Editor’s Note: In a special session titled “Clinical Trials That May Change Your Practice” at the 2023 Infectious Diseases Week (IDWeek 2023), Dr. George R. Thompson III of University of California Davis Medical Center presented a fascinating report on “Clinical Trials in Fungal Diseases That May Change Your Practice”. He also granted an interview with “Infectious Disease Frontline”(IDF) after the conference.
George R. Thompson III, MD
University of California Davis Medical Center, USA
Clinical Trials in Fungal Diseases That May Change Your Practice
In response to the growing threat of fungal infections and issues like drug resistance, the World Health Organization (WHO) released its first-ever list of 19 fungi that pose a threat to human health in October 2022. Thompson discussed clinical trials that could impact the practice of treating fungal infections.
Rezafungin
Rezafungin is a new echinocandin class first-line drug with once-weekly dosing, providing improved stability and pharmacokinetics (PK). Phase 3 studies, including ReSTORE and ReSPECT, are currently underway for treating candidemia and invasive candidiasis, as well as fungal infection treatment in allogeneic hematopoietic stem cell transplant patients. The ReSTORE study has shown that rezafungin’s overall cure rates at 14 days (59% vs. 61%) and 30-day all-cause mortality (24% vs. 21%) for candidemia and invasive candidiasis are non-inferior to caspofungin, and its safety profile is acceptable.
Ibrexafungerp
Ibrexafungerp is a fourth-generation novel triterpenoid antifungal agent with a different structure than other glucan synthase inhibitors (echinocandins), resulting in less impact on common FKS mutations and drug interactions. Phase 3 studies, including FURI, CARES, and MARIO, are currently ongoing. The single-arm open-label FURI study demonstrates complete and partial response rates of 56.5% in the treatment of invasive candidiasis, candidemia, mucocutaneous candidiasis, and aspergillosis.
Fosmanogepix
Fosmanogepix is a fungal glycosylphosphatidylinositol (GPI) anchor protein maturation pathway inhibitor, crucial for transporting mannoproteins to the fungal cell membrane and cell wall. Several Phase 2 studies have reported its positive efficacy in candidemia, vulvovaginal candidiasis, and ocular candidiasis.
Cryptococcosis
The standard induction therapy is liposomal amphotericin B (AMB) plus 5-flucytosine (5FC) intravenous for 1-2 weeks or liposomal amphotericin B (L-AMB) intravenous once (10 mg/kg). Conventional formulations of liposomal amphotericin B have toxic side effects, such as renal toxicity, anemia, thrombophlebitis, and electrolyte imbalances. Research has explored new lipid nanocrystal oral formulations of liposomal amphotericin B (LNC).
Endemic Mycoses
Histoplasmosis is a major AIDS-defining illness in Latin America, and L-AMB is the treatment of choice. A multicenter randomized trial used three induction treatments: L-AMB 400 mg/day, L-AMB 10 mg/kg single dose, itraconazole; L-AMB 3 mg/kg for two weeks. The results indicated that the 14-day clinical response rates for the single-dose, two-dose, and control groups were 84%, 69%, and 74%, respectively (P=0.69), demonstrating that a single 10 mg/kg L-AMB induction therapy is safe.
Aspergillosis and Mucormycosis
Real-world studies show that breakthrough invasive fungal diseases (IFD) are not common among patients receiving triazole prophylaxis. Candida and Aspergillus species are the most common breakthrough pathogens. Discontinuation of triazole therapy due to adverse reactions is rare. These findings support prophylactic strategies with isavuconazole, posaconazole, and voriconazole for high-risk patients.
Furthermore, Olorofim is a novel oral-active dihydroorotate dehydrogenase (DHODH) inhibitor targeting pyrimidine biosynthesis in fungi, showing antifungal activity. A phase 2 trial for refractory, resistant, or intolerant cases demonstrated a 42-day response rate of 43%.
Expert Interview
IDF: Good afternoon Dr. Thompson. First of all, just wanted to thank you for having this interview with us. The first question is, in your presentation you discovered the clinical trials in fungal disease. Could you give us a sneak peek into how those trials are involving and the impacts they may have on clinical practice and how do your findings, especially in relationship to isavuconazole and the ways of fungine fit into this narrative?
Dr. Thompson: Yeah, thanks. That’s a great question. I think it’s really helpful with the increasing number of patients we see each year with fungal diseases to have new options available. The majority of the new drugs are in phase two trials, so we really are looking forward to the results of phase three trials. But a lot of these drugs have new mechanisms of action, so resistance, hopefully we can find new treatment options for and really reduce the amount of side effects related to antifungal therapy.
IDF: And for the second question, your recent publications offer new insights into the treatment of fungal infections, notably with application of isavuconazole and the ways of fungine. What have been the most significant findings from your research and the healthcare professions to be aware of? And how might these findings influence the treatment protocols for invasive fungal infections?
Dr. Thompson: Yeah, another great question. So I say that the Conozol has been compared to really the standard of care in the treatment of aspergillosis, but has a lot fewer side effects compared to voriconozol. So that’s a much safer option, the care of your patients. And then to move on to rezafungin in the treatment of invasive candidiasis, compared to caspofungin, it clears blood cultures more quickly and has really the same side effect profile. So I think both of those really have potential benefits compared to current options.
IDF: And for the third question, in one of your articles, you highlighted the challenge associated with diagnosing Coccidioidomycosis.due to its non -specific presentation and lack of clinical insuspation. How do you see the future of diagnostic for this fungal disease improving and what role does clinical awareness play in the timely and accurate diagnosis?
Dr. Thompson: Yeah, the diagnosis of coxidium mycosis is complicated because people don’t often think about it. And if you don’t think about it, you definitely can’t diagnose it because the diagnostic tests we have are pretty good, but we really need to have them ordered to have a positive result. So it’s really important when you see a patient to take a travel history, see if they’ve been exposed to some of these diseases, and then order the proper tests.
IDF: Okay, Given your extensive work in invasive fungal infections, can you share your perspective on the broader implications of your research for global health? How do you envision the evolution of antifungal agents and treatment approaches in the coming years, especially in light of increasing drug resistance and the advent of next-generation antifungals?
Dr. Thompson: I think that as we travel more broadly across the world, more and more of our patients are traveling, that puts them at risk for an increasing number of different infections, which requires us to have a breadth of expertise we’ve not needed to have in the past. Improvements in both diagnosis and treatment are really of paramount importance to treat these agents correctly and get our patients better. But drug resistance is going to continue to be a problem and really why we need all of these new antifungal agents in an attempt to get around this.
