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New treatment options for mycotic infections in the immunocompromised patient

New treatment options for mycotic infections in the immunocompromised patient. Małgorzata MIKULSKA, MD, PhD Associate Professor of Infectious Diseases University of Genoa, Department of Health Sciences Ospedale Policlinico San Martino Genoa, Italy.

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New treatment options for mycotic infections in the immunocompromised patient

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  1. New treatment options for mycotic infections in the immunocompromised patient Małgorzata MIKULSKA, MD, PhD Associate Professor of Infectious Diseases University of Genoa, Department of Health Sciences Ospedale Policlinico San Martino Genoa, Italy

  2. Available antifungalsDo we need others? 18 antifungalsintroduced, but… • Three mainclasses • Onlyazoles are oral • Onlyazoles are AI approved for prophylaxis • Lesstoxicoptions (echinocandins) suboptimal for aspergillosis • Azoleresistant aspergillosis > need for effective, lesstoxic and oraloptions

  3. New azoles – 1Triazoles • Ravuconazole • Phase 2 studystarted in 2004 - ”Ravuconazole in Preventing Fungal Infections in Patients Undergoing Allogeneic Stem Cell Transplantation” … • Discontinued for IFI in 2007, for Chagas in 2009 2. Albaconazole (oral) - now only studied for its use in treating superficial fungal infections (onychomycoses) 3. Isavuconazole

  4. Fewer side effects • Liver • Skin • Eyedisorders (hallucinations) 527 patients Primary endpoint: all-cause mortality day 42: 19% vs 20% Isavuconazole: loading dose ev 200mg tid for 2 days > 200mg/die ev or oral

  5. Rare fungi, including mucormycosis, recruited from 34 centres • Primary endpoint • independent data review committee-determined • overall response – i.e. complete or partial response (treatment success) by day 42 (6 weeks) • April 2008 - June 2013 • 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19–179, range 2–882) • Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analyzed for day-42 all cause mortality • 21 patients: 52% HM, 19% DM • 6 weeks response • 0% complete response • 4/37 (11%) had a partial response • 16 (43%) had stable IFD • 1 (3%) had IFD progression • 3 (8%) had missing assessments • 13 (35%) had died Day-42 crude all-cause mortality in 7/21 (33%) primary-treatment isavuconazole cases was similar to 13/33 (39%) amphotericin B-treated matchedcontrols (p=NS). FDA: approved for mucormycosis EMA: mucormycosisin patients for whom amphotericin B is inappropriate

  6. Isavuconazole versus Caspofungin in the Treatment of Candidemia and Other Invasive Candida Infections: The ACTIVE Trial Kullberg BJ, Viscoli C,. Pappas PG, et al. • Successful overall response at EOIVT (at least 10 days) was 60.3% of patients in the ISV arm, and 71.1% in the CASPO arm, adjusted difference [95%CI] -10.8 [-19.9, -1.8] • The secondary endpoints, all-cause mortality, and safety were similar between arms, while median time to clearance of the bloodstream was comparable in both groups

  7. Drug interactions Groll AH et al. ClinPharmacolDrugDev. 2016; Kim T et al. J ClinPharmTher. 2015

  8. Drug interactions

  9. Azoles and QT abnormalities • Voriconazole and posaconazole (and FQ and macrolides, and...) • Isavuconazole Keirns et al. 2017

  10. Isavuconazole levels in 19 patients JAC 2019 accepted

  11. New azoles – 2Tetrazole • Oteseconazole, also known as VT-1161 • Phase 2 in onychomycoses • Phase 2 in recurrent vulvovaginal candidiasis (RVVC) - REVIVE study by Sobet et al. IDSOG Annual Meeting: 0-7% vs 52% in placebo arm • Am J ObstetGynecol. 2018 • Mycovia Pharmaceuticals has commenced two Phase lll clinical trials called VIOLET to investigate the safety and efficacy of VT1161 for the treatment of patients with RVVC – 2018-2020 NCT03562156 • 150mg capsule once daily for 7 days, followed by once weekly for 11 weeks Undescribed resistance mechanisms of C. albicans to triazole- and tetrazole-based sterol demethylase inhibitors Nishimoto et al. AAC2018

  12. RESAFUNGIN Active against Candida, including C. auris in mouse models Active against Aspergillus, includingazole-R A. fumigatus isolates and crypticspecies Candidemia and invasive candidiasis • Phase 2 completed • Phase 3 initiated Sept 2018 400 mg/weekly Phase 1 planned for 2019

  13. CD101 Compared to Caspofungin Followed by Oral Step Down in Subjects With Candidemia and/or Invasive Candidiasis-Bridging Extension (STRIVE)CD101 IV 400 mg on Day 1 and Day 8, with an optional dose of 400 mg on Day 15 (for all subjects) Optional dose of 400 mg on Day 22 (only for subjects with IC), if needed.

  14. 1972 – first echinocandin discovered in PCP research

  15. Antifungalprophylaxis in allogeneic HSCT

  16. ReSPECT Trial RZF 400mg/200mg 2019

  17. SCY078 = Ibrexafungerp (Scynexis) • Novelclass - triterpenoids - structurally-distinct glucan synthase inhibitors • Active against Candida, Aspergillus, Pneumocystis • Including C. auris and echinocandin-resistant C. glabrata • Including azole-resistant strains of A. fumigatus • Oral and ev (liposomal) formulations • FDA Fast Track and Orphan Drug Designation

  18. SCY078 = IbrexafungerpRecent trials Oral SCY-078 vs Standard-of-Care Following IV Echinocandin in the Treatment of Invasive Candidiasis 22 patients Results 750mg/day GI AE Pappas et al. ECCMID 2017

  19. SCY078 = IbrexafungerpOngoing trials 1. VANISH A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Oral Ibrexafungerp (SCY-078) vs. Placebo in Subjects with Acute Vulvovaginal Candidiasis (outpatient) Started 2018 2. Open-Label Study to Evaluate the Efficacy and Safety of SCY-078 in Patients With Candidiasis Caused by Candida auris (CARES) First patientincluded 3. Open-Label Study to Evaluate Efficacy and Safety of SCY-078 in Patients With Refractory or Intolerant Fungal Diseases (FURI) • Tablets - loading dose of 750 mg BID on days 1 and 2 followed by 750 mg QD • Favorable Response in 20 patients 2019 ECCMID Ongoing 4. Study to Evaluate the Safety and Efficacy of the Combination Therapy of Ibrexafungerp (SCY-078) With Voriconazole in Patients With Invasive Pulmonary Aspergillosis (SCYNERGIA) Phase 2, primary objective safety, 60 patients expected Recruiting

  20. Amplyx Pharmaceuticals • Small molecule - enzymeinhibitor of Gwt1 (GPI-anchoredwall transfer protein 1 ) Inhibition of mannoprotein production >affectscellwallintegrity and biofilmformation • Broadspectrum • Activity: Candida, Aspergillus, Rhizopus, Fusarium, Scedosporium, Cryptococcus • Oral and IV formulations • In mouse modelsgoodpenetrationinto brain and eye • Goodtollerability and safety, also in AML patients Phase 2 recruiting An Open-Label Study to Evaluate the Efficacy and Safety of APX001 in Non Neutropenic Patients With Candidemia, With or Without Invasive Candidiasis, Inclusive of Patients With Suspected Resistance to Standard of Care Antifungal Treatment

  21. VL-2397 • A novel mechanism of action, with a potential to be complementary or synergistic with the existing classes of antifungals • Precise target inside the fungal cell remains uncertain but localizes within fungi such as A. fumigatus, as it is taken up by the specific siderophore iron transporter 1 (Sit1) • Rapid fungal cell kill activity demonstrated in preclinical models, which was faster than marketed antifungals • Activity against • Aspergillus (also azole-R) • Candida • Cryptococus • Trichosporon • Low propensity for P450 drug-drug interactions. Astellas ICAAC 2014

  22. Phase 2 study in invasive aspergillosis Opened 02/2018, expectedcompletion 12/2019 (NCT03327727) Discontinued in 2019 after 4 patients due to slow accrural Business decision

  23. F901318 (F2G Ltd., Eccles, UK) –lead compound of the orotomides • Olorofim (F901318) reversibly inhibits dihydroorotate dehydrogenase and interferes with pyrimidine biosynthesis (blocks hyphae growth) • Potent activity against A. fumigatus and A flavus, including triazole-resistant strains, Penicillium spp, Coccidiodes immitis, Histoplasma capsulatum, Blastomyces dermatitidis, Fusarium spp, Scedosporium prolificans • Oral • Active in mouse model in CNS coccidioidomycosis • Phase II study recruiting NCT03583164 - Evaluate F901318 Treatment of Invasive Fungal Infections in Patients Lacking Treatment Options (FORMULA-OLS) • Phase II study NCT03036046 - Safety and Pharmacokinetics of Oral F901318 (Fluconazole and Posaconazole) in AML Leukaemia (SAFEGUARDFP) discontinued

  24. Conclusions • Improved options available -isavuconazole • Interesting new entries, all in phase 2 or 3: • Echinocandin once weekly, in prophylaxis • New oral and iv glucan synthetase inhibitor • iberxafungerp • Three drug classes using novel sites of action • Active also against resistant strains

  25. Nucci M and Perfect JR. Clinical Infectious Diseases 2008

  26. Thank you for your attention

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