Phase 2 EL219 Versus Liposomal Amphotericin B or Voriconazole for Early Antifungal Therapy

Summary

The purpose of this study is to determine if EL219 is safe and effective compared to liposomal amphotericin B (LAmB) or voricanozole for early treatment of invasive mould infections

Timeline

Start

2026-02-13

Primary completion

2026-12

Completion

2026-12

Publications

• Background Adler-Moore J, Lewis RE, Bruggemann RJM, Rijnders BJA, Groll AH, Walsh TJ. Preclinical Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Antifungal Activity of Liposomal Amphotericin B. Clin Infect Dis. 2019 May 2;68(Suppl 4):S244-S259. doi: 10.1093/cid/ciz064.
• Background AmBisome® (amphotericin B) liposome for injection [Prescribing Information]. Foster City, CA: Gilead Sciences, Inc.; 2022.
• Background AmBisome Liposomal 50 mg Powder for dispersion for infusion [Summary of Product Characteristics]. Foster City, CA: Gilead Sciences, Inc.; May 2024.
• Background Anderson TM, Clay MC, Cioffi AG, Diaz KA, Hisao GS, Tuttle MD, Nieuwkoop AJ, Comellas G, Maryum N, Wang S, Uno BE, Wildeman EL, Gonen T, Rienstra CM, Burke MD. Amphotericin forms an extramembranous and fungicidal sterol sponge. Nat Chem Biol. 2014 May;10(5):400-6. doi: 10.1038/nchembio.1496. Epub 2014 Mar 30.
• Background Bowden R, Chandrasekar P, White MH, Li X, Pietrelli L, Gurwith M, van Burik JA, Laverdiere M, Safrin S, Wingard JR. A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis in immunocompromised patients. Clin Infect Dis. 2002 Aug 15;35(4):359-66. doi: 10.1086/341401. Epub 2002 Jul 25.
• Background Burke MD, He X, Cook C, Petrov GA, Long S, Coffin MD. Stability enhancement of drug layered pellets in a fixed dose combination tablet. AAPS PharmSciTech. 2013 Mar;14(1):312-20. doi: 10.1208/s12249-012-9911-3. Epub 2013 Jan 15.
• Background Chamilos G, Luna M, Lewis RE, Chemaly R, Raad II, Kontoyiannis DP. Effects of liposomal amphotericin B versus an amphotericin B lipid complex on liver histopathology in patients with hematologic malignancies and invasive fungal infections: a retrospective, nonrandomized autopsy study. Clin Ther. 2007 Sep;29(9):1980-6. doi: 10.1016/j.clinthera.2007.09.016.
• Background Cornely OA, Maertens J, Bresnik M, Ebrahimi R, Dellow E, Herbrecht R, Donnelly JP. Efficacy outcomes in a randomised trial of liposomal amphotericin B based on revised EORTC/MSG 2008 definitions of invasive mould disease. Mycoses. 2011 Sep;54(5):e449-55. doi: 10.1111/j.1439-0507.2010.01947.x. Epub 2010 Oct 11.
• Background Cornely OA, Maertens J, Bresnik M, Ebrahimi R, Ullmann AJ, Bouza E, Heussel CP, Lortholary O, Rieger C, Boehme A, Aoun M, Horst HA, Thiebaut A, Ruhnke M, Reichert D, Vianelli N, Krause SW, Olavarria E, Herbrecht R; AmBiLoad Trial Study Group. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis. 2007 May 15;44(10):1289-97. doi: 10.1086/514341. Epub 2007 Apr 9.
• Background Davis SA, Vincent BM, Endo MM, Whitesell L, Marchillo K, Andes DR, Lindquist S, Burke MD. Nontoxic antimicrobials that evade drug resistance. Nat Chem Biol. 2015 Jul;11(7):481-7. doi: 10.1038/nchembio.1821. Epub 2015 Jun 1.
• Background Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, Clancy CJ, Wingard JR, Lockhart SR, Groll AH, Sorrell TC, Bassetti M, Akan H, Alexander BD, Andes D, Azoulay E, Bialek R, Bradsher RW, Bretagne S, Calandra T, Caliendo AM, Castagnola E, Cruciani M, Cuenca-Estrella M, Decker CF, Desai SR, Fisher B, Harrison T, Heussel CP, Jensen HE, Kibbler CC, Kontoyiannis DP, Kullberg BJ, Lagrou K, Lamoth F, Lehrnbecher T, Loeffler J, Lortholary O, Maertens J, Marchetti O, Marr KA, Masur H, Meis JF, Morrisey CO, Nucci M, Ostrosky-Zeichner L, Pagano L, Patterson TF, Perfect JR, Racil Z, Roilides E, Ruhnke M, Prokop CS, Shoham S, Slavin MA, Stevens DA, Thompson GR, Vazquez JA, Viscoli C, Walsh TJ, Warris A, Wheat LJ, White PL, Zaoutis TE, Pappas PG. Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis. 2020 Sep 12;71(6):1367-1376. doi: 10.1093/cid/ciz1008.
• Background Empiric antifungal therapy in febrile granulocytopenic patients. EORTC International Antimicrobial Therapy Cooperative Group. Am J Med. 1989 Jun;86(6 Pt 1):668-72. doi: 10.1016/0002-9343(89)90441-5.
• Background European Medicines Agency. Good practice guide on recording, coding, reporting, and assessment of medication errors (EMA/762563/2014). 2015.
• Background Clinical Trials Regulation (EU) No. 536/2014 of the European Parliament and the Council of 16 April 2014 on Clinical Trials on Medicinal Products for Human Use, and Repealing Directive 2001/20/EC Text with EEA relevance - Annex III.
• Background Fiorcari S, Maffei R, Vallerini D, Scarfo L, Barozzi P, Maccaferri M, Potenza L, Ghia P, Luppi M, Marasca R. BTK Inhibition Impairs the Innate Response Against Fungal Infection in Patients With Chronic Lymphocytic Leukemia. Front Immunol. 2020 Aug 28;11:2158. doi: 10.3389/fimmu.2020.02158. eCollection 2020.
• Background Fleming RV, Kantarjian HM, Husni R, Rolston K, Lim J, Raad I, Pierce S, Cortes J, Estey E. Comparison of amphotericin B lipid complex (ABLC) vs. ambisome in the treatment of suspected or documented fungal infections in patients with leukemia. Leuk Lymphoma. 2001 Feb;40(5-6):511-20. doi: 10.3109/10428190109097650.
• Background Garbuzenko O, Zalipsky S, Qazen M, Barenholz Y. Electrostatics of PEGylated micelles and liposomes containing charged and neutral lipopolymers. Langmuir. 2005 Mar 15;21(6):2560-8. doi: 10.1021/la0479105.
• Background Gillis EP, Burke MD. A simple and modular strategy for small molecule synthesis: iterative Suzuki-Miyaura coupling of B-protected haloboronic acid building blocks. J Am Chem Soc. 2007 May 30;129(21):6716-7. doi: 10.1021/ja0716204. Epub 2007 May 9. No abstract available.
• Background Girmenia C, Aversa F, Busca A, Candoni A, Cesaro S, Luppi M, Pagano L, Rossi G, Venditti A, Nosari AM; Sorveglianza Epidemiologica delle Infezioni Fungine nelle Emopatie Maligne; Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer; Gruppo Italiano Malattie Ematologiche dell'Adulto; Associazione Italiana Ematologia ed Oncologia Pediatrica; Gruppo Italiano Trapianto di Midollo Osseo. A hematology consensus agreement on antifungal strategies for neutropenic patients with hematological malignancies and stem cell transplant recipients. Gruppo Italiano Malattie Ematologiche dell'Adulto, Gruppo Italiano Trapianto di Midollo Osseo, Associazione Italiana Ematologia ed Oncologia Pediatrica, Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer and Sorveglianza Epidemiologica delle Infezioni Fungine nelle Emopatie Maligne. Hematol Oncol. 2013 Sep;31(3):117-26. doi: 10.1002/hon.2031. Epub 2012 Oct 5.
• Background Gray KC, Palacios DS, Dailey I, Endo MM, Uno BE, Wilcock BC, Burke MD. Amphotericin primarily kills yeast by simply binding ergosterol. Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2234-9. doi: 10.1073/pnas.1117280109. Epub 2012 Jan 17.
• Background Hong Y, Ramzan I, McLachlan AJ. Hepatobiliary disposition of liposomal amphotericin B in the isolated perfused rat liver. J Pharm Sci. 2005 Jan;94(1):169-76. doi: 10.1002/jps.20239.
• Background Jarvis JN, Lawrence DS, Meya DB, Kagimu E, Kasibante J, Mpoza E, Rutakingirwa MK, Ssebambulidde K, Tugume L, Rhein J, Boulware DR, Mwandumba HC, Moyo M, Mzinganjira H, Kanyama C, Hosseinipour MC, Chawinga C, Meintjes G, Schutz C, Comins K, Singh A, Muzoora C, Jjunju S, Nuwagira E, Mosepele M, Leeme T, Siamisang K, Ndhlovu CE, Hlupeni A, Mutata C, van Widenfelt E, Chen T, Wang D, Hope W, Boyer-Chammard T, Loyse A, Molloy SF, Youssouf N, Lortholary O, Lalloo DG, Jaffar S, Harrison TS; Ambition Study Group. Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis. N Engl J Med. 2022 Mar 24;386(12):1109-1120. doi: 10.1056/NEJMoa2111904.
• Background Lepak AJ, VanScoy B, Rubino C, Ambrose PG, Andes DR. In vivo pharmacodynamic characterization of a next-generation polyene, SF001, in the invasive pulmonary aspergillosis mouse model. Antimicrob Agents Chemother. 2024 Mar 6;68(3):e0163123. doi: 10.1128/aac.01631-23. Epub 2024 Feb 6.
• Background Lewandowska A, Soutar CP, Greenwood AI, Nimerovsky E, De Lio AM, Holler JT, Hisao GS, Khandelwal A, Zhang J, SantaMaria AM, Schwieters CD, Pogorelov TV, Burke MD, Rienstra CM. Fungicidal amphotericin B sponges are assemblies of staggered asymmetric homodimers encasing large void volumes. Nat Struct Mol Biol. 2021 Dec;28(12):972-981. doi: 10.1038/s41594-021-00685-4. Epub 2021 Dec 9.
• Background Miceli MH, Chandrasekar P. Safety and efficacy of liposomal amphotericin B for the empirical therapy of invasive fungal infections in immunocompromised patients. Infect Drug Resist. 2012;5:9-16. doi: 10.2147/IDR.S22587. Epub 2012 Jan 11.
• Background Mohamed M, Abu Lila AS, Shimizu T, Alaaeldin E, Hussein A, Sarhan HA, Szebeni J, Ishida T. PEGylated liposomes: immunological responses. Sci Technol Adv Mater. 2019 Jun 26;20(1):710-724. doi: 10.1080/14686996.2019.1627174. eCollection 2019.
• Background Morelle C, Mukherjee A, Zhang J, Fani F, Khandelwal A, Gingras H, Trottier J, Barbier O, Leprohon P, Burke MD, Ouellette M. Well-Tolerated Amphotericin B Derivatives That Effectively Treat Visceral Leishmaniasis. ACS Infect Dis. 2021 Aug 13;7(8):2472-2482. doi: 10.1021/acsinfecdis.1c00245. Epub 2021 Jul 20.
• Background Nasillo V, Lagreca I, Vallerini D, Barozzi P, Riva G, Maccaferri M, Paolini A, Forghieri F, Fiorcari S, Maffei R, Martinelli S, Atene CG, Castelli I, Marasca R, Potenza L, Comoli P, Manfredini R, Tagliafico E, Trenti T, Luppi M. BTK Inhibitors Impair Platelet-Mediated Antifungal Activity. Cells. 2022 Mar 16;11(6):1003. doi: 10.3390/cells11061003.
• Background Palacios DS, Dailey I, Siebert DM, Wilcock BC, Burke MD. Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities. Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):6733-8. doi: 10.1073/pnas.1015023108. Epub 2011 Feb 28.
• Background Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Nguyen MH, Segal BH, Steinbach WJ, Stevens DA, Walsh TJ, Wingard JR, Young JA, Bennett JE. Executive Summary: Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Aug 15;63(4):433-42. doi: 10.1093/cid/ciw444.
• Background Scardina T, Fawcett AJ, Patel SJ. Amphotericin-Associated Infusion-Related Reactions: A Narrative Review of Pre-Medications. Clin Ther. 2021 Oct;43(10):1689-1704. doi: 10.1016/j.clinthera.2021.09.011. Epub 2021 Oct 23.
• Background Segal BH, Almyroudis NG, Battiwalla M, Herbrecht R, Perfect JR, Walsh TJ, Wingard JR. Prevention and early treatment of invasive fungal infection in patients with cancer and neutropenia and in stem cell transplant recipients in the era of newer broad-spectrum antifungal agents and diagnostic adjuncts. Clin Infect Dis. 2007 Feb 1;44(3):402-9. doi: 10.1086/510677. Epub 2007 Jan 2.
• Background Stone NR, Bicanic T, Salim R, Hope W. Liposomal Amphotericin B (AmBisome((R))): A Review of the Pharmacokinetics, Pharmacodynamics, Clinical Experience and Future Directions. Drugs. 2016 Mar;76(4):485-500. doi: 10.1007/s40265-016-0538-7.
• Background Stott KE, Moyo M, Ahmadu A, Kajanga C, Gondwe E, Chimang'anga W, Chasweka M, Leeme TB, Molefi M, Chofle A, Bidwell G, Changalucha J, Unsworth J, Jimenez-Valverde A, Lawrence DS, Mwandumba HC, Lalloo DG, Harrison TS, Jarvis JN, Hope W, Martson AG. Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis. J Antimicrob Chemother. 2022 Dec 23;78(1):276-283. doi: 10.1093/jac/dkac389.
• Background Szebeni J, Simberg D, Gonzalez-Fernandez A, Barenholz Y, Dobrovolskaia MA. Roadmap and strategy for overcoming infusion reactions to nanomedicines. Nat Nanotechnol. 2018 Dec;13(12):1100-1108. doi: 10.1038/s41565-018-0273-1. Epub 2018 Oct 22.
• Background VFEND® (voriconazole) tablets, for oral use; and (voriconazole) for injection, for intravenous use [Prescribing Information]. New York, NY: Roerig Division of Pfizer Inc.; 2024.
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• Background Vukovic L, Khatib FA, Drake SP, Madriaga A, Brandenburg KS, Kral P, Onyuksel H. Structure and dynamics of highly PEG-ylated sterically stabilized micelles in aqueous media. J Am Chem Soc. 2011 Aug 31;133(34):13481-8. doi: 10.1021/ja204043b. Epub 2011 Aug 9.
• Background Wilcock BC, Endo MM, Uno BE, Burke MD. C2'-OH of amphotericin B plays an important role in binding the primary sterol of human cells but not yeast cells. J Am Chem Soc. 2013 Jun 12;135(23):8488-91. doi: 10.1021/ja403255s. Epub 2013 Jun 3.
• Background Woerly EM, Roy J, Burke MD. Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction. Nat Chem. 2014 Jun;6(6):484-91. doi: 10.1038/nchem.1947.
• Background Yang YL, Xiang ZJ, Yang JH, Wang WJ, Xu ZC, Xiang RL. Adverse Effects Associated With Currently Commonly Used Antifungal Agents: A Network Meta-Analysis and Systematic Review. Front Pharmacol. 2021 Oct 29;12:697330. doi: 10.3389/fphar.2021.697330. eCollection 2021.
• Background Yoshida M, Tamura K, Masaoka T, Nakajo E. A real-world prospective observational study on the efficacy and safety of liposomal amphotericin B in 426 patients with persistent neutropenia and fever. J Infect Chemother. 2021 Feb;27(2):277-283. doi: 10.1016/j.jiac.2020.10.005. Epub 2020 Oct 24.
• Background Zarakas MA, Desai JV, Chamilos G, Lionakis MS. Fungal Infections with Ibrutinib and Other Small-Molecule Kinase Inhibitors. Curr Fungal Infect Rep. 2019 Sep;13(3):86-98. doi: 10.1007/s12281-019-00343-9. Epub 2019 Jul 5.
• Background Zhang Y, Holland E, Dinh A, Au D, Sun L. Bombesin-drug conjugates in targeted therapy for small cell lung cancer. Am J Cancer Res. 2022 Mar 15;12(3):927-937. eCollection 2022.
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• Background Ambisome 1997. FDA Center for Drug Evaluation and Research Approval Package: Pharmacology Review. New drug application 50-740 AmBisome. FDA, Washington DC.
• Background Bekersky I, Boswell GW, Hiles R, Fielding RM, Buell D, Walsh TJ. Safety and toxicokinetics of intravenous liposomal amphotericin B (AmBisome) in beagle dogs. Pharm Res. 1999 Nov;16(11):1694-701. doi: 10.1023/a:1018997730462.
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• Background Dezsi L, Meszaros T, Orfi E, Fulop TG, Hennies M, Rosivall L, Hamar P, Szebeni J, Szenasi G. Complement Activation-Related Pathophysiological Changes in Anesthetized Rats: Activator-Dependent Variations of Symptoms and Mediators of Pseudoallergy. Molecules. 2019 Sep 9;24(18):3283. doi: 10.3390/molecules24183283.
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• Background Neoral (cyclosporine) soft gelatin capsules [Summary of Product Characteristics]. London, UK: Novartis Pharmaceuticals UK Ltd; 2023.
• Background PROGRAF® (tacrolimus) capsules, for oral use [Prescribing Information]. Northbrook, IL: Astella Pharma US, Inc.; 2022.
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• Background Szebeni J, Muggia F, Gabizon A, Barenholz Y. Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and prevention. Adv Drug Deliv Rev. 2011 Sep 16;63(12):1020-30. doi: 10.1016/j.addr.2011.06.017. Epub 2011 Jul 14.
• Background Tissot F, Agrawal S, Pagano L, Petrikkos G, Groll AH, Skiada A, Lass-Florl C, Calandra T, Viscoli C, Herbrecht R. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica. 2017 Mar;102(3):433-444. doi: 10.3324/haematol.2016.152900. Epub 2016 Dec 23.

Drugs

Indications