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FUSIDIC ACID) AS CHRONIC ANTIBIOTIC SUPPRESSIVE THERAPY in PATIENTS with STAPHYLOCOCCAL BONE OR JOINT INFECTIONS Idweek 2018 Amanda J

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FUSIDIC ACID) AS CHRONIC ANTIBIOTIC SUPPRESSIVE THERAPY in PATIENTS with STAPHYLOCOCCAL BONE OR JOINT INFECTIONS Idweek 2018 Amanda J P290 SAFETY AND EFFECTIVENESS OF ORAL SODIUM FUSIDATE (FUSIDIC ACID) AS CHRONIC ANTIBIOTIC SUPPRESSIVE THERAPY IN PATIENTS WITH STAPHYLOCOCCAL BONE OR JOINT INFECTIONS IDWeek 2018 Amanda J. Sheets, PhD1; Donald R. Graham, MD2; Rabih O. Darouiche, MD3; Andrew Strayer, PharmD1 San Francisco, CA, USA 1-844-MED-MLNT October 4, 2018 1Melinta Therapeutics, Inc., Chapel Hill, NC, 2Springfield Clinic, Springfield, IL, 3Michael E. DeBakey VA Medical Center, Houston, TX [email protected] ABSTRACT RESULTS Background: Fusidic acid (FA) is an anti-staphylococcal agent used to treat chronic bone and joint infections (BJI) due to the availability of an oral Baseline Post-BL Companion Subject Age Inclusionary, Co-infecting Outcome at formulation and its MRSA activity. Though used widely throughout the world for decades, FA is not approved in the US. Sex Infection FA MIC FA MIC Antibiotic Reason for Failure/Indeterminate Response Duration of Study Drug Exposure (as of the Interim Analysis) ID (y) Pathogen(s) Month 6 visit Methods: To evaluate the safety and effectiveness of FA as chronic suppressive therapy in patients with staphylococcal BJI, we enrolled 30 patients in (µg/mL) (µg/mL) (1-2 weeks) a prospective, single-arm, multi-center study in the US. Eligible patients had refractory infections that could not be managed surgically and/or had not 1 71 M Osteomyelitis MRSA -- Vancomycin Success responded to previous antibiotic treatment. In Part A of the study, all patients received 6 months of oral FA. In the first 1-2 weeks, patients could receive 2 82 M PJI/ knee CoNS, Corynebacterium sp. -- Doxycycline Success a companion antibiotic. Clinical success was based on lack of need for surgery or additional antibiotics. After all patients completed Part A of the study, an interim analysis was performed. In Part B of the study (ongoing), patients who completed Part A and require continued suppressive therapy may 3 59 F PJI/ knee MSSA 0.25 Cephalexin Success continue to receive FA for a total of 24 months. 4 53 M PJI/ knee MRSA 0.12 ND Daptomycin Success M Results: Most patients (83%) had orthopedic hardware infections. Therapy was considered successful at the 6-month visit in 18 patients (60%). 5 62 F PJI/ knee MRSE 8 Doxycycline Success Microbiological persistence was observed in 8 patients, with 3 cases of decreasing FA susceptibility (including 1 case of resistance). Among 29 patients 6 87 M PJI/ hip CoNS -- Doxycycline Success who experienced a treatment-emergent adverse event (TEAE), the most frequently reported events were: UTI (n=9), peripheral edema/swelling (n=8), nausea/dyspepsia (n=7). Seven patients experienced TEAEs related to study drug; mild gastrointestinal disorders were most common. Two treatment- 7 52 M Hardware/ knee MSSA 0.25 Linezolid Success related events (unrelated to therapeutic failure) led to discontinuation of study drug. 8 74 F PJI/ knee CoNS -- TMP-SMX Success Conclusion: Patients with refractory BJI have few treatment options. In our study, 60% of infections were effectively suppressed for 6 months with FA 9 62 F PJI/ knee MRSA -- Tedizolid Success treatment. The frequency of TEAEs was high, though not unexpected in this population with many chronic diseases. FA was well-tolerated with few 10 67 M PJI/ hip MSSA 0.25 0.5 Daptomycin Success patients experiencing treatment-related AEs leading to study drug discontinuation. FA administered chronically as monotherapy may lead to decreasing M susceptibility and treatment failure in some patients; thus, combination therapy may be warranted for this indication. 11 64 F PJI/ spine MSSA -- Cephalexin Failure Failure to meet success criteria 12 35 M Osteomyelitis MSSA -- Vancomycin Success INTRODUCTION 13 50 F Hardware/ elbow CoNS, Corynebacterium sp. -- Doxycycline Success 14 46 M Osteomyelitis MSSA -- Cephalexin Failure Failure to meet success criteria Sodium Fusidate (active as fusidic acid [FA]) 15 66 M PJI/ shoulder MRSE, Cutibacterium acnes 0.25 0.25 Minocycline Failure Failure to meet success criteria M 1 • Only marketed member of the fusidane class of antibiotics, initially identified from Fusidium coccineum in 1960 . Inhibits protein synthesis and bacterial growth R by binding to the ribosomal translocase, elongation factor G (EF-G), preventing dissociation of the EF-G-DP complex from the ribosome2. 16 53 F Hardware/ spine MRSA -- 4 (FA ) Doxycycline Success M • Oral and topical FA have been used widely to treat staphylococcal infections due to its potent MRSA activity. Not available in the US. 17 49 M Hardware/ spine MSSA -- Levofloxacin Success • A novel oral front-loading dose regimen is based on extensive PK/PD modeling, designed to optimize efficacy and spectrum while preventing resistance. 18 58 M PJI/ ankle MSSA, Corynebacterium sp. 0.25 Cefazolin Success • Safety/Efficacy of the loading dose regimen was demonstrated in a Phase 3 registrational trial in patients with acute bacterial skin and skin structure infections 19 66 M Septic arthritis/ knee MSSA 0.25 Cephalexin Success 3 (ABSSSI) completed in 2017. FA demonstrated non-inferiority to linezolid for the primary endpoint of early clinical response at 48-72 hours . 20 51 F Hardware/ ankle MSSA 0.12 Vancomycin Success BJI: Oral FA is commonly used outside the US to treat bone and prosthetic joint infections, often in combination with rifampin (RIF); however, a FA/RIF 21 61 M PJI/ spine MSSA -- Cefazolin Success pharmacokinetic interaction reduces FA blood levels by 40-50%, which may negatively impact clinical outcomes4. LEGEND 22 53 M Osteomyelitis MRSA 0.25 ND Daptomycin Indeterminate Lost to follow up M ET Study Objective: The purpose of this study is to evaluate the safety and effectiveness of FA (front-loading dose regimen) as chronic suppressive Study drug exposure monotherapy in patients with refractory staphylococcal bone and joint infections (BJI). 23 61 F PJI/ hip MRSA -- TMP-SMX Failure AE (additional antibiotics required) ET R ET Observation for relapse References: 1) Godtfredsen et al. Fusidic acid: a new antibiotic. Nature. 1962; 193:987. 2) Chung et al. Purification and characterization of elongation factor G from bovine liver mitochondria. J Biol Chem 1990; 265:21000-21004. 3) Cardenas et al. Results of a 24 92 M PJI/ knee MRSA 0.06 32 (FA ) Doxycycline Failure Failure to meet success criteria M phase 3 trial comparing oral sodium fusidate (fusidic acid) versus oral linezolid for treatment of acute bacterial skin and skin structure infections (ABSSSI). Abstr. 2017 ASM Microbe, abstr LB21. 4) Pushkin et al. A randomized study evaluating oral fusidic acid (CEM-102) in combination with oral rifampin compared with standard-of-care antibiotics for treatment of prosthetic joint infections: a newly identified drug-drug interaction. Clin Infect Dis. 2016; 63:1599-1604. 25 64 M PJI/ knee CoNS, Streptococcus agalactiae -- 0.5 Cefazolin Failure Failure to meet success criteria, AE (additional antibiotics required) M ET Clinical Success 26 66 M PJI/ knee MSSA 0.12 0.5 Vancomycin Failure Failure to meet success criteria, AE (additional antibiotics required) M ET Clinical Failure METHODS 27 66 M PJI/ knee CoNS -- Cephalexin Failure Failure to meet success criteria ET Indeterminate 28 29 M PJI/ spine MRSA 0.12 Daptomycin Indeterminate Lost to follow up ET Enrollment Criteria: Staphylococcal BJI that could not be managed surgically and/or had not responded to previous antibiotic treatment. ET Early Termination 29 65 F PJI/ hip MRSA -- Vancomycin Indeterminate Lost to follow up ET FA Treatment Regimen: 1500 mg PO Q12h for 2 doses, then 600 mg by mouth Q12h thereafter, for 6 months (minimum); up to 24 months. M Positive Culture 30 51 M PJI/ knee MRSA -- Doxycycline Failure Failure to meet success criteria, AE (additional antibiotics required) ET Companion and Adjunctive Therapy: Companion antibiotics (IV or oral) were to be taken with FA for the first 1-2 weeks of the study. Selected by the Investigator; RIF was not allowed. Limited adjunctive antibiotic therapy was allowed for treatment of co-infections. Abbreviations: PJI, prosthetic joint infection, MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible S. aureus; MRSE, methicillin-resistant Staphylococcus epidermidis, CoNS, coagulase-negative staphylococci; Visit Month: M3 M6 M9 M12 M15 M18 M21 M24 MIC, minimum inhibitory concentration (inclusionary pathogen); Post-BL, post-baseline; ND, not done; FAR, fusidic acid resistant (MIC interpretation based on EUCAST breakpoints); TMP-SMX, trimethoprim/sulfamethoxazole; AE, adverse event. Primary Endpoint End of Study Fusidic Acid Most Common Events by Fusidic Acid Fusidic Acid Visit Schedule: Month 6 M24 Safety Outcomes TEAEs Related to Study Drug Enrollment M9 M12 M15 M18 M21 (N=30) Preferred Term (>2 patients) (N=30) (N=30) CONCLUSIONS Screening Study Part A (oral FA) Study Part B (continued suppressive FA monotherapy or observation) Any Treatment-Emergent Adverse Event (TEAE) 29 (97%) Any Adverse Event 29 (97%) Leading to study drug discontinuation 3 (10%) • Patients received 33-671 days of FA therapy (mean: 253 days) as of this interim analysis, Severe TEAE 10 (33%) Urinary tract infection 9 (30%) Staphylococcal infection (therapeutic failure) 1 (3%) and have since received up to 723 days FA (mean: 300 days) as of 01Sep2018. Primary Endpoint: Proportion of patients who meet all the criteria for clinical success at the 6-Month Visit. TEAE Related to Study Drug 7 (23%) Nausea 4 (13%) Abdominal pain upper/decreased appetite 1 (3%) • Oral FA treatment effectively suppressed 60%
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