„Dalbavancin – nova terapijska mogućnost“ Doc. dr. sc. Ivan Puljiz Klinika za infektivne bolesti

1. „Dalbavancin – nova terapijska mogućnost“ Doc. dr. sc. Ivan Puljiz Klinika za infektivne bolesti "Dr. Fran Mihaljević", Zagreb Zagreb, 16. 05. 2018.

2. U.S. Market Opportunity Market is larger when expanded to include MSSA and oral step-down therapies Source: Stanford Group June 2007, AMR 2010

3. Using data from the 2000–2004 US Healthcare Cost and Utilization Project National Inpatient Sample, we found that total hospital admissions for skin and soft tissue infections increased by 29% during 2000–2004; admissions for pneumonia were largely unchanged. These results are consistent with recent reported increases in community-associated methicillin-resistant Staphylococcus aureus infections. Edelsberg J, et al. Emerg Inf Dis 2009;15:1516-8. The overall incidence of SSTIs increased 40% from 2.4 million in 2000 to 3.3 million in 2012. From 2000 to 2012, the incidence of patients with at least one hospital visit for SSTI increased 38%, ambulatory visits increased 46%, and emergency department visits increased 56%. The total spent on the treatment of SSTIs tripled, from $4.4 billion in 2000 to $13.8 billion in 2012. Lee GC, et al. Value in Health 2015;18:245.

4. From: Suaya H, et al. BMC Infect Dis 2014;14:296-304. From: Gunderson CG, et al. Cellulitis: Am J Med 2011;124(12):1113-22.

6. FDA cSSTIs - ABSSSI

7. FDA cSSTIs - ABSSSI

8. FDA SSTIc – ABSSSI Systemic signs of infection An elevated body temperature >38°C; White blood cell count >12,000 cells/mm3; A manually performed white blood differential count with >10% band forms, regardless of peripheral white blood cell count.

9. Alternatives to Vancomycin for persons who require parenteral therapy for cSSSI secondary to MRSA FDA-approved indication: Ceftaroline Dalbavancin Daptomycin Tedizolid Oritavancin Telavancin Tigecycline Quinpristin-dalfopristin Recommendation: Selection of specific agent(s) is dependent on multiple factors such as site of infection, co-morbidities, presence of polxmicrobial infection

10. Dalbavancin: Mechanism of Action Dalbavancin is a semisynthetic glycopeptide (lipoglycopeptide) which interferes with peptidoglycan cross-linking in the cell wall by binding to the D-ala-D-ala terminus of stem peptides. From: Streit JM, et al. Diagn Microbiol Infect Dis. 2004;48:137-43.

11. Chemical structure of dalbavancin From: Jordan RS, et al. Infect Dis Ther. 2015;4:245-58.

13. Tolerability, pharmacokinetics, and serum bactericidal activity of intravenous dalbavancin in healthy volunteers Bactericidal activity was demonstrated in serum at 7 days in all subjects receiving single doses of >or=500 mg. All doses were well tolerated. The long half-life and maintenance of serum bactericidal activity against MRSA for 1 week suggest that weekly dosing may be feasible. Mean dalbavancin concentrations in plasma following administration of single 30-min intravenous infusion doses (n = 3 per group). From: Leighton A, et al. Antimicrob Agents Chemother 2004;48:940-5.

14. Pharmacokinetics Mean concentrations (±SD) of dalbavancin in plasma and skin blister fluid through study Day 7 following administration of a single 1000 mg iv dose. From: Nicolau DP. J Antimicrob Chemother. 2007;60(3):681-684.

15. Once-Weekly Dalbavancin versus Standard-of-Care Antimicrobial Regimens for Treatment of Skin and Soft-Tissue Infections. In a randomized, controlled, open-label, phase 2 proof-of-concept trial, adults received 1100 mg of dalbavancin (as a single intravenous infusion), 1000 mg of dalbavancin intravenously and then 500 mg intravenously 1 week later, or a prospectively defined standardof-care regimen. A gram-positive pathogen was isolated from samples obtained from 41 (66%) of 62 patients at baseline; Staphylococcus aureus was the most prevalent species (83% of pathogens). Clinical success rates at a follow-up visit (test of cure) were 94.1% among patients treated with 2 doses of dalbavancin, 61.5% among patients treated with 1 dose of dalbavancin, and 76.2% among patients treated with a standard-of-care regimen. All treatment regimens were well tolerated; drug-related adverse reaction rates were similar across the 3 groups. These findings suggest that a regimen of 2 doses of dalbavancin administered 1 week apart is effective in the treatment of complicated, gram-positive bacterial SSTIs and warrants further study. Seltzer E, et al. CID 2003;37:1298-1303.

16. Clinical experience Complicated skin and skin structure infection caused by Gram (+) including MRSA (phase II; controlled, randomized) 42 pts Vancomycin, ceftriaxone, cefazolin or clindamycin for 7-21 days Dalbavancin 15 mg/kg day 1 + 7.5 mg/kg day 8 SUCCESS: bacteriological clinical 73 % 94 % 64 % 76 % Seltzer E. et al. 13th ECCMID 2003, Glasgow. Selzer et al 13th ECCMID (2003)

17. Efficacy and safety of weekly dalbavancin therapy for catheter-related bloodstream infection caused by gram-positive pathogens. Conclusions: Dalbavancin thus appears to be an effective and well-tolerated treatment option for adult patients with CR-BSIs caused by CoNS and S. aureus, including MRSA. From: Raad I, et al. Clin Infect Dis. 2005;40(3):374-80.

18. Randomized, Double-Blind Comparison of Once-Weekly Dalbavancin versus Twice-Daily Linezolid Therapy for the Treatment of Complicated Skin and Skin Structure Infections Methods. In a phase 3 noninferiority study, patients with complicated SSSIs, including infections known or suspected to involve MRSA, were randomized (ratio, 2 : 1) in a double-blind manner to receive dalbavancin (1000 mg given intravenously on day 1 and 500 mg given intravenously on day 8) or linezolid (600 mg given intravenously or intravenously/orally every 12 h for 14 days). Efficacy was assessed by determining clinical and microbiological responses at the end of therapy and at the test-of-cure visit. Conclusions. Two doses of dalbavancin (1000 mg given on day 1 followed by 500 mg given on day 8) were as well tolerated and as effective as linezolid given twice daily for 14 days for the treatment of patients with complicated SSSI, including those infected with MRSA. From: Jauregui LE, et al. Clin Inf Dis 2005;41:1407-15.

19. Dalbavancin: Unique Pharmacokinetic Profile Dalbavancin’s pharmacokinetic profile enables: Broad tissue distribution Continuous cidality Once weekly dosing Maintenance of high plasma concentration From: Dorr MB, et al. J Antimicrob. Chemother 2005;55 (Supp S2):25-30.

20. Once-weekly Dalbavancin versus daily conventional therapy for skin infection METHODS: We randomly assigned patients to receive dalbavancin intravenously on days 1 and 8 or vancomycin intravenously for at least 3 days with the option to switch to oral linezolid to complete 10 to 14 days of therapy. RESULTS: Analysis of the primary end point showed noninferiority of dalbavancin in both DISCOVER 1 and DISCOVER 2. In the pooled analysis, 525 of 659 patients (79.7%) in the dalbavancin group and 521 of 653 (79.8%) in the vancomycin-linezolid group had an early clinical response indicating treatment success. Adverse events and study days with an adverse event were less frequent in the dalbavancin group than in the vancomycin-linezolid group. The most common treatment-related adverse events in either group were nausea, diarrhea, and pruritus. CONCLUSIONS: Once-weekly intravenous dalbavancin was not inferior to twice-daily intravenous vancomycin followed by oral linezolid for the treatment of acute bacterial skin and skin-structure infection. From: Boucher H, et al. N Engl J Med 2014;370:2169-79.

21. Once-weekly Dalbavancin versus daily conventional therapy for skin infection DISCOVER 1 DISCOVER 2 Boucher H, et al. N Engl J Med 2014;370:2169-79.

22. Pharmacokinetics, Safety and Tolerability of Single Dose Dalbavancin in Children 12-17 Years of Age.* Conclusions: Given dalbavancin exposures documented in children 12-17 years of age, and recognized dose proportionality, appropriate dosing can be modeled for pediatric phase 3 trials in acute bacterial skin and skin structure infections, to achieve the same exposure that is reported to be safe and effective in adults. Dalbavancin Pharmacokinetics and Safety in Children 3 Months to 11 Years of Age.** CONCLUSIONS: Dalbavancin pediatric dosing that matched adult exposure was identified. Overall, dalbavancin was well tolerated in our study population. *From: Bradley JS, et al. Pediatr Infect Dis J. 2015;34(7):748-52. **From: Gonzaletz D, et al. Pediatr Infect Dis J. 2017;36(7):645-53.

23. A Randomized Clinical Trial of Single-Dose Versus Weekly Dalbavancin for Treatment of Acute Bacterial Skin and Skin Structure Infection. METHODS: This study was a randomized, double-blind trial in patients aged >18 years with ABSSSIs. Patients were randomized to dalbavancin 1500 mg either as a single intravenous (IV) infusion or 1000 mg IV on day 1 followed 1 week later by 500 mg IV. RESULTS: Six hundred ninety-eight patients were randomized. Demographic characteristics were similar on each regimen, although there were more patients with methicillin-resistant Staphylococcus aureus (MRSA) at baseline on the 2-dose regimen (36/210 [17.1%] vs 61/220 [27.7%]). Dalbavancin delivered as a single dose was noninferior to a 2-dose regimen (81.4% vs 84.2%; difference, -2.9% [95% CI, -8.5% to 2.8%]). Clinical outcomes were also similar at day 14 (84.0% vs 84.8%), day 28 (84.5% vs 85.1%), and day 14 in clinically evaluable patients with MRSA in a baseline culture (92.9% vs 95.3%) in the single- and 2-dose regimens, respectively. CONCLUSIONS: A single 1500-mg infusion of dalbavancin is noninferior to a 2-dose regimen, has a similar safety profile, and removes logistical constraints related to delivery of the second dose. Dunne MW, et al. Clin Inf Dis 2016;62:545-51.

24. Dalbavancin concentrations in plasma, bone, and related tissues From: Dunne M, et al.Antimicrob Agents Chemother 2015;359:1849-55.

25. Linear plot of the population mean predicted amount of dalbavancin in bone versus time, overlaid upon the observed data From: Dunne M, et al.Antimicrob Agents Chemother 2015;359:1849-55.

26. Simulated mean concentration-time profiles with 1,500 mg i.v. on days 1 and 8 in plasma and bone (upper panels) and with 1,000 mg i.v. on day 1 and 500 mg i.v. weekly in plasma and bone (lower panels) From: Dunne MW, et al. Antimicrob Agents Chemother 2015;59:1849-55.

27. Abstract Due to a high rate of relapse, osteomyelitis remains difficult to treat, requiring prolonged parenteral therapy. MICs for 41 consecutive Staphylococcus species recovered from patients with osteomyelitis were determined for dalbavancin, daptomycin, doxycycline, levofloxacin, linezolid, vancomycin, trimethoprim-sulfamethoxazole, rifampin, and vancomycin. Strains of vancomycin-intermediate Staphylococcus aureus (VISA) and heteroresistant VISA were included for additional comparison. Except for rifampin, dalbavancin was the most active agent tested. Dalbavancin is given once a week, making treatment of infections such as osteomyelitis potentially more convenient and thus could help reduce the rate of hospitalizations and outpatient costs. From: Citron DM, et al. Diagn MicrobiolInfect Dis 2014;79:38-40.

28. Antimicrobial Activity of Dalbavancin and Comparator Agents Tested against Gram-Positive Clinical Isolates Causing Bone and Joint Infections in United States (US) Medical Centers (2011–2016)* Conclusion: Dalbavancin demonstrated potent in vitro activity against common gram-positive isolates causing BJI (2011–2016) and appears to be a viable candidate for treating BJI/osteomyelitis caused by gram-positive cocci. Dalbavancin in-vitro activity obtained against Gram-positive clinical isolates causing bone and joint infections in US and European hospitals (2011-2016).** Conclusion: Dalbavancin appears to be a viable candidate for treating BJI/osteomyelitis caused by Gram-positive cocci. *From: Hader HS, et al. Open Forum Infect Dis. 2017;4(Suppl.1):373. **From: Pfaller MA, et al. Int J Antimicrob Agents 2018;51:608-11.

29. METHODS: A mid-sternal wound was surgically induced in anaesthetized rats. A clinical strain of MRSA was injected into the sternum to establish infection. Rats were treated intraperitoneally for 7 or 14 days with dalbavancin, vancomycin or saline. RESULTS: Treatment with dalbavancin was superior to treatment with saline for 7 days (0.75 log reduction in bone cfu) or 14 days (>3 log reduction in bone cfu) and similar to treatment with vancomycin. Additionally, dalbavancin was also effective in reducing systemic dissemination of MRSA. CONCLUSIONS: Dalbavancin is effective in the treatment of MRSA rat sternal osteomyelitis. From: Barnea Y, et al. J Antimicrob Chemother 2016;71:460-3.

30. Dalbavancin for the Treatment of Osteomyelitis in Adult Patients Two phase 1 studies (bone penetration study and extended-duration dosing study) provided data for PK modeling to determine dalbavancin dose for osteomyelitis • A two-dose, 1500 mg once-weekly regimen was proposed for osteomyelitis − Regimen would provide tissue exposure at or above dalbavancin MIC99.9 of 0.12 µg/mL for S aureus for entire treatment duration up to 8 weeks − Two-dose regimen of 1500 mg on day 1 and 1500 mg on day 8 would also achieve similar area under the curve (AUC) as a regimen of 1000 mg followed by 4 weekly doses of 500 mg Conclusion: Long half-life of dalbavancin allows once-weekly dosing and maintains serum concentrations above the MIC90 for most Gram-positive pathogens, including S aureus over at least 6 weeks • Good bone penetration of dalbavancin after a short dosing regimen is relevant for osteomyelitis • The 2-dose, once-weekly regimen may offer advantages to patients and physicians − Eliminates need for prolonged IV access − Optimizes adherence for infection requiring treatment duration of 4–6 weeks • Dalbavancin was well tolerated in this adult population • Interim results of our phase 2 study suggest that treatment of adult osteomyelitis Jandourek A, et al. ECCMID, Madrid 21-24. Apr2018

31. Pharmacodynamics

32. In vitro activity of gram-positive organisms and anaerobes against dalbavancin. From: Saravolatz LD et al. Clin Infect Dis. 2008;46(4):577-583.

33. Antimicrobial Activity of Dalbavancin Tested against Staphylococcus aureus with Decreased Susceptibility to Glycopeptides, Daptomycin, and/or Linezolid from United States (US) Medical Centers Conclusion: Dalbavancin retained potent in vitro activity against S. aureus isolates, displaying decreased susceptibility to agents commonly used to treat serious infections and was consistently more potent than comparator agents. From: Hader HS, et al. Open Forum Infect Dis. 2017;4(Suppl.1):378.

35. DALBAVANCIN Parsippany, NJ: Durata Therapeutics U.S. Limited; 2016.

36. Clinicians Response to Treatment Setting Using Dalbavancin 86% of respondents believe that >10% of SSSI patients, currently admitted to the hospital, could be treated as an outpatient with dalbavancin Institutional burden is a factor for assessing benefit Q: Will your hospital/institution factor in the savings from administrative benefits, such as lower burden on nursing time, in assessing the cost/benefit of this drug? Q: What percent of SSSI patients currently admitted to the hospital could now be treated on an outpatient basis over the entire course of treatment due to this product’s profile? ePocrates market research, May 2009, 150 physicians

37. Improved Reduced Reduction in Total Treatment Costs are Expected to Drive Adoption Decreased length of stay Potential admission avoidance Less indwelling catheters No therapeutic drug monitoring Less ancillary supply utilization Shorter nursing time Lower drug preparation frequency Less drug wastage Improved patient convenience, compliance, and satisfaction ePocrates market research, May 2009, 150 physicians

38. Dalbavancin - osnovne značajke Semisintetski lipoglikopeptid Veže se na D-alanyl-D-alanyl na terminalnom stablu pentapeptida u peptidoglikanu staničnog zida bakterije i time prevenira križno vezanje Interferira s sintezom staničnog bakterijskog zida. Dugo poluvrijeme eliminacije Dobra distribucija u mnoga tkiva Zbog slabije resorpcije daje se u intravenskom obliku

39. Farmakokinetika Dalbavancin nije supstrat, induktor niti inhibitor CYP450 izoenzima Vezanje za proteine plazme - 93% Ima dva metabolita: OH-dalbavancin i MAG (manozilglikon) koji nisu detektirani u plazmi i nemaju značaj za aktivnost dalbavancina. Dalbavancin se izlučuje renalnim i ekstrarenalnim (feces) putem, a većina lijeka eliminira se nepromijenjen urinom. U osoba s težim (Crcl <30 ml/min) oštećenje funkcije bubrega potrebno je reducirati dozu lijeka za 25%. Ne postoji dovoljno istraživanja za pacijente s umjerenim i teškim oštećenjem jetre, no dalbavancin se može dati u toj sklupini s oprezom.

40. Farmakodinamika BHS, skupina A, B, C, G Str. pneumoniae (uključujući rezistentne sojeve) Str. agalactiae Str. milleri grupe (S.anginosus, S.intermedius, S.constellatus) Staph. epidermidis Staph. lugdunensis Staph. aureus (MSSA) Staph. aureus (MRSA) Enterococcus (izuzev VanA-VRE) Saravolatz LD et al. Clin Infect Dis. 2008;46(4):577-583. Hellmark B. et al. Clin Microbiol Infect 2009;15(3):238-44. Biedenbach DJ, et al. J Clin Microb 2007;45(3):998-1004.

41. Farmakodinamika Clostridium spp. Peptostreptococcus spp. Propionibacterium spp. Actinomyces spp. Bacillus spp. Corynebacterium spp. L. monocytogenes Saravolatz LD et al. Clin Infect Dis. 2008;46(4):577-583.

42. Kontraindikacije i mjere opreza Preosjetljivost na dalbavancin ili drugu komponentu sastojka Trudnoća (kategorija C) Oprez - dojenje Oprez – umjerena ili teško oštećenje jetre Teže oštećenje bubrega – reducirati dozu Oprez – i.v. infuzija <30 minuta

43. Indikacije Komplicirane infekcije kožeimekihčesti – drugalinija: • Celulitis/erizipel • Inficiranodijabetičkostopalo • Infekcije kirurškerane • Nozokomijalnicelulitis

44. Moguće/poželjne indikacije Spondylodiscitis (MRSA, KNS, Enterococcus) Osteomijelitis (MRSA, KNS, Enterococcus) Septički artritis (MRSA, KNS, Enterococcus) Postoperativna infekcija rane (MRSA, KNS, Enterococcus)

45. Doziranje i trajanje liječenja cSSTI 1x 1500 mg i.v. jednokratno ili 1x1000 mg i.v. (1. dan) + 1x500 mg (8. dan) Infekcije lokomotornog sustava 1x1500 mg i.v. (1. dan) + 1500 mg (8. dan) ili 1x1500 mg i.v. (1. dana) + 500 mg svaki tjedan

46. Dalbavancin - prednosti Djeluje na rezistentne gram pozitivne bakterije (MRSA) Dugi poluživot (5-7 dana) Tjedna primjena Vezanje za proteine (>90%) Mogućnost ambulantnog liječenja Dobro se podnosi Potencijal za mnoge indikacije