Efficacy and Safety of Tedizolid and Linezolid in IV Drug Users in a Pooled Phase 3 Philippe Prokocimer, MD 4747 Executive Drive, Suite 1100 Population of Patients With Acute Bacterial Skin and Skin Structure Infections San Diego, CA 92121 858 352 2600 Carisa De Anda1, Edward Fang1, Anita F. Das2, Philippe Prokocimer1 [email protected] 676 1Cubist Pharmaceuticals, San Diego, CA; 2InClin, San Mateo, CA ABSTRACT METHODS (CONT’D) RESULTS

INTRODUCTION. Tedizolid is a novel oxazolidinone antibacterial with potent activity against a wide range of Gram-positive . ESTABLISH-1 patients received oral therapy exclusively, whereas ESTABLISH-2 patients first . IV drug users constituted 27.6% (183/664) of the tedizolid treatment group and 30.8% . Early clinical response rates with tedizolid and linezolid were similar in patients who did or . Overall AE rates were similar in both treatment groups for both IV drug users and non-IV drug pathogens, including methicillin-resistant (MRSA). Two Phase 3 clinical trials demonstrated the non- received IV therapy for 24 hours and could then be switched to oral study drug when (206/668) of the linezolid group. did not use IV drugs (Figure 1). users. inferior efficacy of tedizolid (200 mg daily for 6 days) to linezolid (600 mg twice daily for 10 days) for treating acute bacterial skin and skin structure infections (ABSSSI.) Since ABSSSI are common in intravenous (IV) drug users, this analysis compares the prespecified clinical improvement criteria were met. efficacy and safety of tedizolid in IV and non-IV drug users. . The most common infection types differed between IV drug users and non-IV drug users in . For IV drug users, the treatment difference between tedizolid and linezolid was 2.9% . Among IV drug users, AE rates were 46.2% and 47.8% in the tedizolid and linezolid groups, Patient Selection both groups (Table 1). (95% CI: –5.0, 10.7). respectively.

METHODS. The primary end point was early clinical response (≥20% reduction from baseline in lesion area at 48 to 72 hours . Key inclusion criteria after the first dose of drug); a secondary efficacy end point was the investigator assessment of clinical response at the . Wound infections (often injection-site infections) were the most common ABSSSI in IV Figure 1. Early Clinical Response at 48- to 72-Hour Visit by IV Drug Use (ITT Population) . Among non-IV drug users, AE rates were 41.5% and 41.2% in the tedizolid and linezolid posttherapy evaluation (PTE, 7 to 14 days after last dose of study drug). An analysis of the pooled Phase 3 population (N = 1333; drug users (tedizolid, 50.8%; linezolid, 53.4%); in non-IV drug users, cellulitis/ groups, respectively. tedizolid, n = 664; linezolid, n = 669) compared efficacy and safety of tedizolid versus linezolid in IV and non-IV drug users. . Diagnosis of ABSSSI (cellulitis/erysipelas, wound infection, or major cutaneous was the most commonly reported ABSSSI (tedizolid, 54.5%; linezolid, 57.5%). Safety assessments included liver function tests and adverse events (AE). abscess) . Infections and infestations (secondary infections) were more common among IV drug Table 1. Type of ABSSSI by IV Drug Use in Pooled Phase 3 Studies (ITT Population) 2 users. RESULTS. IV drug users comprised 27.6% (183/664) of the tedizolid and 30.8% (206/669) of the linezolid treatment arms. . Lesion surface area ≥75 cm ; wound infections and abscesses also required erythema Wound infections were the most common type of ABSSSI in IV drug users (50.8% and 53.4% in tedizolid and linezolid groups, extending ≥5 cm from the edge of the wound or abscess to the lesion margin IV Drug Use No IV Drug Use respectively), whereas cellulitis/erysipelas was most common in non-users (54.5% and 57.5%, respectively). In both treatment . Changes in laboratory parameters, including liver function, were similar with tedizolid and groups, the most common baseline pathogen in IV drug users was S. aureus (73.6% and 76.5% for tedizolid and linezolid, Tedizolid Linezolid Tedizolid Linezolid o linezolid treatment in both subgroups. respectively). For both treatment groups, early clinical response at the 48–72 hour visit and investigator-assessed clinical . At least 1 regional or systemic sign of infection (lymphadenopathy, temperature ≥38 C Type of Infection N = 183 N = 206 N = 481 N = 463 response rates at the PTE was similar in IV and non-IV drug users. Overall AE rates were similar in IV and non-IV drug users [fever], white blood cell count ≥10 000 cells/mm3 or <4000 cells/mm3, or immature (46.2% for tedizolid vs 41.5% for linezolid, 47.8% vs 41.2%, respectively). Changes in laboratory parameters including liver function tests were also similar. neutrophils >10%) Cellulitis/erysipelas, n (%) 39 (21.3) 41 (19.9) 262 (54.5) 266 (57.5)

. Suspected/documented Gram-positive pathogen CONCLUSION. In patients treated with tedizolid or linezolid in the ESTABLISH-1 and ESTABLISH-2 Phase 3 clinical trials, the Major cutaneous abscess, n (%) 51 (27.9) 55 (26.7) 117 (24.3) 111 (24.0) efficacy and safety profile was similar between IV and non-IV drug users. . Age ≥18 years (ESTABLISH-1) and ≥12 years (ESTABLISH-2) CONCLUSIONS Wound infection, n (%) 93 (50.8) 110 (53.4) 102 (21.2) 86 (18.6) . Key exclusion criteria INTRODUCTION IV, intravenous. . The efficacy of tedizolid and linezolid, as reflected by early clinical response and clinical . Uncomplicated or Gram-negative ABSSSI response at PTE, was similar in IV drug users and non-IV drug users. . Acute bacterial skin and skin structure infections (ABSSSI) are common among intravenous . The most common baseline pathogens among IV drug users in both treatment groups were (IV) drug users and can result in more serious complications and hospitalization.1 . Use of any systemic or topical antibiotic with Gram-positive activity within 96 hours S. aureus (tedizolid, 73.6; linezolid, 76.5%) and the anginosus Group . S. aureus, including MRSA, was the dominant causative pathogen in patients reporting IV drug (tedizolid,14.4%; linezolid, 20.2%) (Table 2). before the first dose of study drug IV, intravenous; ITT, intent-to-treat. use. However, clinicians should remain aware of ABSSSI caused by oral streptococci in these . ABSSSI are most frequently caused by Gram-positive pathogens, with patients, which may be due to the common practice among IV drug users of licking the needle . Importantly, 8.6% and 11.8% of ABSSSI in tedizolid-treated and linezolid-treated IV drug Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), the most common . Previous unsuccessful treatment at same infection site before injection. 2-4 users, respectively, were caused by streptococcal species that generally form part of the oral . No differences in clinical success rates at PTE were observed between treatments or pathogen implicated in serious skin infections worldwide. between IV drug users and non-IV drug users (Figure 2). . Infections close to prosthetic devices, severe sepsis, or known bacteremia at time of flora (including S. mitis, S. salivarius, S. sanguinis, and S. viridans Group) and are not typical enrollment skin pathogens. This may be due to the common practice among IV drug users of licking the . Tedizolid and linezolid had similar safety profiles in IV drug users and non-IV drug users. . Tedizolid, the active moiety of tedizolid phosphate, is a novel oxazolidinone antibacterial needle before injection.11 . For IV drug users, the treatment difference between tedizolid and linezolid was with potent activity against a wide range of Gram-positive pathogens, including resistant . –1.0% (95% CI: –6.8, 4.2). strains such as MRSA and vancomycin-resistant enterococci.5-7 Confirmed immunocompromised status (recent history of opportunistic infections Table 2. Baseline Pathogens in IV Drug Users (MicroITT Population) with active underlying cause or receipt of systemic immunosuppressive therapy) Tedizolid Linezolid Figure 2. Investigator Assessment of Clinical Response at PTE by IV Drug Use (CE-PTE . Two Phase 3 trials, ESTABLISH-1 and ESTABLISH-2, demonstrated the noninferior efficacy of End Points N = 129 N = 153 Population) tedizolid (200 mg daily for 6 days) compared to linezolid (600 mg twice daily for 10 days) in Pathogen n % n % patients with ABSSSI.8,9 . The primary end point was ≥20% reduction in lesion area 48 to 72 hours after first dose of Gram-positive aerobes 125 96.9 149 97.4 drug (early clinical response) without having received nonstudy systemic antibacterial ACKNOWLEDGMENTS . Tedizolid was recently approved for the treatment of patients with ABSSSI caused by agents for any reason within 72 hours of the first dose. Staphylococcus aureus 95 73.6 117 76.5 S. aureus, including methicillin-resistant isolates, various Streptococcus spp, and MRSA 38 29.5 46 30.1 10 MSSA 57 44.2 72 47.1 Editorial support for this poster was provided by ApotheCom ScopeMedical, Yardley, PA, and funded by Cubist Pharmaceuticals, faecalis. . A key secondary end point was investigator assessment of clinical response at the Lexington, MA. posttherapy evaluation (PTE; late response, 7-14 days after the last dose of study drug). Streptococcus anginosus Group 26 20.2 22 14.4 . Pooled data from the ESTABLISH-1 and ESTABLISH-2 trials were used to evaluate the efficacy and safety of tedizolid in IV drug users and non-IV drug users. . Safety evaluations included adverse event (AE) reports and laboratory tests. 2 1.6 7 4.6 Streptococcus salivarius 2 1.6 2 1.3 Analysis Populations REFERENCES Streptococcus sanguinis 4 3.1 2 1.3 METHODS . The intent-to-treat (ITT) population comprised all randomized patients. 1. Gordon RJ et al. N Engl J Med. 2005;353:1945-1954. Streptococcus viridans Group 3 2.3 7 4.6 2. Moran GJ et al. J Emerg Med. 2013;44:e397-e412. Study Design . The microbiologic ITT (microITT) population comprised patients with at least 1 Gram- Gram-positive anaerobes 7 5.4 6 3.9 3. Dukic VM et al. PLoS One. 2013;8:e52722. 4. European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe 2012. Annual Report of the positive ABSSSI pathogen isolated at baseline. perfringens 4 3.1 2 1.3 European Antimicrobial Resistance Surveillance Network (EARS-Net). Stockholm: ECDC; 2012. . ESTABLISH-1 (ClinicalTrials.gov identifier, NCT01170221) and ESTABLISH-2 (NCT01421511) 5. Brown SD et al. Antimicrob Agents Chemother. 2010;54:2063-2069. were randomized, double-blind, double-dummy, multicenter, multinational, noninferiority . The clinically evaluable at PTE (CE-PTE) population comprised patients who completed the Gram-negative aerobes 4 3.1 5 3.3 6. Schaadt R et al. Antimicrob Agents Chemother. 2009;53:3236-3239. Phase 3 clinical trials in patients with ABSSSI. end-of-therapy and PTE assessments without any concomitant systemic antibiotic therapy 7. Thomson KS et al. Antimicrob Agents Chemother. 2013;57:2892-2895 Gram-negative anaerobes 0 0 2 1.3 or other confounding events or factors. 8. Prokocimer P et al. JAMA. 2013;309:559-569. . Patients were randomly assigned 1:1 to receive tedizolid 200 mg once daily for 6 days IV, intravenous; microITT, microbiologic intent-to-treat, patients with at least 1 Gram-positive ABSSSI pathogen at baseline; CE-PTE, clinically evaluable at PTE; IV, intravenous; PTE, posttherapy evaluation. 9. Moran GJ et al. Lancet Infect Dis. 2014;14:696-705. (N = 664) or linezolid 600 mg twice daily for 10 days (N = 669). MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus. 10. SIVEXTRO® (tedizolid phosphate) [prescribing information]. Lexington, MA: Cubist Pharmaceuticals US; 2014. 11. Deutscher M et al. Int J Drug Policy. 2008;19:342-345.

This study was funded by Cubist Pharmaceuticals IDWeek 2014 Annual Meeting October 8-12, 2014; Philadelphia, PA