141. Novel Antifungals

There's nothing new under the sun... except for these new antifungals which we will now educate you on! 

• One's an inhaled azole (OK not that new)
• One's sort of an echinocandin (shut up)
• Two are unpronounceable (but related to fungicides which we're using already)

And Alyssa and Jame are joined by Dr Neil Stone, ID:IOTS Podcast Novel Antifungal Agent Correspondent, to guide you through it all! 

Transcript

Jame 0:00

Hi everyone. Welcome to the IT'S podcast. That's infectious disease insight of three specialists. I'm Jane, that's Alyssa. This is Neil, and we are going to tell you everything you need to know about infectious disease. Alyssa, how you doing?

Alyssa 0:10

I am good. Thank you. Yeah. How are you?

Jame 0:13

I'm fine. Neil. How's it going?

Neil 0:15

Great. Delighted to be back with you.

Jame 0:18

Were you ever on with us?

Neil 0:19

I'm a, an old friend of the show already. I've done at least a couple. I did an episode with you on rear Molds as well.

Jame 0:25

That's right. Okay. Okay. Welcome back to the show.

Neil 0:28

Thank you.

Jame 0:28

Neil Stone is a consultant in infectious disease at university called London Hospital, and an associate professor at UCL. Neil, welcome to the show.

Neil 0:37

you. Great to be here.

Jame 0:38

Alyssa, you have summoned us all for this episode. What are we going to be discussing today?

Alyssa 0:42

Before we get started, I just wanted to know if anyone wanted a Starburst. Do you know, do you remember what these were called?

Jame 0:51

They were called opal fruits.

Alyssa 0:52

Would you like one?

Jame 0:54

I'm that

Alyssa 0:54

Go, on.

Jame 0:54

That old as well.

Neil 0:55

Fruits. I remember al fruits. That was around the time when Snickers used to be called a marathon

Jame 1:00

Yeah, I remember that. Oh I remember the controversy about the renaming.

Alyssa 1:04

Would you like to take one? Oh, no. You can. You can. It's an al.

Neil 1:10

Oh, know. I know where this is going.

Jame 1:13

That was much better than Callum's normal. Standard. Well done. Well done. And what a coincidence that is Alyssa, because what are we discussing today?

Alyssa 1:20

So in this episode we are gonna discuss novel antifungal classes in drugs that are in late stages of clinical development. So these include abrea, fungi Opal Conazole, all Lofi and fos, manga.

Neil 1:36

I was just about to congratulate you in your flawless pronunciation of these bizarre names. stumble at the end is allowed. I think that was a pretty good effort.

Jame 1:45

is this how you pronounce these things? These things are an absolute nightmare in in various meetings.

Neil 1:50

so some people say fo managed epics and some say false manage epics, and it's the same people who will say, Asper compared to aspergillus be controversy, which will rage for decades to

Jame 2:01

Oh, fantastic. As a Twitter alumnus, like you recognizes, nothing promotes engagement like rage.

Neil 2:08

absolutely.

Jame 2:09

Why is this important? Why do we need new agents as if we didn't already know?

Alyssa 2:13

So currently we've got huge challenges with regard to the antifungal drugs that are available to us. So currently there's only three main classes of antifungal drugs in, in clinical use. So the azoles, kinins, and the polyenes. And drug discovery has been really limited in the last few decades. So there's only been one new class in the last two decades, which was the Kinins and only two new agents in the last 10 years. Eyes of Econazole in 2015 and Resif funky in 2024. Um,

Jame 2:46

Unlike the antibacterials pipeline, which is relatively strong compared to this.

Alyssa 2:50

Absolutely. And then these therapeutic options. Not only are they already limited, but then further issues like drug interactions toxicity limitations due to how they're administered. So kinins can only be given IV fur, further reduces options. And then recently we're seeing emergence of drug resistant fungal pathogens. So candida, iris azo resistance and aspergillus and rise in more difficult to treat rare yeast and mold infections. So new agents are urgently needed

Jame 3:25

I see. Okay. That's fairly depressing, but I guess all of these antifungal episodes have been fairly depressing so far.

Alyssa 3:32

You have any comments, Neil, on the the challenges?

Neil 3:35

Yeah, so I think first of all you said, you mentioned that most episodes on fungal disease and antifungals are quite depressing, really. So I think this is a very hopeful episode actually. 'cause we're talking about novel antifungals, and novel isn't a word that goes along very well historically with anything to do with mycology. But we're in better place now I think, than we have been for some time with lots of new agents coming through. But yeah the current landscape is pretty pathetic really. And that's a legacy of decades of underinvestment. And you're right, Alyssa, you were saying we've only really got three major classes for invasive fungal infection. And in fact, the Azo class, that's the only orally available class as it stands for serious fungal disease, which is pretty hopeless. But hopefully there are things changing and that's what this is episode's all about.

Alyssa 4:19

Amazing. Yeah, I thought we'd start with the Brea Fungi first and, and that's because whilst it's not currently licensed in the uk it has been approved for use in the US by the FDA and that was approved back in 2021. And this is the first member of a novel class called the Terpenoid Antifungal Drug Class. So Neil, do you want to take us through a bit more about this new agent?

Neil 4:46

firstly, I think I dunno what they were smoking when they chose the name I, Brix of Funer, because it really is quite unbelievably weird. So I think we could probably shed a bit of light on that. Because you know p on the end is especially bizarre, isn't it? IB bricks of fungi. it does come from the fact that it's a tri terpenoid. So the, that's where they got

Alyssa 5:06

Okay.

Neil 5:07

fun because it treats fungi, andrex, I have no idea

Jame 5:10

Yeah, there's, there, there's a paper where they were initially going to name it as another an oral ana Canon. And then the manufacturer put in some requests that their mechanism of action was significantly different enough that it deserves to be in its own class. Now why didn't, they didn't call the Nic OIDs? I'll never know. But anyway they've done it and it's got this ridiculous name. but as you're about to tell us, Neil, the mechanism of action is virtually exactly the same as the NIC hand. So go ahead.

Neil 5:40

It is. Yeah. It's, I think it's for, it's got a weird name. It's for all intents and purposes and a kind of canon, although the pharmacologists, purists will be listening to this, having a seizure. As I said that, because actually the chemical structure of it is very different from the other. I kind of canons, hence it's got a different name, but it's. much exactly the same mechanism of action works on the cell wall, inhibits one, three B, 2D, glucan, syn phase. So essentially in terms of

Jame 6:06

Mechanism of

Neil 6:08

in terms of spectrum of activity it's very similar to can, and for all intents and purposes. So I think anyone out there listening to that, who's thinking about where you might wanna use this drug in the future, we're probably all pretty familiar. I would say by now with the kind of canin. So if you have in your head that it's very similar in terms of what it does and which organisms act against that's a pretty good

Jame 6:29

to start.

Neil 6:29

putting aside the, chemical structure for the purist. But for

Jame 6:33

Yeah.

Neil 6:33

purposes it's pretty much the same.

Jame 6:35

Yeah. And it's binding that thing in a slightly different binding site, but the end result is similar.

Neil 6:41

And I guess big unique selling point for this is that it's orally available Potentially pretty massive breakthrough. 'cause I think everyone listening will be aware that they cans as they stand are all intravenous.

Jame 6:53

you ever used this?

Neil 6:54

I have not because but I guess we'll come onto a bit more about what it treats and what it's licensed for. I think as it stands, we're in February, 2026 here in the uk it's not available because besides licensing issues, there's been a big manufacturing problem recently. And it's just been not being produced for a long period of time because of some manufacturing problems. So getting hold of it has proved for me, actually impossible. But hopefully that will change. Maybe by the time people listen to this, that situation may have changed. So it's actually now on impossible to actually get, physically get hold of the drugs. It stands. I have not actually used it before.

Alyssa 7:31

I just wanted to ask if I mean I know resistance to akin of canines is fairly rare anyway, but because of that difference in binding site, theoretically, if you had an kin canine resistant candida, would a Brea Fungi be potentially effective?

Neil 7:47

I think that's a tricky question. I'm not sure we know that. I guess that's where pharmacokinetics comes into play. So for example, Reza Fun, you get much higher and the pharmacokinetic are so different that you can even overcome some resistance because of its different pk. Whether that's going to be the case for our Brex fungo, I'm not sure. But potentially but I think essentially, until we learn a bit more about this drug I think for now essentially in terms of spectrum of activity and resistance, we're gonna have to pretty much anchor it against what we know about the kind of cans until we learn otherwise.

Jame 8:20

Let's talk now a little bit about the spectrum. So it's active against your standard yeasts and standard molds. So candida species, aspergillus, pneumas is gii. It's meant to have activity. then other more small fry stuff like alternaria and Claudias bom species and some fungal di morphs. It is less active against other molds like spor and spora, and it has no activity. Again, rales in the very heterogeneous fusarium genus of molds. Neil, there's been a couple of trials done that were, three studies to get abr. Rex Fungi puts licensing indication with the FDA. could you tell us about them?

Neil 9:04

so really the most important one, which led to FDA approval in the US was something called the Vanish trial, which was aung versus placebo for vulva vaginal candiditis. And this was a, it was a phase three RCT,

Jame 9:17

And a point to note there, Neil, is this how most antifungals get their initial licensing authorization? If they want like a yeasty kind of thing, they'll do a vulva vaginal trial and then.

Neil 9:29

I think in this case it did make sense to go for that first because it's, it's an anti candida. It's a very good anti candida drug. Candid ISIS is extraordinarily common, so recruiting patients was never going to be a problem. In terms of numbers, you're right, it's a little bit analogous to, whenever there's a new antibacterial that comes through on the market, they always choose skin and soft tissue infection to do the trials on because, there was so much, cellulitis around, it's super easy, there's no shortage of patients, and you can get pretty quick and clean results to get it approved. So I think in this case, it made complete sense to go for vulva, vaginal candidiasis and also there's a real need involved. Vaginal candidiasis, not the glamorous part of infectious disease, but it's extraordinarily common problem, which causes a lot of misery for of women around the world. So I think it, I think that was a choice of indication was a pretty good one to start with. The big controversy was that it was against placebo.

Alyssa 10:18

Yes.

Neil 10:19

that is. You could argue the toss on that. Is that an ethical thing to do, to say to women with vi vaginal candidiasis, which is not gonna kill you. But it's pretty miserable when there are other treatments available. There's fluconazole and there's boric acid, and there's nystatin, and there's all sorts of other things. So for me I think, okay, it's done and dusted and finished now, I think I would've been uncomfortable with that at the time

Jame 10:42

A bit like the women in the study. Yeah.

Neil 10:44

So I think, I think obviously, it got ethical approval and it was all above board in that sense.

Jame 10:49

How did it get ethical approval? 'cause you, It's not like we don't know how to do non-inferiority trials even in the late 2010s.

Neil 10:57

A non-inferiority trial I think would've been just fine for this. It was shown to be more effective than placebo. Not surprisingly giving something was better than doing nothing. But even then there was only about a 60% response rate, which is not amazing. Wasn't this extraordinary magic So when didn't respond, and there are all sorts of reasons for that. And one of the drawbacks of all vaginal candid ISIS to study is it's not just about the yeast. There are so many other factors It's about dysbiosis, it's about antibiotics, it's about a vaginal pH, it's about hormonal changes. It's such a multifactorial condition. So it's really

Jame 11:37

the end goal is not sterilization of the field. Exactly. Yeah.

Neil 11:40

Cure it. And so you know, I think there are lots of issues with that, it is what it is. And FDA, which surprisingly, because they're incredibly struck sometimes, thought that was okay and approved it. It was approved in the states. It was, they realized that I bri Aung 'cause not a name that was gonna fly in terms of, people buying it pharmacy. So they called it Brex of fem, clearly going for the, the vaginal candid ISIS angle there. And it's got pink and purple packaging. It's all, feminine. That's clearly the market that we're going for.

Jame 12:08

Is it on the market in the US right now

Neil 12:11

so it's licensed and it's available in the us but there are two problems with it in the States. One is it's extraordinarily expensive. I don't actually know how much, but it's a lot. And secondly, because of the manufacturing problems, I think globally, it's not actually available. So it's really stalled in that sense. But that's where we're up to in terms of licensing.

Alyssa 12:30

I did see a paper, actually I think it was by the British Journal of General Practice or something list, looking at a cost effective analysis of if a Brea Fungi were to be introduced into the UK to treat VVC. And it was, thousands of pounds more than flu collars of,

Neil 12:46

Yeah.

Alyssa 12:47

And I think, like you said, because the trial wasn't a non-inferiority, comparing it to fluconazole, it's very difficult then to justify using that as a treatment, unless I guess it's, somebody who's failed the first and second line options.

Jame 13:02

But that will always be the case. Like when this new stuff comes in, it won't be used as the default. It'll be used for edge cases.

Neil 13:09

much.

Jame 13:09

put something here, Alyssa, about the potential future role and mentioning an IV formulation, which seems to be the opposite of what we wanted to do with our Brexit fungi, but do you want to chat about that?

Alyssa 13:18

Yeah. So in development other potential roles for reif fungi for treatment of invasive candidiasis, including candida, Aris, and Glabrata, using an IV preparation which is yeah, under development and study. Treatment of resistant invasive pulmonary osis is another potential. And then using it as an oral step down treatment for invasive candidiasis after an initial IV canine canine therapy.

Jame 13:46

Okay. So in terms of dosing for vulva candida, it's 300 milligrams twice daily. And for recurrent VVC, you would give milligrams oral. Twice daily for one day, and you would repeat that every month for six months. Treating for one day a month. There it's available as a tablet and the IV preparation is still under investigation. In terms of bioavailability, it's about 35 to 50%. It's very lipophilic, very similar to the ec canons and very highly protein bound. And so has a large volume of distribution. It's metabolized mostly by C four fifties. Mostly three, a four Similar to a lot of drugs that we've been talking about and is excreted predominantly in feces and only 1% in urine. So this is not gonna be useful annoyingly for urinary tract infections, much like, the IC cans, that high protein binding and lipophilicity means that it's half-life is quite long, between 20 and 30 hours, which may in the future support a once daily dosing strategy. Don't know if like doxycycline, we dose it twice daily in the interest of tolerance of side effects or something like that. In terms of penetrance, Good penetrance to most tissues with the exception of CNS and eye. And you've put adipose tissue as well, which is a bit surprising, Alyssa, if it's lipophilic. But I guess just 'cause it's distributing in across tissue planes doesn't mean it's actually going into adipose tissue.

Alyssa 15:11

So with regard to toxicity, side effects and interactions. So it's been generally found to be safe and well tolerated within the clinical trials with few adverse effects. I think the most common side effects were GI disturbance, so diarrhea, nausea and vomiting, abdominal discomfort and headaches. And the main drug drug interactions to note are because it's metabolized by C three, A four strong inhibitors of CYP three A four, such as clarithromycin atazanavir, ritonavir, and ail antifungal drugs can increase the exposure to a brea fun up. So in those cases. Of co-administration reduction of the dose of the BRE of Fungis recommended, I think, to 150 milligrams bd. And then of note from the clinical trials, there was no evidence of QTC, interval PR prolongation.

Jame 16:09

This is the the only one of these meds that I've ever used in anger. So we got this on a named patient basis from the company years ago in Nado Royal Infirmary. I can't remember if Callum was involved in that case as well, but this was somebody in whom the only thing we could use was a Nick and a Canon, and was keep them on oped forever or try and get this. Drug and then they say, we'll give you the drug as long as you give us the data as to whether or not it worked or not. We thought that was a pretty good deal. And I can't remember any other details of the case and whether or not it worked, but I know that it took the consultants several weeks to get access to this medication for the patient.

Neil 16:49

Just to, I guess to, to add to that, there was a phase two trial on open label trial called Fury, FURI, where it was exactly that kind of scenario really, where patients didn't have other options and that this drug would fit for their particular circumstances and data was essentially recorded. And, that, that seemed very promising. But again, that was a non-randomized open-label phase two study. So I think we've got a bit to go with this. I do think it's an interesting indication for vulva, vaginal candidiasis and similar, I think that's, that could be a useful adjunct 'cause it's so hard to treat. are increasingly seeing patients with severe mucocutaneous candidiasis, for example, who are immune suppressed and it's resistant to the azos I still think it's got lots of potential and it'll come, but we're not quite there yet.

Jame 17:30

Is there an invasive trial coming

Neil 17:32

there was an open label phase three trial called the care study specifically for Candida or Candida Aris. 'cause then that's another obvious indication 'cause most of them are can susceptible and therefore I Brix fun group susceptible but I think haven't seen a result for that yet.

Jame 17:47

Let's do OPO Conazole. So we've talked about NIC Handin mimic. Now let's talk about true aol which full disclosure I'd never really heard of before a little while ago. So this is an inhaled tri aol which is in late stage clinical development. It doesn't have a license anywhere as far as I can tell but it has been used in the UK on a compassionate use basis for patients with cous or life-threatening pulmonary aspergillosis. So this is your lung therapy coming from the. side of things for invasive fungal infection in the lungs. It's got no systemic absorption as far as I'm aware, and I've not heard of it been giving anything other than as an inhalation. It's mechanism vaccine is exactly the same as the other oles disrupting the fungal cell membrane through inhibiting air gosl synthesis. And the spectrum of activity is against the yeast, predominantly candida and crypto occus genus, but also has activity against aspergillus in r opus. It is not active against aspergillus, Niger Lithia and fusarium. So Lith is one of the mucor. So presumably like the other AALS doesn't work against the Mucor particularly well. Neil, over to you.

Neil 19:01

Yeah, so I think what the theme of these new drugs in mycology Is that either they're a completely new mechanism of activity and we'll come onto some of those later, or they're. Familiar mechanisms of activity with a different delivery system. So we've just spoken about Irea fungi, which is essentially like an akin canon, but can be given orally. This time we've got an aal but the novelty about it is it can be given nebulized and inhaled as you said. And main application you would think of would be mainly invasive pulmonary aspergillosis and getting it the drug to the site of infection. we know that pulmonary aspergillosis has got poor outcomes for lots of reasons. Any new drug is obviously going to be helpful. So the novelty of this is that a, an effective antifungal getting to the site of infection is very promising. Particularly for example, the lung transplant cohort who are very susceptible to this patients with, cystic fibrosis or any other group who are very prone to and at risk of invasive osis. So definitely very interesting and certainly novel drug. We've never had anything like this before in ology. There have been attempts just on that point in the past where inhaled or nebulized amphotericin B has been used. But that has never been very well established. Dosing protocols are quite idiosyncratic from center to center. The data on it was never great, had problems were causing bronchospasm. So the concept has been tested before, but I think this is a complete, completely different step up in terms of a drug, which is specifically for nebulized inhaled therapy.

Alyssa 20:30

So I guess the main sort of treatment potential roles for this drug are gonna be, treatment of invasive pulmonary sullos as an adjunct to systemic antifungals use in prophylaxis. Prevention of pulmonary sullos in high risk patients and then use in chronic and allergic bronchopulmonary, osis. So those seem to be the three main potential areas. Neil, do you want to talk a bit more about high progress is going with regard to trials and,

Neil 21:06

so it's been through a few studies already. So it started off essentially with a compassionate use program where you can sometimes get a hold of these drugs on a case by case name to patient basis. So there was some data collected on, a handful of these patients who'd received this drug as a salvage therapy and seemed to do very well. One case series I think I saw was something like nine patients who were not responding to standard of case therapy. They had this drug added in an eight out of nine responded. So that seemed quite promising, but obviously that's small numbers and non-randomized. then we had something called the upper S study, which is a phase two trial that was looking particularly at, prevention essentially. So prophylaxis and that was a hundred patients and that seemed to be quite promising. But of course, we are most interested ultimately in the phase three randomized controlled trials. And there has been one recruiting called Opera T, which was where patients with invasive pulmonary aspergillosis would have inhaled o conazole, added as an adjunctive therapy, to standard of care. So this was going to be the landmark key study, which was going to hopefully get this license, but fairly hot off the press news or just at the beginning of January, is that unfortunately that study has been terminated because the interim safety board detected a signal of actually worse outcomes than the patients getting the new Conazole. So that's quite a blow really for this drug. And I think it, it's quite disappointing. Putting aside obviously that I'm not gonna speak for the company. I'd imagine that they're pretty upset about it from a financial perspective. But us as doctors and infectious disease doctors, we want new drugs coming through. But of course, we have to be guided by the study results. Haven't seen the detail of that study to pick apart, what's happened there. It's a very surprising result to me. I think I was probably expecting that maybe it wouldn't make a massive difference to add it on, but certainly wasn't expecting it for that comes to be worse, whether that's an artifact or a true signal. I, I don't know yet. But I, that's the whole point of doing phase three trials, right? And we need to be guided by that. So I think there's a. big question you might know about this drug. Will that be the death blow to it? I don't know. Or will it have other applications? Will there be more studies? Does it still have a role in prophylaxis? That's all Absolutely. Up in the air at the

Jame 23:14

Yeah, because sometimes the drug companies, they'll get a result like this and they will decide that bringing it to market is now no longer financially viable. Even if there could be a role for it, in some parts they just can it.

Neil 23:27

Let's be honest they'll have lost a lot of money on this now, and that, that would be their main consideration I think.

Jame 23:31

Yeah but the most expensive trials are the last ones you do. The phase three is to get it over the line. They're the big ones. They're the ones where you really sink a load of your cash. It's about 500 million pounds to develop a drug from start to finish. But the of money you're spending is semi exponential.

Alyssa 23:47

Yeah, and I guess it will, it'll be really interesting to, see the data from the interim analysis. But one thing I'd I've had in the back of my mind was, it'd be interesting to see was this higher mortality, attributable to Opel Conazole, or is it just that this is quite diverse group of patients? It would be really useful to have more granular analysis of that cause of higher mortality in the OC Conazole group. Yeah, hopefully it, it could be salvaged for.

Neil 24:17

It could be. I was thinking about why this might be, 'cause as I said don't think I would've been hugely surprised if it didn't make much difference. But for it to actually cause a worse outcome seems to me very surprising. Unless it was causing a lot of severe bronchospasm, for example.

Jame 24:31

Or lung fibrosis. You can't just shove crap into your lungs and expect nothing to happen.

Neil 24:36

But I think, we should say we're just speculating here.

Jame 24:38

Too enough.

Neil 24:38

but, there's no question it's a disappointing result but, it's a great example. You've gotta do the trials and the studies and something might look fabulous in phase two and doesn't come through in phase three, and that's why we do them. So

Jame 24:50

Yeah.

Neil 24:50

there's a lesson there as well.

Jame 24:52

Let's jump now to some truly novel agents. So though, not if you're a wheat crop let's talk about alo film. Neil,

Neil 25:01

yeah, so this is a really interesting drug. So the drugs we've discussed so far have essentially been novel delivery route for drugs that we know about, but this is really a novel one. So this drug called m rather than an phim.

Jame 25:13

Oh, sorry.

Neil 25:13

So this is a completely novel drug called an ide, is an and it basically in inhibits an enzyme called dihydro orate dehydrogenase and inhibits perine biosynthesis causing fungal cell death. And the most important thing about that is it's novel. So none of the drugs we have,

Jame 25:33

Okay.

Neil 25:33

drugs we have at the moment to anything like that. So completely novel, which of course is exciting and has potential advantages,

Jame 25:40

I see.

Neil 25:41

terms of resistance. Yeah.

Jame 25:42

So as cotrimoxazole inhibits purine synthesis, so fil inhibits perine synthesis in fungi.

Neil 25:50

Exactly I would need to double check this actually, but I think this is a fungal specific enzyme that we don't have in

Jame 25:56

Yeah.

Neil 25:57

which is for

Jame 25:57

Yeah.

Neil 25:58

because historically one of the reasons we have so anti's, few antifungal drugs and the reasons they're toxic is because your carry outs like fungi and our cell all are not very different from fungal cells, not just cell walls, which means that a lot of drugs, which target fungi, target human cells. This is a fungal specific enzyme, which is again, very advantageous in terms of reducing human cell toxicity.

Jame 26:18

And in terms of spectrum here we've got a load of molds and a load of fungal di morphs. It's less at against the fusarium genus. And you've put here, Alyssa, that it's not really active against yeasts or the rales. So this puts it in a very kind of odd 'cause usually the drugs that we talk about are very active against the use, much less active against the mold. And this is the flip of that.

Neil 26:42

It's a really important point that this is a it's an anti mold drug. And certainly in vitro in the lab it's a hugely promising drug. The mics, mics, IC ology is a bit of a minefield, but from what we've seen in the lab, low ics to a number of very important molds, but absolutely right. Really important to note that it's not yeast at all.

Jame 27:03

In a way that's a good thing because that means that we won't be tempted to use it for yeast infections and therefore drive a MR in environmental molds.

Neil 27:10

I think you're right. So broad spectrum is not always better as we've learned the hard way with antibacterials. I think in terms of no yeast activity, I think the one area where this could be problematic going forward is, for example, in the immunosuppressed hemato oncology transplant population where you're not quite sure if they've got aspergillus, you think they might, or you want to prophylax them against fungal diseases. Candid is also important in that cohort. So if you're going to be using this new drug aorm for that purpose, you're still probably gonna have to add in perhaps fluconazole or an azo on kind of can, 'cause you wanna cover off the yeast possibility as well, and you're gonna end up using more drugs. So I think in that particular setting that could be problematic. But otherwise, if you're really going for mold treatment, then yeah, I think more targeted therapy is, has its advantages over ultra broad spectrum antimicrobials.,

Alyssa 28:00

So with that in mind potential future roles for this drug I think are mainly gonna be treatment of invasive mold disease particularly multi-drug resistant molds. Where like Cetosporium and Lamento spora, where other options are really limited. And also potentially treatment of endemic Myas such as COIO Mycosis. Neil, would you like to talk through some of the trials that we've had to date, looking at these potential applications?

Neil 28:32

Yep. So I think that

Alyssa 28:32

I.

Neil 28:32

good summary of where we might use this. So there was a pretty large open label phase two study using alloren for invasive fungal disease in patients who didn't have any other options. Again, must say this non-randomized open label, but this is for exactly those cases where they had very difficult to treat mold infections including CNS infections, deep-seated mold infections, which were either azo resistant or they couldn't tolerate in other drugs so they would reach for em. And generally, outcomes were really quite impressive. Good tolerability success and about a third of cases, which is, pretty good because we know that invasive mold, disease has a high mortality to start with. Once it's refractory, your chance of survival and response become very slim. So I think that was actually quite promising. There've been various. Case series, case reports of success. But really as we've seen with OPO Conazole, it's really all about the phase three study. So there is a phase three study currently recruiting called oasis, which is a randomized control trial, of alloren versus treatment with AmBisome as initial therapy for patients with invasive aspergillosis. So that's going to be critical, that's recruiting globally.. The spectrum is really impressive, as you said. Where I've used it, just going on personal experience here is, patients with refractory aspergillosis, particular particularly CNS disease, 'cause we know at least from preclinical studies, it does seem to penetrate into the central nervous system pretty well, which is a particularly difficult niche of invasive mold treatments to treat. Also used it in cases of some of the endemic mycosis. So you mentioned cocci. Mycosis. So that's not something we see very much in the UK 'cause it's non endemic to here, but. Parts of the world, particularly the Americas, it's relatively common. It can be very hard to treat and very refractory to treatment. And we've had some very complex cases where we've actually reached for alloren other unusual rare mold infections. We did an episode at one point on the rare mold infections like Lamento, Sporin infection, spo, where you don't have many other options. AOR looks both in vitro and based on case series and case reports looks to be very promising. And again, this is purely anecdotal but we have had a couple of cases where I work of patients with disseminated ski DYS spor or Lamento Spora, which has been refractory to therapy and have had very good response to lofi. So of course, we need to see the phase three trials. But so far, I would say of all of the new drugs, this is pretty much up there as. The most exciting, I would say, because of what we've seen so far. It seems to be well tolerated. It can be given orally, which is really important as well. cause some gi upset, some LSV dysfunction, but nothing that can't be managed. I think and some really impressive results so far, I think I'm gonna go out there and put a prediction and remember just for those listening that I said in 2019, that I didn't think COVID was gonna be a big deal at all. So my record of predictions is rotten. But I'm still gonna have a go at this and say that, I think most of us will be using a law firm in some capacity within the next five years, and I think it's going to become a mainstay of the antifungal armory going forward. I may have completely jinxed it now, but it's very promising and exciting.

Jame 31:40

So promising though that a bunch of valor film like drugs are already in USAs, pesticides and antifungal resistance is rising in. Those environmental molds. And so this agent, which is novel to us, already got resistance to worry about it and compete with.

Neil 32:00

so that's really important. I should caveat my optimism by saying I have no conflict of interest either. So I'm not trying to push this drug at all. But you're right it's a worry. So we know that particularly molds and aspergillus are very, susceptible to developing resistance because of use in agriculture. This is the perfect example of the one health paradigm of antimicrobial resistance. That if we don't deal with exposure in the environment, particularly with fungi, it's going to become resistant before we even have a chance. There is a very similar compound already being used in agriculture, which is potentially a disaster if we make the molds resistant before they infect us, and you can see why it happens. So to get a new pesticide or a new art agricultural. Antifungal from development to market takes about two years. So it is a regulatory process, but it's less robust than in humans. Whereas to get a drug into human use takes about 10 years. So they've got an eight year headstart and they're huge economic considerations. So if if there's a lot of them like exposure, we might get resistance very quickly, which would be a real shame. If we don't follow this one health paradigm we've really got no chance.

Jame 33:05

Let me just finish off with a bit on the pharmacology. So it's available orally and and the phase three trials are focusing on the oral formulation. It's between 45 to 68% bioavailable, so moderate bioavailability. Much like abre, fun air pits lipophilic and highly protein bound, very good tissue distribution. And in terms of toxicity, about 10% of the phase two B trial participants got a reversible liver injury, either by dose adjustment or stopping the drug. 10% have mild self-limiting GI intolerance but it is susceptible to three a four. inducers inhibitors. Your PC brass and your AO devices drugs. Pick whichever mnemonic you like. Phos, phono, phos, manga, Vasic. I'm just covering all the bases here. Neo pic of pronunciation and let loose.

Neil 33:59

call it force managed epics.

Jame 34:01

Fine.

Neil 34:02

call it

Jame 34:02

Then that is the Official Idiots Podcast pronunciation. Also,

Neil 34:07

So we'll stick with that.

Alyssa 34:08

So just to give a bit of an introduction, so this is a novel class of antifungal. So it's a GW one enzyme inhibitor. It's currently in phase three of clinical development. Phos noga pick is the prodrug. So following administration, it's then converted in vivo to the active form, which is manga picks. And this is by host phosphatase. It's got broad spectrum of activity against both yeasts and molds. And there are IV and oral formulations in development. So Neil, I'll hand over to you to talk a bit more about this.

Neil 34:49

Yeah, so again, this is another agent which has got a novel mechanism of activity. you mentioned, GWT inhibitor. So I think about this in very simple terms. So it affects a scaffold protein of the fungal cell wall. So if you think about a scaffolding on a building, it holds this, the cell together. If you inhibit the production of these scaffold proteins, the way I picture it is that if you stop those. proteins being produced, you lose the scaffold of the cell wall and it becomes floppy and essentially dies. So it's putting it into simple terms. That's how it works. Much like Alloren, this is completely novel mechanism of action. Which again, has obvious advantages in terms of barriers of resistance hopefully most of these organisms have not been exposed to this drug before, which makes it a very exciting new drug. In terms of spectrum. One of the great attractions of the phos manic epics, as I call it, is not only the novel mechanism of action, but it's extraordinarily broad spectrum. So it's really at least in vitro, we await the clinical data, but it's in vitro effectiveness is against an incredible range of. Fungal pathogens across yeasts and across molds, including very resistant yeast like candida, orus. It seems to be very effective. And importantly, it has some activity against the mucor. One of the groups of organisms, which has been really poorly served historically, has been mucor causing mucormycosis. And even most of the new drugs, do not have good activity against the but phos manic epics does, at least in vitro. So we desperately need new drugs for that, it's effective against crypto caucus, as I mentioned, candida orris moles. So really extraordinarily broad spectrum, which is e exciting. And that means, there's a huge potential here for its use across all these disease types. And that also means we're going to need a whole lot of studies, I think, for all of these different diseases until we can figure out where it's best to use. But yeah, so novel mechanism of action, IV and oral and ultra board spectrum. So lots and lots of boxes being ticked here for a new antifungal.

Jame 36:49

But there's a big hole here in that it's, for some reason it's not active against Canada Cruise eye. Presumably Cruise Eye just has some sort of difference in its GPI anchor proteins that Foss manic epics can't target.

Neil 37:02

Yeah. Exactly right. And I think that is a hole in it. Like most ultra broad spectrum drugs, including antibacterials and similarly, there are always one or two little gaps there.

Alyssa 37:10

Sunil, do you want to run through some of the. The trials that, that are supporting these potential uses.

Neil 37:16

So because of its extraordinary range, it means there's a whole raft of trials for all the different disease groups. And there've been a whole series of phase twos which have come out. So there's been a phase two trial for the treatment of Candidemia, which was published in JAC not long ago, which seemed to be specifically for Candida Aus as well, treatment of candidemia invasive candidiasis. That was, if that's underway, and I don't think it's been published yet. And as you said, a phase two trial of treatment for, invasive mold infections with limited treatment options. But similarly to the study we discussed with I brex of fungi open label, rarer molds or aspergillus where other treatments have failed, is all well and good and most of them seem very promising and by and large, without going to the sort of fine detail of all of them, the general theme is that they're generally well tolerated. They seem to be pretty effective. But it's all about the phase three trials and there's a whole raft of phase three trials actually ongoing at the moment so just to pick out some key ones here, there's something called the Forward IM Study, which is for invasive mold infections particularly aspergillus, but also rare molds compared to standard of care. For Candidemia Invasive Candidiasis, this is a trial called the FAST IC Study, which is a global phase three study, randomized controlled study comparing IV phos manic epics with an oral switch to cask fungi for treatment of candidemia and candidiasis. So these are really the main two, for one for mold, one for yeast, and I think all eyes are on that really, because we could go on and on about phase two trials and all seems great and wonderful, phase three is what it's all about. So I think those are the two key studies we need to look out for.

Jame 38:51

Yeah, just to finish off on the pharmacology so that it can be oral or iv. It's highly bioavailable. So it's over 90% and has a long half life of two and a half days, which would like. For once daily dosing, which is music to my ears. And in terms of toxicity, I think you guys have covered it as well. It's generally well tolerated. It causes some GI disturbance that's minor at best, but that's about it.

Alyssa 39:16

Neil, do you know much about the tissue penetrance of phos noga? Does it have any CNS

Neil 39:21

so

Alyssa 39:22

activity?

Neil 39:23

I don't, and I, there's very little human data out there. I think there are some preclinical models. So one problem with it so one of the huge gaps in my college has been treating urinary tract infections, and unfortunately, none of these new drugs really get. Concentrate the urine at all, including Foss man epics or I Brix fungi. So that's a big gap. So we know that in terms of CNS penetration I think it potentially does. I think we have to be a bit careful about that. I think there are some limited preclinical data, which suggests it does much like a lofi. That's a really key question though. Particularly in ology about drug penetration. And it's something we only learn about often, in the years after we start using it. For example, AmBisome Amaracin b liposomal, it's got really remarkable pharmacokinetics where it accumulates massively in the liver and spleen and that's got all sorts of implications and it took quite a long time for that to come out clinically. So I think lots of these drugs don't want to. To overstate drug penetration 'cause the data is so limited and we don't really have any human data in it. But potential or FM potentially Man, epic CNS penetration. Yes, it looks like it could do. There are some case reports and case series and phase two studies suggesting that both mano epics and aor FIM have been effective in CNS infections because that is a real challenge as we know. 'cause a lot of the current antifungals, don, we don't think confidently actually get into the central nervous system.

Jame 40:45

No, it's all about protected sites. I never thought the, I would think of the urinary tract as a protected site, but in terms of antifungals, I do.

Neil 40:52

Seems to be.

Jame 40:53

And then you finish off Alyssa with this great. Spectrum of activity table for all the new agents including razor fungi actually against various agents that are in the WHO priority patterns list. This is from Gel Etal 2021. An absolute masterclass of doing a heap map table. there anything else to add, Neil?

Neil 41:16

So I think that's, it's a great paper that actually by, Martin Hogo who's an Austrian mycologist. And it's a lovely table to see, I think for those of you who get the chance to look at it I think that the, it highlights the problem area. So the problem area are the Absolutely. There's lots of red, unfortunately even for the new drugs, But otherwise a pretty good spectrum. The other big. Problem area other than urine penetration, which is has not been taken forward by any of these new drugs, are the fusarium species. So still we don't have any magic bullet relief for fusarium. We've had this problem with Osis for some time that is very strained dependent, that some are azo resistant and are azo susceptible. I think that's going to be an ongoing problem with new drugs as well

Jame 41:58

let me ask you about that, Neil. My, my understanding that similar to what's been happening with the strep cock high and the other molds, is that people are now realizing that fusarium is actually a heterogeneous load of different species that are not very closely related to each other. It's just that they aren't asper. And so they've been lumped the fusarium category. So of course, you're not gonna be able to find drugs that work against all of them because they're very different species. Is there a plan to divide and conquer and to separate them out

Neil 42:28

I'm not aware of that. I think you make a good point. We've been through this with candida species that they've all been renamed because it turns out that, ca, candida, cruza, and candida, a pecans are actually different species. We just lumped them together as candida because they cause similar infections and they grow as white blobs in a plate. Fum similarly. with that though, so even within species, for example, Erum Solani, which would be one of the more common ones, there is huge strain to strain differences in susceptibility

Jame 42:56

Okay.

Neil 42:57

you might identify and say it's a solani, you still don't know if, for example, VRA cortisol is actually gonna work until you do susceptibility testing. So it's a really tricky species to deal with. And unfortunately, of the new drugs, none of them are completely reliably effective against em. Species, man looks the most promising. Alloren not reliable at all, maybe against some species and hyper fun. It's like the kind of can, which is not gonna work against fum. So that, that's a real gap. New drugs are great and fantastic but are not that many new ones coming through. I would argue that although, as a mycologist, especially delighted to have all these new drugs, we probably ultimately need better diagnostics because if we can't diagnose these properly, but we can't treat them properly.

Jame 43:40

Yeah. And also maybe less immunocompromised population because those are the guys that are prone to invasive fungal disease or a better immunocompromised population. So instead of just knocking out every single B cell or T cell, or this thing or that thing, actually using some of the newer second and third generation, more subtle immunosuppressants to achieve whatever desired clinical outcome you've got without absolutely completely screwing the body's ability to deal with fungal disease, for example.

Neil 44:10

I think that comes to the point that, especially with mycology, host factors are absolutely central.

Jame 44:15

Yeah.

Neil 44:16

can have the most fabulous antifungal drugs in the world, and it's still not gonna work if the host is so immunosuppressed that they're not gonna survive whatever you do. So I think that's probably a sobering take on this, but I don't think anybody would argue against the fact that it's obviously a good thing that there are new antifungals

Jame 44:32

That's okay. Neil, we always like to end on a depressing point.

Neil 44:35

Especially in my

Alyssa 44:36

Can we enter a different point?

Jame 44:38

If you insist Alyssa. All right. Okay. Just trying to cheer us all up.

Alyssa 44:42

trying to chew you up, like a Brea Fungi is just the most ridiculous name. It sounds ridiculous. It always makes me think of, the Budweiser advert you know the Budweiser advert with those three frogs where they like go Bud Wise.

Neil 44:59

Oh yeah. Okay.

Alyssa 45:00

I reckon we can do that with a Brex of hunger. Yeah, Brea.

Neil 45:04

Fun.

Jame 45:05

A, that's gonna be a nightmare to edit. By the way, I hope you guys I hope you guys realize that,