The development history of glycopeptide drugs is anything but normal. Daptomycin (Cubicin®) was abandoned by Lilly but resurrected by Francis Tally at Cubist by adjusting the dosing schedule to once daily and careful uptitration. The drug did superbly in a landmark endocarditis trial and everything looked rosy. Then we learned that daptomycin is neutralized by surfactant and ineffective in pneumonia, an unexpected finding at the time. Nonetheless, daptomycin became a commercial success story.
Telavancin (Vibativ®) had no such problem: a Phase 2 trial showed excellent activity in pulmonary infection, to the point that superiority over vancomycin was postulated. Remember, vancomycin is not the greatest drug for respiratory infections: it had lower clinical response rates than linezolid in at least 2 well-controlled trials. Unfortunately, despite a large and probably super-expensive Phase 3 program in nosocomial pneumonia, superiority over vancomycin proved elusive. 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.
Dalbavancin (Dalvance®) has a distinguishing feature: a remarkably long half-life (approx. 9-12 days) which allows weekly dosing. This could be a game changer as it makes outpatient antibiotic therapy (OPAT) a lot easier than with vancomycin. We expected FDA approval already in 2010 but were surprised to learn that regulators had reservations because of study execution issues. Details are a bit murky but the change in guidelines from “cSSSI” to “ABSSSI” with its new entry criteria and endpoints certainly played a role. And then there were some undefined “GMP” issues. In a repeat Phase 3 program all these issues were addressed and dalbavancin performed flawlessly[i]. In May 2014, Dalvance was approved by FDA with a loading dose of 1 g and a second dose of 500 mg.
Oritavancin’s (Orbactiv®) Phase 3 program is not far behind dalbavancin. It is a drug with an even longer half-life (approx. 350 hours) easily providing above-MIC coverage for > 10 days. Corey [ii] reports in the NEJM that a single-dose (1200 mg) of oritavancin showed efficacy comparable to vancomycin 7-10 days in ABSSSI. 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. The new PDUFA date is set for August 2014.
So, at long last, we will have 2 new MRSA drugs with very special pharmacokinetics. Looking into my crystal ball, I see good uses for both. The market will decide how they stack up against old faithful vancomycin and whether small differences in activity matter. I am certain that pharmacokinetics matter.
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. 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). 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. It begs the question: Can they do better than vancomycin and beat fidaxomicin (Dificid®)?
ABSSSI = acute bacterial skin / soft tissue infection
CDI = C. difficile infection
cSSSI = complicated skin / skin structure infections
GMP = Good Manufacturing Practice
HAP/VAP = hospital-acquired / ventilator-associated pneumonia
MIC = minimal inhibitory concentration
MRSA = methicillin-resistant S. aureus
NEJM = New England Journal of Medicine
OPAT = outpatient antibiotic therapy
PDUFA = Prescription Drug User Fee Act
[i] N Engl J Med 2014; 370:2169
[ii] N Engl J Med 2014; 370:2180
Dalvance rec’d FDA approval on May 23, 2014
Orbactiv rec’d FDA approval on Aug. 6, 2014