Rezafungin

Rezafungin

CAS 1396640-59-7

WeightAverage: 1226.411
Monoisotopic: 1225.602719729

Chemical FormulaC₆₃H₈₅N₈O₁₇

FDA APPROVED 3/22/2023, Rezzayo, To treat candidemia and invasive candidiasis
Drug Trials Snapshot

2-[[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-6-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-11,20,25-trihydroxy-3,15-bis[(1R)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-18-[[4-[4-(4-pentoxyphenyl)phenyl]benzoyl]amino]-1,4,7,13,16,22-hexazatricyclo[22.3.0.0^9,13]heptacosan-21-yl]oxy]ethyl-trimethylazanium

• Rezafungin ion
• Rezafungin cation
• CD-101
• SP-3025
• G013B5478J

Rezafungin, sold under the brand name Rezzayo (by Melinta Therapeutics), is a medication used for the treatment of invasive candidiasis.^[2] It is an echinocandin antifungal^[1][4] that acts as a fungal β-glucan synthase inhibitor.^[5]

Rezafungin was approved for medical use in the United States in March 2023,^[1][6][5] and in the European Union in December 2023.^[2][3]

CAS No. : 1631754-41-0

Rezafungin acetate  (Synonyms: Biafungin acetate; CD101 acetate; SP-3025 acetate)

Rezafungin acetate (Biafungin acetate) is a next-generation, broad-spectrum, and long-lasting echinocandin. Rezafungin acetate shows potent antifungal activity against Candida spp., Aspergillus spp., and Pneumocystis spp..

YN

https://doi.org/10.1021/acs.jmedchem.4c02079
J. Med. Chem. 2025, 68, 2147−2182

Rezafungin (Rezzayo). Rezafungin (2) is a secondgeneration echinocandin that was discovered by Seachaid
Pharmaceuticals and developed by Cidera Therapeutics. The
once weekly intravenously administered drug is used to treat
candidemia and invasive candidiasis and to prevent invasive
fungal diseases in blood and bone marrow transplant patients.23
Rezafungin was designed to improve the pharmacokinetic
properties of the USFDA-approved first-generation echinocandins anidulafungin, caspofungin, and micafungin, enabling less
frequent dosing. Mechanistically, echinocandins exert their
antifungal activity by inhibiting β-(1→3)-glucan synthase, a
transmembrane protein complex essential for the synthesis of an
important polysaccharide component of the fungal cell wall.
This noncompetitive inhibition destabilizes the cell wall, leading
to osmotic imbalance and fungal cell death.24 Rezafungin was
approved by the USFDA in March 2023 for use in patients 18
years and older.25
An elegant semisynthesis of rezafungin from anidulafungin
(2.1) was reported by Cidera Therapeutics that circumvented

chemical instability including potential racemization of the
parent compound (Scheme 3).26,27 The semisynthetic sequence26 begins with boronate formation between the 1,2-diol
of 2.1 and 3,4-dimethoxyphenylborane (2.2) utilizing azeotropic distillation, maintaining a constant volume of THF.
Addition of a solution of choline chloride, TFA, and TFAA in
MeCN to the slurry of boronate ester 2.3 gave the choline ether.
Selective ether formation at the hemiaminal hydroxyl group
occurred due to its increased reactivity compared to the other
free hydroxyls in the compound.27 The specific boronate ester
used in this sequence was found to be beneficial at minimizing
the amount of a diastereomer impurity (at the hemiaminal)
formed in the choline conjugation, though the authors of the
patent shared that this was unexpected given the remote boronic
acid from the hemiaminal that participated in conjugation. A
95:5 α:β selectivity of the conjugation was achieved under acidic
conditions, and preferential crystallization of the α-isomer while
maintaining solution equilibrium enabled control of the βisomer to less than 2.0%. Work up of the reaction using
ammonium acetate and ammonium hydroxide provided crude
rezafungin. Ion exchange chromatography was used to remove3,4-dimethyoxyphenyl boronic acid, eluting with ammonium
acetate to afford rezafungin (2). Using this synthetic sequence, a
purity of 98.49% was reported with only minor amounts of
racemization observed (0.77% undesired diastereomer and
0.51% unwanted epimer at the benzylic center).

(24) Denning, D. W. Echinocandins: a new class of antifungal. J.
Antimicrob. Chemother. 2002, 49, 889−891.
(25) Cidara Therapeutics and Melinta Therapeutics announce FDA
approval of RezzayoTM (Rezafungin for injection) for the treatment of
candidemia and invasive candidiasis. Cidera Therapeutics, March 22,

2023. https://www.cidara.com/news/cidara-therapeutics-andmelinta-therapeutics-announce-fda-approval-of-rezzayo-rezafunginfor-injection-for-the-treatment-of-candidemia-and-invasivecandidiasis/ (accessed February 2024).
      (26) Cidara Therapeutics. Synthesis of echinocandin antifungal agent.
      WO 2019241626 A1, 2019.
      (27) Jamison, J. A.; LaGrandeur, L. M.; Rodriguez, M. J.; Turner, W.
      W.; Zeckner, D. J. The synthesis and antifungal activity of nitrogen
      containing hemiaminal ethers of LY303366. J. Antibiot. (Tokyo) 1998,
      51, 239−42

.

SYN

Hughes, D., et al. (2022). Synthesis of echinocandin antifungal agent. (U.S. Patent No. 11,524,980 B2). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/34/d5/c2/1a8cdcfb3fe3db/US11524980.pdf

https://patentscope.wipo.int/search/en/detail.jsf?docId=US327113930&_cid=P11-MAORN7-73998-1

Example 9. Synthesis of Compound 1 from the 3,4-dimethoxyphenylboronate Ester of Anidulafungin—Coupling in the Presence of TFAA

Tetrahydrofuran (700 mL) and anidulafungin (108.44 g) were charged to a 1 L reactor. 3,4-Dimethoxyphenylboronic acid (21.0 g) was then charged and the mixture was stirred at 18-22° C. The reaction mixture was azeodried by distillation of tetrahydrofuran and simultaneous addition of fresh tetrahydrofuran (7.0 L). A constant volume solvent swap to acetonitrile was carried out by addition of acetonitrile (2.1 L) and simultaneous vacuum distillation. After complete turnover to acetonitrile, further distillation was carried out to reduce the volume to 420 mL.

In a separate vessel, the following were combined with stirring: choline chloride (172 g), acetonitrile (217 mL), trifluoroacetic acid (142 mL), and trifluoroacetic anhydride (8.6 mL). This solution was then added to the slurry containing the anidulafungin boronate ester and the resulting mixture was stirred at 15° C. for 8 hours. The reaction was quenched by charging cooled (T<10° C.) solution of ammonium acetate (4.2 M, 221 mL) to the reactor at once followed by addition of chilled (T<10° C.)) water (221 mL). Then, a cooled (10° C.) solution of ammonium hydroxide (9.0 M, 126.4 mL) was added. The final pH was adjusted to pH 4.0-4.6 by addition of ammonium hydroxide. The crude reaction mixture was diluted with water:acetonitrile (3:1, 6 L) and stored at −20° C.

Results: compound 1, 76.8%, compound 1 beta-diastereomer, 0.8%.

A reduction in the level of compound 1 beta-diastereomer has allowed for replacement of the HPLC purification with medium pressure chromatography (MPLC) using a coarser grade of C18 silica (25 to 50 μm). The 3,4-dimethoxyphenyl boronic acid can be separated by ion-exchange capture, eluting with 100 mM ammonium acetate (pH 4.5) in water:acetonitrile 50:50 v:v, which affords salt exchange from trifluoroacetate to acetate.

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US10702573	No	2020-07-07	2033-03-14
US9526835	No	2016-12-27	2033-03-14
US8722619	No	2014-05-13	2032-03-02
US11197909	No	2021-12-14	2038-07-14
US11654196	No	2023-05-23	2032-03-02
US11712459	No	2023-08-01	2037-03-15
US11819533	No	2023-11-21	2038-07-11

Medical uses

In the United States, rezafungin is indicated in adults who have limited or no alternative options for the treatment of candidemia and invasive candidiasis.^[1]

In the European Union, rezafungin is indicated for the treatment of invasive candidiasis in adults.^[2]

Rezafungin, while remaining a hydrophilic compound, exhibits a volume of distribution more than twice that of caspofungin.^[7] This pharmacokinetic property has supported its investigation for the treatment of deep-seated Candida infections, including osteomyelitis.^[8][9]

Legal status

Rezafungin was approved for medical use in the United States in March 2023,^[1][10][11] The FDA granted the application for rezafungin orphan drug, fast track, and priority review designations.^[12]

In October 2023, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Rezzayo, intended for the treatment of invasive candidiasis in adults.^[2] The applicant for this medicinal product is Mundipharma GmbH.^[2] Rezafungin was approved for medical use in the European Union in December 2023.^[3]

Rezafungin is a member of the family of echinocandins that inhibits 1,3-beta-D-glucan synthase. It is developed by Cidara Therapeutics and approved for the treatment of candidaemia and invasive candidiasis in patients aged >= 18 years who have limited or no alternative treatment options. It is an echinocandin, a quaternary ammonium ion, an antibiotic antifungal drug, an azamacrocycle, a homodetic cyclic peptide and an aromatic ether.

Brand names

Rezafungin is the international nonproprietary name.^[13]

Rezafungin is sold under the brand name Rezzayo.^[2]

References

1. ^ Jump up to:^{a b c d e} “Rezzayo- rezafungin injection, powder, lyophilized, for solution”. DailyMed. 8 June 2023. Retrieved 26 December 2023.
2. ^ Jump up to:^{a b c d e f g} “Rezzayo EPAR”. European Medicines Agency (EMA). 12 October 2023. Retrieved 27 December 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
3. ^ Jump up to:^a b c “Rezzayo Product information”. Union Register of medicinal products. 22 December 2023. Retrieved 26 December 2023.
4. ^ Zhao Y, Perlin DS (September 2020). “Review of the Novel Echinocandin Antifungal Rezafungin: Animal Studies and Clinical Data”. Journal of Fungi. 6 (4): 192. doi:10.3390/jof6040192. PMC 7712954. PMID 32998224.
5. ^ Jump up to:^a b Syed YY (June 2023). “Rezafungin: First Approval”. Drugs. 83 (9): 833–840. doi:10.1007/s40265-023-01891-8. PMID 37212966. S2CID 258831091.
6. ^ “Rezzayo approved by FDA amid rapid Candida auris spread”. thepharmaletter.com. 23 March 2023.
7. ^ Albanell-Fernández M (January 2025). “Echinocandins Pharmacokinetics: A Comprehensive Review of Micafungin, Caspofungin, Anidulafungin, and Rezafungin Population Pharmacokinetic Models and Dose Optimization in Special Populations”. Clinical Pharmacokinetics. 64 (1): 27–52. doi:10.1007/s40262-024-01461-5. PMC 11762474. PMID 39707078.
8. ^ Grasselli Kmet N, Luzzati R, Monticelli J, Babich S, Conti J, Bella SD (March 2025). “Salvage therapy of complicated Candida albicans spondylodiscitis with Rezafungin”. European Journal of Clinical Microbiology & Infectious Diseases. doi:10.1007/s10096-025-05117-5. PMID 40163284.
9. ^ Viceconte G, Buonomo AR, Esposito N, Cattaneo L, Somma T, Scirocco MM, et al. (April 2024). “Salvage Therapy with Rezafungin for Candida parapsilosis Spondylodiscitis: A Case Report from Expanded Access Program”. Microorganisms. 12 (5): 903. doi:10.3390/microorganisms12050903. PMC 11123963. PMID 38792732.
10. ^ “Novel Drug Approvals for 2023”. U.S. Food and Drug Administration (FDA). 22 December 2023. Retrieved 27 December 2023.
11. ^ “Drug Approval Package: Rezzayo”. U.S. Food and Drug Administration (FDA). 18 April 2023. Retrieved 27 December 2023.
12. ^ New Drug Therapy Approvals 2023 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2024. Archived from the original on 10 January 2024. Retrieved 9 January 2024.
13. ^ World Health Organization (2018). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 79”. WHO Drug Information. 32 (1). hdl:10665/330941.

External links

• “Rezafungin Injection”. U.S. Food and Drug Administration. 18 April 2023.

Clinical data
Trade names	Rezzayo
Other names	Biafungin; CD101
AHFS/Drugs.com	Monograph
MedlinePlus	a623021
License data	US DailyMed: Rezafungin
Routes of administration	Intravenous
Drug class	Antifungal
ATC code	J02AX08 (WHO)
Legal status
Legal status	US: ℞-only[1]EU: Rx-only[2][3]
Pharmacokinetic data
Excretion	Feces
Identifiers
CAS Number	1396640-59-7
PubChem CID	78318119
DrugBank	DB16310
UNII	G013B5478J
KEGG	D11197
ChEBI	CHEBI:229680
Chemical and physical data
Formula	C63H85N8O17+
Molar mass	1226.412 g·mol−1

1. Lamoth F: Novel Therapeutic Approaches to Invasive Candidiasis: Considerations for the Clinician. Infect Drug Resist. 2023 Feb 22;16:1087-1097. doi: 10.2147/IDR.S375625. eCollection 2023. [Article]
2. Miesel L, Lin KY, Ong V: Rezafungin treatment in mouse models of invasive candidiasis and aspergillosis: Insights on the PK/PD pharmacometrics of rezafungin efficacy. Pharmacol Res Perspect. 2019 Nov 20;7(6):e00546. doi: 10.1002/prp2.546. eCollection 2019 Dec. [Article]
3. Thompson GR 3rd, Soriano A, Cornely OA, Kullberg BJ, Kollef M, Vazquez J, Honore PM, Bassetti M, Pullman J, Chayakulkeeree M, Poromanski I, Dignani C, Das AF, Sandison T, Pappas PG: Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial. Lancet. 2023 Jan 7;401(10370):49-59. doi: 10.1016/S0140-6736(22)02324-8. Epub 2022 Nov 25. [Article]
4. Ong V, Wills S, Watson D, Sandison T, Flanagan S: Metabolism, Excretion, and Mass Balance of [(14)C]-Rezafungin in Animals and Humans. Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0139021. doi: 10.1128/AAC.01390-21. Epub 2021 Oct 18. [Article]
5. FDA Approved Drug Products: REZZAYO (rezafungin) injection for intravenous use (March 2023) [Link]
6. Globe News Wire: Cidara Therapeutics and Melinta Therapeutics Announce FDA Approval of REZZAYO (rezafungin for injection) for the Treatment of Candidemia and Invasive Candidiasis [Link]
7. EMA Summary of Product Characteristics: REZZAYO (rezafungin) solution for infusion [Link]

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