Jeff Stein, President & CEO of Cidara Therapeutics Shares Insights on the P-III ReSTORE Trial of Rezafungin to Treat Candidemia
- Jeff talked about the results from the P-III ReSTORE Trial evaluating rezafungin in the treatment of candidemia/invasive candidiasis at ECCMID 2022
- Jeff also spoke about Cidara’s collaboration with Mundipharma for the commercialization of Rezafungin
- The interview sheds light on Cidara’s vision to develop transforming treatments to improve the standard of care for patients facing serious diseases
Smriti: Please give our readers a comparative view of P-II (STRIVE) vs P-III (ReSTORE) evaluating Rezafungin
Jeff Stein: Both P-II (STRIVE) and P-III (ReSTORE) evaluated the safety and efficacy of rezafungin in the treatment of candidemia and/or invasive candidiasis against the current standard of care, caspofungin. STRIVE assessed the safety, tolerability, and efficacy of two different once-weekly dosing regimens for intravenous rezafungin versus standard once-daily dosing of intravenous caspofungin. These data informed the dosing regimen for patients in the ReSTORE trial.
The results from both trials were positive. The Phase 3 ReSTORE trial demonstrated non-inferiority of once-weekly rezafungin to once-daily caspofungin for each primary endpoint: all-cause mortality on day 30 for the U.S. FDA (23.7% for rezafungin vs 21.3% with caspofungin) and global cure at day 14 for the EMA (59.1% for rezafungin vs 60.6% for caspofungin). An integrated analysis of the STRIVE and ReSTORE trials (pooled data from both trials), which together provide the basis for approval, showed additional positive results, including 18.7% for all-cause mortality on day 30 with rezafungin vs 19.4% with caspofungin, 60.0% for negative blood culture at 24 hours with rezafungin vs 49.1% with caspofungin, and at 48 hours 77.7% with rezafungin vs 63.5% with caspofungin.
An intriguing trend that was observed in both the STRIVE and ReSTORE studies was that patients on rezafungin were discharged from the ICU earlier than patients who received caspofungin. In STRIVE, patients on rezafungin spent a median of five fewer days in the ICU than patients who received caspofungin. In ReSTORE, the difference nearly doubled with patients on rezafungin spending a median of 9.5 fewer days in the ICU than patients who received caspofungin. This difference was captured as a prespecified exploratory endpoint in the ReSTORE study.
In both STRIVE and ReSTORE trials, safety, and tolerability outcomes were consistent with the safety profiles of both rezafungin and caspofungin.
Smriti: How have the results from P-II (STRIVE) & P-III (ReSTORE) clinical trials affected Rezafungin’s potential to become the first treatment option for candidemia/invasive candidiasis in a long time?
Jeff Stein: Innovation in the space has indeed been slow, despite the need for additional treatment options for critically ill patients suffering from candidemia and/or invasive candidiasis. This fact underscores the importance of these trials.
Our Phase 3 ReSTORE trial demonstrated that rezafungin dosed once-weekly is non-inferior to the current standard of care, caspofungin, dosed once-daily. Data from our Phase 2 STRIVE trial show that rezafungin met its objectives for safety, efficacy, and tolerability in treating patients with candidemia and/or invasive candidiasis and was statistically superior to caspofungin on time to negative blood culture (speed of clearing Candida from the blood).
If approved, rezafungin could become the first new treatment option for these patients in over a decade, and the first-ever once-weekly echinocandin.
Smriti: Explain the details (MOA, ROA, formulations, etc.) of Rezafungin
Jeff Stein: Rezafungin is a next-generation echinocandin being developed for both the treatment and prevention of serious fungal infections, such as candidemia and invasive candidiasis. Rezafungin is an antifungal in the echinocandin class, a group of molecules that are known for their strong safety profile and minimal drug-drug interactions. It acts by inhibiting the synthesis of the polysaccharides that make up the fungal cell wall, preventing the growth of the fungus. Rezafungin’s long half-life allows for once-weekly intravenous dosing instead of once-daily intravenous dosing with the current standard of care, caspofungin. Rezafungin’s structure and its properties are specifically engineered to preserve its safety advantages and improve pharmacology to treat fungal infections.
Smriti: Shed some light on your collaboration with Mundipharma.
Jeff Stein: In 2019, we entered into a strategic partnership with Mundipharma in a deal valued at $568 million plus double-digit royalties in the teens on tiers of annual net sales, to develop and commercialize rezafungin. Under the terms of the agreement, Mundipharma has exclusive commercialization rights to rezafungin outside the U.S. and Japan.
Smriti: Can we talk about the reason why Cidara chose Caspofungin for the comparative study of Rezafungin?
Jeff Stein: As mentioned above, caspofungin dosed once daily is the current standard of care for patients with candidemia and/or invasive candidiasis. In the ReSTORE trial, data demonstrated non-inferiority of once-weekly rezafungin to once-daily caspofungin.
Smriti: Give us a brief understanding of what makes the PK/PD profile of Rezafungin unique and how it helps towards quicker fungal clearance for patients
Jeff Stein: While rezafungin is an echinocandin, its structure has been engineered for enhanced stability and safety. These improvements allow rezafungin to be dosed once weekly and enable higher amounts of the drug to get into the bloodstream faster, which in turn leads to more rapid clearance of Candida from the blood than standard echinocandins. This was corroborated in both the STRIVE and ReSTORE clinical trials.
Smriti: What are your plans for the approval of Rezafungin?
Jeff Stein: In July, we announced that we submitted an NDA to the FDA for rezafungin for the treatment of candidemia and invasive candidiasis. The NDA submission was based on positive results from the global ReSTORE Phase 3 and STRIVE Phase 2 trials. We expect to be assigned a PDUFA target action date in the first quarter of 2023 if the NDA is accepted for review following application validation.
Additionally, we announced that we entered into a license agreement with Melinta Therapeutics under which Cidara granted Melinta an exclusive license to commercialize rezafungin in the U.S. in a deal valued at $460 million plus low double digits to mid-teens royalties on net sales.
We are currently assessing the efficacy of rezafungin for the prevention of invasive fungal disease through our ongoing Phase 3 ReSPECT clinical trial in patients who are undergoing allogeneic blood and marrow transplantation.
About the Author:
Dr. Stein is the President, CEO, and Director at Cidara Therapeutics. Dr. Stein holds a B.S. in marine biology and an M.S. in Biology from California State University—Long Beach and a Ph.D. in Biochemistry and Molecular Biology from the University of California, San Diego. Dr. Stein conducted his postdoctoral research as an Alexander Hollaender Distinguished Postdoctoral Fellow at the California Institute of Technology. He has also served as a Principal Scientist with Diversa Corporation and the Agouron Institute.
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