A second phase 3 trial of Motif Bio’s antibiotic iclaprim has hit its primary endpoint. The data tee Motif Bio up to file for approval of a drug that was knocked back by the FDA in 2009 and almost sunk the biotech 12 months ago.
In the trial of 600 patients with acute bacterial skin and skin structure infections (ABSSSI), iclaprim held its own against vancomycin, one of the incumbent antibiotics. The iclaprim arm recorded an early clinical response rate of 78.3%, as compared to 76.7% in the vancomycin cohort. That result was enough for the trial to hit its primary endpoint of noninferiority.
Iclaprim also matched vancomycin against the predefined secondary clinical cure endpoint.
Publication of the data comes six months after Motif Bio released a similar set of results from the first of the two phase 3 trials. With iclaprim performing comparably to vancomycin in both trials, Motif Bio plans to file for approval from the FDA in the first quarter of next year.
That will mark the end of iclaprim’s multiyear journey back to the FDA. Roche spinoff Arpida got as far as an advisory committee in 2008, only for the experts to savage its submission and the FDA to follow their lead and reject the drug.
Criticism of the original filing centered on its failure to dispel doubts about the efficacy of iclaprim. Arpida used a 12.5% noninferiority margin, rather than the 10% favored by the FDA, and delivered data that left some of the experts convened by the FDA thinking iclaprim was inferior to linezolid.
The addition of a questionable safety profile, particularly relating to iclaprim’s prolongation of QT intervals, left the panelists with little reason to be flexible about the noninferiority margin.
“QTc is certainly an issue. It's very difficult to know the exact consequences of elevated QTc but those issues are also influential. So it's not a setting where I can say there's safety issues that are favorable and that in some sense could argue for adjusting the margin,” Thomas Fleming, professor of biostatistics at the University of Washington, said (PDF) at the 2008 meeting.
Motif Bio now looks set to take iclaprim back to the FDA armed with data that show it meeting the 10% bar for noninferiority, albeit against a different comparator than was used in the previous trials. A meta-analysis published in 2015 found the old and current comparators—linezolid and vancomycin—have equivalent efficacy in ABSSSI, although some earlier reviews suggest the former has the edge.
That leaves some scope for the FDA to question the efficacy data but, given vancomycin is widely used in the treatment of ABSSSI, the results in support of iclaprim are meaningful. Reviewers will also look for evidence of iclaprim’s effect on QT intervals. The 2008 panelists saw this as a cause to restrict use of iclaprim but not necessarily a barrier to its approval altogether.
Motif Bio’s share price increased more than 30% following publication of the top-line data, moving the stock back up toward the levels it hovered around for much of 2015 and 2016. The stock fell into a trough 12 months ago, around the time Motif Bio warned it lacked the money to keep going.
A Nasdaq IPO and placement in Europe gave Motif Bio the means to reach its first phase 3 trial readout, rescuing the biotech and ultimately leading iclaprim to the cusp of a return to the FDA.