Introduction 

I was the patient representative on the FDA Advisory Antimicrobial Drugs Advisory Committee (AMDAC) that met on January 24, 2023, to consider whether to recommend the approval of a new anti-fungal drug Rezafungin. The indication was the treatment of candidemia (an infection of a fungus, Candida in the blood) and invasive candidiasis (a systemic infection with Candida). This is a summary of my thoughts on the meeting and Rezafungin.

I have to say that I was a little bit out of my element at this meeting. I originally thought that the topic of the meeting was going to be fungal infections after a transplant or chemotherapy or preventing fungal infections. However, patients with quite a few underlying conditions (including having had chemo and/or a transplant) who had Candidemia or Invasive Candidiasis were included in this indication. There is a separate, ongoing trial looking at preventing fungal infections in transplant patients using Rezafungin. 

Overview of the Rezafungin Trials 

The first-line treatment for Candida is with antifungal drugs in the echinocandin class. The existing echinocandins are Micafungin (Mycamine), Eraxis (Anidulafungin) and Canicidas (Caspofungin). Rezafungin is an addition to that class, derived from Anidulafungin, but modified so it can be given weekly instead of daily. 

There were two clinical trials that formed the basis of the evidence for Rezafungin. The trials compared Rezfungin to Caspofungin. The first trial called STRIVE (which I think stands for something, although I am not sure what) was a Phase II (smaller) trial that compared two dosages of Rezafungin (both had a 400 mg initial dose, followed by weekly doses of either 400 mg or 200 mg) against Casofungin. After the first part of the trial, it was determined that 400/400mg dosing was no more effective than the 400/200 dosing, so the latter was used for the rest of the trial.  The trial enrolled 76 patients in the 400/400 Rezafungin group, 46 in the 400/200 group and 61in the caspofungin group.

The second trial was a larger Phaee III mutli-center, randomized double blind trial, called ReSTORE (I am also not sure what this stands for). It was designed to show that Rezafungin was non-inferior (i.e. at least as good as) Caspofingin. This trial used the 400/200 mg dosing. This trial enrolled 93 patients in the Rezafungin arm and 94 in the Caspofungin arm. 

In both trials, patients in the Rezafungin arm received daily infusions, giving Rezafungin on the first day and a placebo (saline alone) infusion on the next 6 days. Patients in the Capofungin arm who responded well after 3 or more days from the start of the trial could be switched to oral fluconazole “stepdown” therapy (fluconazole is an antifungal in a different class that is available orally). Patients in the Rezafungin arm would receive a placebo pill if they were deemed to be appropriate for stepdown therapy.  

FDA generally requires 2 well done Phase III trials. Given that there is an “unmet need” for better antifungal drugs, FDA used a “flexible development program” that requires less evidence for an approval. In this case, the approval requested was for a “limited use indication”.  Although there were some questions about the quality of the data in some cases, overall, the committee agreed that there did not seem to be any significant safety concerns (at least compared to Caspofungin) and Rezafungin seemed to have similar efficacy. 

Interesting Notes from the Meeting 

If you are interested in the details of trials, you can dive into the briefing materials. I will point out some interesting bits in this section. 

One area of concern for echinocandins is infusion reactions. In the ReSTORE trial there were no infusion reactions in the Caspofungin arm while there were 4 patients who had reactions in the Rezafungin arm. However, 2 of the patients who had reactions, had them on Day 3, a day on which they would have been getting a placebo. Overall, while medical personnel who are prescribing and giving Rezafungin should be on the lookout for infusion reactions, I don’t think it is a major concern. 

There is some hope that Rezafungin would be useful for deep tissue (intraabdominal and peritoneal) invasive candidiasis. This is based in part on the fairly large initial (loading dose) as well as the long-lasting effects of the drug. However, there is little data to back that up as only a few patients have gotten the drug for deep tissue infections. 

The FDA noted that in the STRIVE study, the patients who were in the Rezafungin 400/200 dose arm had a higher chance of mycological eradication (that is cultures for Candida were negative) at day 5 (82.6%) compared to the patients in the 400/400 dose arm (71.7%). However, at day 5, patients in both arms had received the exact same amount of the drug (400 mg, in the first dose). I am not sure what to make of this anomaly. 

Conclusion 

We recommended 14-1 for approval. My opinion is that Rezafungin is a useful drug, comparable to the existing drugs in the echinocandins class, with a modest benefit – weekly dosing instead of daily. In the discussion, it was felt that the best candidates initially for this drug are patients who would likely have difficulty coming in for daily infusions, which was generally not a population treated in the trial, as all patients received daily infusions of one of the drugs or an infusion of a placebo. It will be interesting to see if Rezafungin does work better than the other drugs for deep tissue infections. 

Further Reading 

Note: The FDA documents (including the ones from the Cidara) seem to go away after a while (perhaps a year, I am not sure). 

Cidara Briefing Document for AMDAC meeting January, 24, 2023, the briefing document from Cidara on Rezafungin.(accessed March 12, 2023) 

FDA Briefing Document for AMDAC meeting, January 24, 2023, the FDA’s briefing on Rezafungin, there is a minor errata to the document. 

January 24, 2023: Antimicrobial Drugs Advisory Committee Meeting Announcement, more information about the meeting, as well as other documents (the FDA slides, the committee members, the above briefing documents). 

Echinocandins, a listing of the existing Echinocandins from drugs.com 

Cidara Therapeutics and Melinta Therapeutics Announce FDA Advisory Committee Recommends Approval of Rezafungin for the Treatment of Candidemia and Invasive Candidiasis, a press release from Cidara on the recommendation to approve Rezafungin or treatment of candidemia and invasive candidiasis