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Amphotericin B, an oral lipid nanocrystal for cryptococcal meningitis, phase 2 results: David Boulware, ECCMID 2023

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Published Online: Apr 19th 2023

Intravenous amphotericin B is a mainstay of treatment in cryptococcal meningitis, in this phase 2 study the efficacy and safety of amphotericin B, a novel, orally absorbed, less-toxic formulation is investigated. It was a pleasure to talk with Prof. David Boulware (University of Minnesota, Minneapolis, USA) to learn more around the prevalence, clinical presentations and prognosis of cryptococcal meningitis in HIV, and to discuss the aims, design and findings from the phase 2 study.

The abstract ‘All oral lipid nanocrystal amphotericin B for cryptococcal meningitis: a phase II randomised trial.‘ (Abstract number: O1137) was presented at ECCMID 2023, 15-18 April, 2023, Copenhagen, Denmark.

Questions

  1. Could you give us a brief overview of cryptococcal meningitis, its prevalence, clinical presentations and prognosis? (0:12)
  2. Could you give us a brief overview of the safety profile of intravenous (IV) amphotericin B and why the development of an orally absorbed, less-toxic formulation is important? (1:06)
  3. What were the aims, design, and inclusion criteria of the phase 2 study? (2:19)
  4. What were the efficacy and safety findings with the oral formulation compared to IV? (3:46)
  5. What could these findings mean for the treatment of cryptococcal meningitis in HIV? (4:57)
  6. What are the next steps for the oral formulation of amphotericin B? (6:18)

Disclosures: David Boulware receives grant/research support from NIH and on the advisory board for Sfunga.

Support: Interview and filming supported by Touch Medical Media Ltd. Interview conducted by Victoria Jones and Katey Gabrysch.

Filmed in coverage of the 33rd European Congress of Clinical Microbiology & Infectious Diseases.

Click here for more content on HIV and fungal infections & for further ECCMID 2023 highlights visit here.

 

Transcript
Could you give us a brief overview of cryptococcal meningitis, its prevalence, clinical presentations and prognosis? (0:12)

Cryptococcal meningitis is a common HIV related infection of the brain, and for a disease you may never have heard about it causes between 15% to 19% of AIDS related mortality globally around the world. It’s primarily in areas where there’s a lot of HIV. Such as in Africa, it’s the most common cause of adult meningitis, not just among HIV people, but due to the burden of HIV among all adults. Cryptococcus usually affects people with very advanced HIV, with very low CD4 counts, and typically under 100. This is basically a common cause still today, either of people who have not started HIV therapy or have had developed biologic failure or stopped taking their HIV medicines.

Could you give us a brief overview of the safety profile of intravenous (IV) amphotericin B and why the development of an orally absorbed, less-toxic formulation is important? (1:06)

The standard therapy that isn’t always available in Africa but now there is actually something called amphotericin, and so it has the nickname of ampho-terrible because it has a lot of side effects and toxicities and is probably one of the most toxic medicine that we use in infectious diseases. It’s well known as it can cause kidney failure, it can cause electrolyte problems, it can cause anaemia, and cause a lot of problems, particularly when you use it for, you know, more than a week at a time. There’s been a lot of work over the past several years to use shorter courses or higher single dose therapy, and there still is a fair amount of toxicity that occurs even with just one week of amphotericin. One of the new therapies that’s been developed is this orally absorbed lipid nanocrystal formulation of the medicine, which is taken up into cells in monocytes and macrophages, and so you get high intracellular concentrations and low extracellular concentrations in the blood, reducing systemic toxicity.

What were the aims, design, and inclusion criteria of the phase 2 study? (2:19)

This is a new formulation that’s not currently available. We did a series of studies that looked at a randomized clinical trial to look and see what was the effect of this medicine. Sounds too good to be true. It’s orally absorbed, it’s non-toxic, but does it actually work? We performed a randomized trial of a total of 141 people. 41 controls got the standard one week of amphotericin with the cytosine the intravenous formulations, and then 100 people got the new oral formulation in a series of four forcer steps. With this, we look at it with and without sort of IV loading doses and the effects were quite impressive. Overall, when we gave two IV loading doses, the 18 week survival was 90%, which is sort of astounding. We conducted the trial in Uganda, which is sort of a resource, somewhat limited setting, and so there’s not as much room for error. I guess that if, you know, people get sick that, you know, there’s not ICU care and dialysis and all the things that we may, may take for granted in Europe or North America, and so with IV load, this is 90% survival with just the all oral combination therapy was 85% survival, which was the same as the control group with the IV amphotericin of 85% survival through 18 weeks.

What were the efficacy and safety findings with the oral formulation compared to IV? (3:46)

Beyond just the survival data there was also several other impressive factors. And so we looked at how fast the fungus was clear in the body. And so is very similar to the IV formulation, where we can look in spinal fluid and do sort of multiple sort of cultures over time and see how quickly the infection has cleared. And so that was very similar to the IV formulation. And then the second thing we looked at was safety and tolerability. And so overall, I think 99% of people tolerated the medicine quite well and were able to take six weeks of the oral formulation quite well without stopping the medicine and without sort of, you know, toxicity problems. When we looked at side effects and the adverse events that happened, it was statistically less common in the oral formulation, so this is a relatively small study of 40 controls and so not a huge study, but the toxicity was about half, and so still this is a sick population with advanced HIV. There are bad things that happen just because they have advanced HIV. But overall, the toxicity was less, it wasn’t zero, but it was just because of the high population. But it was statistically less than the IV formulation, which is impressive with such a small study.

What could these findings mean for the treatment of cryptococcal meningitis in HIV? (4:57)

Most people don’t think of cryptococcal meningitis, that’s not the thing they’re worried about. But amphotericin is a broad spectrum antifungal, and so there are a lot of fungal infections that people have in the world, with some that are serious, with some less serious. But this is really a proof of concept, and that if we can treat a, you know, serious, life threatening fungal infection of the brain, that’s 100% fatal, other less serious fungal infections can also be treated. With the emergence of a number of resistant fungus, there’s been in the news lately of Candida auris has been this new sort of multidrug resistant yeast that’s been sort of propagating around the world, this could be a treatment for that. It’s just another broad spectrum antifungal that’s orally absorbed, and we don’t really have that many of those, and the antifungals we do that actually are oral are quite limited, and if you develop resistance to that, then you’re kind of stuck. So you’re stuck with IV therapy or in some cases no treatment whatsoever, therefore this is potentially for those resistant fungus’, you know, potentially a good long term therapy. It’s not currently available in Europe and North America, but it’s something that we’re working towards, and towards the final studies to get it approved and available for patients.

What are the next steps for the oral formulation of amphotericin B? (6:18)

So what’s the future? I’m an academic investigator, so our studies were funded by the National Institutes of Health and the US. The compound is made by a small biotech biopharma company called Matinas Biopharma, and they’re working to develop this, towards both EMA approval in Europe as well as FDA approval in the US. There’s a bunch of steps one has to jump through in order to prove that the medicines, you know, both effective as well as safe, and they’re continuing to do those studies – and how quickly those get done is sometimes a matter of resources and how much money one has to investigate all those things. But they’re certainly moving that forward and hopefully this will be available sometime in the future.

Subtitles and transcript are autogenerated.

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