Results of a Global Phase 3 Study of Delafloxacin (DLX) Compared to Vancomycin With Aztreonam (VAN) in Acute Bacterial Skin and Skin Structure Infections (ABSSSI)

RESULTS CONCLUSIONS Melinta Therapeutics 203-624-5606 info@melinta.com ID Week 2015 San Diego, CA, USA Oct. 7-11, 2015 Background: Delafloxacin (DLX) is an investigational broad-spectrum fluoroquinolone in development for treatment of skin infections. Methods: Multicenter, randomized, double-blind trial of adults with wound, burn, major abscesses, or cellulitis (≥75 cm2 and at least two systemic signs). Patients were randomized 1:1 to receive either DLX 300 mg IV BID or VAN 15 mg/kg IV with aztreonam BID for 5-14 days. The primary endpoint for the FDA was response at 48-72 hours with ≥20% reduction in lesion size. The secondary endpoint was investigator-assessed response based on complete resolution of signs and symptoms (cure) at the follow up (FU, day 14±1) and late follow up (LFU, day 21-28) visits. Results: 660 patients were randomized, of whom 63% were male with mean age 45.8 years. Average lesion size was 307 cm2; 39% of patients had cellulitis, 25% abscesses, 35% wound, and 1% burn infections. In addition, 19% received a single dose of short-acting antibiotic prior to enrollment. A majority of patients (490; 74%) had pathogens identified at baseline. S. aureus (324) was the most frequent isolate; 52% (169/324) were methicillin-resistant S. aureus (MRSA). Bacteremia was seen in 2% of patients. Efficacy data for the intent-to-treat (ITT) and microbiologically evaluable (ME) populations are presented below. Key Outcomes DLX n/Total (%) VAN n/Total (%) Delta (95% CI) Objective response 48-72 hours (ITT) 259/331 (78.2) 266/329 (80.9) 2.60 (-3.57, 8.78) Investigator-assessed response at FU (ITT) (Cure) 172/331 (52.0) 166/329 (50.5) -1.51 (-9.11, 6.11) Investigator-assessed response at LFU (ITT) (Cure) 233/331 (70.4) 219/329 (66.6) -3.83 (-10.89, 3.27) Microbiological response at FU (ME) with MRSA infection 58/58 (100.0) 65/66 (98.5) -1.52 (-8.14, 4.79) The overall percentage of patients with at least one treatmentemergent adverse event (TEAE) was higher for VAN (59.2) compared with DLX (47.5). The AE incidence by 5% or more of patients was similar across treatment arms, and the most frequent AEs were infection, infusion site extravasation, diarrhea, nausea, and headache. Conclusions: DLX was comparable with VAN in treatment of ABSSSI based on the early objective response as well as investigatorassessed response at FU and LFU. DLX was also comparable with VAN in treating patients with MRSA. DLX appears well tolerated with a lower percentage of patients with TEAEs compared with VAN. Delafloxacin (DLX) is an investigational anionic antibiotic of the fluoroquinolone (FQ) class distinguished by in vitro antibacterial activity against gram-positive organisms including both methicillinand quinolone-resistant strains of S. aureus (MRSA, QRSA). Delafloxacin is more active than levofloxacin (LVX) against most gram-positive pathogens, including LVX-nonsusceptible isolates, and is 32-fold more active than LVX against MRSA isolates.1 Delafloxacin has been evaluated in previous Phase 2 trials in complicated skin and skin structure infections.2-4 In a previous Phase 2 acute bacterial skin and skin structure infection (ABSSSI) study, objective measures of efficacy documented that performance of delafloxacin was comparable with linezolid and vancomycin + aztreonam (VAN) in the cessation of spread of the skin lesion and in lesion size reduction of at least 20% at 48-72 hours. In that exploratory study delafloxacin had a significantly higher investigator assessment of cure compared with vancomycin + aztreonam.4 Post hoc analyses in this exploratory study suggested a potential treatment benefit with delafloxacin in the obese population. STUDY DESIGN • Stratified, randomized, double-blind, Phase 3, multicenter study of intravenous (IV) delafloxacin compared with vancomycin + aztreonam for the treatment of ABSSSIs. • Patients had wounds, burns, major abscesses, or cellulitis of ≥75 cm2 in size; at least 2 systemic signs of infection; and met the entry criteria. • Patients were randomly assigned in a 1:1 ratio to receive either delafloxacin 300 mg IV BID or vancomycin + aztreonam 15 mg/kg IV every 12 hours with aztreonam BID for 5-14 days; aztreonam was discontinued once gram-negative infection was not confirmed. • Patients were evaluated at screening, daily on treatment, at follow up (FU, day 14±1 day), and at late follow up (LFU, day 21-28). • Efficacy was evaluated through assessments of signs and symptoms of infection; measurement of lesion size by digital planimetry; and culture and susceptibility testing of bacterial isolates. • Enrollment was stratified by baseline infection type and prior antibiotic use. ENDPOINTS AND ANALYSES • Primary endpoint: Proportion of patients who achieved an objective response at 48-72 hours following initiation of treatment, based on at least a 20% decrease in lesion size with no further antibiotics; major procedures; or death in the intent-to-treat (ITT) population. • Differences in response rates were calculated as vancomycin + aztreonam treatment group minus delafloxacin treatment group; confidence interval (CI) was calculated using Miettinen and Nurminen method without stratification. • Secondary efficacy endpoint: Investigator-assessed response based on complete resolution of signs and symptoms (cure) at FU and LFU visits. • This study required that patients were completely cured (ie, no signs or symptoms), not merely improved (ie, some symptoms remain, but the patient has improved to an extent that no additional antibiotic treatment is necessary), for the positive investigator response. Improved responses were considered failures for purposes of the primary analysis as a more stringent criterion. • Other secondary endpoints included microbiologic response to treatment, patient-reported pain, and health-related quality of life measures.5