The development history of glycopeptide drugs is anything but normal.\u00a0 Daptomycin (Cubicin\u00ae) was abandoned by Lilly but resurrected by Francis Tally at Cubist by adjusting the dosing schedule to once daily and careful uptitration.\u00a0 The drug did superbly in a landmark endocarditis trial and everything looked rosy.\u00a0 Then we learned that daptomycin is neutralized by surfactant and ineffective in pneumonia, an unexpected finding at the time.\u00a0 Nonetheless, daptomycin became a commercial success story.<\/p>\n
Telavancin (Vibativ\u00ae) had no such problem: a Phase 2 trial showed excellent activity in pulmonary infection, to the point that superiority over vancomycin was postulated.\u00a0 Remember, vancomycin is not the greatest drug for respiratory infections: \u00a0it had lower clinical response rates than linezolid in at least 2 well-controlled trials.\u00a0 Unfortunately, despite a large and probably super-expensive Phase 3 program in nosocomial pneumonia, superiority over vancomycin proved elusive.\u00a0 Numerous warnings about adverse events (cardiac, renal, pregnancy, injection site reactions) and lack of truly differentiating features (it is administered daily) continue to hamper market uptake.<\/p>\n
Dalbavancin (Dalvance\u00ae) has a distinguishing feature: a remarkably long half-life (approx. 9-12 days) which allows weekly dosing.\u00a0 This could be a game changer as it makes outpatient antibiotic therapy (OPAT) a lot easier than with vancomycin.\u00a0 We expected FDA approval already in 2010 but were surprised to learn that regulators had reservations because of study execution issues.\u00a0 Details are a bit murky but the change in guidelines from \u201ccSSSI\u201d to \u201cABSSSI\u201d with its new entry criteria and endpoints certainly played a role.\u00a0 And then there were some undefined \u201cGMP\u201d issues.\u00a0 In a repeat Phase 3 program all these issues were addressed and dalbavancin performed flawlessly[i].\u00a0 \u00a0In May 2014, Dalvance was approved by FDA with a loading dose of 1 g and a second dose of 500 mg.<\/p>\n
Oritavancin\u2019s (Orbactiv\u00ae) Phase 3 program is not far behind dalbavancin.\u00a0 It is a drug with an even longer half-life (approx. 350 hours) easily providing above-MIC coverage for > 10 days.\u00a0 Corey [ii] reports in the NEJM that a single-dose (1200 mg) of oritavancin showed efficacy comparable to vancomycin 7-10 days in ABSSSI.\u00a0 Earlier trials in cSSSI – submitted in 2008 – had different dosing regimens (lower dose, daily dosing) and did not enroll sufficient MRSA cases for FDA approval.\u00a0 The new PDUFA date is set for August 2014.<\/p>\n
So, at long last, we will have 2 new MRSA drugs with very special pharmacokinetics.\u00a0 Looking into my crystal ball, I see good uses for both.\u00a0 The market will decide how they stack up against old faithful vancomycin and whether small differences in activity matter.\u00a0 I am certain that pharmacokinetics matter.<\/p>\n
Additional indications besides HAP\/VAP may be too difficult to obtain but exploratory studies should be feasible for endocarditis, osteomyelitis, or as suppressive therapy for infected prostheses that cannot be removed.\u00a0 I am impressed with the single dose efficacy of oritavancin but I see significant commercial opportunities for both drugs, esp. in chronic outpatient therapy (OPAT).\u00a0 Not to forget C. difficile: oritavancin has already been studied in CDI and there is little doubt all those Lilly drugs will do as well as vancomycin.\u00a0 It begs the question: Can they do better than vancomycin and beat fidaxomicin (Dificid\u00ae)?<\/p>\n
Abbreviations:<\/strong> References: UPDATED 8\/14\/2014:<\/strong> The development history of glycopeptide drugs is anything but normal.\u00a0 Daptomycin (Cubicin\u00ae) was abandoned by Lilly but resurrected by Francis Tally at Cubist by adjusting the dosing schedule to once daily and careful uptitration.\u00a0 The drug did superbly in a landmark endocarditis trial and everything looked rosy.\u00a0 Then we learned Continue reading Here They Are: Dalbavancin and Oritavancin \u2013 The New Long-Acting Lipoglycopeptides<\/span>
\nABSSSI = acute bacterial skin \/ soft tissue infection
\nCDI = C. difficile infection
\ncSSSI = complicated skin \/ skin structure infections
\nGMP = Good Manufacturing Practice
\nHAP\/VAP = hospital-acquired \/ ventilator-associated pneumonia
\nMIC = minimal inhibitory concentration
\nMRSA = methicillin-resistant S. aureus
\nNEJM = New England Journal of Medicine
\nOPAT = outpatient antibiotic therapy
\nPDUFA = Prescription Drug User Fee Act<\/p>\n
\n<\/strong>[i] N Engl J Med 2014; 370:2169
\n[ii] N Engl J Med 2014; 370:2180<\/p>\n
\nDalvance rec’d FDA approval on May 23, 2014
\nOrbactiv rec’d FDA approval on Aug. 6, 2014<\/p>\n","protected":false},"excerpt":{"rendered":"