Lefamulin: a novel pleuromutilin antibiotic class George Dimopoulos MD, PhD, FCCP, FCCM, FECMM

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1 : a novel pleuromutilin antibiotic class George Dimopoulos MD, PhD, FCCP, FCCM, FECMM Department of Critical Care, University Hospital ATTIKON National and Kapodistrian University of Athens, Medical School gdimop@med.uoa.gr

2 Faculty disclosure ( )

3 Pleuromutilin Antibacterial Agents Pleuromutilin antibiotics are semisynthetic derivatives of pleuromutilin isolated from an edible mushroom OH O R O 14 H O Pleuromutilin R = OH Veterinary use: tiamulin and valnemulin Human use: retapamulin Pleurotus mutilus (Clitopilus scyphoides) Source: James Lindsey's Ecology of Commanster Site, 2006 Formulations in development 150 mg IV every 12 hours administered over 60 min 600 mg PO every 12 hours Demonstrated proof of concept in a phase 2 study of acute bacterial skin and skin structure infections (ABSSSI) was shown to be non-inferior to moxifloxacin in two phase 3, pivotal studies for the treatment of CABP in adults Data on File. Nabriva Therapeutics, plc. 2018

4 - Mechanism of Action Binds to the 50S subunit of the bacterial ribosome at 4 distinctive binding sites in highly conserved core of the ribosomal peptidyl transferase center (PTC) Highly selective for binding to bacterial ribosomes Unique binding site results in a lack of cross-resistance with other antibiotic classes Eyal, Z., et al. (2016). Nature Scientific Reports Dec:2-8 Paukner S et al. ECCMID 2017; Poster EP-405

5 in the PTC is tied up into the PTC by a variety of interactions H-bonds between and the PTC 23S rrna C2063 G2061 A2503 PTC H-bonds and other possible interactions 23S rrna C2063 G2061 A2503 S. aureus ribosome t-rna in P-site

6 In Vitro Spectrum of Activity n MIC90 [mg/l] S. pneumoniae M. catarrhalis1 779 Organism Organism n MIC90 [mg/l] 0.12 L. pneumophila C. pneumoniae M. pneumoniae H. influenzae1 S. aureus (including HA-MRSA, CAMRSA and MSSA) Not affected by increasing antibiotic resistance observed in CABP pathogens1: Cephalosporin/ fluoroquinolone/ macrolide/ PR S. pneumoniae Macrolide-resistant Mycoplasma spp. S. pneumoniae resistant to macrolides or to levofloxacin showed 100% susceptibility to lefamulin (SENTRY surveillance with S. pneumoniae isolates collected world-wide)3 1. Paukner, S et al. ASM MICROBE New Orleans, LA May 2017, 2. Waites, KB et al. Antimicrob Agents Chemother 2017 Feb; 61(2) 3. Paukner, S et al. SENTRY surveillance global dataset ad hoc report

7 PK/PD - Target Attainment Probability % Probabilities of overall PK-PD target attainment based on the day 1 AUC:MIC ratio targets associated with a 1-log10 CFU reduction from baseline Pathogen Region SENTRY 2015 PO AUC:MIC (fasted/fed) ELF Plasma ELF Plasma S. pneumoniae Global / / 99.9 S. aureus Global / / 99.7 Key PK/PD parameter driving efficacy is the 24 h AUC/MIC Bioavailability of 600 mg IR tablet IV AUC:MIC Absolute bioavailability = 25.8 % (fasted state) and 21.0 % (fed state after a high calorie/high fat meal) Target attainment analyses (based on pop PK model, surveillance data and pre-clinical AUC/MIC ratio targets)

8 - Predicted Change in Log CFU 24 Hours After IV or Oral Administration

9 Burden of CABP in Europe Approximately 3,370,000 cases of pneumonia annually1 Incidence of all-cause pneumonia (EU) /100,000 population2 varied by country, age, group, study, and time-period of hospitalized CAP-all causes (EU) /100,000 population2 Incidence increased consistently with age Mortality rate for CAP 9.1% (from <1% to as high as 48%) especially when patients with CAP are treated in the ICU3,4 Annual costs associated with pneumonia (EU) : 10.1 billion1 Primarily due to hospitalization (which accounts for 5.7 billion) and lost work productivity (accounting for 3.6 billion) In individuals countries: UK: annual costs ~440 million pounds sterling5 Spain: annual hospitalization costs ~ $137 million in Pneumonia. In: European lung white book. 2nd ed. Sheffield, UK: European Respiratory Society/European Lung Foundation. 2003:55e65, 2. Torres A et al. Respiratory Medicine. 2018;137:6-13, 3. Welte T et al. Thorax. 2012;67:71 79, 4. Arnold FW et al. Respiratory Medicine. 2013;107: , 5. Brown PD et al. Lancet 1998;352: Monge V et al. Eur J Public Health 2001;11: 362 4

10 Evaluation Against Pneumonia (LEAP) LEAP 1 and 2 Trial Design Overview of Phase 3 CABP Program LEAP 1 (IV to Oral) Trial ~550 adult patients with PORT Risk Class III 1:1 randomization: lefam vs. moxiflo ± linezolid Rx for 7 days (10 days for MRSA) PORT Risk Class III vs. IV and V 25% of patients : PORT risk class of IV or V Special Protocol Assessment with FDA LEAP 2 (Oral) Trial ~740 adult patients with PORT Risk Class II-IV 1:1 randomization: lefamulin vs. moxifloxacin 5 days lefamulin / 7 days moxifloxacin PORT Risk Class II vs. III and IV 50% of patients : PORT risk class of III or IV Study design for both trials was identical, except LEAP 1 required patients to receive at least 3 days of IV therapy, patients received 7 days of therapy in both arms, and the addition of linezolid to the moxifloxacin arm was permitted, if MRSA was suspected LEAP 2 was all oral, patients received either 5 days of lefamulin (+ placebo) or moxifloxacin for 7 days, and linezolid was not permitted to be added to the moxifloxacin arm

11 LEAP Phase 3 Clinical Trials FDA Primary Endpoint: ECR LEAP 2 (Oral) LEAP 1 (IV-to-Oral) Percentage Responders 100% 80% 87.3% 90.8% 90.2% 90.8% 60% 40% 20% 0% FDA - ECR Moxifloxacin (±linezolid) Delta (95% CI) -2.9 (-8.5, 2.8) ECR = Early Clinical Response Moxifloxacin Delta (95% CI) 0.1 (-4.4, 4.5) 11

12 LEAP Phase 3 - EMA Primary Endpoint Outcomes EMA Primary Endpoint: IACR in mitt and CE at TOC LEAP 1 LEAP 2 LEAP % 89.1% 86.9% 89.4% Percentage Responders 100% 80% 81.7% 84.2% LEAP % 93.6% 60% 40% 20% 0% IACR mitt Delta (95% CI) -2.6 (-8.9, 3.9) IACR = Investigator Assessment of Clinical Response IACR CE - TOC Moxifloxacin (±linezolid) Delta (95% CI) -1.6 (-6.3, 3.1) 12 Moxifloxacin Delta (95% CI) -2.5 (-8.4, 3.4) Delta (95% CI) -3.9 (-8.2, 0.5)

13 LEAP Phase 3 AEs in IV and Oral Gastrointestinal SOC Hepatobiliary SOC TEAEs in 13.1% and 10.1% of patients receiving lefamulin and moxifloxacin (±linezolid), respectively TEAEs in 0.9% and 0.9% of patients receiving lefamulin and moxifloxacin (±linezolid), respectively TEAEs in 2.5% and 3.1% of patients receiving lefamulin and moxifloxacin (±linezolid), respectively Diarrhea/ Loose Stools was observed in 7.3% and 3.9% of patients receiving lefamulin and moxifloxacin (±linezolid), respectively** Low incidence of liver enzyme elevation in both treatment groups consistent with CABP patient population Changes in QT interval of potential clinical concern were uncommon and of similar frequency between treatment groups Cardiac Disorders SOC System Organ Class (SOC) *Linezolid was provided in LEAP 1 for suspected MRSA **Diarrhea rates for lefamulin and moxifloxacin individually for LEAP 1 were 0.7% and 7.7%, and for LEAP 2 were 12.2% and 1.1%, respectively. 13

14 Pipeline Program Indications Discovery Pre-clinical Phase 1 Phase 2 Phase 3 NDA/ MAA Filing Comments CABP NDA filing expected in Q4 2018, MAA Q ABSSSI Phase 2 complete IV Fosfomycin cuti NDA filing expected in Q & Fosfomycin Pediatric Indications Phase 1 initiated (IV) (IV/oral) STIs, HABP/VABP, Osteomyelitis, Prosthetic Joint Infections Potential indications BC-7013 (Topical) usssi Phase 1 complete (IV/oral)

15 Global view Inhibits protein synthesis by specifically targeting the peptidyl transferase center (PTC) Active in vitro against MRSA,VRE, Pen NS, S.pneumoniae Activity against Legionella pneumophila, lower MICs for Vanco- NS E. faecium than for Vanco-S strains Low in vitro development of antimicrobial resistance Unaffected by an organism s resistance to other antibiotics PD index : AUC / MIC Available for step-down (IV to oral) therapy