The ceftaroline (Teflaro®) program was executed at a time when FDA was debating a new CABP Guidance with new outcome measures: no longer was the time-honored TOC assessment acceptable, instead improvement on Day 3-5 was to become the new primary endpoint. FDA made other significant changes to the old 1998 Guidance as well, like a tightening of entry criteria (requiring selection of more severely ill patients) and adding a no-prior-antibiotic rule (based on the often misunderstood Pertel publication [1]). Conducting anti-infective trials during this time was not for the faint of heart, and any of the newly introduced criteria could have ‘sunk’ the ceftaroline NDA submission.
However, ceftaroline passed the AIDAC review (Sept. 2010) with flying colors [2], a feat for which I give much credit to the outstanding team at Cerexa that managed the drug during Phase 3. Of course, it helps to have an excellent horse in the race: ceftaroline response rates beat the comparator (ceftriaxone/Rocephin®) – at least numerically – in almost every analysis set, sometimes with nice p-values <0.05. Even the FDA reviewer liked what he saw.
In a recent editorial [3] Welte comments on the ceftaroline Phase 3 trial published in the same journal issue and the program at-large.
His comments deserve, well, further comment:
First point he makes is about the rather large PK/PD differences between ceftaroline and ceftriaxone and how these may have affected outcomes and given ceftaroline an advantage. He postulates that the large differences in protein binding (20% vs 95%), the longer infusion time, a higher penetration into pulmonary tissue, and a higher intrinsic kill rate may have contributed to the superior and earlier treatment responses seen with ceftaroline.
My comment: A big MAYBE. Faster killing was postulated to be a differentiating factor for other drugs before. Daptomycin (compared to vancomycin) and moxifloxacin (compared to non-fluoroquinolones) looked really good based on in-vitro data. Unfortunately, what was easily demonstrable in the test tube could not be proven in the clinical trial program, at least not reproducibly. There was 1 daptomycin study in cSSSI which showed faster symptom resolution but this finding was not confirmed in a follow-up trial. Sorry, there goes my belief system!
Same story with moxifloxacin where a single study (in which Welte participated [5]) showed a faster response. Sadly, publication bias and marketing efforts seem to have pushed the positive results into the limelight while non-confirmatory data did not get the same attention. In fact, a thorough review of published trials concluded that “moxifloxacin does not differ significantly compared to other fluoroquinolones or other classes of antibiotics in clinically relevant outcomes for the treatment of adult patients with community acquired pneumonia’.[4] I am unable to find a publication of the moxifloxacin QUICK study which also did not confirm a ‘faster efficacy’ claim. Whatever it was that made ceftaroline look good, it was not simply PK that made the difference.
Second point the editorialist makes is about the low number of sick patients included in CABP trials. The mortality rate in the Phase 3 ceftaroline trial being only 1% gives the impression that this study does not reflect the ‘real world’ where CAP is associated with rates of 20%. Hence, he suggests that many more patients with PORT scores of 5 should be included in CABP studies.
My comment: I would agree in principle. This is not a new argument by any stretch: FDA had similar concerns and pushed up the disease severity requirements significantly. The new Guidelines specifically demand that “75 percent of patients in trials have PORT scores of III or higher”. CABP trial may never have mortality rates of 20% (a figure often quoted in the literature) but the 1% rate seems very low indeed.
Having said that, there is no reason why future ceftaroline CABP trials could not explore sicker patient populations. In my humble opinion, a stepwise exploration of an antibiotic’s efficacy makes more sense: not everything can or needs to be studied during the registration phase; there is plenty of opportunity to further expand the label and explore the usefulness of a drug in Phases 3b and 4.
Case in point: the MoxiRapid trial cited by Welte [5] was done fairly late in the life cycle of moxifloxacin. Let’s also not forget the daptomycin experience: When Cubist tested the drug in CABP (comparator: ceftriaxone!), it became evident that it was inferior and did not perform en par with the SOC. It would have been a nightmare if the majority of patients enrolled had been in the PORT 5 category. Give drugs a chance!
Many drugs have expanded their label into ‘difficult’ indications in a process which required time, learning and building the safety and efficacy database. Often, an upward adjustment in dosing was needed to address the more challenging infection types. Highly resistant pathogens, or the immune compromised and severely ill populations are usually not tested in the early stages of drug development, and for good reasons. Few remember that IV ciprofloxacin started as a 200 mg and 300 mg IV q12h drug in Europe, even failed in an early EORTC trial [6], but then became an excellent performer at doses of 400 mg IV q12h and q8h for severe infections.
It seems there is some research in clinical research after all…
Abbreviations:
PORT Pneumonia Patient Outcomes Research Team
PSI Pneumonia Severity Index
EORTC European Organization for Research on Treatment of Cancer
AIDAC Anti-Infective Drug Advisory Committee
SOC Standard of Care
cSSSI complicated skin-skin structure infection
TOC Test-of-Cure visit
References:
[1] Pertel CID 2008; 46:1142
[2] http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM230379.pdf
[3] www.thelancet.com/infection Vol 15 February 2015, p. 132
[4] http://www.ti.ubc.ca/moxifloxacin-community-acquired-pneumonia
[5] Welte CID 2005; 41:1697
[6] Meunier Antimicrob Agents Chemother. 1991; 35: 873
