data. There's also an ongoing study, a clinical, trial phase two study in South Africa, an HIV infected patients run by one of my colleagues, Sean Mann from St. George's, but also supported by Mandy Farmer of Cori with Resa Funkin against Cori alone for PCP

Jame 12:39

what is treatment not as

Tihana 12:41

As treatment. So essentially there are two on if you like, there's a completed study and then there's an ongoing, I'm just posting into the chat, the clinical trials.gov registration for that one.

Jame 12:54

Ah, perfect.

Tihana 12:55

And it's the RESPECT trial is the one that's the prophylaxis one that's just completed recruitment. So those are ongoing studies which will tell us really what other situations we can use resin. But certainly we have found it the most useful in our practice in the oat setting and not necessarily always for its licensed indication.

Jame 13:19

Are you using it routinely for opat or are you using it as the in select cases, or are you defaulting to that as your, as you're hand of choice?

Tihana 13:30

We are. And the reason being, and again, in our paper by Harriet Davidson published in JAC, we did a local, if you like, not a formal cost effectiveness analysis, but we looked at nurse times. So we use Baxter as a company and Casper Fungin as our OPAC and antibiotic of choice. The nurses have to go in daily and they also end up using the, Elastomeric devices for caco, which are costly as is the nurse time. And actually when you balance that out against weekly when the patients would come in to an infusion suite at St. George's, and an PACT nurse administers the weekly Resa funkin, we looked at the time of the nursing. time and the setup and the elastomeric devices and in our practice. That has that looks to be actually resin works out In oat,

Alyssa 14:28

Would you use, would you have a long line in for those patients who were coming in for weekly? No. So they just have a cannula put in when they

Tihana 14:35

they just have a cannula put in. And similarly, our patients with chronic mucosal can Who need repeated courses

Jame 14:42

courses

Tihana 14:43

they have a cannula put in. And that's another attractive thing because it reduces risk of having, so we also put into our article the number of line days saved by having this method, which is another factor to consider.

Alyssa 14:59

And what about thinking about an invasive canid patient who was discharged on sung, what about monitoring? Would you do, because usually we might, do blood like, a couple of times a week or something. Would you still do that with the.

Tihana 15:14

No, we wouldn't. We've been doing it, like I said, in my clinical experience.'cause let's not forget that resin is just a chemical modification of anular fungi, which most of us have good experience of, with just an additional side chain that mediates this attractive long half-life. So we, would just do monitoring. as you would for anyone on oats just once a week when they come in and do the routine bloods, which includes electrolytes and LFTs We've not experienced and again, we surveyed the published cases. To date. There's no suggestion of a safety issue.

Jame 15:52

no. Same with Devan that a long acting agents, they seem to be as safe, if not safer than their once a day counterparts. So that's good. That was a full throated support of raise fungi. Are there any downsides to raise fungi that you want to flag

Tihana 16:07

The only one is cost in terms of for inpatients and in the NHS. But no, I don't see any downsides, and I think it's an excellent addition to our limited antifungal arsenal because let's face it, for candida, we may use, azoles and Akin Canin is our first line. And again, for aspergillus, it's very useful having this. And again, because the chronic pulmonary aspergillosis population is predominantly an outpatient one, having something that doesn't need to be given daily, especially if you are using it in combinations with azoles. Just to finally end on. This whole issue of aspergillus and akin dens. There there have been clinical trials the Kiran MA study published in invasive. aspergillosis where There's suggestive data. There's actually a 10%. difference in mortality. But the p value was not statistically significant in the VRI and plus anular against VRI alone in the MAR study published in Annals of Internal Medicine. However, because the, study was probably underpowered and the P value was not statistically significant, the guidelines have never recommended combination therapy. They recommend it as an alternative, et cetera. There's been an attempt to do an improved power study, of combination therapy in aspergillosis. By the Dutch, Belgian group, but unfortunately that under recruited and had to close. So this is still a poorly understood and studied issue. Nevertheless, my personal, again, clinical off the record, not necessarily in the guidelines, is if you have a sick patient,

Jame 18:01

Off the record. So we're not recording this, are we? We're not about to broadcast this out to the great unwashed. Fine. Go

Tihana 18:06

Invasive asper osis. If you've got a very sick patient and you don't have Azo, TDM on site.'cause let's not forget with Rory, you don't know up to a third of patients might be subtherapeutic while you are waiting to get your azo levels. If a patient's very sick, I would very much favor using a combination therapy upfront for that. And similarly, I do think an area where we could consider using combinations. Would be in this chronic, pulmonary aspergillosis, especially the immunocompromised group, which is why I'm very glad and that MDI Pharma have taken this on board. Although, unfortunately, combination studies are not something that drug companies will generally do. It needs to be investigator led because of the fact that to get a license that we discussed in a condition they need to do it as monotherapy. So yes, there is a, study, it's not being used upfront, it's you being used for salvage. But at least again, a kind of cans are being formally studied for this outpatient setting.

Jame 19:14

yeah. And just coming back to the issue of cost, the list of price in the BNF for ROF Fungi is 2000 pounds for a 200 milligram infusion. So if you are loading, you're going to be giving them 4,000 pounds worth of drug upfront, assuming that you don't drop one of the vials on the way to the patient. But to translate it another way, that is four inpatient days. So the patient sits in a bed getting three meals and getting their OB checked once a day. That is 500 pounds a day. So if you are able to get them out four days early, then you have. You are cost neutral in terms of a 200 milligram infusion. So I guess those inpatient bed day savings that you're mentioning, and I suppose there is this nationwide drive for more hospital at home and PAC services in both England and Scotland. So this will be another tool in the arsenal as far as that's concerned.

Tihana 20:07

I

Jame 20:07

I'm gonna wrap up at this point unless there's anything else to say.

Tihana 20:10

all I would say is that, antimicrobials and I've been sitting on a nice panel to look at this, A nice antifungal panel there is essentially attempts now to make antimicrobial prescribing a subscription type service. So this may really change, shift the field for sung. But essentially the challenge with new antifungals is paying for them and they have to be pricey upfront because of the costs in associated, huge costs in development and clinical trials. However, there may be a move towards models and that's already happening for antimicrobials where you pay a set fee just to have it on your formulary.

Jame 20:57

Yeah we've talked about this before, the subscription

Tihana 20:59

yeah,

Jame 20:59

for Kef, Avi Atrium might be going on there, et cetera. And particularly because Rein and other neuro antifungals are being targeted increasingly towards the WHO priority pathogens list, which you've mentioned Alyssa a while ago. Now I think that this stuff is just ripe for the subscription model and that seems to me the only way that we are going to get new drugs made. Because at the moment, the second you produce something like a plasma mycin or a kol, we say, thank you very much. This is no reserve and you will

Alyssa 21:30

Yeah.

Jame 21:31

And that just doesn't work. Like the, the drug company is far better off making sildenafil clone and then just selling it in pharmacies to the patients directly in America. And they will make so much more money that there, there's no reason to go into antimicrobials. So you either pay lots for it upfront, which is the current model, and hope that it doesn't get stewarded into oblivion by us basically, or your government subscribed to it Netflix style. And then you can use as much or as little of it as you like, but at least you've got it

Tihana 22:05

so yeah, so nicer now trying to develop criteria. The antimicrobial criteria are now being piloted and they're now trying to do the same for antifungals. So I welcome that. move because as you say, I love that phrase stewarded into oblivion. You're absolutely right. We do need these drugs. And therefore we do need to use them in appropriate patients.

Jame 22:32

Yeah. Yeah. And having them, it's like a condom. You'd rather have it, not need it, than need it and not have it. Yes. There we go.

Tihana 22:40

and on that note,

Jame 22:41

On that bombshell Tianna, thanks very much for coming on the show.

Alyssa 22:45

Yeah. Thank you so much Han as always. You're absolutely excellent and yeah, really explained things well. So thank you so much. Really value your input.

Tihana 22:55

no problem. And lovely to meet you, Jane. Have a good Christmas, both of you.

Jame 23:00

by you. Oh,

Alyssa 23:00

Yeah.

Jame 23:01

thanks. But we, I'm gonna release this after Christmas, so I'm going to have to cut that. Thanks for that little bit of extra work.

Speaker 2 23:06

This Psychology episode was produced with support from the British Society for Medical Psychology. The BSMM brings together clinicians and academics in the study of fungal disease. For more information on the benefits of membership and details of their annual conference, visit bsm.org.